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{
"abstract": "OBJECTIVE\nTo investigate the association between tobacco smoking and disease activity, treatment adherence and treatment responses in patients with AS treated with their first tumour necrosis factor-alpha inhibitor (TNFi) therapy in routine care.\n\n\nMETHODS\nObservational cohort study based on the Danish nationwide DANBIO registry. Kaplan-Meier plots, Cox and logistic regression analyses by smoking status (current/never/previous) were calculated for treatment adherence and BASDAI 50%/20 mm-response. Additional stratified analyses were performed for gender and TNFi-type.\n\n\nRESULTS\nOf 1576 AS patients included in the study, 1425(90%) had known smoking status (current/never/previous: 43%/41%/16%). The median follow-up time was 2.02 years (IQR 0.69-5.01). At baseline, current smokers compared with never smokers had longer disease duration (4 years (1-12)/2 years (0-10)), higher BASDAI (61 mm (47-73)/58 mm (44-70)), BASFI (53 mm (35-69)/46 mm (31-66)) and BASMI (40 mm (20-60)/30 mm (10-50)) scores (all P < 0.01). Current and previous smokers had shorter treatment adherence than never smokers (current: 2.30 years (1.81-2.79) (median (95% CI)); previous: 2.48 years (1.56-3.40), never: 4.12 years (3.29-4.95)), P < 0.0001). Similar results were found in multivariate analyses (current versus never smokers, HR 1.41 (95% CI 1.21-1.65), P < 0.001), most pronounced among men. Current smokers had poorer 6 months' BASDAI50%/20 mm-response rate than never smokers (42%/58%, P < 0.001). In multivariate analyses, current smokers had lower odds of achieving BASDAI50%/20 mm-response than never smokers, both overall (OR 0.48 (95% CI 0.35-0.65), P < 0.0001) and for the different TNFi-types (adalimumab 0.45 (0.27-0.76)/etanercept 0.24 (0.10-0.61)/infliximab 0.57 (0.34-0.95)).\n\n\nCONCLUSIONS\nIn this study of TNFi-treated AS patients in clinical practice, current and previous smokers had significantly poorer patient-reported outcomes at baseline, shorter treatment adherence and poorer treatment response compared with never smokers.",
"affiliations": "Department of Rheumatology, Gentofte University Hospital, Copenhagen, Denmark, The Danish Rheumatologic Database, Rigshospitalet, Glostrup Hospital, Glostrup, Denmark, glintborg@dadlnet.dk.;Department of Rheumatology, Gentofte University Hospital, Copenhagen, Denmark.;The Danish Rheumatologic Database, Rigshospitalet, Glostrup Hospital, Glostrup, Denmark, Copenhagen Centre for Arthritis Research, Centre for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup Hospital, Glostrup, Denmark, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark';Zitelab Aps, Copenhagen, Denmark.;Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark.;Department of Rheumatology, Rigshospitalet, Glostrup Hospital, Glostrup, Denmark.;Department of Rheumatology, Esbjerg Hospital, Esbjerg, Denmark.;Department of Rheumatology, Svendborg Hospital, Svendborg, Denmark.;Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark.;Department of Rheumatology, Holbæk Hospital, Holbæk, Denmark.;Department of Rheumatology, Odense University Hospital, Odense, Denmark.;Department of Rheumatology, Vejle Hospital, Vejle, Denmark.;Department of Rheumatology, Rigshospitalet, Glostrup Hospital, Glostrup, Denmark.;Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark.;Department of Rheumatology, Køge Hospital, Køge, Denmark.;Department of Rheumatology, Silkeborg University Hospital, Silkeborg, Denmark.;Department of Rheumatology, Slagelse Hospital, Slagelse, Denmark.;Department of Rheumatology, Horsens Hospital, Horsens, Denmark.;Department of Rheumatology, Holstebro Hospital, Holstebro, Denmark.;Department of Rheumatology, Randers Hospital, Randers, Denmark and.;Department of Rheumatology, Sygehus Vendsyssel, Hjørring, Denmark.;Department of Rheumatology, Gentofte University Hospital, Copenhagen, Denmark.",
"authors": "Glintborg|Bente|B|;Højgaard|Pil|P|;Lund Hetland|Merete|M|;Steen Krogh|Niels|N|;Kollerup|Gina|G|;Jensen|Jørgen|J|;Chrysidis|Stavros|S|;Jensen Hansen|Inger Marie|IM|;Holland-Fischer|Mette|M|;Højland Hansen|Torben|T|;Nilsson|Christine|C|;Espesen|Jakob|J|;Nordin|Henrik|H|;Rasmussen Loft|Anne Gitte|AG|;Pelck|Randi|R|;Lorenzen|Tove|T|;Flejsborg Oeftiger|Sussi|S|;Unger|Barbara|B|;Jaeger|Frank|F|;Mosborg Petersen|Peter|P|;Rasmussen|Claus|C|;Dreyer|Lene|L|",
"chemical_list": "D018501:Antirheumatic Agents; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha",
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/kev392",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": "55(4)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "Ankylosing spondylitis; Outcome; Routine care; Smoking; Tumour necrosis factor-alpha inhibitors",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D003718:Denmark; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D012042:Registries; D012907:Smoking; D013167:Spondylitis, Ankylosing; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "659-68",
"pmc": null,
"pmid": "26628579",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Impact of tobacco smoking on response to tumour necrosis factor-alpha inhibitor treatment in patients with ankylosing spondylitis: results from the Danish nationwide DANBIO registry.",
"title_normalized": "impact of tobacco smoking on response to tumour necrosis factor alpha inhibitor treatment in patients with ankylosing spondylitis results from the danish nationwide danbio registry"
} | [
{
"companynumb": "DK-JNJFOC-20160712077",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GOLIMUMAB"
},
"drugadditional": null,
"... |
{
"abstract": ": This case report describes a patient with opioid use disorder who developed cardiac toxicity secondary to non-medical use of loperamide. At recommended doses, loperamide remains in the periphery to treat diarrhea. At high doses, loperamide causes central nervous system (CNS) opioid agonism. Complications of high-dose loperamide have been documented, including cardiotoxicity, and death. This is particularly important in light of the ongoing opioid epidemic. This case presents a patient with sequela of high-dose loperamide as an illicit opioid replacement and the subsequent loperamide toxicity, including significant QTc prolongation. Abrupt cessation of his high-dose loperamide use resulted in opioid withdrawal symptoms, which were treated with buprenorphine. Buprenorphine was selected to avoid possible worsening of QTc secondary to an additional medication, such as methadone. To our knowledge, this is the first description of the use of buprenorphine for treatment of loperamide-associated opioid use disorder. Non-medical use of loperamide requires increased recognition by the health care community, including both physicians and pharmacists, because it can result in marked and life-threatening toxicity.",
"affiliations": "Department of Psychiatry, Maine Medical Center, Portland ME (LAW); Department of Psychiatry, Tufts University School of Medicine, Medford, MA (LAW); Department of Pharmacy, Maine Medical Center, Portland, ME (ASN); Department of Consult Liaison Psychiatry, Maine Medical Center, Portland, ME (CWR); Department of Psychiatry, Tufts University School of Medicine, Medford, MA (CWR); School of Pharmacy, Husson University, Bangor, ME (SDN); Tufts University School of Medicine, Medford, MA (SDN); Department of Pharmacy, Maine Medical Center, Portland, ME (SDN).",
"authors": "Wolfrum|Lee A|LA|;Nordmeyer|Aimee S|AS|;Racine|Christopher W|CW|;Nichols|Stephanie D|SD|",
"chemical_list": "D000930:Antidiarrheals; D002047:Buprenorphine; D008139:Loperamide",
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000472",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1932-0620",
"issue": "13(3)",
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": "D000328:Adult; D000930:Antidiarrheals; D002047:Buprenorphine; D006801:Humans; D008133:Long QT Syndrome; D008139:Loperamide; D008297:Male; D009293:Opioid-Related Disorders; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "101306759",
"other_id": null,
"pages": "245-247",
"pmc": null,
"pmid": "30379781",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Loperamide-Associated Opioid Use Disorder and Proposal of an Alternative Treatment with Buprenorphine.",
"title_normalized": "loperamide associated opioid use disorder and proposal of an alternative treatment with buprenorphine"
} | [
{
"companynumb": "US-JNJFOC-20181201825",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LOPERAMIDE HYDROCHLORIDE"
},
"drugadditional": "1... |
{
"abstract": "Cyclin-dependent kinase (CDK) 4/6 inhibitors represent a new class of targeted therapy options for the treatment of estrogen receptor-positive (ER+) human epidermal growth factor 2-negative (HER2-) metastatic breast cancer. There are currently no published prospective data on the safety of use of radiation treatment with palbociclib.\nWe describe the case of a patient with metastatic breast cancer who received radiation treatment to a metastatic supraclavicular lymph node to planned 60 Gy in 30 fractions while on palbociclib, a selective inhibitor of CDK4/6. The patient developed early radiation toxicities including esophagitis and dermatitis that progressed to a severe left neck skin breakdown in the radiation field, resulting in the need for hospitalization. She had a break in treatment but was able to finish the radiation without palbociclib. Her tumor responded well to the treatment and her side effects healed.\nTo our knowledge this is the first case to report on concurrent palbociclib and radiation use, with resultant enhanced radiation effects that required hospitalization for symptom management. Several preclinical studies have shown synergistic effects of radiation and both in vivo and in vitro experiments resulting in improved survival and decreased cell proliferation, respectively, through enhanced G1 cell cycle arrest.\nThis case highlights the importance of using caution when combining radiation with the new targeted therapies. Until more data becomes available, physicians are recommended to exercise clinical judgment when deciding on whether to continue or discontinue a CDK4/6 inhibitor in a patient who may need radiation.",
"affiliations": "Department of Radiation Oncology, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0711, USA.;Department of Pharmacy, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX 77030, USA.;Department of Internal Medicine, Hematology/Oncology Division, Houston Methodist Hospital, 6550 Fannin Street, Houston, TX 77030, USA.;Department of Radiation Oncology, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX 77030, USA.",
"authors": "Messer|Jay A|JA|;Ekinci|Ekim|E|;Patel|Tejal A|TA|;Teh|Bin S|BS|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.1016/j.rpor.2019.03.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1507-1367",
"issue": "24(3)",
"journal": "Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology",
"keywords": "Breast cancer; Palbociclib; Radiosensitizing; Radiotherapy",
"medline_ta": "Rep Pract Oncol Radiother",
"mesh_terms": null,
"nlm_unique_id": "100885761",
"other_id": null,
"pages": "276-280",
"pmc": null,
"pmid": "30948930",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "20171502;20354191;23138228;23634254;23708653;24098593;24922006;26030518;26433823;26728409;26947331;27370397;27701148;27959613;28690875;28964534;30056081;30118901;30336956",
"title": "Enhanced dermatologic toxicity following concurrent treatment with palbociclib and radiation therapy: A case report.",
"title_normalized": "enhanced dermatologic toxicity following concurrent treatment with palbociclib and radiation therapy a case report"
} | [
{
"companynumb": "US-PFIZER INC-2019142498",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PALBOCICLIB"
},
"drugadditional": "1",
... |
{
"abstract": "The USA is currently facing a serious opioid misuse epidemic that started with increased prescribing of oxycodone and the inclusion of pain as a fifth vital sign, and eventually resulted in massive overdose mortality. In Europe, including the Netherlands, the medical use of opioids (mainly oxycodone) has also increased since 2009, but an increase in proxies for opioid misuse has not yet been described.\n\n\n\nFor this retrospective, multi-source database study, data were requested from several national databases in the Netherlands to evaluate the following time trends: (1) number of people with opioid prescriptions, (2) number of hospital admissions related to opioid intoxication, (3) number of people treated for opioid use disorder, and (4) number of people who died from opioid poisoning. Data were presented as the number per 100 000 inhabitants, using population data over the years 2008-17 from Statistics Netherlands (Centraal Bureau voor de Statistiek). Data about the number of people with opioid prescriptions was obtained from the Drug Information Project (Genees- en hulpmiddelen Informatie Project) database hosted by the Dutch National Health Care Institute (Zorginstituut Nederland). Data about opioid-related hospital admissions between 2008 and 2017 were obtained from the Dutch National Hospital Care Basic Registration (Landelijke Basisregistratie Ziekenhuiszorg), a database managed by Dutch Hospital Data. Data about addiction treatment were obtained from the National Alcohol and Drugs Information System (Landelijk Alcohol en Drugs Informatie Systeem). Data on opioid mortality between 2008 and 2017 were obtained from the cause-of-death statistics database hosted by Statistics Netherlands. Each database covered almost the entire population of the Netherlands.\n\n\n\nBetween 2008 and 2017, the overall number of prescription opioid users nearly doubled from 4109 per 100 000 inhabitants to 7489 per 100 000 inhabitants, mainly because the number of oxycodone users quadrupled from 574 to 2568 per 100 000 inhabitants. In the same period, the number of opioid-related hospital admissions tripled from 2·5 to 7·8 per 100 000 inhabitants, and between 2008 and 2015 the number of patients in addiction care for opioid use disorders other than heroin increased from 3·1 to 5·6 per 100 000 inhabitants. Opioid-related mortality was stable between 2008 and 2014 with 0·21 deaths per 100 000 inhabitants, but after 2014 it increased to 0·65 per 100 000 inhabitants in 2017.\n\n\n\nPrescription opioid use increased substantially between 2008 and 2017, and several proxies for misuse show a parallel increasing trend. Although the Netherlands is far from the opioid epidemic faced by the USA, safe opioid prescribing guidelines should be implemented to prevent further escalation and to keep opioid painkillers available for those in need.\n\n\n\nRadboud University Nijmegen Medical Centre.",
"affiliations": "Department of Clinical Pharmacy, Canisius-Wilhelmina Hospital, Nijmegen, Netherlands. Electronic address: a.kalkman@cwz.nl.;Department of Clinical Pharmacy, Canisius-Wilhelmina Hospital, Nijmegen, Netherlands; Department of Pharmacology and Toxicology, Radboud University Medical Centre, Nijmegen, Netherlands.;Department of Pain Management and Palliative Care, Canisius-Wilhelmina Hospital, Nijmegen, Netherlands; Department of Anesthesiology, Pain and Palliative Care, Radboud University Medical Centre, Nijmegen, Netherlands.;Department of Psychiatry, Amsterdam University Medical Centre, Location AMC, University of Amsterdam, Amsterdam, Netherlands.;Department of Psychiatry, Radboud University Medical Centre, Nijmegen, Netherlands; Nijmegen Institute for Scientist-Practitioners in Addiction, Radboud University, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands.",
"authors": "Kalkman|Gerard Arnoldus|GA|;Kramers|Cornelis|C|;van Dongen|Robert T|RT|;van den Brink|Wim|W|;Schellekens|Arnt|A|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "England",
"delete": false,
"doi": "10.1016/S2468-2667(19)30128-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "4(10)",
"journal": "The Lancet. Public health",
"keywords": null,
"medline_ta": "Lancet Public Health",
"mesh_terms": "D000701:Analgesics, Opioid; D062787:Drug Overdose; D011307:Drug Prescriptions; D006801:Humans; D009426:Netherlands; D009293:Opioid-Related Disorders; D010818:Practice Patterns, Physicians'; D012189:Retrospective Studies",
"nlm_unique_id": "101699003",
"other_id": null,
"pages": "e498-e505",
"pmc": null,
"pmid": "31444001",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Trends in use and misuse of opioids in the Netherlands: a retrospective, multi-source database study.",
"title_normalized": "trends in use and misuse of opioids in the netherlands a retrospective multi source database study"
} | [
{
"companynumb": "NL-JNJFOC-20191027628",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Mycobacterium haemophilum is a fastidious nontuberculosis Mycobacterium that must be considered in the differential diagnosis of infections in immunocompromised patients. Mycobacterium haemophilum typically is a pathogen of the cutaneous or subcutaneous tissue and also presents as septic arthritis, osteomyelitis, pulmonary disease, and lymphadenitis. We report a 32-year-old man with past medical history of kidney transplantation, endocarditis, gastrointestinal bleeding, and hypertension, complaining of multiple painful nodular lesions since 3 months earlier. A tissue biopsy and polymerase chain reaction detected Mycobacterium haemophilum. Atypical mycobacterial species like Mycobacterium haemophilum should be assessed in immunocompromised patients positive for acid fast staining and negative for Mycobacterium tuberculosis.",
"affiliations": "Infectious Diseases and Tropical Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. tehrani.shabnam89@yahoo.com.",
"authors": "Abolghasemi|Sara|S|;Abbasi|Fatemeh|F|;Tehrani|Shabnam|S|;Nafar|Mohsen|M|;Nasiri|Mohammad Javad|MJ|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1735-8582",
"issue": "12(5)",
"journal": "Iranian journal of kidney diseases",
"keywords": null,
"medline_ta": "Iran J Kidney Dis",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D002481:Cellulitis; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008297:Male; D009164:Mycobacterium Infections; D018393:Mycobacterium haemophilum",
"nlm_unique_id": "101316967",
"other_id": null,
"pages": "312-314",
"pmc": null,
"pmid": "30367024",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cutaneous Infection With Mycobacterium haemophilum in an Immunocompromised Patient.",
"title_normalized": "cutaneous infection with mycobacterium haemophilum in an immunocompromised patient"
} | [
{
"companynumb": "IR-BAUSCH-BL-2018-036070",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LOSARTAN"
},
"drugadditional": "3",
... |
{
"abstract": "Coronavirus disease 2019 (COVID-19), which began in China, caused a global pandemic. Few studies have shown the benefit of hydroxychloroquine (HY) ± azithromycin (AZ) for treating COVID-19. Concerns of QT prolongation and increased risks of torsade's de pointes (TdP) with this combination have been raised since each agent can individually prolong the QT interval. This retrospective, observational study included hospitalized patients treated with HY and AZ from March 2020 to May 2020 at a large community hospital. Serial assessments of the QT interval were performed. Our aim is to evaluate the safety and characterize the change in QTc interval and arrhythmic events in COVID-19 patients treated with HY/AZ. A total of 21 COVID patients who received at least four days of HY and AZ were included in this study. Mean baseline was QTc 403 ms, mean maximum QTc was 440 ms, mean change in QTc was 36 ms. Only one patient (4.8%) developed prolonged QTc > 500 ms. No patient had a change in QTc of 60 ms or more. No patient developed TdP. Fifteen patients (71.4%) had hypoxia on admission, with only two patients (9.5%) required oxygen of 1-2 L at discharge. 80.9% of patients have been discharged home or inpatient rehabilitation.",
"affiliations": "Department of Internal Medicine, Huntsville Hospital, AL, USA. Electronic address: ushachowdhary.y@gmail.com.;Department of Infectious Disease, Huntsville Hospital, AL, USA. Electronic address: ali_hasoun@yahoo.com.;Department of Cardiology, Huntsville Hospital, AL, USA.;Department of Pharmacology, Huntsville Hospital, AL, USA.",
"authors": "Yendrapalli|Usha|U|;Ali|Hassoun|H|;Green|Jacqueline L|JL|;Edwards|Jonathan|J|",
"chemical_list": "D006886:Hydroxychloroquine; D017963:Azithromycin",
"country": "England",
"delete": false,
"doi": "10.1016/j.jiph.2021.09.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-0341",
"issue": "14(11)",
"journal": "Journal of infection and public health",
"keywords": "Azithromycin; COVID-19; Hydroxychloroquine; QT interval; Torsade de pointes",
"medline_ta": "J Infect Public Health",
"mesh_terms": "D017963:Azithromycin; D000086382:COVID-19; D066126:Cardiotoxicity; D006801:Humans; D006886:Hydroxychloroquine; D012189:Retrospective Studies; D000086402:SARS-CoV-2",
"nlm_unique_id": "101487384",
"other_id": null,
"pages": "1668-1670",
"pmc": null,
"pmid": "34627063",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "26660066;32150618;32289548;32347743;32344177;32064853;30145917;32936252;32205204;33934125;32623082",
"title": "Effects of cardiac toxicity of combination therapy with hydroxychloroquine and azithromycin in COVID-19 patients.",
"title_normalized": "effects of cardiac toxicity of combination therapy with hydroxychloroquine and azithromycin in covid 19 patients"
} | [
{
"companynumb": "US-NOVARTISPH-NVSC2021US280568",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE SULFATE"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nPneumomediastinum is a rare complication of COVID-19 pneumonia, which may or may not be associated with invasive ventilatory support. Therefore, the report and findings associated with its evolution can be of great contribution in the management of this unknown disease.\n\n\nMETHODS\nHere, we present a series of four patients with severe pneumomediastinum requiring intensive care unit. These patients developed pneumomediastinum before or during orotracheal intubation (OTI) or without OTI. The four patients were three men and one woman with a mean age of 60.5 years (48-74 years). No patients had a known history of lung disease or traumatic events, except for one patient who had a history of smoking, but who was without parenchymal disease. All intubations were performed without complications. No cases of pneumomediastinum occurred after tracheostomy, and none of the patients had tomographic or bronchoscopic evidence of tracheal injury. Although the pneumomediastinum observed in our cases was apparently not related to a violation of the aerodigestive track, this complication was associated with a worse prognosis.\n\n\nCONCLUSIONS\nPneumomediastinum is a rare complication of COVID-19 pneumonia, and the most likely etiopathogenesis is severe pulmonary involvement, which may or may not be associated with invasive ventilatory support. Future studies with a greater number of cases should elucidate the relationship of pneumomediastinum to a probable prognostic factor.",
"affiliations": "Division of General Surgery and Trauma, Department of Surgery, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC/FMUSP), Dr. Enéas de Carvalho Aguiar Av. 255. Cerqueira Cesar, São Paulo, 05402-000, Brazil. sergio.damous@hc.fm.usp.br.;Division of General Surgery and Trauma, Department of Surgery, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC/FMUSP), Dr. Enéas de Carvalho Aguiar Av. 255. Cerqueira Cesar, São Paulo, 05402-000, Brazil.;Division of General Surgery and Trauma, Department of Surgery, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC/FMUSP), Dr. Enéas de Carvalho Aguiar Av. 255. Cerqueira Cesar, São Paulo, 05402-000, Brazil.;Division of General Surgery and Trauma, Department of Surgery, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC/FMUSP), Dr. Enéas de Carvalho Aguiar Av. 255. Cerqueira Cesar, São Paulo, 05402-000, Brazil.;Division of General Surgery and Trauma, Department of Surgery, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC/FMUSP), Dr. Enéas de Carvalho Aguiar Av. 255. Cerqueira Cesar, São Paulo, 05402-000, Brazil.;Division of General Surgery and Trauma, Department of Surgery, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC/FMUSP), Dr. Enéas de Carvalho Aguiar Av. 255. Cerqueira Cesar, São Paulo, 05402-000, Brazil.;Division of General Surgery and Trauma, Department of Surgery, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC/FMUSP), Dr. Enéas de Carvalho Aguiar Av. 255. Cerqueira Cesar, São Paulo, 05402-000, Brazil.;Division of General Surgery and Trauma, Department of Surgery, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC/FMUSP), Dr. Enéas de Carvalho Aguiar Av. 255. Cerqueira Cesar, São Paulo, 05402-000, Brazil.;Division of General Surgery and Trauma, Department of Surgery, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC/FMUSP), Dr. Enéas de Carvalho Aguiar Av. 255. Cerqueira Cesar, São Paulo, 05402-000, Brazil.;Division of General Surgery and Trauma, Department of Surgery, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC/FMUSP), Dr. Enéas de Carvalho Aguiar Av. 255. Cerqueira Cesar, São Paulo, 05402-000, Brazil.",
"authors": "Damous|Sérgio Henrique Bastos|SHB|http://orcid.org/0000-0003-1374-225X;Dos Santos Junior|Jones Pessoa|JP|;Pezzano|Álvaro Vicente Alvarez|ÁVA|;Chams|Mohamad Abdul Majid|MAM|;Haritov|Nathaly|N|;Waksman|Ricardo|R|;Lima|Helber Vidal Gadelha|HVG|;Dos Santos Miranda|Jocielle|J|;Rasslan|Roberto|R|;Utiyama|Edivaldo Massazo|EM|",
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"doi": "10.1186/s40001-021-00585-9",
"fulltext": "\n==== Front\nEur J Med Res\nEur J Med Res\nEuropean Journal of Medical Research\n0949-2321\n2047-783X\nBioMed Central London\n\n585\n10.1186/s40001-021-00585-9\nCase Report\nPneumomediastinum complicating COVID-19: a case series\nhttp://orcid.org/0000-0003-1374-225X\nDamous Sérgio Henrique Bastos sergio.damous@hc.fm.usp.br\n\ndos Santos Junior Jones Pessoa jonespessoa@hotmail.com\n\nPezzano Álvaro Vicente Alvarez alvaro.vicente@hc.fm.usp.br\n\nChams Mohamad Abdul Majid mohamad.chams@hc.fm.usp.br\n\nHaritov Nathaly nathaly.haritov@hc.fm.usp.br\n\nWaksman Ricardo ricardo.waksman@hc.fm.usp.br\n\nLima Helber Vidal Gadelha helber.vidal@hc.fm.usp.br\n\ndos Santos Miranda Jocielle jocielle.miranda@hc.fm.usp.br\n\nRasslan Roberto roberto.rasslan@hc.fm.usp.br\n\nUtiyama Edivaldo Massazo edivaldo.utiyama@hc.fm.usp.br\n\ngrid.411074.7 0000 0001 2297 2036 Division of General Surgery and Trauma, Department of Surgery, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC/FMUSP), Dr. Enéas de Carvalho Aguiar Av. 255. Cerqueira Cesar, São Paulo, 05402-000 Brazil\n26 9 2021\n26 9 2021\n2021\n26 11411 11 2020\n16 9 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nPneumomediastinum is a rare complication of COVID-19 pneumonia, which may or may not be associated with invasive ventilatory support. Therefore, the report and findings associated with its evolution can be of great contribution in the management of this unknown disease.\n\nCase presentation\n\nHere, we present a series of four patients with severe pneumomediastinum requiring intensive care unit. These patients developed pneumomediastinum before or during orotracheal intubation (OTI) or without OTI. The four patients were three men and one woman with a mean age of 60.5 years (48–74 years). No patients had a known history of lung disease or traumatic events, except for one patient who had a history of smoking, but who was without parenchymal disease. All intubations were performed without complications. No cases of pneumomediastinum occurred after tracheostomy, and none of the patients had tomographic or bronchoscopic evidence of tracheal injury. Although the pneumomediastinum observed in our cases was apparently not related to a violation of the aerodigestive track, this complication was associated with a worse prognosis.\n\nConclusion\n\nPneumomediastinum is a rare complication of COVID-19 pneumonia, and the most likely etiopathogenesis is severe pulmonary involvement, which may or may not be associated with invasive ventilatory support. Future studies with a greater number of cases should elucidate the relationship of pneumomediastinum to a probable prognostic factor.\n\nKeywords\n\nCOVID-19\nSARS-CoV-2\nPneumomediastinum\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nPneumomediastinum is a frequent sign of clinical concern with potentially threatening consequences [1]. It can be classified as primary pneumomediastinum, which is also called spontaneous pneumomediastinum and is defined as the presence of air in the mediastinum without any defined cause [2]; secondary pneumomediastinum develops as a consequence of a distinct underlying pathology or thoracic injury, resulting in intrathoracic dissection of air through the mediastinal planes [1].\n\nThe lungs of patients with COVID-19 have significant interstitial involvement with edema, protein exudates, vascular congestion and inflammatory changes with low compliance and reduced elastance [3]. Therefore, when there is a pressure gradient between the alveoli and the pulmonary interstitium in the fibrotic and hypoelastic lung, alveolar rupture and the consequent leakage of air into the interstitium can occur. Due to the pressure gradient between the pulmonary periphery and the mediastinum, the air present in the pulmonary interstitium flows toward the pulmonary hilum and the mediastinum [4].\n\nThe Hospital das Clínicas is the largest public tertiary hospital in the state of São Paulo, Brazil. It has approximately 900 beds, with approximately 300 intensive care beds. In the context of the COVID-19 pandemic, the hospital was entirely dedicated to the care of COVID-19 as the State’s main referral center for serious cases. Here, we report a series of four cases of patients diagnosed with COVID-19 who developed pneumomediastinum.\n\nCase series\n\nWe present the cases of four patients with COVID-19 disease verified through nasotracheal SARS-CoV-2 PCR or chest computerized tomography (CT) who were referred to our department from April to July 2020. We recorded the baseline patient characteristics, including comorbidities, ventilation data, information regarding the signs of pneumomediastinum and its diagnosis, ongoing management and outcome. Consent for the use of anonymized data and imaging was obtained from the next of kin.\n\nThese patients developed pneumomediastinum before or during orotracheal intubation (OTI) or without OTI. The data are summarized in Table 1. The four patients were three men and one woman with a mean age of 60.5 years (48–74 years). No patients had a known history of lung disease or traumatic events, except for one patient who had a history of smoking but who was without parenchymal disease. All intubations were performed without complications. No cases of pneumomediastinum occurred after tracheostomy, and none of the patients had tomographic or bronchoscopic evidence of tracheal injury.Table 1 Case series of patients who developed pneumomediastinum during COVID-19 infection\n\n\tAge\tComorbidities\tSARS-CoV-2 PCR\tLung severity score on chest CT scans (%)\tPneumomediastinum\tOro-tracheal intubation\tPEEP (cmH2O)\tBronchoscopy\t\nCase 1\t50\tChronic arterial hypertension and kidney transplantation\tNegative\t> 50\t10th day\tNo\t–\tNo\t\nCase 2\t70\tEx-smoker and diabetic\tPositive\t> 50\t18th day\tYes\t8–10\tYes\t\nCase 3\t48\tNone\tPositive\t> 50\t14th day\tYes\t8–10\tYes\t\nCase 4\t74\tMastectomy\tPositive\t> 50\t20th day\tYes\t8–10\tNo\t\nCT computerized tomography\n\nCase 1\n\nA 50-year-old man was admitted to our hospital after transfer from a basic health unit with a chest CT compatible with viral infection by SARS-CoV-2. He had cough, respiratory distress, myalgia, fever and episodes of diarrhea for 10 days, and he was using ceftriaxone and clarithromycin with oxygen support. In his medical history, the patient reported tabagism, systemic hypertension, a kidney transplant 6 years previously, and the use of tacrolimus, everolimus and prednisone. In our service, we request laboratory tests, including a nasopharyngeal swab PCR test, to confirm infection with SARS-CoV-2 and perform an additional chest CT. Although the admission test was negative for SARS-CoV-2, chest CT showed multiple ground-glass pulmonary opacities with scattered foci of consolidation, which were multifocal and bilateral with an estimated extent greater than 50% [5, 6] that were compatible with viral pneumonia, in addition to extensive anterior, middle and posterior pneumomediastinum dissecting the bilateral anterior cervical plane (Fig. 1A, B). Soon after tomography was performed, there was rapid deterioration of the respiratory condition requiring orotracheal intubation (OTI). In the intensive care unit, piperacillin + tazobactam, vancomycin, oseltamivir and corticosteroids were introduced. During disease progression, there was clinical worsening with hemodynamic instability, and it was not possible to perform complementary exams, such as upper digestive endoscopy and bronchoscopy. Over the next 10 days, the patient was maintained on high doses of vasoactive drugs (norepinephrine and vasopressin) and suffered from multiple system dysfunction that resulted in death.Fig. 1 Chest CT scans or radiograph of the chest showing pneumomediastinum (black arrows). A, B Case 1. C, D Case 2. E, F Case 3. G, H Case 4. Red arrows: chest drainage\n\nCase 2\n\nA 70-year-old man who was diabetic was admitted to our hospital on the 13th day after the onset of flu-like symptoms with invasive ventilatory support and chest CT showing suspected infection by SARS-CoV-2. Ceftriaxone, azithromycin, heparin and oseltamivir were used. He was directed to the intensive care unit, his antibiotics were changed (piperacillin/tazobactam and vancomycin), and support was started with vasoactive drugs. The nasopharyngeal swab PCR test was positive. On the 18th day, the patient was placed in a prone position as an adjuvant therapy for improving ventilation.\n\nAfter a favorable response, it was decided to suspend the neuromuscular block, decrease sedation and decrease the parameters of the invasive mechanical ventilation. After 24 h, the patient presented subcutaneous emphysema in the cervical and thoracic regions without worsening of the ventilatory parameters. On chest CT, there was extensive subcutaneous emphysema and pneumomediastinum with multiple ground-glass pulmonary opacities associated with thickening of the interlobular septa with an estimated extent greater than 50% (visual analysis) [5, 6] (Fig. 1C, D). During disease progression, bronchoscopy and tracheostomy were performed without complications. After 28 days in the intensive care unit with treatment with tigecycline for carbapenem-resistant Klebsiella pneumoniae in the tracheal secretions, the patient presented with hemodynamic worsening, which progressed to death.\n\nCase 3\n\nA 48-year-old man without comorbidities was admitted to our service on mechanical ventilation 12 days after the onset of flu-like symptoms. Intubation without complications by another service was reported. The test for SARS-CoV-2 (nasopharyngeal swab PCR) was positive. Ceftriaxone and prophylactic anticoagulation were started. On the 2nd day after admission, the patient presented subcutaneous emphysema on chest CT, showing massive emphysema in the anterior and posterior cervical regions and chest wall with pneumomediastinum, left nonhypertensive pneumothorax and pneumoperitoneum, and multiple ground-glass opacities that were multifocal with consolidation and an extent greater than 50% (visual area) [5, 6] (Fig. 1E, F). Thoracic drainage was performed on the left lung with a pigtail drain without complications, and bronchoscopy was performed without evidence of airway injury. During progression, the patient underwent percutaneous tracheostomy and treatment with meropenem + vancomycin. He is currently undergoing home rehabilitation without the need for oxygen therapy.\n\nCase 4\n\nA 74-year-old female patient with a history of left mastectomy for malignant breast cancer was undergoing adjuvant chemotherapy with paclitaxel. There was no pulmonary or pleural metastasis. She was admitted to our service after 17 days of progression of the symptoms of cough, myalgia and dyspnea. The nasopharyngeal swab PCR test for SARS-CoV-2 showed a positive result. She was given piperacillin + tazobactam and prophylactic heparin, and azithromycin was added. On the 3rd day of hospitalization, the patient progressed with deterioration of respiratory function requiring orotracheal intubation, which was performed without complications, and she was referred to the intensive care unit. Eight hours after OTI, the patient developed extensive subcutaneous emphysema and decreased auscultation in the right chest, with suspicion of pneumothorax and right chest drainage. She was placed on mechanical ventilation, which was volume-controlled, with a PEEP of 7 (cmH2O), an FiO2 of 80% and a SatO2 of 97%. Chest CT showed multiple ground-glass pulmonary opacities, which were sometimes associated with thickening of the interlobular septa and fine reticulate between consolidations, and presented a diffuse distribution with an estimated extent of pulmonary involvement on tomography greater than 50% (visual analysis) [5, 6]. Soft tissue emphysema was observed in the bilateral chest wall with extension into the superficial and deep planes of the cervical region and extensive pneumomediastinum. A thoracic drain was placed on the right side with the end in the medial region of the hemithorax (Fig. 1G, H). The patient progressed to refractory shock, which was not directly related to pneumothorax or pneumomediastinum. The antimicrobial regimen was expanded by introducing meropenem and vancomycin, and hemodynamic support was optimized. Despite all measures, the patient progressed to multiple organ dysfunction 48 h after OTI. Bronchoscopy was not performed due to the patient’s clinical condition, but there was no evidence of tracheal injury on tomography.\n\nDiscussion\n\nDue to the COVID-19 pandemic, there are currently reports of pneumomediastinum as a rare complication of COVID-19 pneumonia. Pneumomediastinum could result directly from the pathogenesis of SARS-CoV-2 (rupture of pulmonary bullae) or secondary to intensive care management due to airway trauma during tracheal intubation, barotraumas or repositioning maneuvers [7–9].\n\nHere, four cases of pneumomediastinum complicating COVID-19 pneumonia were presented. We did not find that this complication was due to iatrogenic causes. Although two of the patients were not subjected to fiberoptic bronchoscopy due to their clinical instability, it was not possible to identify any airway discontinuity by computed tomography. The patient in case 1 had not even been intubated when he presented with pneumomediastinum. Additionally, the other patients maintained a low positive end-expiration pressure of 8–10 cmH2O.\n\nAll cases presented with more than 10 days of disease, and more than 50% showed pulmonary involvement by chest CT, which evolved into severe dyspnea with a PEEP between 8 and 10 and had an unfavorable outcome (death). It was not possible to correlate pneumothorax with pneumomediastinum or OTI as a possible cause, as there was no difficulty in terms of OTI. It is assumed, then, that pneumomediastinum must have been secondary to the pulmonary deterioration caused by COVID-19, including the formation of pulmonary fibrosis and the rupture of bubbles in the mediastinum. The patients in cases 3 and 4 even had evidence of extraperitoneal air dissection, as shown in Fig. 1. We hypothesized that reactive pleural thickening associated with COVID-19 prevents air from spreading to the pleural space; therefore, some cases do not show evidence of pneumothorax [7, 10].\n\nKong et al. [11] reported a case of pneumomediastinum in an elderly patient after 14 days of illness, and it was not possible to determine any causal event, similar to our cases. Unlike the patients in our case series, this patient evolved satisfactorily with conservative treatment. Pneumomediastinum was a chest CT finding in a 23-year-old patient who was totally asymptomatic, with no emphysema or pneumothorax, and 7 days later, this patient showed complete resolution of the pneumomediastinum [9].\n\nThere have been two other reports of pneumomediastinum in young patients with COVID-19 without previous illnesses or traumas, who presented completely different courses of disease. The first patient, who was 37 years old, developed mediastinal emphysema and pneumothorax. No abnormalities, such as a small bulla or emphysema, were observed in the initial chest CT, which was performed while the patient was receiving noninvasive mechanical ventilation in the intensive care unit. The authors suggest that mediastinal emphysema results from a sudden increase in alveolar pressure, causing alveolar rupture and air leakage with interstitial emphysema. The patient recovered with oxygen therapy [8]. In the other case, a 36-year-old patient succumbed to illness after 2 days due to respiratory failure and acute respiratory distress despite supportive care [7]. This second case is similar to the cases in our case series.\n\nIn another case series, five patients developed pneumomediastinum 4 h–14 days after tracheal intubation. All patients were invasively ventilated due to respiratory compromise with severe hypoxemia despite receiving maximal ward-based oxygen therapy. One patient developed pneumomediastinum immediately following prone positioning maneuvers [12]. In these cases, pneumomediastinum was secondary to barotrauma or repositioning maneuvers, unlike that observed in our series, in which it was not possible to associate pneumomediastinum with a causal factor besides COVID-19 infection.\n\nAlthough the pneumomediastinum observed in our cases was apparently not related to a violation of the aerodigestive track, this complication was associated with a worse prognosis [7]. Although death does not appear to be directly related to pneumomediastinum in most cases, three of the four patients died. This must indicate that they were in an advanced phase of COVID-19.\n\nConclusion\n\nPneumomediastinum is a rare complication of COVID-19 pneumonia, and the most likely etiopathogenesis is severe pulmonary involvement, which may or may not be associated with invasive ventilatory support. Future studies with a greater number of cases should elucidate the relationship of pneumomediastinum to a probable prognostic factor.\n\nAbbreviations\n\nOTI Oro-tracheal intubation\n\nCT Computerized tomography\n\nAcknowledgements\n\nWe thank Luciana Lamarão Damous for the manuscript correction.\n\nAuthors’ contributions\n\nAll authors participated in patient care, description of the clinical case and separation of images for publication. In addition, SHBD drafted the manuscript. EMU: critical revision of the article for important intellectual content and final approval of the version to be submitted. All authors read and approved the final manuscript.\n\nFunding\n\nNo funding was received.\n\nAvailability of data and materials\n\nThe dataset supporting the conclusions of this article is included within the article.\n\nDeclarations\n\nEthics approval and consent to participate\n\nConsent for the use of anonymized data and imaging was obtained from the next of kin.\n\nConsent for publication\n\nAll authors read and approved the final manuscript.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Caceres M Braud RL Maekawa R Weiman DS Garrett HE Secondary pneumomediastinum: a retrospective comparative analysis Lung 2009 187 341 346 10.1007/s00408-009-9164-4 19697084\n2. Macklin MT Macklin CC Malignant interstitial emphysema of the lungs and mediastinum as an important occult complication in many respiratory diseases and other conditions: interpretation of the clinical literature in the light of laboratory experiment Medicine 1944 23 281 358 10.1097/00005792-194412000-00001\n3. Guan WJ Ni ZY Hu Y Liang WH Ou CQ He JX Clinical characteristics of coronavirus disease 2019 in China N Engl J Med 2020 10.1056/NEJMoa2002032 32220206\n4. Macklin MT Macklin CC Malignant interstitial emphysema of the lungs and mediastinum as an important occult complication in many respiratory diseases and other conditions: interpretation of the clinical literature in the light of laboratory experiment Medicine 1944 23 281 358 10.1097/00005792-194412000-00001\n5. Chate RC Fonseca EKUN Passos RBD Teles GBS Shoji H Szarf G Presentation of pulmonary infection on CT in COVID-19: initial experience in Brazil J Bras Pneumol 2020 46 2 e20200121 10.36416/1806-3756/e20200121 32294718\n6. Lomoro P Verde F Zerboni F Simonetti I Borghi C Fachinetti C Natalizi A Martegani A COVID-19 pneumonia manifestations at the admission on chest ultrasound, radiographs, and CT: single-center study and comprehensive radiologic literature review Eur J Radiol Open 2020 7 100231 10.1016/j.ejro.2020.100231 32289051\n7. Wang J Su X Zhang T Zheng C Spontaneous pneumomediastinum: a probable unusual complication of coronavirus disease 2019 (COVID-19) pneumonia Korean J Radiol 2020 21 5 627 628 10.3348/kjr.2020.0281 32323507\n8. Sun R Liu H Wang X Mediastinal emphysema, giant bulla, and pneumothorax developed during the course of COVID-19 pneumonia Korean J Radiol 2020 21 5 541 544 10.3348/kjr.2020.0180 32207255\n9. Kolani S Houari N Haloua M Lamrani YA Boubbou M Serraj M Aamara B Maaroufi M Alami B Spontaneous pneumomediastinum occurring in the SARS-COV-2 infection IDCases 2020 21 e00806 10.1016/j.idcr.2020.e00806 32395425\n10. Liu J Liu S The management of coronavirus disease 2019 (COVID-19) J Med Virol 2020 10.1002/jmv.25965 33314141\n11. Kong N Gao C Xu MS Xie YL Zhou CY Spontaneous pneumomediastinum in an elderly COVID-19 patient: a case report World J Clin Cases 2020 8 16 3573 3577 10.12998/wjcc.v8.i16.3573 32913866\n12. Wali A Rizzo V Bille A Routledge T Chambers A Pneumomediastinum following intubation in COVID-19 patients: a case series Anaesthesia 2020 10.1111/anae.15113 32375200\n\n",
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"title": "Pneumomediastinum complicating COVID-19: a case series.",
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"abstract": "Electron microscopy (EM), real-time polymerase chain reaction (PCR) and conventional PCR were used to identify viruses associated with infection in 2 transplantation patients. An autologous haematopoietic stem cell, liver and renal transplant recipient was found to be positive for simian virus 40 (SV40). Dual BK virus and SV40 infection was found in a heart and renal transplantation patient. SV40 infection can occur in immunocompromised patients.",
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"abstract": "A 65 year old patient who was exposed to topical bovine thrombin during cardiac surgery developed markedly prolonged clotting times and a severe bleeding diathesis. Mixing studies with normal plasma failed to correct the clotting times. Platelet transfusions, immunosuppressive and immunomodulatory therapies were ineffective, but plasmapheresis was effective in decreasing clotting times and in the resolution of clinical bleeding events. The patient's purified IgG reacted with bovine thrombin by immunoblotting and enzyme-linked immunosorbent assay (ELISA). However, the IgG reacted minimally with human thrombin. In view of the severe bleeding, a coexisting inhibitor was sought. The patient's factor V activity was 1% of normal and was not corrected by mixing with normal plasma, demonstrating the presence of an inhibitor against factor V. The patient's IgG reacted with both bovine and human factor V. Immunoblotting localized the site of antibody binding to the light chain of activated bovine factor V. Detectable amounts of bovine factor V were found in commercial bovine thrombin preparations by ELISA. The data suggest that patients exposed to topical bovine thrombin may develop antibodies to thrombin and factor V. Anti-thrombin antibodies may mask coexisting factor V inhibitors responsible for clinical bleeding.",
"affiliations": "Department of Medicine, Stanford University Medical Center, CA 94305.",
"authors": "Zehnder|J L|JL|;Leung|L L|LL|",
"chemical_list": "D000906:Antibodies; D007074:Immunoglobulin G; D005165:Factor V; D013917:Thrombin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "76(10)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000287:Administration, Topical; D000368:Aged; D000818:Animals; D000906:Antibodies; D002318:Cardiovascular Diseases; D002417:Cattle; D004797:Enzyme-Linked Immunosorbent Assay; D005165:Factor V; D006470:Hemorrhage; D006801:Humans; D015151:Immunoblotting; D007074:Immunoglobulin G; D008297:Male; D013917:Thrombin",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "2011-6",
"pmc": null,
"pmid": "2242423",
"pubdate": "1990-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Development of antibodies to thrombin and factor V with recurrent bleeding in a patient exposed to topical bovine thrombin.",
"title_normalized": "development of antibodies to thrombin and factor v with recurrent bleeding in a patient exposed to topical bovine thrombin"
} | [
{
"companynumb": "US-PFIZER INC-2019005504",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THROMBIN"
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"drugadditional": "3",
... |
{
"abstract": "Therapy-related myeloid neoplasms (tMN) are serious late effects of the treatment of cancer with poor response to conventional treatment. Azacitidine (AZA) has been used to treat patients with tMN but current data are retrospective. We present here 47 tMN patients prospectively enrolled as a specific cohort in the E1905 study. TheE1905 study was a randomized phase 2 study (NCT00313586) testing 10 d of AZA (50 mg/m(2) /d) +/- the histone deacetylase inhibitor entinostat (4 mg/m(2) /d PO day-3 and day-10). A total of 47 patients [29 therapy-related myelosyspastic syndrome (t-MDS) and 18 therapy-related acute myeloid leukaemia (t-AML)] were recruited to the study. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4, significantly higher in patients treated with AZA (6 cycles vs. 3 cycles, P = 0·008). Haematological normalization rates were 46% in monotherapy and 17% in the combination arm. Median overall survivals were 13 and 6 months, respectively. The novel 50 * 10 schedule of azacitidine appears effective, with response rates, when given as single agent, comparable to those for patients with de novo MDS/AML treated on the same protocol. However, the combination of AZA and entinostat was associated with increased toxicity and could not be recommended for treatment of tMN.",
"affiliations": "Section of Hematology, Yale Cancer Center, New Haven, CT, USA.;ECOG-ACRIN Biostatistics Center, Dana-Farber Cancer Institute, Boston, MA, USA.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.;Section of Hematology, Yale Cancer Center, New Haven, CT, USA.;Hematology Division, Stanford University Cancer Center, Stanford, CA, USA.;Johns Hopkins University, Baltimore, MD, USA.;University of Wisconsin, Madison, WI, USA.;Cleveland Clinic, Cleveland, OH, USA.;Johns Hopkins University, Baltimore, MD, USA.;North Division, Montefiore Medical Center, Bronx, NY, USA.;Indiana University Cancer Center, Indianapolis, IN, USA.;University of Michigan Medical School, Ann Arbor, MI, USA.;The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai School of Medicine, New York, NY, USA.;University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.;Leukemia Service, Memorial Sloane-Kettering Cancer Center, New York, NY, USA.;Division of Hematology, Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN, USA.;Section of Hematology, Yale Cancer Center, New Haven, CT, USA.",
"authors": "Prebet|Thomas|T|http://orcid.org/0000-0002-6872-625X;Sun|Zhuoxin|Z|;Ketterling|Rhett P|RP|;Zeidan|Amer|A|;Greenberg|Peter|P|;Herman|James|J|;Juckett|Mark|M|;Smith|Mitchell R|MR|;Malick|Lisa|L|;Paietta|Elisabeth|E|;Czader|Magdalena|M|;Figueroa|Maria|M|;Gabrilove|Janice|J|;Erba|Harry P|HP|;Tallman|Martin S|MS|;Litzow|Mark|M|;Gore|Steven D|SD|;|||",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D011725:Pyridines; C118739:entinostat; D001374:Azacitidine",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.13832",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "172(3)",
"journal": "British journal of haematology",
"keywords": "acute myeloid leukaemia; azacitidine; histone deacetylase inhibitor; myelodysplasia; therapy related",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D001549:Benzamides; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D016609:Neoplasms, Second Primary; D011725:Pyridines; D016896:Treatment Outcome",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "384-91",
"pmc": null,
"pmid": "26577691",
"pubdate": "2016-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "11090046;11921269;9058730;9916800;16403407;16921040;17179232;19230772;19383969;19357394;19546476;19880497;20026804;20456354;20940414;21714648;22853048;22740453;23332452;23432727;23499498;24663049",
"title": "Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study.",
"title_normalized": "azacitidine with or without entinostat for the treatment of therapy related myeloid neoplasm further results of the e1905 north american leukemia intergroup study"
} | [
{
"companynumb": "US-CELGENE-USA-2015121861",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ENTINOSTAT"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCalciphylaxis in a nondialysis patient is a rare condition and is characterized by calcific deposition in tissue. We present a case of calciphylaxis in a nondialysis patient who was diagnosed by clinical presentation and skin biopsy and was treated with sodium thiosulfate with improvement of skin lesions.\n\n\nMETHODS\nA 43-year-old female with type 2 diabetes and atrial fibrillation taking oral anticoagulation medication presented with reddish drainage from the right buttock. On physical examination, a large perirectal abscess overlying necrosis was found. She also developed acute kidney injury with creatinine of 3.7 mg/dL at peak from 0.8 mg/dL at baseline. She received antibiotics intravenously and wound debridement. During hospitalization, she developed areas of numerous painful erythematous lesions with central dusky necrosis on bilateral lower extremities. Punch biopsy was done, which initially revealed small-vessel vasculitis. However, those lesions did not respond to steroid therapy. A second biopsy was done showing extensive fat necrosis and medial calcification of vessel walls consistent with calciphylaxis. She was treated with high-flow oxygen and sodium thiosulfate intralesionally and intravenously for 6 months. The lesions remarkably reduced in size and were less painful on follow-up.\n\n\nCONCLUSIONS\nHigh-dose oxygen and sodium thiosulfate could potentially be effective treatments for calciphylaxis in nondialysis patients.",
"affiliations": "Department of Internal Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, Cooperstown, NY, USA, and.;Department of Internal Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, Cooperstown, NY, USA, and.;Department of Internal Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, Cooperstown, NY, USA, and.",
"authors": "Sanguankeo|Anawin|A|;Thamcharoen|Natanong|N|;Upala|Sikarin|S|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.5414/CNCS108959",
"fulltext": "\n==== Front\nClin Nephrol Case StudDustriClinical Nephrology. Case Studies2196-5293Dustri-Verlag Dr. Karl Feistle 10.5414/CNCS108959Case ReportNephrologyCalciphylaxis in a nondialysis patient treated with sodium thiosulfate and high dose of oxygen Sanguankeo Anawin 12Thamcharoen Natanong 1Upala Sikarin 121 Department of Internal Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, Cooperstown, NY, USA, and2 Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, ThailandSikarin Upala, MD Department of Internal Medicine, Bassett Medical Center, 1 Atwell Road, Cooperstown, NY 13326, USA sikarin.upala@ bassett.org2017 6 7 2017 5 38 41 4 7 2015 22 8 2016 © Dustri-Verlag Dr. K. Feistle2017 This is an open-access article distributed under the terms of the Creative\nCommons Attribution License, which permits unrestricted use, distribution, and\nreproduction in any medium, provided the original work is properly cited.Background: Calciphylaxis in a nondialysis patient is a rare condition and is characterized by calcific deposition in tissue. We present a case of calciphylaxis in a nondialysis patient who was diagnosed by clinical presentation and skin biopsy and was treated with sodium thiosulfate with improvement of skin lesions. Case: A 43-year-old female with type 2 diabetes and atrial fibrillation taking oral anticoagulation medication presented with reddish drainage from the right buttock. On physical examination, a large perirectal abscess overlying necrosis was found. She also developed acute kidney injury with creatinine of 3.7 mg/dL at peak from 0.8 mg/dL at baseline. She received antibiotics intravenously and wound debridement. During hospitalization, she developed areas of numerous painful erythematous lesions with central dusky necrosis on bilateral lower extremities. Punch biopsy was done, which initially revealed small-vessel vasculitis. However, those lesions did not respond to steroid therapy. A second biopsy was done showing extensive fat necrosis and medial calcification of vessel walls consistent with calciphylaxis. She was treated with high-flow oxygen and sodium thiosulfate intralesionally and intravenously for 6 months. The lesions remarkably reduced in size and were less painful on follow-up. Conclusion: High-dose oxygen and sodium thiosulfate could potentially be effective treatments for calciphylaxis in nondialysis patients. \n\ncalciphylaxisnondialysissodium thiosulfate\n==== Body\nIntroduction \nCalciphylaxis or calcific uremic arteriolopathy (CUA) is a rare complication in end-stage renal disease (ESRD) patients, particularly in dialysis-dependent patients [1]. Presentation for this condition mostly occurs in high-adipose tissue areas and is characterized by painful ischemic necrotic plaque/nodules that can progress to ischemic ulcers and eventually become complicated by infection. Although the pathophysiology of calciphylaxis is still poorly understood, it is believed that calciphylaxis is associated with disorders of calcium, phosphate, and parathyroid hormone homeostasis in end-stage kidney disease [2]. Calciphylaxis in a non-dialysis patient is a rare form of this condition in the absence of end-stage kidney disease and renal transplantation. We present a case of calciphylaxis in a nondialysis patient who was resuscitated and treated successfully with improvement of the lesions. \n\nCase presentation \nA 43-year-old female was admitted for perirectal abscess. Her comorbid conditions included hypertension, obstructive sleep apnea, type 2 diabetes, atrial fibrillation, morbid obesity, and rheumatoid arthritis (treated with chronic steroid therapy). The patient’s current presentation began with 1 month of reddish drainage from the right buttock. She reported no trauma, fever, or other systemic symptoms. On physical examination, she had a large perirectal abscess sized 12.24 × 8.56 cm with overlying necrosis and extensive erythema up to the lower back with discharge of brown-red material. Her creatinine was 3.7 mg/dL, which increased from her baseline of 0.8 mg/dL. She was started on intravenous cefoxitin and clindamycin. The findings revealed 10 – 12 cm of necrosis and left perirectal abscess involving the ischiorectal fossa but not extending to the rectum. Postoperatively, she was transferred to the ICU as she was hypotensive, requiring vasopressor infusion. The patient was taken to the operating room multiple times for debridement and split-thickness skin grafts from her left posterior thigh. Her condition continued to improve, and she was able to be moved out of the ICU. Her creatinine came back to 1 mg/dL. \n\nOn hospital day 17, she developed areas of numerous severely sharp, painful erythematous lesions with central dusky necrosis and subsequently ulcerated lesions ranging in size from 1 to 5 cm on the bilateral lower extremities (Figure 1). Punch biopsy from these lesions was done. The final pathologic diagnosis was small-vessel vasculitis. It was thought that the lesions were pyoderma gangrenosum related to her underlying rheumatoid arthritis. Her steroid dose was increased to prednisone 30 mg daily for lesion treatment. The labs were sent off for the genetic hypercoagulable panel, including protein C, protein S, cryofibrinogen, reptilase time, DRVVT screen ratio, prothrombin G20210A mutation, lupus anticoagulant, and antithrombin III, which were all negative. The patient was discharged to a short-term rehab facility as her condition had improved. Three days later, she was readmitted again for sepsis syndrome due to infected ulcers on the bilateral lower extremities. She developed fever up to 38.2 °C and was hypotensive. Broad-spectrum antibiotic, vancomycin, and piperacillin-tazobactam were initiated again. Since the patient had numerous non-healing bilateral lesions on her lower extremities, which did not respond to steroids, skin biopsy of the same lesion was performed again and sent to a pathology laboratory in a tertiary facility. Final pathology showed extensive fat necrosis and lymphohistiocytic inflammatory cell infiltrate. Medial calcification of vessel walls was seen focally, and some pockets of neutrophils were visible. These findings were consistent with calciphylaxis. On review of the record, the patient also had secondary hyperparathyroidism due to vitamin D deficiency (Table 1). Her calcium and phosphorus were in the normal range. The intact parathyroid hormone (PTH) was mildly elevated at 88 pg/mL (14 – 72 pg/mL). Total vitamin D level was 11 ng/mL (31 – 100 ng/mL). Consequently, she was started on treatment with 15 L of oxygen by facemask for 2 hours a day, sodium thiosulfate 25 g intravenously 5 days per week, and sodium thiosulfate intralesional injections every 7 days. Daily prednisone 30 mg was maintained for rheumatoid arthritis treatment. Oxycodone, oral morphine, gabapentin, and acetaminophen were used to control the ulcer pain. Vitamin D level was repleted with cholecalciferol 1,000 µg per day. \n\nOn 6-month follow-up, the ulcerated lesions had satisfactorily improved (Figure 2). Two out of four ulcer regions on her lower extremities were healed. The two remaining were in the process of healing. She has made good improvement in physical function. \n\nDiscussion \nAs in our patient, although it is rare, calciphylaxis can occur in patients without ESRD requiring dialysis. Sepsis was the leading cause of death, and overall mortality rate was 52% for the nondialysis patients with calciphylaxis [2]. Clinical features of calciphylaxis skin lesions range from palpable firm calcified subcutaneous tissue, livedo reticularis, reticulate purpura, and violaceous plaque related to severe pain at the lesions [3]. Definite diagnosis can be obtained by lesion margin biopsy demonstrating vascular calcification, small artery proliferation leading to microthrombosis and tissue ischemia as seen in our patient [4]. The pathogenesis of calciphylaxis is still poorly understood. In uremic calciphylaxis, it is believed that pathogenesis is related to an imbalance of calcium-phosphorous metabolism leading to calcification of vascular structure. However, dysregulation of calcium and phosphorus alone cannot be applied as a cause of calciphylaxis in a nondialysis patient. Hypercoagulability has also been suggested to play a significant role in this condition [5]. In a systematic review, primary hyperparathyroidism, connective tissue diseases, alcoholic liver disease, malignancies, diabetes, chemotherapy-induced protein C and S deficiency, Crohn disease, POEMS syndrome, vitamin D deficiency, weight loss, corticosteroid use, warfarin use, and osteomalacia treated with nadroparin calcium were reported to be associated with calciphylaxis in nondialysis patients [2]. Our patient’s risk factors for calciphylaxis included secondary hyperparathyroidism due to vitamin D deficiency, diabetes, female sex, obesity, rheumatoid arthritis, and warfarin use. Differential diagnoses for calciphylaxis in nondialysis patients are peripheral vascular disease, vasculitic diseases, antiphospholipid syndrome, heparin-induced skin necrosis, purpura fulminans, and warfarin-induced skin necrosis [6]. The clinician should rule out all possibilities that can mimic this condition and look for the cause of calciphylaxis in a nondialysis patient by evaluating renal function, serum calcium, phosphorus, parathyroid hormone, vitamin D, liver enzymes, coagulation and hypercoagulation status, autoimmune disease, and malignancy. This patient did not have hypercoagulable syndrome. \n\nAt present, there is no standard treatment of calciphylaxis due to limited clinical studies and cases. Treatment for calciphylaxis patients requires a multidisciplinary approach. Intravenous sodium thiosulfate and removing potential triggers are the main medical treatment for calciphylaxis. Successful treatment with intralesional sodium thiosulfate injection was also reported [7]. Supportive treatment, such as pain control and wound care, are also very important as patients mostly suffer from severe pain complicated by wound infection. Various modalities of wound management have been reported with effective results, including hyperbaric oxygen therapy and sterile maggot therapy [5, 6]. In addition to typical thiosulfate infusion, we planned to initiate treatment with hyperbaric oxygen, but the patient had financial issues. High-dose oxygen therapy was applied for substitution with good effect. There has been no evidence of high-dose oxygen therapy for calciphylaxis in a nondialysis patient before; this method is more convenient than hyperbaric oxygen. Therefore, high-dose oxygen could potentially be applied for calciphylaxis in substitution of hyperbaric treatment. \n\nConflict of interest \nAll authors declare no conflict of interest. \n\nFigure 1. Necrotic lesion on right lower extremity. \nFigure 2. Healed lesion after 6 months. \n\nTable 1. Markers of secondary hyperparathyroidism.\n\tInitial presentation\tFollow-up at 3 months\t\nTotal calcium (8.4 – 10.2 mg/dL)\t9.3\t9.2\t\nIonized calcium (4.2 – 5.5 mg/dL)\t5.5\t3.4\t\nPhosphorus (2.5 – 4.9 mg/dL)\t3.9\t3.2\t\nAlkaline phosphatase (38 – 125 U/L)\t159\t229\t\nPTH (14 – 72 pg/mL)\t88\t133\t\n25-hydroxyvitamin D (20 – 50 ng/mL)\t11\t26\n==== Refs\nReferences\n1 \nAngelis M \nWong LL \nMyers SA \nWong LM \nCalciphylaxis in patients on hemodialysis: a prevalence study. \nSurgery .\n1997 ;\n122 :\n1083 –1089, discussion 1089-1090. .\n9426423 \n2 \nNigwekar SU \nWolf M \nSterns RH \nHix JK \nCalciphylaxis from nonuremic causes: a systematic review. \nClin J Am Soc Nephrol .\n2008 ;\n3 :\n1139 –1143 .\n18417747 \n3 \nDaudén E \nOñate MJ \nCalciphylaxis. \nDermatol Clin .\n2008 ;\n26 :\n557 –568 .\n18793990 \n4 \nMochel MC \nArakaki RY \nWang G \nKroshinsky D \nHoang MP \nCutaneous calciphylaxis: a retrospective histopathologic evaluation. \nAm J Dermatopathol .\n2013 ;\n35 :\n582 –586 .\n23328789 \n5 \nNigwekar SU \nKroshinsky D \nNazarian RM \nGoverman J \nMalhotra R \nJackson VA \nKamdar MM \nSteele DJ \nThadhani RI \nCalciphylaxis: risk factors, diagnosis, and treatment. \nAm J Kidney Dis .\n2015 ;\n66 :\n133 –146 .\n25960299 \n6 \nJeong HS \nDominguez AR \nCalciphylaxis: Controversies in Pathogenesis, Diagnosis and Treatment. \nAm J Med Sci .\n2016 ;\n351 :\n217 –227 .\n26897281 \n7 \nStrazzula L \nNigwekar SU \nSteele D \nTsiaras W \nSise M \nBis S \nSmith GP \nKroshinsky D \nIntralesional sodium thiosulfate for the treatment of calciphylaxis. \nJAMA Dermatol .\n2013 ;\n149 :\n946 –949 .\n23760631\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2196-5293",
"issue": "5()",
"journal": "Clinical nephrology. Case studies",
"keywords": "calciphylaxis; nondialysis; sodium thiosulfate ",
"medline_ta": "Clin Nephrol Case Stud",
"mesh_terms": null,
"nlm_unique_id": "101638685",
"other_id": null,
"pages": "38-41",
"pmc": null,
"pmid": "29043146",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "9426423;23328789;18417747;26897281;23760631;25960299;18793990",
"title": "Calciphylaxis in a nondialysis patient treated with sodium thiosulfate and high dose of oxygen.",
"title_normalized": "calciphylaxis in a nondialysis patient treated with sodium thiosulfate and high dose of oxygen"
} | [
{
"companynumb": "US-ZYDUS-018957",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nMethotrexate (MTX) is the first-line disease-modifying antirheumatic drug in rheumatoid arthritis (RA). However, this anchor may cause some side effects that may range from nausea to mortality. The clinical features of MTX toxicity are under-researched. In this study, we aimed to find out the potential predisposing factors and outcomes of the MTX toxicity (n = 31).\n\n\nMETHODS\nThe data were collected from 31 patients whose ages ranged from 25 to 81 years, who were suffering from immune-mediated inflammatory diseases and major MTX-related toxicity.\n\n\nRESULTS\nOut of 31 patients, six (19.4%) used MTX every day, and 13 (41.9%) patients had renal insufficiency who were admitted to the hospital because of mucositis (90.3%) and fever (71%). While using MTX, 27 patients (87.1%) were discharged after the treatment and four patients (12.9%) died.\n\n\nCONCLUSIONS\nAlthough MTX has high efficacy for the toxicity ratio, wrong use and dosage of MTX may be harmful to patients. Thus, patients should be informed about the proper use of MTX.",
"affiliations": "Division of Rheumatology, Faculty of Medicine, Uludağ University, Bursa, Turkey.;Division of Rheumatology, Faculty of Medicine, Uludağ University, Bursa, Turkey.;Division of Rheumatology, Faculty of Medicine, Uludağ University, Bursa, Turkey.;Division of Rheumatology, Faculty of Medicine, Uludağ University, Bursa, Turkey.;Division of Rheumatology, Faculty of Medicine, Uludağ University, Bursa, Turkey.;Division of Rheumatology, Faculty of Medicine, Uludağ University, Bursa, Turkey.",
"authors": "Dalkilic|Ediz|E|;Coskun|Belkıs Nihan|BN|http://orcid.org/0000-0003-0298-4157;Yağız|Burcu|B|;Tufan|Ayşe Nur|AN|;Ermurat|Selime|S|;Pehlivan|Yavuz|Y|",
"chemical_list": "D018501:Antirheumatic Agents; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1111/1756-185X.13339",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-1841",
"issue": "21(8)",
"journal": "International journal of rheumatic diseases",
"keywords": "methotrexate; methotrexate toxicity; renal insufficiency",
"medline_ta": "Int J Rheum Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D003141:Communicable Diseases; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005334:Fever; D006801:Humans; D008297:Male; D008508:Medication Errors; D008727:Methotrexate; D008875:Middle Aged; D052016:Mucositis; D011696:Purpura, Thrombocytopenic; D051437:Renal Insufficiency; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D014421:Turkey",
"nlm_unique_id": "101474930",
"other_id": null,
"pages": "1557-1562",
"pmc": null,
"pmid": "30146743",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Methotrexate intoxication: Beyond the adverse events.",
"title_normalized": "methotrexate intoxication beyond the adverse events"
} | [
{
"companynumb": "TR-ACCORD-071721",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OMEPRAZOLE"
},
"drugadditional": null,
"dru... |
{
"abstract": "Babesiosis is a tick-borne infectious disease, caused by an intraerythrocytic parasite of the genus Babesia. It has clinical, biological and microbiological similarities with Plasmodium related infections. In rare cases, babesiosis may be complicated by hemophagocytic lymphohistiocytosis, which occurs preferentially in the immunodeficient patient. We report here the case of a non-immunocompromised patient living in Manhattan, New York hospitalized for a complicated babesiosis of a hemophagocytic lymphohistiocytosis. After 7 days of hospitalization and treatment by azithromycin 500 mg/day and atovaquone 750 mg twice a day, the patient was discharged with an improvement in clinical symptoms and biological parameters.",
"affiliations": "Service de médecine interne, Groupe hospitalier Paris Saint-Joseph, Paris, France.;Service de microbiologie clinique, Groupe hospitalier Paris Saint-Joseph, Paris, France.;Service de médecine interne, Groupe hospitalier Paris Saint-Joseph, Paris, France.;Équipe mobile de microbiologie clinique, Groupe hospitalier Paris Saint-Joseph, Paris, France.;Service de microbiologie clinique, Groupe hospitalier Paris Saint-Joseph, Paris, France.;Service de médecine interne, Groupe hospitalier Paris Saint-Joseph, Paris, France.;Service de microbiologie clinique, Groupe hospitalier Paris Saint-Joseph, Paris, France.;Service de microbiologie clinique, Groupe hospitalier Paris Saint-Joseph, Paris, France.",
"authors": "Voisin|Olivier|O|;Monpierre|Lorra|L|;Le Lorc'h|Erwan|E|;Pilmis|Benoit|B|;Le Monnier|Alban|A|;Mourad|Jean-Jacques|JJ|;Senghor|Yaye|Y|;Mizrahi|Assaf|A|",
"chemical_list": "D017963:Azithromycin; D053626:Atovaquone",
"country": "France",
"delete": false,
"doi": "10.1684/abc.2021.1675",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-3898",
"issue": "79(5)",
"journal": "Annales de biologie clinique",
"keywords": "Babesia; babesiosis; hemophagocytic lymphohistiocytosis; malaria",
"medline_ta": "Ann Biol Clin (Paris)",
"mesh_terms": "D053626:Atovaquone; D017963:Azithromycin; D001403:Babesia; D001404:Babesiosis; D006801:Humans",
"nlm_unique_id": "2984690R",
"other_id": null,
"pages": "456-459",
"pmc": null,
"pmid": "34782311",
"pubdate": "2021-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A typical babesiosis in an immunocompetent patient.",
"title_normalized": "a typical babesiosis in an immunocompetent patient"
} | [
{
"companynumb": "FR-NOVARTISPH-NVSC2021FR280451",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN"
},
"drugadditional": "3",
... |
{
"abstract": "An outbreak of anticonvulsant intoxication occurred in epileptic patients in Australia during 1968-9. All affected patients studied in Brisbane were taking one brand of phenytoin. In 87% of them the blood phenytoin levels were above the therapeutic range. Reduction of phenytoin dosage relieved the intoxication in all patients. The excipient in the responsible phenytoin capsules had been changed several months before the outbreak, and this change was probably related causally to the altered blood phenytoin concentrations.",
"affiliations": null,
"authors": "Tyrer|J H|JH|;Eadie|M J|MJ|;Sutherland|J M|JM|;Hooper|W D|WD|",
"chemical_list": "D014677:Pharmaceutical Vehicles; D013431:Sulfates; D010672:Phenytoin; D007785:Lactose; D002118:Calcium",
"country": "England",
"delete": false,
"doi": "10.1136/bmj.4.5730.271",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1447",
"issue": "4(5730)",
"journal": "British medical journal",
"keywords": null,
"medline_ta": "Br Med J",
"mesh_terms": "D001315:Australia; D002118:Calcium; D004196:Disease Outbreaks; D004339:Drug Compounding; D004827:Epilepsy; D006801:Humans; D007785:Lactose; D014677:Pharmaceutical Vehicles; D010672:Phenytoin; D011041:Poisoning; D013431:Sulfates",
"nlm_unique_id": "0372673",
"other_id": null,
"pages": "271-3",
"pmc": null,
"pmid": "5475846",
"pubdate": "1970-10-31",
"publication_types": "D016428:Journal Article",
"references": "5972681;5679541;5681227",
"title": "Outbreak of anticonvulsant intoxication in an Australian city.",
"title_normalized": "outbreak of anticonvulsant intoxication in an australian city"
} | [
{
"companynumb": "AU-PFIZER INC-2018370952",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PHENYTOIN SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a family of drugs, which taken as a group, represents one of the most frequently prescribed around the world. Thus, not surprisingly NSAIDs, along with anti-infectious agents, list on the top for causes of Drug-Induced Liver Injury (DILI). The incidence of liver disease induced by NSAIDs reported in clinical studies is fairly uniform ranging from 0.29/100 000 [95% confidence interval (CI): 0.17-051] to 9/100 000 (95% CI: 6-15). However, compared with these results, a higher risk of liver-related hospitalizations was reported (3-23 per 100 000 patients). NSAIDs exhibit a broad spectrum of liver damage ranging from asymptomatic, transient, hyper-transaminasemia to fulminant hepatic failure. However, under-reporting of asymptomatic, mild cases, as well as of those with transient liver-tests alteration, in conjunction with reports non-compliant with pharmacovigilance criteria to ascertain DILI and flawed epidemiological studies, jeopardize the chance to ascertain the actual risk of NSAIDs hepatotoxicity. Several NSAIDs, namely bromfenac, ibufenac and benoxaprofen, have been withdrawn from the market due to hepatotoxicity; others like nimesulide were never marketed in some countries and withdrawn in others. Indeed, the controversy concerning the actual risk of severe liver disease persists within NSAIDs research. The present work intends (1) to provide a critical analysis of the dissimilar results currently available in the literature concerning the epidemiology of NSAIDS hepatotoxicity; and (2) to review the risk of hepatotoxicity for each one of the most commonly employed compounds of the NSAIDs family, based on past and recently published data.",
"affiliations": null,
"authors": "Bessone|Fernando|F|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v16.i45.5651",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "16(45)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D019317:Evidence-Based Medicine; D006801:Humans; D018570:Risk Assessment; D012307:Risk Factors; D056737:Safety-Based Drug Withdrawals; D012720:Severity of Illness Index",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "5651-61",
"pmc": null,
"pmid": "21128314",
"pubdate": "2010-12-07",
"publication_types": "D016421:Editorial; D016454:Review",
"references": "12021934;18987620;18821716;9731437;10673086;7469624;10863862;8425699;1446877;17723920;1422399;8268277;12426524;12890847;10562933;4810329;16689558;10726966;16354388;18177922;19063590;19174782;19638570;16875903;12879991;8297198;15298630;10445569;16456879;19834119;19074762;15206996;2327391;11735663;17304660;10492497;15325831;10383524;15880319;17967156;9732947;16083708;8759674;20374223;17113426;12842950;5576002;15030049;11292587;19625223;2371992;12368551;18853438;12137558;12016548;11535846;1955140;10234601;11087881;15308513;12175641;19948161;7657288;16691302;3092908;19949916;15139498;10979111;17612044;14655069;1608854;12465736;11227244;11149228",
"title": "Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage?",
"title_normalized": "non steroidal anti inflammatory drugs what is the actual risk of liver damage"
} | [
{
"companynumb": "AR-PFIZER INC-2016088802",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PIROXICAM"
},
"drugadditional": null,
... |
{
"abstract": "We carried out the first matched retrospective cohort study aimed at studying the safety and efficacy of extracorporeal photopheresis (ECP) for bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT). Medical records of 1325 consecutive adult patients who underwent HCT between 2005 and 2015 were reviewed. Seventy-four patients (median age, 51 years) with a diagnosis of BOS were included in the study. After propensity-score matching for BOS severity, 26 patients who underwent ≥3 months of ECP were matched to 26 non-ECP-treated patients, who were assigned an index date corresponding to the ECP start date for their matched pairs. The rate of decline in FEV1 percentage predicted (FEV1PP) decreased after ECP initiation (and after index date in the non-ECP group), with no significant difference between the 2 groups (P = .33). On a multivariable analysis that included baseline transplant and pulmonary function test variables, matched related donor HCT (HR, .1; 95% CI, .03 to .5; P = .002), ECP (HR, .1; 95% CI, .01 to .3; P = .001), and slower rate of decline in FEV1PP before the ECP/index date (HR, .7; 95% CI, .6 to .8; P = .001) were associated with a better overall survival. At last follow-up, non-ECP-treated patients were more likely to be on >5 mg daily dose of prednisone (54% versus 23%; P = .04) and had a greater decline in their Karnofsky performance score (mean difference, -9.5 versus -1.6; P = .06) compared with ECP-treated-patients. In conclusion, compared with other BOS-directed therapies, ECP was found to improve survival in HCT patients with BOS, without significantly impacting measured pulmonary functions. These findings need prospective validation in a larger patient cohort.",
"affiliations": "Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Scottsdale, Arizona.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona.;Division of Hematology, Mayo Clinic, Jacksonville, Florida.;Division of Transfusion Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Transfusion Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Transfusion Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Transfusion Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Transfusion Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Scottsdale, Arizona.;Division of Hematology, Mayo Clinic, Rochester, Minnesota. Electronic address: patnaik.mrinal@mayo.edu.",
"authors": "Hefazi|Mehrdad|M|;Langer|Kimberly J|KJ|;Khera|Nandita|N|;Adamski|Jill|J|;Roy|Vivek|V|;Winters|Jeffrey L|JL|;Gastineau|Dennis A|DA|;Jacob|Eapen K|EK|;Kreuter|Justin D|JD|;Gandhi|Manish J|MJ|;Hogan|William J|WJ|;Litzow|Mark R|MR|;Hashmi|Shahrukh K|SK|;Yadav|Hemang|H|;Iyer|Vivek N|VN|;Scott|J P|JP|;Wylam|Mark E|ME|;Cartin-Ceba|Rodrigo|R|;Patnaik|Mrinal M|MM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2018.04.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "24(9)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Bronchiolitis obliterans syndrome; Extracorporeal photopheresis; Graft-versus-host disease; Hematopoietic cell transplantation",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D001989:Bronchiolitis Obliterans; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D017893:Photopheresis; D012129:Respiratory Function Tests; D016019:Survival Analysis; D019172:Transplantation Conditioning; D055815:Young Adult",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1906-1913",
"pmc": null,
"pmid": "29679771",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Extracorporeal Photopheresis Improves Survival in Hematopoietic Cell Transplant Patients with Bronchiolitis Obliterans Syndrome without Significantly Impacting Measured Pulmonary Functions.",
"title_normalized": "extracorporeal photopheresis improves survival in hematopoietic cell transplant patients with bronchiolitis obliterans syndrome without significantly impacting measured pulmonary functions"
} | [
{
"companynumb": "US-MALLINCKRODT-T201802256",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METHOXSALEN"
},
"drugadditional": null,
... |
{
"abstract": "We compared the effects on lower urinary tract symptoms and bladder outlet obstruction of combination therapy with α1-blocker and 5α-reductase inhibitor or a switch to 5α-reductase inhibitor monotherapy. We determined the factors influencing changes in lower urinary tract symptoms after α1-blocker withdrawal.\n\n\n\nA total of 140 outpatients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia received combination therapy with silodosin 8 mg per day and dutasteride 0.5 mg per day for 12 months. Of the patients 132 were randomized to continue combination therapy or switched to dutasteride monotherapy through silodosin withdrawal as the monotherapy group. Parameter changes from before randomization to 12 months after randomization were assessed based on subjective symptoms and urodynamic findings of voiding and storage function.\n\n\n\nEfficacy analysis included 57 patients on combination therapy and 60 on monotherapy. The change in I-PSS (International Prostate Symptom Score) after randomization was -0.7 and -0.6 in the combination therapy and monotherapy groups, respectively. The bladder outlet obstruction index changed from 46.1 to 41.8 in the combination therapy group and from 42.9 to 39.9 in the monotherapy group. No significant differences in subjective symptoms and bladder outlet obstruction were observed between the 2 groups. However, storage function decreased in the monotherapy group and lower urinary tract symptoms deteriorated significantly after the switch to dutasteride monotherapy in patients with a higher body mass index.\n\n\n\nWe found that α1-blocker withdrawal from combination therapy was reasonable and tolerable with regard to the effect on lower urinary tract symptoms and bladder outlet obstruction. However, withdrawal must be performed carefully in patients with a high body mass index.",
"affiliations": "Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: yoshi44@med.nagoya-u.ac.jp.;Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.",
"authors": "Matsukawa|Yoshihisa|Y|;Takai|Shun|S|;Funahashi|Yasuhito|Y|;Majima|Tsuyoshi|T|;Kato|Masashi|M|;Yamamoto|Tokunori|T|;Gotoh|Momokazu|M|",
"chemical_list": "D058891:5-alpha Reductase Inhibitors; D058668:Adrenergic alpha-1 Receptor Antagonists; D007211:Indoles; C095285:silodosin; D000068538:Dutasteride",
"country": "United States",
"delete": false,
"doi": "10.1016/j.juro.2017.05.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-5347",
"issue": "198(4)",
"journal": "The Journal of urology",
"keywords": "5-alpha reductase inhibitors; adrenergic alpha-antagonists; drug substitution; lower urinary tract symptoms; urinary bladder neck obstruction",
"medline_ta": "J Urol",
"mesh_terms": "D058891:5-alpha Reductase Inhibitors; D058668:Adrenergic alpha-1 Receptor Antagonists; D000368:Aged; D004359:Drug Therapy, Combination; D000068538:Dutasteride; D006801:Humans; D007211:Indoles; D059411:Lower Urinary Tract Symptoms; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011470:Prostatic Hyperplasia; D016896:Treatment Outcome; D001748:Urinary Bladder Neck Obstruction; D014563:Urodynamics",
"nlm_unique_id": "0376374",
"other_id": null,
"pages": "905-912",
"pmc": null,
"pmid": "28499730",
"pubdate": "2017-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Effects of Withdrawing α1-Blocker from Combination Therapy with α1-Blocker and 5α-Reductase Inhibitor in Patients with Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: A Prospective and Comparative Trial Using Urodynamics.",
"title_normalized": "effects of withdrawing 1 blocker from combination therapy with 1 blocker and 5 reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia a prospective and comparative trial using urodynamics"
} | [
{
"companynumb": "JP-STRIDES ARCOLAB LIMITED-2018SP001097",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SILODOSIN"
},
"drugadditional"... |
{
"abstract": "Majocchi granuloma (MG) is a rare dermal and subcutaneous fungal infection. We report a rare case of MG on the face of a six-year-old child caused by Trichophyton mentagrophytes after long term use of topical corticosteroids and other inadequate topical medications. He was treated with griseofulvin 25 mg/kg/day for 35 days unsuccessfully and successful treatment was obtained with terbinafine.",
"affiliations": "Department of Pediatrics, Division of Pediatric Dermatology, Federal University of Paraná Hospital de Clínicas da UFPR, Curitiba, Paraná. nara_frota@yahoo.com.br.",
"authors": "André|Nara Frota|NF|;Canato|Mariana|M|;Zanatta|Danielle Arake|DA|;Gomes|Iwyna França|IF|;Abage|Kerstin Taniguchi|KT|;Carvalho|Vânia Oliveira|VO|",
"chemical_list": "D000935:Antifungal Agents; D006118:Griseofulvin; D000077291:Terbinafine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "24(12)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000935:Antifungal Agents; D002648:Child; D003881:Dermatomycoses; D005148:Facial Dermatoses; D006118:Griseofulvin; D006801:Humans; D008297:Male; D000077291:Terbinafine; D014005:Tinea; D017211:Treatment Failure",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30677803",
"pubdate": "2018-12-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Majocchi granuloma on a child's face.",
"title_normalized": "majocchi granuloma on a child s face"
} | [
{
"companynumb": "BR-LEO PHARMA-316800",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MOMETASONE FUROATE"
},
"drugadditional": "3",
... |
{
"abstract": "Mycobacterium paraffinicum has been newly recognized as a species. A case of symptomatic pulmonary infection caused by M. paraffinicum is described, and as far as we know, this is the first case of the organism as a human pathogen.",
"affiliations": "Department of Medicine, Emory University, Atlanta, Georgia, USA.",
"authors": "Chan|Austin W|AW|;Kabbani|Sarah|S|;Staton|Gerald|G|;Kraft|Colleen S|CS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1128/JCM.03107-13",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0095-1137",
"issue": "52(4)",
"journal": "Journal of clinical microbiology",
"keywords": null,
"medline_ta": "J Clin Microbiol",
"mesh_terms": "D000369:Aged, 80 and over; D001431:Bacteriological Techniques; D005260:Female; D006801:Humans; D009161:Mycobacterium; D009165:Mycobacterium Infections, Nontuberculous; D018410:Pneumonia, Bacterial; D013902:Radiography, Thoracic; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "7505564",
"other_id": null,
"pages": "1281-3",
"pmc": null,
"pmid": "24452164",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "2196726;1663284;19653819;5093414;19915104;18080676;18987345;23460013;20087178;18367564;1742195;12709349;13395358;6236748",
"title": "Mycobacterium paraffinicum causing symptomatic pulmonary infection.",
"title_normalized": "mycobacterium paraffinicum causing symptomatic pulmonary infection"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2014-01561",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
"dr... |
{
"abstract": "BACKGROUND\nThere have been few reports of hepatitis C virus (HCV) treatment results with interferon-based regimens in indigenous populations.\n\n\nOBJECTIVE\nTo determine interferon-based treatment outcome among Alaska Native and American Indian (AN/AI) population.\n\n\nMETHODS\nIn an outcomes study of 1,379 AN/AI persons with chronic HCV infection from 1995 through 2013, we examined treatment results of 189 persons treated with standard interferon, interferon plus ribavirin, pegylated interferon plus ribavirin and triple therapy with a protease inhibitor. For individuals treated with pegylated interferon and ribavirin, the effect of patient characteristics on response was also examined.\n\n\nRESULTS\nSustained virologic response (SVR) with standard interferon was 16.7% (3/18) and with standard interferon and ribavirin was 29.7% (11/37). Of 119 persons treated with pegylated interferon and ribavirin, 61 achieved SVR (51.3%), including 10 of 46 with genotype 1 (21.7%), 38 of 51 with genotype 2 (74.5%) and 13 of 22 with genotype 3 (59.1%). By multivariate analysis, SVR in the pegylated interferon group was associated with female sex (p=0.002), estimated duration of infection (p=0.034) and HCV genotype (p<0.0001). There was a high discontinuation rate due to side effects in those treated with pegylated interferon and ribavirin for genotype 1 (52.2%). Seven of 15 genotype 1 patients treated with pegylated interferon, ribavirin and telaprevir or boceprevir achieved SVR (46.7%).\n\n\nCONCLUSIONS\nWe had success with pegylated interferon-based treatment of AN/AI people with genotypes 2 and 3. However, there were low SVR and high discontinuation rates for those with genotype 1.",
"affiliations": "Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA.;Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA.;Arctic Investigations Program, Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Anchorage, AK, USA.;Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA.;Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA.;Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA.;Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA.;Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA.;Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA.",
"authors": "Livingston|Stephen E|SE|;Townshend-Bulson|Lisa J|LJ|;Bruden|Dana J T|DJ|;Homan|Chriss E|CE|;Gove|James E|JE|;Plotnik|Julia N|JN|;Simons|Brenna C|BC|;Spradling|Philip R|PR|;McMahon|Brian J|BJ|",
"chemical_list": "D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a",
"country": "United States",
"delete": false,
"doi": "10.3402/ijch.v75.30696",
"fulltext": "\n==== Front\nInt J Circumpolar HealthInt J Circumpolar HealthIJCHInternational Journal of Circumpolar Health1239-97362242-3982Co-Action Publishing 3069610.3402/ijch.v75.30696Original Research ArticleResults of interferon-based treatments in Alaska Native and American Indian population with chronic hepatitis C Livingston Stephen E. 1Townshend-Bulson Lisa J. 1Bruden Dana J. T. 2Homan Chriss E. 1Gove James E. 1Plotnik Julia N. 1Simons Brenna C. 1Spradling Philip R. 3McMahon Brian J. 12*1 Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA2 Arctic Investigations Program, Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Anchorage, AK, USA3 Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA* Correspondence to: Brian J. McMahon, 3900 Ambassador Drive, Anchorage, AK 99508, USA, Email: bmcmahon@anthc.orgResponsible Editor: Anders Koch, Statens Serum Institut, Denmark.\n\n29 3 2016 2016 75 10.3402/ijch.v75.3069610 12 2015 22 2 2016 28 2 2016 © 2016 Stephen E. Livingston et al.2016This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material for any purpose, even commercially, provided the original work is properly cited and states its license.Background\nThere have been few reports of hepatitis C virus (HCV) treatment results with interferon-based regimens in indigenous populations.\n\nObjective\nTo determine interferon-based treatment outcome among Alaska Native and American Indian (AN/AI) population.\n\nDesign\nIn an outcomes study of 1,379 AN/AI persons with chronic HCV infection from 1995 through 2013, we examined treatment results of 189 persons treated with standard interferon, interferon plus ribavirin, pegylated interferon plus ribavirin and triple therapy with a protease inhibitor. For individuals treated with pegylated interferon and ribavirin, the effect of patient characteristics on response was also examined.\n\nResults\nSustained virologic response (SVR) with standard interferon was 16.7% (3/18) and with standard interferon and ribavirin was 29.7% (11/37). Of 119 persons treated with pegylated interferon and ribavirin, 61 achieved SVR (51.3%), including 10 of 46 with genotype 1 (21.7%), 38 of 51 with genotype 2 (74.5%) and 13 of 22 with genotype 3 (59.1%). By multivariate analysis, SVR in the pegylated interferon group was associated with female sex (p=0.002), estimated duration of infection (p=0.034) and HCV genotype (p<0.0001). There was a high discontinuation rate due to side effects in those treated with pegylated interferon and ribavirin for genotype 1 (52.2%). Seven of 15 genotype 1 patients treated with pegylated interferon, ribavirin and telaprevir or boceprevir achieved SVR (46.7%).\n\nConclusions\nWe had success with pegylated interferon-based treatment of AN/AI people with genotypes 2 and 3. However, there were low SVR and high discontinuation rates for those with genotype 1.\n\npegylated interferondiscontinuationindigenous populationlongitudinal studysustained virologic response\n==== Body\nThe approval and use of direct-acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection has dramatically improved efficacy and safety as well as decreased treatment duration. However, pegylated interferon may still be used, although it is no longer the standard of care for treatment.\n\nThe first treatment licensed in the United States and other countries for hepatitis C was standard interferon, which required subcutaneous injections thrice weekly. In the 1990s, this was combined with ribavirin and resulted in an increase in efficacy. From 2001 to 2011, the standard of care for hepatitis C treatment was pegylated interferon and ribavirin, with duration of 48 weeks for genotype 1 and 24 weeks for genotypes 2 and 3. Many studies on pegylated interferon and ribavirin reported overall sustained virologic response (SVR) rates of 40–45% in genotype 1 and 70–80% in genotypes 2–3, defining SVR as undetectable serum HCV RNA 24 weeks after the end of treatment (1,2). The majority of patients in these studies were Caucasian. Among non-whites, higher SVR rates in genotype 1 were reported in Asian Americans (3–5) compared with North American Hispanics and African Americans (3,5–8). This difference is partially explained by the distribution of the IL28B gene in different ethnic populations, which is strongly related to response (9). The advent of triple therapy for genotype 1 infection in 2011 with the addition of first-generation protease inhibitors increased SVR rates up to 70–75% in clinical trials but resulted in a worsened side effect profile and greater discontinuation (10,11).\n\nFew reports of treatment results in indigenous populations are published, including Alaska Native and American Indian (AN/AI) people. We retrospectively examined our treatment results with interferon-based regimens in a cohort of AN/AI people living in Alaska.\n\nMethods\nAlaska Hepatitis C Cohort (AK-HepC)\nIn 2013, Alaska reported approximately 143,000 AN/AI (labor.alaska.gov). The Alaska Native Tribal Health Consortium, Liver Disease and Hepatitis Program (ANTHC LDHP) maintains a clinical registry of AN/AI people who are infected with HCV. There are 3,118 AN/AI persons identified as anti-HCV antibody seropositive in the ANTHC LDHP Hepatitis C Registry; of those, 2,573 are confirmed HCV positive by either recombinant immunoblot assay or HCV RNA. The majority of these people live in urban areas. Due to potential serious adverse events of interferon-based therapy and the non-availability of lab testing, few people were treated outside of these urban areas. As previously described, routes of hepatitis C transmission identified by participants included intravenous drug use (60.1%) and blood transfusion (14.1%) (12), with similar risk factors and viral genotype distribution to the National Health and Nutrition Examination Survey (13).\n\nThe ANTHC LDHP has enrolled 1,379 AN/AI persons into a long-term outcomes cohort study of chronic HCV infection that began in 1995; the AK-HepC study outcomes through 2013 were examined. All AN/AI people positive for anti-HCV and HCV RNA in the registry were invited to join AK-HepC study. Genotype distributions in this cohort were: 64% for genotype 1, 20% for genotype 2, 15% for genotype 3 and <1% for genotype 4.\n\nTreatment decisions were made based on treatment eligibility factors. These included but were not limited to patient preference, no report of drug and alcohol use in the 6 months, amount of liver fibrosis, absence of poorly controlled psychiatric conditions or concurrent medical conditions, and absence of decompensated cirrhosis (14,15). Prior to 2001, individuals were treated with either standard interferon alone or standard interferon and ribavirin for 24–48 weeks. Starting in 2001, all individuals received pegylated interferon alfa-2a or alfa-2b plus ribavirin according to American Association for the Study of Liver Diseases (AASLD) guidelines (16). Individuals with genotype 1 were treated with pegylated interferon, ribavirin and a protease inhibitor after the approval of boceprevir and telaprevir in mid-2011, also according to AASLD guidelines (17).\n\nAll individuals involved in this study provided informed written consent. This study was approved by the Alaska Area and Centers for Disease Control and Prevention Institutional Review Boards and the Board of Directors of the Alaska Native Tribal Health Consortium and Southcentral Foundation.\n\nLaboratory testing\nTesting for HCV RNA was performed until 2007 as previously described (18). Since 2007 testing for HCV RNA has been performed either at Quest Diagnostics (Seattle, WA) or at the Alaska Native Medical Center laboratory using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Test Kit (Roche Molecular Systems, Inc., USA), with an initial lower limit of quantification of 43 IU/mL and current lower limit of 15 IU/mL. HCV genotyping was performed as described previously (19), and since 2008 by HCV genotype LIPA, RT-PCR and reverse hybridization of the 5’ UTR and core region of the HCV genome (Quest Diagnostics, Seattle, WA). Alanine aminotransferase (ALT) testing was performed at the ANMC laboratory (Abbott Laboratories, Abbot Park, IL, USA) or in regional health care facilities. An ALT level of ≤40 U/L was defined as normal.\n\nStatistical analysis\nWe examined the association of SVR with patient characteristics for individuals treated with pegylated interferon and ribavirin. We defined SVR as undetectable HCV RNA 24 weeks after the end of treatment. We also examined the association of SVR with the achievement of rapid virologic response (RVR), which we defined as undetectable HCV RNA at 4 weeks of treatment. We used the likelihood ratio chi-square test to compare SVR in dichotomous variables. We used the Cochran–Mantel–Haenszel test when controlling for HCV genotype. We used logistic regression to test for associations between continuous covariates and SVR. For a multivariate variable model in an intention to treat analysis, we considered covariates with a univariable p<0.25. The model was built using purposeful forward selection and the Wald chi-square statistic. All p-values were two-sided and a value less than 0.05 was considered statistically significant. All analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC).\n\nWe did not perform statistical analysis for those treated with standard interferon-containing regimens (interferon alone or interferon with ribavirin) or with triple therapy including a protease inhibitor because of small sample size in these groups.\n\n\nResults\nTreatment with standard interferon\nBetween 1992 and 1998, 18 persons were treated with standard interferon for 48 weeks and 3 achieved SVR (16.7%, Table 1). This included 1 of 10 with genotype 1 and 1 of 6 with genotype 3. Genotype was unknown on an additional person who achieved SVR and results were not available on one person with genotype 2 who was lost to follow-up. Three of nine females and none of 8 males with known results achieved SVR. Mean age at the time of treatment was 40.2 years. Demographic data were otherwise limited on this group.\n\nTable 1 Hepatitis C treatment sustained virologic response by regimen and genotype in a cohort of Alaska Native and American Indian people\n\nTreatment regimen\tNumber treated\tSVR (%)a\n\tGenotype 1 SVR\tGenotype 2 SVR\tGenotype 3 SVR\t\nInterferon\t18b\n\t3 (16.7)\t1/10 (10%)\t0/1 (0%)\t1/6 (16.7%)\t\nInterferon/ribavirin\t37\t11 (29.7)\t2/12 (16.7%)\t3/9 (33.3%)\t6/16 (37.5%)\t\nPegylated interferon/ribavirinc\n\t119d\n\t61 (51.3)\t10/46 (21.7%)\t38/51 (74.5%)\t13/22 (59.1%)\t\nPegylated interferon/ribavirin/telaprevir or boceprevire\n\t15\t7 (46.7)\t7/15 (46.7%)\t–\t–\t\na SVR=Sustained virologic response, defined as undetectable HCV RNA 24 weeks after the end of treatment and expressed as intention to treat results.\n\nb Includes 1 person with genotype 2 whose treatment results were unknown. Genotype on 1 person who achieved SVR was unknown.\n\nc Eight persons were treated twice with pegylated interferon/ribavirin and results from first treatment course are reported. Three achieved SVR with the second treatment course.\n\nd Includes 2 persons who achieved an end-of-treatment response but were lost to follow-up.\n\ne Five of twelve persons treated with telaprevir (41.7%) and 2 of 3 treated with boceprevir (66.7%) achieved SVR.\n\nTreatment with standard interferon and ribavirin\nBetween 1997 and 2002, 37 persons were treated with standard interferon and ribavirin. Those with genotype 1 were treated for 48 weeks; those with genotypes 2 and 3 were treated for 24 weeks. Eleven achieved SVR (29.7%, Table 1). SVR results by genotype were as follows: 2 of 12 with genotype 1 (16.7%); 3 of 9 with genotype 2 (33.3%) and 6 of 16 with genotype 3 (37.5%). Two persons with genotype 1 had been previously treated with standard interferon. One of those achieved SVR. Three persons with genotype 3 had been previously treated with standard interferon and none of these achieved SVR with standard interferon and ribavirin. None of the 9 persons with genotype 1a achieved SVR versus 2 of 3 with genotype 1b. Six of 17 females achieved SVR (35.3%) and 5 of 20 males achieved SVR (25%). Mean age at the time of treatment was 43 years for both males and females.\n\nTreatment with pegylated interferon and ribavirin\nBaseline characteristics\nA total of 139 treatment regimens with pegylated interferon and ribavirin were started on 119 patients with genotypes 1, 2 and 3, of whom 114 (95.8%) were treatment naïve. Genotype 1 treatment length was 48 weeks; genotypes 2 and 3, 24 weeks. Genotype distribution was as follows: genotype 1, 46 (38.7%); genotype 2, 51 (42.9%); and genotype 3, 22 (18.5%). Nine persons were treated twice and 3 persons were treated 3 times. Of those re-treated, 8 were treated twice with pegylated interferon and ribavirin. Treatment results and patient characteristics were analysed on the first pegylated interferon and ribavirin treatment course for these 8 persons. The others were previously treated with standard interferon or standard interferon and ribavirin. Two persons were HIV positive and were included in the results. Two persons included in the results were hepatitis B surface antigen positive. Gender distribution was nearly equal, with 59 males (49.6%) and 60 females (50.4%). Mean age at treatment initiation was 44.7 years (44.2 males, 45.1 females). Mean body mass index (BMI) was 29.4 (29.0 females, 29.7 males). Mean ALT at the start of treatment was 105.7 (range 15–629) and was available for 117 patients. Mean HCV RNA at the start of treatment was 4,096,347 IU/mL and was available for 107 patients. Liver biopsies were performed on 78 patients prior to treatment and 22 (28.2%) had bridging fibrosis or cirrhosis (Table 2). Duration of infection could be estimated on 110 patients, with the following results by 10-year intervals: <10, 29 patients; 10–20, 31 patients; 20–30, 27 patients; and >30, 23 patients.\n\nTable 2 Baseline characteristics of Alaska Native and American Indian people treated with pegylated interferon and ribavirin\n\nCharacteristic\tOverall (%)\tGenotype 1 (%)\tGenotype 2 (%)\tGenotype 3 (%)\t\nNumber treated\t119\t46 (38.7)\t51 (42.9)\t22 (18.5)\t\nMale gender\t59 (49.6)\t19 (41.3)\t29 (56.9)\t11 (50)\t\nFemale gender\t60 (50.4)\t27 (58.7)\t22 (43.1)\t11 (50)\t\nMean age, yearsa\t44.7\t43.8\t45.4\t44.6\t\nMean BMIa,b\n\t29.4\t30.0\t28.4\t30.4\t\nMean ALTa,c\n\t105.7\t96.7\t121.4\t87.5\t\nMean HCV RNAa,d\n\t4,096,347\t2,516,909\t6,821,071\t1,341,314\t\nLiver biopsy\t78\t39\t26\t13\t\nAdvanced fibrosise\t22 (28.2)\t10 (25.6)\t7 (26.9)\t5 (38.5)\t\na Mean of characteristic at start of treatment.\n\nb BMI=body mass index.\n\nc ALT=alanine aminotransferase; available for 117 of 119 patients.\n\nd HCV RNA, IU/mL, available for 107 of 119 patients.\n\ne Advanced fibrosis on liver biopsy, defined as Ishak 3–6.\n\nOverall treatment results\nOf 119 persons, 61 achieved SVR (51.3%, Table 1). This includes 2 persons who had end-of-treatment undetectable HCV RNA but were then lost to follow-up. Thirty-nine persons discontinued treatment due to side effects (32.8%) and 12 failed treatment (10.1%). Excluding the 2 persons who lost to follow-up, 8 of the 117 with results available relapsed (6.8%). Of the 8 persons treated twice with pegylated interferon and ribavirin, 3 achieved SVR during the second treatment. Of the 2 HIV-positive persons, one, with genotype 1a, achieved SVR and the second, with genotype 2b, failed treatment.\n\nTreatment was discontinued by the provider in 4 persons with retinal cotton wool exudates, including 2 with blurred vision and 1 with diabetes mellitus. Treatment was discontinued in 2 persons due to hyperthyroidism, including one also with atrial fibrillation. Anaemia was common, with 23 persons whose haemoglobin decreased to <10 gm/dL, including 6 with haemoglobin <8.5 gm/dL.\n\nRibavirin dose reductions were made in 31 persons, primarily for anaemia, 2 for nausea and vomiting and 1 for an elevated creatinine. Eighteen of these also had pegylated interferon dose reduction, due primarily to neutropenia. Of these 31 persons, 17 achieved SVR. Another 13 persons had dose reductions of pegylated interferon only and 8 of these achieved SVR. Seven people were treated with erythropoietin for anaemia.\n\nGenotype 1 results\nOf 46 persons (21.7%) with genotype 1, 10 achieved SVR when treated with pegylated interferon and ribavirin (Table 3). This included 7 of 34 with genotype 1a (20.6%) and 3 of 8 with genotype 1b (37.5%, p=0.36). Four persons had either genotype 1a/1b or could not be subtyped and none of those achieved SVR. The majority of those who did not achieve SVR discontinued treatment due to side effects (24 of 46, 52.2%), whereas 9 were treatment failures (19.5%) and 3 relapsed (6.5%). If those who discontinued due to side effects are omitted, 10 of 22 achieved SVR. Multiple side effects were reported by those who discontinued treatment, including flu-like symptoms, fatigue, nausea and vomiting, depression, anxiety and pain. These changes and the blurred vision resolved after treatment discontinuation (45.5%).\n\nTable 3 Results of pegylated interferon–ribavirin treatment of Alaska Native and American Indian people\n\nGenotype\t\tNumber\tSVRa (%)\tFailureb (%)\tRelapsec (%)\tDiscontinuedd (%)\t\n1a\t\t34\t7 (20.6)\t5 (14.7)\t3 (8.8)\t19 (55.9)\t\n1b\t\t8\t3 (37.5)\t2 (25)\t0 (0)\t3 (37.5)\t\nOthere\t\t4\t0 (0)\t2 (50)\t0 (0)\t2 (50)\t\n\tTotal\t46\t10 (21.7)\t9 (19.5)\t3 (6.5)\t24 (52.2)\t\n2\t\t51f\t38 (74.5)\t3 (5.9)\t3 (6.1)\t9g (17.6)\t\n3\t\t22f\t13 (59.1)\t1 (4.5)\t2 (9.1)\t6 (27.3)\t\na SVR=Sustained Virologic Response, defined as undetectable HCV RNA 24 weeks after the end of treatment.\n\nb Failure=<2-log drop of HCV RNA at week 12 or detectable HCV RNA at end-of-treatment course.\n\nc Relapse=detectable HCV RNA within 6 months after undetectable at the end of treatment.\n\nd Discontinued=treatment discontinued due to side effects.\n\ne Other=genotype 1a/1b (2) or no subtype identified (2).\n\nf Includes 2 persons with genotype 2 who achieved end-of-treatment response and then were lost to follow-up.\n\ng Includes 2 who achieved SVR despite discontinuation.\n\nTesting for RVR was performed in 25 patients, and 6 achieved RVR (40%). Of these, 2 achieved SVR (33%) and 4 discontinued treatment due to side effects. Of the 19 who did not achieve RVR, 2 achieved SVR (10.5%, p=0.23 compared to those who achieved RVR), 8 discontinued due to side effects, 7 failed treatment and 2 relapsed.\n\n\nGenotype 2 results\nOf 51 persons started on pegylated interferon and ribavirin for genotype 2, 38 achieved SVR (74.5%, Table 3). This group includes 2 persons who completed treatment but were lost to follow-up after achieving an end-of-treatment response. Nine persons discontinued treatment due to side effects (17.6%) and 2 of these achieved SVR; 3 were treatment failures (6.1%) and 3 relapsed after achieving an end-of-treatment response (6.1%).\n\nOf 36 persons tested, 29 achieved RVR (80.6%). Of those who achieved RVR, 26 achieved SVR (89.7%), whereas only 2 of 7 persons who did not have an RVR achieved SVR (28.6%, p=0.003).\n\nGenotype 3 results\nOf 22 persons started on pegylated interferon and ribavirin for genotype 3, 13 achieved SVR (59.1%, Table 3). Six persons discontinued treatment due to side effects (27.3%); 2 relapsed (9.5%) and 1 failed treatment (4.5%).\n\nOf 14 persons tested, 8 achieved RVR (57.1%); these 8 also achieved SVR. All 6 who did not achieve RVR did not achieve SVR also (p<0.001 compared to those who achieved RVR).\n\nEffect of patient characteristics on treatment response\nUnivariate analysis was performed comparing persons achieving SVR versus those not achieving SVR. Only HCV genotype (p<0.01), baseline haemoglobin level (p=0.03), and estimated duration of infection by 10-year intervals (p=0.02) were associated with treatment response (Table 4). IL28B genotype was available in only 20 persons with genotype 1. Six persons were IL28B genotype CC and 2 of these achieved SVR, whereas none of the 14 persons with genotypes CT or TT achieved SVR (p=0.08). IL-28b testing was not conducted in this cohort until 2011. Therefore, the numbers were too small for further analysis. By multivariate analysis, SVR was associated with female sex (p=0.03, OR 3.1, CI 1.2–8.2); estimated duration of HCV infection (p=0.03, OR for a 10-year increase 1.5, CI 1.0–2.2), and HCV genotype (p<0.0001) (Table 5). Odds ratio for SVR comparing genotype 2 versus 1 was 14.0 (CI 4.6–42.4) and for genotype 3 versus 1 was 7.1 (CI 2.0–25.1).\n\nTable 4 Factors related to hepatitis C treatment sustained virologic responsea in Alaska Native and American Indian people treated with pegylated interferon and ribavirin\n\nFactor\tLevel\tNumber\tSVR (n)\tP\t\nSex\tFemale\t60\t55% (33)\t0.17\t\n\tMale\t59\t43% (25)\t\t\nAge\t<40 years\t31\t45% (14)\t0.39\t\n\t40–49 years\t40\t43% (17)\t\t\n\t50+ years\t48\t56% (27)\t\t\nHCV genotype\t1\t46\t22% (10)\t<0.01\t\n\t2\t51\t69% (35)\t\t\n\t3\t22\t59% (13)\t\t\nBody mass index\t<25\t29\t38% (11)\t0.40\t\n\t25–29\t40\t53% (21)\t\t\n\t30+\t50\t52% (26)\t\t\nDiabetes–pre-diabetes\tYes\t41\t54% (22)\t0.29\t\n\tNo\t65\t43% (28)\t\t\nEstimated duration of HCV infection\t<10 years\t29\t38% (11)\t0.02\t\n\t10–20 years\t31\t35% (11)\t\t\n\t20–30 years\t27\t59% (16)\t\t\n\t30+ years\t23\t65% (15)\t\t\nBaseline HCV RNA (IU/mL)\t<500,000\t33\t55% (18)\t0.14\t\n\t≥500,000–<3,000,000\t36\t44% (16)\t\t\n\t≥3,000,000\t38\t37% (14)\t\t\nAdvanced fibrosis (Ishak≥3)\tYes\t22\t45% (10)\t0.43\t\n\tNo\t56\t36% (20)\t\t\nBaseline ALT levelb\n\t<40\t24\t58% (14)\t0.46\t\n\t40–<80\t40\t45% (18)\t\t\n\t80–<120\t21\t48% (10)\t\t\n\t120+\t33\t45% (15)\t\t\nBaseline Hgb levelc\n\t<14\t30\t60% (18)\t0.03\t\n\t≥14\t39\t33% (13)\t\t\nBaseline ANC leveld\n\t<4\t30\t50% (15)\t0.52\t\n\t≥4\t22\t41% (9)\t\t\nBaseline platelet counte\n\t<200\t36\t42% (15)\t0.35\t\n\t200–<300\t45\t51% (23)\t\t\n\t≥300\t36\t53% (19)\t\t\n\t≥1.5\t28\t32% (9)\t\t\nTSH\t<1.5\t51\t45% (23)\t0.26\t\n\t>1.5\t28\t32% (9)\t\t\na Sustained virologic response was defined as undetectable HCV RNA 24 weeks after the end of treatment.\n\nb ALT=alanine aminotransferase, expressed as units/litre.\n\nc Hgb=haemoglobin, expressed in grams/decilitre.\n\nd ANC=absolute neutrophil count, 109 per litre.\n\ne Platelet count, 103 per microliter.\n\nTable 5 Factors significantly related by multivariate analysis to hepatitis C treatment sustained virologic response in Alaska Native and American Indian people treated with pegylated interferon and ribavirin\n\nFactor\tMultivariate P-value\tComparison\tOdds ratio of SVR (confidence interval)\t\nGenotype\t<0.0001\t2 vs. 1\t14.0 (4.6, 42.4)\t\n\t\t3 vs. 1\t7.1 (2.0, 25.1)\t\nGender\t0.03\tFemale vs. male\t3.1 (1.2, 8.2)\t\nEstimated duration of HCV infection\t0.03\t10-year increase\t1.5 (1.0, 2.2)\t\na Sustained virologic response (SVR) was defined as undetectable HCV RNA 24 weeks after the end of treatment.\n\nTreatment with pegylated interferon, ribavirin and first-generation protease inhibitors\nA total of 15 persons with genotype 1 received triple therapy with pegylated interferon, ribavirin and telaprevir or boceprevir. Of these, 6 had been previously treated with pegylated interferon and ribavirin. Those receiving triple therapy included 8 females and 7 males, with mean age 48.7 years, mean BMI 34.1 and mean HCV RNA at start 3,148,150 IU/mL, including 13 with HCV RNA >400,000 IU/mL. Twelve of 14 persons with liver biopsy results had bridging fibrosis or cirrhosis. IL28B genotype was tested on 14 persons and showed 4 with CC, 8 CT and 2 TT. Eleven persons had genotype 1a; 2 had genotype 1b and 2 could not be subtyped.\n\nSeven of 15 persons achieved SVR (46.7%, Table 1). Five of 12 persons (41.7%) treated with telaprevir achieved SVR, compared with 2 of 3 (66.7%) treated with boceprevir. Six persons achieved RVR, and 5 of those also achieved SVR. Three persons were eligible for response-guided therapy and all 3 achieved SVR with a 24-week course. Of the 8 persons treated with triple therapy who did not achieve SVR, 4 failed treatment and 4 discontinued due to side effects.\n\nNotable side effects included 6 patients on telaprevir who developed a rash during weeks 1–3, none of whom required discontinuation due to the rash. In addition, 9 patients on telaprevir developed haemoglobin <10 during treatment, including 3 with haemoglobin <8.5. Two were treated with erythropoietin and 1 of these 2 also received a blood transfusion. Four persons required a decrease in pegylated interferon dosage during treatment.\n\nOf those previously treated with pegylated interferon and ribavirin, one also was treated with consensus interferon and ribavirin and relapsed both times before achieving SVR with telaprevir triple therapy. One person achieved SVR with boceprevir triple therapy. Of the other 4 persons, 2 failed triple therapy and 2 discontinued due to side effects.\n\nDiscussion\nOverall hepatitis C treatment results for AN/AI people with standard interferon-containing regimens were generally poor, with SVR rates of 16.7% for standard interferon alone and 29.7% for standard interferon plus ribavirin. This was similar to SVR rates reported in a 1999 literature review (20), for a 48-week treatment course with these early regimens.\n\nWe found SVR rates with pegylated interferon and ribavirin of only 21.3% in genotype 1 patients. This is much lower than results from clinical trials, (1,2,21) and represents the real-life experience of interferon-based treatment (22). These results are similar to those reported in African Americans, including the IDEAL trial, which reported a 22% SVR for African Americans compared to 44% for Caucasians (5). Two other trials found SVR rates in African Americans significantly lower than Caucasians (6,7). Dropout rates due to side effects for African Americans in these 2 trials were 19 and 22%, respectively, and those in several large trials were reported to be 10–15% (1,2), whereas a US Veterans Administration study reported that only 22% of over 10,000 patients completed a treatment course for hepatitis C (20). In our cohort, 48.9% (23 of 47 persons) with genotype 1 discontinued treatment due to side effects. This high dropout rate may partially explain the low SVR rates. If those who discontinued treatment due to side effects are omitted, our SVR rate was 41.7%. SVR rates in Asian Americans have \nbeen reported to be 56–65%, which is higher than for other ethnic groups, but only 35–38% in Hispanic Americans (3–5). We did not find a statistically significant influence of IL28B genotype on our HCV genotype 1 SVR rate, as we had IL28B data on only 20 of 46 participants. As in a “real-life” setting, the Alaska Hepatitis C cohort is comprised of a genetically heterogenous population, thus we are unable to determine whether treatment outcomes are due to specific genetic factors in this study population.\n\nWe found only 3 other reports in the literature of hepatitis C treatment results in indigenous populations. One of these was a prospective trial of pegylated interferon and ribavirin treatment in 46 Canadian Aboriginal persons and 55 Caucasians with genotype 1 (23). Investigators found a statistically significant lower SVR rate in Aboriginal people (35% vs. 55%, p=0.047). Premature treatment termination, baseline normal ALT values and fatty liver on ultrasound were associated with outcome on multivariate analysis. Another Canadian study retrospectively examined pegylated interferon and ribavirin treatment results in 44 persons who identified themselves as Aboriginal Canadians in a large nationwide study (24). Overall SVR rates were 47.7% in Aboriginal and 46.5% in non-Aboriginal patients. Results were also similar between the groups by genotype. Finally, in a brief report, 22 Australian indigenous persons (18 were genotype 1) were started on pegylated interferon and ribavirin and 4 of 8 with results available achieved SVR (25). Results were not reported by genotype.\n\nObserved SVR rates in genotype 2 and 3 patients were slightly lower than those reported in some studies. SVR rates for our cohort were 74.5% for genotype 2 and 59.1% for genotype 3, whereas other studies have reported overall SVR rates for genotypes 2 and 3 combined to be about 80% (1,2,20,26). We had relatively high dropout rates due to side effects for these genotypes, 17.6% for genotype 2 and 27.3% for genotype 3.\n\nBy multivariate analysis we found that female sex, estimated duration of HCV infection by 10-year increase and genotype were independently associated with SVR in individuals treated with pegylated interferon and ribavirin. The association of female sex with SVR has not often been reported (1,27) although one small study found such an association, primarily in women under age 40 (28). If estimated duration of infection were considered a surrogate marker for fibrosis, then individuals with a longer duration of infection might be expected to have more advanced fibrosis and a lower SVR rate. We cannot explain why the SVR rate increased with estimated duration of infection and the literature does not appear to address this. As previously published results have shown dramatic differences in treatment eligibility among this cohort, perhaps these pre-existing factors influenced the resulting treatment outcome (14).\n\nOur treatment of genotype 1 patients with triple therapy was primarily limited to individuals who previously failed pegylated interferon and ribavirin treatment and/or who had advanced fibrosis. Although we did not perform statistical evaluation of these results due to small numbers, our treatment experience was similar to others in terms of patient side effects (29).\n\nLimitations of this study relate to its retrospective nature and limited demographic data in the early years of treatment prior to the advent of pegylated interferon use. In addition, we did not have a comparison group in our study and thus we could only compare our results to those from other studies.\n\nIn conclusion, we have had success with interferon-based treatment of AN/AI population with chronic hepatitis C with genotypes 2 and 3. However, we have had high discontinuation and low SVR rates in genotype 1. We are now actively treating individuals with newer DAA regimens that are better tolerated, have a shorter duration of treatment and have significantly higher SVR rates (30). The arrival of interferon-free DAA treatment is improving access to hepatitis C treatment for Alaska Native and American Indian people living in Alaska.\n\nAcknowledgements\nWe thank Annette Hewitt, A.N.P., for helpful suggestions and review of the manuscript. We thank all study participants.\n\nDisclaimer\nThe findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention.\n\nFinancial Support\nThis work was supported by the Centers for Disease Control and Prevention (U01 PS001097; U01 PS004113) and with in-kind support from Arctic Investigations Program/NCEZID and Division of Viral Hepatitis/NCHSSTP, Centers for Disease Control and Prevention Not a clinical trial.\n\nConflict of interest and funding\nThe authors do not have a commercial or other association that might pose a conflict of interest.\n==== Refs\nReferences\n1 Fried MW Shiffman ML Reddy KR Smith C Marinos G Goncales FL Jr Pegylated alfa-2a plus ribavirin for chronic hepatitis C virus infection N Engl J Med 2002 347 975 82 12324553 \n2 Hadziyannis SJ Sette H Jr Morgan TR Balan V Diago M Marcellin P Pegylated alfa-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose Ann Intern Med 2004 140 346 55 14996676 \n3 Hu KQ Freilich B Brown RS Brass C Jacobson IM Impact of Hispanic or Asian ethnicity on the treatment outcomes of chronic hepatitis C: results from the WIN-R trial J Clin Gastroenterol 2011 45 720 6 21836471 \n4 Missiha S Heathcote J Arenovich T Khan K Impact of Asian race on response to combination therapy with peginterferon alfa-2a and ribavirin in chronic hepatitis C Am J Gastroenterol 2007 102 2181 8 17640318 \n5 Muir AJ Hu KQ Gordon SC Koury K Boparai N Noviello S Hepatitis C treatment among racial and ethnic groups in the IDEAL trial J Viral Hepat 2011 18 e134 43 21108699 \n6 Muir AJ Bornstein JD Killenberg PG Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites N Engl J Med 2004 350 2265 71 15163776 \n7 Jeffers L Cassidy W Howell CD Hu S Reddy KR Peginterferon alfa-2a [40kd] and ribavirin for black American patients with chronic HCV genotype 1 Hepatology 2004 39 1702 8 15185312 \n8 Pearlman BL Hepatitis C virus infection in African Americans Clin Infect Dis 2006 42 82 91 16323096 \n9 Ge D Fellay J Thompson AJ Simons JS Shianna KV Urban TJ Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance Nature 2009 461 399 401 19684573 \n10 Price JC Murphy RC Shvachko VA Pauly MP Manos NM Effectiveness of telaprevir and boceprevir triple therapy for patients with hepatitis C virus infection in a large integrated care setting Dig Dis Sci 2014 59 3043 52 25102983 \n11 Ioannou GN Beste LA Green PK Similar effectiveness of boceprevir and telaprevir treatment regimens for hepatitis C virus infection on the basis of a nationwide study of veterans Clin Gastroenterol Hepatol 2014 12 1371 80 24361415 \n12 McMahon BJ Hennessy TW Christensen C Bruden D Sullivan DG Homan C Epidemiology and risk factors for hepatitis C in Alaska Natives Hepatology 2004 39 325 32 14767985 \n13 Denniston MM Jiles RB Drobeniuc J Klevens RM Ward JW McQuillan GM Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010 Ann Intern Med 2014 160 293 300 24737271 \n14 Livingston SE Townshend-Bulson LJ Bruden DL McMahon BJ Homan CE Gove JE Treatment eligibility in Alaska Native and American Indian persons with hepatitis C virus infection Int J Circumpolar Health 2012 71 1 7 22564468 \n15 Bruden DL McMahon BJ Hennessy TW Christensen C Homan CE Williams JL Estimating the date of hepatitis C virus infection from patient interviews and antibody tests on stored sera Am J Gastroenterol 2004 99 1517 22 15307870 \n16 Ghany MG Strader DB Thomas DL Seeff LB Diagnosis, management, and treatment of hepatitis C: an update Hepatology 2009 49 1335 74 19330875 \n17 Ghany MG Nelson DR Strader DB Thomas DL Seef LB An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases Hepatology 2012 54 1433 44 21898493 \n18 Livingston SE Deubner H Bruden DL McMahon BJ Homan CE Townshend-Bulson LJ Factors associated with the progression of fibrosis on liver biopsy in Alaska Native and American Indian persons with chronic hepatitis C Can J Gastroenterol 2010 24 445 51 20652161 \n19 Davidson F Simmonds P Ferguson JC Jarvis LM Dow BC Follett EA Survey of major genotypes of hepatitis C using RFLP of sequences amplified from the 5’ non-coding region J Gen Virol 1995 6 1197 204 7730804 \n20 McHutchinson JG Poynard T Combination therapy with interferon and ribavirin for the initial treatment of chronic hepatitis C Semin Liver Dis 1999 19 Suppl 1 57 65 10349693 \n21 Manns MP McHutchison JG Gordon SG Rustgi VK Shiffman M Reindollar R Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial Lancet 2001 358 958 65 11583749 \n22 Butt AA McGinnis KA Skanderson M Justice AC Hepatitis C treatment completion rates in routine clinical care Liver Int 2010 30 240 50 19889081 \n23 Minuk GY O'Brien M Hawkins K Emokpare D McHattie J Harris P Treatment of chronic hepatitis C in a Canadian Aboriginal population: results from the PRAIRIE study Can J Gastroetnerol 2013 27 707 10 \n24 Cooper CL Bailey RJ Bain VG Anderson F Yoshida EM Krajden M Outcomes of peginterferon alpha-2a and ribavirin hepatitis C therapy in Aboriginal Canadians Can J Gastroenterol 2008 22 677 80 18701944 \n25 Davis JS Kulatunga AC Hajkowicz K Outcomes for indigenous and non-indigenous patients who access treatment for hepatitis C in the Top End of the Northern Territory Med J Aust 2013 199 23 23829250 \n26 Shiffman ML Suter F Bacon BR Nelson D Harley H Sola R Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3 N Engl J Med 2007 357 124 34 17625124 \n27 Narciso-Schiavon JL de Lucca Schiavon L Carvalho-Filho RJ Peghini J Sampaio El Batah PN Gender influence on treatment of chronic hepatitis C genotype 1 Rev Soc Bras Med Trop 2010 43 217 33 20563484 \n28 Jian-Wu Y Li-Jie S Young-Hua Z Peng K Bing-Zhu Y Impact of sex on virologic response rates in genotype 1 chronic hepatitis C patients with peginterferon alpha-2a and ribavirin treatment Int J Inf Dis 2011 15 e740 6 21803628 \n29 Hézode C Fontaine H Dorival C Larrey D Zoulim F Canva V Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicenter cohort of the French Early Access Program [ANRS C020-CUPIC]-NCT01514890 J Hepatol 2013 59 434 41 23669289 \n30 American Association for the Study of Liver Diseases and Infectious Diseases Society of America Recommendations for testing, managing and treating hepatitis C [cited 2014 Aug 11]. Available from: http://www.hcvguidelines.org\n\n",
"fulltext_license": "CC BY",
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"journal": "International journal of circumpolar health",
"keywords": "discontinuation; indigenous population; longitudinal study; pegylated interferon; sustained virologic response",
"medline_ta": "Int J Circumpolar Health",
"mesh_terms": "D000328:Adult; D000368:Aged; D000413:Alaska; D000072957:Alaskan Natives; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007198:Indians, North American; D016898:Interferon-alpha; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D018570:Risk Assessment; D016896:Treatment Outcome",
"nlm_unique_id": "9713056",
"other_id": null,
"pages": "30696",
"pmc": null,
"pmid": "27029671",
"pubdate": "2016",
"publication_types": "D023362:Evaluation Study; 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": "11583749;12324553;14767985;14996676;15163776;15185312;15307870;7730804;10349693;16323096;17625124;17640318;18701944;19330875;19684573;19889081;20563484;20652161;21108699;21836471;21898493;21803628;22564468;23829250;23669289;24340315;24737271;24361415;25102983",
"title": "Results of interferon-based treatments in Alaska Native and American Indian population with chronic hepatitis C.",
"title_normalized": "results of interferon based treatments in alaska native and american indian population with chronic hepatitis c"
} | [
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"abstract": "Most published cases of cytomegalovirus infection in pregnancy relate to congenital abnormalities in neonates infected in early pregnancy, while the mother remains asymptomatic. We describe a diagnostically challenging case of an immunosuppressed woman with scleroderma who developed deranged liver function tests attributed to intrahepatic cholestasis of pregnancy and haemolysis, elevated liver enzymes and low platelets syndrome but was ultimately found to have disseminated cytomegalovirus. Cytomegalovirus can present in a myriad of ways. Clinicians caring for immunocompromised pregnant women should consider cytomegalovirus as a possible differential diagnosis when reviewing abnormal liver function tests.",
"affiliations": "De Swiet Obstetric Medicine Centre, Queen Charlotte's & Chelsea Hospital, Imperial College Healthcare NHS Trust, London, UK.;De Swiet Obstetric Medicine Centre, Queen Charlotte's & Chelsea Hospital, Imperial College Healthcare NHS Trust, London, UK.;De Swiet Obstetric Medicine Centre, Queen Charlotte's & Chelsea Hospital, Imperial College Healthcare NHS Trust, London, UK.;De Swiet Obstetric Medicine Centre, Queen Charlotte's & Chelsea Hospital, Imperial College Healthcare NHS Trust, London, UK.;De Swiet Obstetric Medicine Centre, Queen Charlotte's & Chelsea Hospital, Imperial College Healthcare NHS Trust, London, UK; Silver Star Unit, Women's Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, Oxfordshire, UK.",
"authors": "Wander|Gurleen|G|;Neuberger|Francesa|F|;Dhanjal|Mandish K|MK|;Nelson-Piercy|Catherine|C|;Soh|May Ching|MC|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1753495X16641807",
"fulltext": null,
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"issn_linking": "1753-495X",
"issue": "9(3)",
"journal": "Obstetric medicine",
"keywords": "HELLP syndrome; Pregnancy; cytomegalovirus infection; immunocompromised; scleroderma",
"medline_ta": "Obstet Med",
"mesh_terms": null,
"nlm_unique_id": "101464191",
"other_id": null,
"pages": "135-7",
"pmc": null,
"pmid": "27630751",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports",
"references": "224385;1325757;16580941;17029132;17317422;1310525;12588074",
"title": "Cytomegalovirus may mimic the presentation of intrahepatic cholestasis and hemolysis, elevated liver enzymes and low platelets in immunosuppressed pregnant women.",
"title_normalized": "cytomegalovirus may mimic the presentation of intrahepatic cholestasis and hemolysis elevated liver enzymes and low platelets in immunosuppressed pregnant women"
} | [
{
"companynumb": "GB-CONCORDIA PHARMACEUTICALS INC.-E2B_00007857",
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"... |
{
"abstract": "Choreoathetoid movements are quite common in cerebral palsy (CP). This is the first report of a patient with choreoathetoid CP who was successfully treated with carbamazepine. Therefore, clinicians should try carbamazepine for involuntary movements in CP patients before pursuing other procudures.",
"affiliations": "Movement Disorders Division Department of Neurology Mayo Clinic Scottsdale Arizona USA.;Morriston Hospital Swansea Wales United Kingdom.;ABM University Health Board Swansea Wales United Kingdom.;Movement Disorders Program Georgia Regents University Augusta Georgia USA.;Movement Disorders Program Georgia Regents University Augusta Georgia USA.;Movement Disorders Program Georgia Regents University Augusta Georgia USA.",
"authors": "Mehta|Shyamal H|SH|;Sawhney|Inder M|IM|;Yoganathan|Kathir|K|;Trumble|Jill P|JP|;Morgan|John C|JC|;Sethi|Kapil D|KD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/mdc3.12002",
"fulltext": null,
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"issn_linking": "2330-1619",
"issue": "1(1)",
"journal": "Movement disorders clinical practice",
"keywords": "carbamazepine; cerebral palsy; dyskinetic cerebral palsy; dystonic‐choreoathetoid cerebral palsy; levetiracetam",
"medline_ta": "Mov Disord Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "101630279",
"other_id": null,
"pages": "82-83",
"pmc": null,
"pmid": "30363927",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports",
"references": "15145637;11483397;11132255;19018837;19576854",
"title": "Treatment of Involuntary Movements with Carbamazepine in Dystonic-Choreoathetoid Cerebral Palsy.",
"title_normalized": "treatment of involuntary movements with carbamazepine in dystonic choreoathetoid cerebral palsy"
} | [
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"companynumb": "US-UCBSA-2016012048",
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"activesubstancename": "CARBAMAZEPINE"
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{
"abstract": "A Fracture Liaison Service (FLS) was set up at Lille University Hospital in 2016. The purpose of this study was to assess persistence with osteoporosis treatment in patients from the FLS over a period of 1 year, and to determine predictors of discontinuation.\n\n\n\nThe study population comprised adults of both genders, aged 50 or over, admitted to Lille University Hospital between January 2016 and January 2019 for a low-trauma fracture and managed in our FLS. Outcomes included (1) persistence rate at 1 year after treatment initiation, (2) persistence rate at 2 years after treatment initiation, (3) persistence rate at 1 and 2 years after treatment initiation according to type of treatment, (4) predictors of non-persistence, and (5) reasons for discontinuing treatment over 1 year after initiation. Persistence was determined using the Kaplan-Meier method.\n\n\n\nIn all, 1224 patients (≥50 years old) with a recent history of low-trauma fracture (≤12 months) were identified. Of these, 380 patients - 79.2% female; mean (SD) age 76 (11) years - were seen at the FLS. In those 380 patients, 410 fractures were found and 360 of them (87.8%) were major fractures, breaking down as follows: vertebra (44%), hip (19%), proximal humerus (10%), and pelvis (8%). Osteoporosis treatment was prescribed for 367 (96.6%) patients and 275 of them began the prescribed treatment. The following anti-osteoporosis drugs were prescribed: zoledronic acid (n=150, 54.5%), teriparatide (n=63, 22.9%), and denosumab (n=39, 14.2%). Oral bisphosphonates were prescribed for a few patients (n=23, 8.4%). Persistence with osteoporosis medication (any class) was estimated at 84.1% (95% CI: 79.1% to 88.1%) at 12-month follow-up, and dropped to 70.3% (95% CI: 63.7% to 75.9%) at 24 months. When drug-specific analyses were performed using the Kaplan-Meier method, persistence rates at 12 and 24 months were found to be higher with denosumab than with any other treatment. Independent predictors of non-persistence at 12 months were 'follow-up performed by a general practitioner (GP)' - Odds Ratio (OR) for GP vs. FLS = 3.68; 95% CI, 1.52 to 8.90, p=0.004 - and 'treatment with zoledronic acid' - OR for zoledronic acid vs. denosumab = 3.39; 95% CI, 1.21 to 9.50, p=0.019; OR for zoledronic acid vs. teriparatide = 8.86; 95% CI, 1.15 to 68.10, p=0.035.\n\n\n\nThis study provides evidence of the success of our FLS in terms of long-term persistence with osteoporosis treatments. However, osteoporosis treatment initiation still needs to be improved.",
"affiliations": "Univ. Lille, CHU Lille, Department of Rheumatology, 59000 Lille, France. Electronic address: anthony.DELBAR.etu@univ-lille.fr.;Univ. Lille, CHU Lille, Department of Rheumatology, 59000 Lille, France. Electronic address: Arnaud.PFLIMLIN@CHRU-LILLE.FR.;Univ. Lille, CHU Lille, Department of Gerontology, 59000 Lille, France. Electronic address: Isabelle.DELABRIERE@CHRU-LILLE.FR.;Univ. Lille, CHU Lille, ULR 2694 - METRICS: Évaluation des technologies de santé et des pratiques médicales, F-59000 Lille, France. Electronic address: camille.ternynck@chru-lille.fr.;Univ. Lille, CHU Lille, Department of Traumatology, 59000 Lille, France. Electronic address: Christophe.CHANTELOT@CHRU-LILLE.FR.;Univ. Lille, CHU Lille, Department of Gerontology, 59000 Lille, France. Electronic address: Francois.PUISIEUX@CHRU-LILLE.FR.;Univ. Lille, CHU Lille, MABlab ULR 4490, Department of Rheumatology, 59000 Lille, France. Electronic address: Bernard.CORTET@CHRU-LILLE.FR.;Univ. Lille, CHU Lille, MABlab ULR 4490, Department of Rheumatology, 59000 Lille, France. Electronic address: julien.paccou@chru-lille.fr.",
"authors": "Delbar|Anthony|A|;Pflimlin|Arnaud|A|;Delabrière|Isabelle|I|;Ternynck|Camille|C|;Chantelot|Christophe|C|;Puisieux|François|F|;Cortet|Bernard|B|;Paccou|Julien|J|",
"chemical_list": "D050071:Bone Density Conservation Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bone.2020.115838",
"fulltext": null,
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"issn_linking": "1873-2763",
"issue": "144()",
"journal": "Bone",
"keywords": "Discontinuation; Fracture; Fracture Liaison Service; Osteoporosis; Persistence",
"medline_ta": "Bone",
"mesh_terms": "D000328:Adult; D000368:Aged; D050071:Bone Density Conservation Agents; D005260:Female; D006761:Hospitals; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis; D058866:Osteoporotic Fractures; D013131:Spine",
"nlm_unique_id": "8504048",
"other_id": null,
"pages": "115838",
"pmc": null,
"pmid": "33385615",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Persistence with osteoporosis treatment in patients from the Lille University Hospital Fracture Liaison Service.",
"title_normalized": "persistence with osteoporosis treatment in patients from the lille university hospital fracture liaison service"
} | [
{
"companynumb": "FR-AMGEN-FRASP2021078121",
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"occurcountry": "FR",
"patient": {
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"activesubstancename": "ERGOCALCIFEROL"
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... |
{
"abstract": "Basal ganglia lesions showing an expansile high signal intensity on T2-weighted MRI are termed the lentiform fork sign. This specific finding is mainly observed in diabetic patients with uremic encephalopathy with metabolic acidosis, although there are also reports in patients with ketoacidosis, dialysis disequilibrium syndrome, intoxication, and following drug treatment (e.g., metformin). A 57-year-old Japanese man on chronic hemodialysis for 4 years because of diabetic nephropathy was admitted to our hospital for relatively rapid-onset gait disturbance, severe dysarthria, and consciousness disturbance. Brain T2-weighted MRI showed the lentiform fork sign. Hemodialysis was performed the day before admission, and laboratory tests showed mild metabolic (lactic) acidosis, but no uremia. Surprisingly, metformin, which is contraindicated for patients with end-stage kidney disease, had been prescribed for 6 months in his medication record, and his sluggish speaking and dysarthria appeared gradually after metformin treatment was started. Thus, the encephalopathy was considered to be related to metformin treatment. He received hemodialysis treatment for 6 consecutive days, and his consciousness disturbance and dysarthria improved in 1 week. At the 8-month follow-up, the size of the hyperintensity area on MRI had decreased, while the mild gait disturbance remained. Considering the rapid onset of gait and consciousness disturbance immediately before admission, diabetic uremic syndrome may also have occurred with metformin-related encephalopathy, and resulted in the lentiform fork sign, despite the patient showing no evidence of severe uremia on laboratory data.",
"affiliations": "Department of Nephrology, University of Miyazaki Hospital, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Department of Nephrology, University of Miyazaki Hospital, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Department of Nephrology, University of Miyazaki Hospital, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Dialysis Division, University of Miyazaki Hospital, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Nephrology, University of Miyazaki Hospital, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Department of Nephrology, University of Miyazaki Hospital, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.",
"authors": "Ishizaki|Yuri|Y|https://orcid.org/0000-0002-6478-900X;Nishizono|Ryuzoh|R|https://orcid.org/0000-0002-8185-618X;Kikuchi|Masao|M|;Inagaki|Hiroko|H|;Sato|Yuji|Y|https://orcid.org/0000-0002-1272-4108;Fujimoto|Shouichi|S|https://orcid.org/0000-0002-0025-4030",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.12688/f1000research.25597.2",
"fulltext": "\n==== Front\nF1000Res\nF1000Res\nF1000Research\n2046-1402\nF1000 Research Limited London, UK\n\n10.12688/f1000research.25597.2\nCase Report\nArticles\nCase Report: A Case of Encephalopathy Presenting the Lentiform Fork Sign on MRI in a Diabetic Dialysis Patient\n[version 2; peer review: 2 approved]\n\nIshizaki Yuri Writing – Original Draft Preparation https://orcid.org/0000-0002-6478-900X\na1\nNishizono Ryuzoh Writing – Review & Editing https://orcid.org/0000-0002-8185-618X\n1\nKikuchi Masao Writing – Review & Editing 1\nInagaki Hiroko Writing – Review & Editing 2\nSato Yuji Writing – Review & Editing https://orcid.org/0000-0002-1272-4108\n12\nFujimoto Shouichi Supervision https://orcid.org/0000-0002-0025-4030\n123\n1 Department of Nephrology, University of Miyazaki Hospital, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan\n2 Dialysis Division, University of Miyazaki Hospital, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan\n3 Department of Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan\na yuri_ishizaki@med.miyazaki-u.ac.jp\nNo competing interests were disclosed.\n\n20 10 2021\n2020\n9 96918 10 2021\nCopyright: © 2021 Ishizaki Y et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nBasal ganglia lesions showing an expansile high signal intensity on T2-weighted MRI are termed the lentiform fork sign. This specific finding is mainly observed in diabetic patients with uremic encephalopathy with metabolic acidosis, although there are also reports in patients with ketoacidosis, dialysis disequilibrium syndrome, intoxication, and following drug treatment (e.g., metformin). A 57-year-old Japanese man on chronic hemodialysis for 4 years because of diabetic nephropathy was admitted to our hospital for relatively rapid-onset gait disturbance, severe dysarthria, and consciousness disturbance. Brain T2-weighted MRI showed the lentiform fork sign. Hemodialysis was performed the day before admission, and laboratory tests showed mild metabolic (lactic) acidosis, but no uremia. Surprisingly, metformin, which is contraindicated for patients with end-stage kidney disease, had been prescribed for 6 months in his medication record, and his sluggish speaking and dysarthria appeared gradually after metformin treatment was started. Thus, the encephalopathy was considered to be related to metformin treatment. He received hemodialysis treatment for 6 consecutive days, and his consciousness disturbance and dysarthria improved in 1 week. At the 8-month follow-up, the size of the hyperintensity area on MRI had decreased, while the mild gait disturbance remained. Considering the rapid onset of gait and consciousness disturbance immediately before admission, diabetic uremic syndrome may also have occurred with metformin-related encephalopathy, and resulted in the lentiform fork sign, despite the patient showing no evidence of severe uremia on laboratory data.\n\nlentiform fork sign\nbasal ganglia lesion\ndiabetic uremic syndrome\nmetformin\nconsciousness disturbance\nThe author(s) declared that no grants were involved in supporting this work.Revised Amendments from Version 1\n\nWe respond to each reviewer's suggestion as follows. 1) We shorten the title to “A Case of Encephalopathy Presenting the Lentiform Fork Sign on MRI in a Diabetic Dialysis Patient”. 2) We corrected “Atrial blood gas” to “Arterial blood gas analysis”. 3) We mentioned the Glasgow Coma Scale Score of E3V4M6 in the first line of the case report section. 4) We discussed more reasons not likely to be ME in our case. The first reason was the thiamin level was not decreased, even though metformin may induce thiamin deficiency. (We added serum thiamin value in the part of the case presentation.) Secondly, the level of metabolic (lactic) acidosis on admission was also much mild not so high. Thirdly, as shown in Fig. 2, although the patient had had sluggish speaking and dysarthria and these findings had been gradually worsening six months before starting taking metformin, the relatively rapid-onset gait disturbance, severe dysarthria, and consciousness disturbance had appeared ten days before admission, which was a subacute progression. We could say that it was difficult to distinguish between ME and DUS, just considering the appearance of the findings. That is why we cannot necessarily diagnose ME, and we listed the two differential diagnoses, ME and/or DUS. 5) We add more three references. Reference #16 is for the explanation of the importance of thiamin level in metformin-induced encephalopathy. Reference #17 and #18 show that our case is not necessarily ME in the perspective of thiamin level in hemodialysis patients.\n==== Body\npmcIntroduction\n\nMetabolic encephalopathy with abnormal basal ganglia lesions has been reported in hemodialysis patients. Ingestion of some types of mushroom, star fruit, and drugs (e.g., anti-herpes virus drugs) can cause encephalopathy in these patients 1– 3 . In particular, diabetic dialyzed patients can present with bilateral symmetrical low densities in the basal ganglia on brain computed tomography (CT), with a bilateral symmetrical hyperintensity in the same area and a lentiform fork sign on T2-weighted MRI 4– 10 . In addition to diabetic uremic syndrome (DUS) 4, 5 , the lentiform fork sign can be observed in severe metabolic acidosis 11– 13 , dialysis disequilibrium syndrome 14 , and metformin-associated encephalopathy (ME) 6, 7 . The pathogenic basis of this sign is considered to relate to cytotoxic edema based on the severity of metabolic acidosis 8, 11 . Intensive dialysis is a therapeutic option for removing the uremic toxins, to correct metabolic acidosis and remove medications. Herein, we present a case of a 57-year-old Japanese man in whom the lentiform fork sign was a clue for the differential diagnosis of ME or DUS. Metformin tends to increase lactate production and result in metabolic acidosis in ME 6, 7, 9, 10 , while chronic hyperglycemia with coexistence of uremic toxins and metabolic acidosis is the main mechanism in DUS 4, 5 . Which of these is the main cause in our case presenting with the lentiform fork sign is discussed below.\n\nCase report\n\nA 57-year-old Japanese man who had been on maintenance hemodialysis three-times weekly for four years because of diabetic nephropathy developed gait and consciousness disturbance (the Glasgow Coma Scale score of E3V4M6), fatigue, numbness in his left upper limb, and a slow response during conversation approximately 10 days before admission. His wife denied him taking mushrooms or star fruit, which can cause consciousness disturbance in hemodialysis patients. There were no abnormal neurologic findings on physical examination. However, bilateral symmetrical basal ganglia lesions were noted on brain CT ( Figure 1a).\n\nFigure 1. a, e Head computed tomography (CT) and b–d head MRI (T2-weighted image). a, b High-resolution lesions in the bilateral symmetrical basal ganglia were evident at admission. c, d The bilateral symmetrical basal ganglia lesions gradually improved on the 18 th hospital day and at three-month follow-up. e However, the basal ganglia lesions remained at eight-month follow-up.\n\nOn admission to our hospital, his consciousness was disturbed, such as he only could open his eyes following calling, and he had difficulty sitting alone. He showed a tonic planter reflex on physical examination. His blood pressure was 190/91 mmHg, and his heart rate was 104 beats per min. Arterial blood gas analysis showed a pH of 7.37, bicarbonate ion of 18.1 mEq/L, and lactic acid of 6.2 mmol/L (normal, 0.5–1.6 mmol/L). Serum vitamin B1 (thiamin) level was 45 ng/mL (normal, 24–66 ng/mL). Serum vitamin B1 (thiamin) level was 45 ng/mL (normal, 24–66 ng/mL). Serum calcium and blood aluminum levels were all within the acceptable range. Kidney function data sampled the day after dialysis, blood urea nitrogen, and serum creatinine were consistent with dialysis. His HbA1c was 5.8% on admission.\n\nBrain MRI showed bilateral symmetrical basal ganglia lesions with an expansile high signal intensity (lentiform fork sign) on T2-weighted sequences ( Figure 1b), which was not seen on MRI taken one-year prior when he developed a right thalamic lacunar infarction.\n\nIn his medication history, he had taken metformin for six months. His wife said that his sluggish speaking and dysarthria appeared gradually after starting metformin treatment ( Figure 2). His plasma metformin concentration was extremely high (25,700 ng/mL). Thus, we considered that metformin may have initially caused the encephalopathy. However, we also considered the possibility of DUS, because his gait and consciousness disturbance appeared relatively rapidly approximately 10 days before hospitalization. DUS typically occurs in uncontrolled uremic patients with diabetic mellitus.\n\nFigure 2. The patient started metformin treatment at six months prior to admission.\n\nSince that time, he developed gradual symptoms of sluggish speaking and dysarthria, while numbness of his left upper limb, gait disturbance, and consciousness disturbance appeared 10 days before admission. He received emergency consecutive hemodialysis for six days, after which he awoke, and was gradually able to walk and talk. *Walking was possible, but wobbling during walking remained at eight-month follow-up.\n\nIn either case, we stopped metformin treatment, and immediately performed intensive hemodialysis (four hours per day) for six days after hospitalization to remove metformin and uremic toxin, and to correct metabolic acidosis. The first dialysis session reduced his lactic acid levels from 6.2 to 1.3 mmol/L. After six consecutive sessions of hemodialysis, his consciousness was restored, and his tonic planter reflex disappeared. After starting meals, linagliptin was chosen as an anti-diabetic drug to replace metformin.\n\nOn the 18 th hospital day, T2-weighted brain MRI revealed a modest improvement in the lentiform fork sign ( Figure 1c). The patient was gradually able to sitting alone, walk, and talk with staff and his wife. He was discharged from our hospital within one month.\n\nAt three-month follow-up, the lentiform fork sign was further improved on brain MRI ( Figure 1d). However, at eight months after the onset, he still complained movement disorders, such as a wobble when walking and body tilting when resting. Brain lesions were still evident on CT scan ( Figure 1e).\n\nDiscussion\n\nHerein, we report a diabetic hemodialysis patient with consciousness disturbance who presented with the lentiform fork sign on T2-weighted brain MRI. This finding appears in the basal ganglia, which is vulnerable to addictive toxins and metabolic products 8, 12 . The lentiform fork sign is comprised of the following elements: 1) the lateral arm, formed by the edematous external capsule and extending from the anterior end of the putamen to the stem; 2) the stem, created by merging of the edematous external and internal capsules at the inferoposterior end of the putamen; and 3) the medial arm, which extends from the stem anteriorly up to one third of the medial edge, where it splits into two slightly less T2/FLAIR-hyperintense branches engulfing the globus pallidus 11, 12, 15 . In the present case, brain MRI showed the same expansile high signal intensity ( Figure 1b). The lentiform fork sign is rare but non-specific. Thus, a differential diagnosis should be considered ( Table 1) 8, 11– 15 , of which ME or DUS may be the cause in the present case.\n\nTable 1. Differential diagnosis of pathological conditions presenting with the lentiform fork sign 8, 11– 15 .\n\na) Uremic encephalopathy *\t\nb) Severe metabolic acidosis\t\nc) Ketoacidosis\t\nd) Dialysis disequilibrium syndrome\t\ne) Intoxication (methanol, ethylene glycol, etc)\t\nf) Drug-induced (metformin)\t\n*The lentiform fork sign mainly occurs in patients with diabetic kidney disease.\n\nThe use of metformin in dialyzed patients can cause drug accumulation in the brain, leading to neurological abnormalities, difficulties of speech and walking, with worsening of sensory disturbance, tiredness, drowsiness, and weakness (i.e., ME) 6, 7, 9, 10 . Metformin is first-line drug used in type 2 diabetes mellitus. However, it is contraindicated in patients with an estimated glomerular filtration rate <30 mL/min/1.73 m 2, because of an increased risk of lactic acidosis. Acidosis can damage the basal ganglia, resulting in cytotoxic edema 7 , which is sometimes irreversible despite intensive hemodialysis to remove metformin and lactic acid, and to correct acidosis. According to the previous reports, hemodialysis patients are at risk for thiamin deficiency which is induced to encephalopathy, because they are in the condition of malnutrition and tend to lose water-soluble vitamins in the hemodialysis procedure 16, 17 . Furthermore, thiamin deficiency may be a possible mechanism in metformin-induced encephalopathy 18 . In our case, thiamin level was not decreased and severe lactic acidosis was not observed. In addition to these, the occurrence of gait disturbance, severe dysarthria, and consciousness disturbance was subacute even though sluggish speaking and dysarthria had been gradually worsening six months before starting taking metformin as shown in Figure 2, and the patient was neither malnutrition nor weight loss. That is why it was not necessarily ME.\n\nAlternatively, DUS is characterized by acute or subacute progression with a variety of movement disorders such as gait disorders, dysarthria, parkinsonism, and consciousness disturbance. DUS can cause bilateral symmetrical basal ganglia lesions on brain CT and T2-weighted MRI 4, 5 in patients with diabetic nephropathy, even if they are not on hemodialysis. To date, approximately 30 cases of DUS have been reported, many of which are Asian. The reported risk factors of DUS include a high level of HbA1c before and at hemodialysis, and increasing metabolic acidosis. Hyperglycemia damages the microvasculature, resulting in a fragile vascular smooth muscle, and the accumulation of uremic toxins and/or metabolic acidosis can damage the blood-brain-barrier, leading to altered metabolism and homeostasis in the brain. This can result in basal ganglia injury, including angiogenic edema, which is reversible and shows favorable prognosis.\n\nThe clinical presentation in our case was not helpful for differentiating ME and DUS, because these symptoms were indistinguishable ( Table 2). Initial hemodialysis improved lactic acidosis, although intensive hemodialysis for six consecutive days was required to improve his consciousness. The lentiform fork sign on MRI improved at first, although brain CT findings at eight-month follow-up showed low density signals in those regions, and his neurological sequelae remained, suggestive of continued cytotoxic edema. ME was likely the main cause of injury in our case. Nevertheless, the patient’s condition worsened relatively rapidly before admission, similar to that seen in DUS. DUS can also contribute to cytotoxic edema in the basal ganglia, and has a variable progression. Thus, DUS may have also contributed to the encephalopathy in our case.\n\nTable 2. Comparison with metformin-encephalopathy (ME) and diabetic uremic syndrome (DUS) 4– 7, 11– 14 .\n\n\tME\tDUS\tPresent case\t\nClinical findings\tsensorium, tiredness,\ndysarthria, gait\ndisorder,\nconsciousness\ndisturbance\tdysarthria, gait\ndisorder,\nparkinsonism,\nconsciousness disturbance\ttiredness, dysarthria,\ngait disorder,\nconsciousness\ndisturbance\t\nOnset\tgradually and\nsubacute\tacute and subacute\tgradually (dysarthria) and subacute\n(gait and consciousness disturbance)\t\nAcidosis\tLactic acidosis\tMetabolic acidosis\tLactic & metabolic acidosis\t\nUremia\t-\t+\t-\t\nHyperglycemia\t-\t+\t-\t\nCT\tlow density area\tlow density area\tlow density area\t\nMRI (T2-weighted)\thigh intense lesion\thigh intense lesion\thigh intense lesion\t\nCharacteristic of edema\tcytotoxic\tvasogenic\tcytotoxic\t\nTherapy\tstop metformin\nintensive hemdialysis\tintensive hemdialysis\tintensive hemdialysis\t\nPrognosis\tremained\tgood\tremained\t\nME, metformin-associated encephalopathy; DUS, diabetic uremic syndrome.\n\nIn summary, we report a diabetic hemodialysis patient with encephalopathy presenting as the lentiform fork sign derived from ME and/or DUS. In dialysis patients showing gait and consciousness disturbance, the lentiform fork sign on brain CT and T2-weighted MRI may be useful for differential diagnosis.\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nConsent\n\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patient.\n\nAcknowledgements\n\nWe thank Edanz Group ( https://en-author-services.edanzgroup.com/) for editing a draft of this manuscript.\n\n10.5256/f1000research.78515.r97746\nReviewer response for version 2\nWu Ping-Hsun 1Referee\n1 Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan\n18 11 2021 Copyright: © 2021 Wu PH\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nVersion 2recommendationapprove\nYuri Ishizaki et al. reported a case of lentiform fork sign on MRI in a dialysis patient. The case presentation is good and well written. I have some questions about this case report. The consciousness disturbance improved after intensive hemodialysis. The hemodialysis dosage and time interval could be mentioned in this paper.\n\nMetformin was prescribed for diabetic hemodialysis patients. In this condition, metformin-associated lactic acidosis may present. In the revised main text, the author mentioned that the level of metabolic (lactic) acidosis on admission was not very high. Please provide the acidosis status (HCO3 level and lactate level) in the main text.\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nYes\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nYes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nPartly\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nYes\n\nReviewer Expertise:\n\nClinical nephrology, hemodialysis, chronic kidney disease\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.78515.r97466\nReviewer response for version 2\nSen Shashwati Sarkar 1Referee https://orcid.org/0000-0002-7226-5492\n\n1 Department of Reproductive Medicine and Surgery, Mohak Superspeciality Hospital, Prayagraj, Uttar Pradesh, India\n8 11 2021 Copyright: © 2021 Sen SS\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nVersion 2recommendationapprove\nThe queries and suggestions have been answered satisfactorily.\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nYes\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nYes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nYes\n\nReviewer Expertise:\n\nEndocrine disorders, Assisted reproductive technology, Infertility, Gynaecology, Obstetrics\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\nIshizaki Yuri University of Miyazaki, Japan\n\n11 11 2021 Dear Shashwati Sarkar Sen,\n\nThank you for your valuable comments and suggestions.\n\nSincerely,\n\nYuri Ishizaki\n\n10.5256/f1000research.28250.r95340\nReviewer response for version 1\nSen Shashwati Sarkar 1Referee https://orcid.org/0000-0002-7226-5492\n\n1 Department of Reproductive Medicine and Surgery, Mohak Superspeciality Hospital, Prayagraj, Uttar Pradesh, India\n27 9 2021 Copyright: © 2021 Sen SS\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nVersion 1recommendationapprove\nSummary: It is prudent to avoid Metformin in Diabetic patients with chronic renal insufficiency. Metformin toxicity can cause lactic acidosis induced encephalopathy eventually leading to multi-organ failure and death. Lentiform fork sign is a specific MRI finding in basal ganglia of these patients probably due to vasogenic edema induced by metabolic acidosis. Suspicion about Metformin intake will help in an early diagnosis and treatment.\n\nA few suggestions to the authors: Restrict the number of words in the title. Too many medical terms are used.\n\nCase Report: Correction - Arterial Blood Gas analysis. \n\nMention the Glasgow Coma Score.\n\nDUS may have a subacute presentation. Yoshiko Nishimura et al. 2 have reported a case of Diabetic Uremic Syndrome where the clinical features developed over 3 months. In your case, ME seems to be the primary diagnosis and DUS may be considered as a differential diagnosis rather than a contributory factor.\n\nAdd these References: Metformin-induced encephalopathy: the role of thiamine 1 .McGarvey et al. (2018) suggested that Metformin may cause thiamine deficiency in patients with end-stage diabetic renal failure, resulting in a specific type of encephalopathy. A quick resolution of the signs and symptoms was observed on stopping the drug in these patients.\n\nA case of subacute Parkinsonism presenting as bilateral basal ganglia lesions by MRI in Diabetic uremic Syndrome. 2\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nYes\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nYes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nYes\n\nReviewer Expertise:\n\nEndocrine disorders, Assisted reproductive technology, Infertility, Gynaecology, Obstetrics\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\nIshizaki Yuri University of Miyazaki, Japan\n\n16 10 2021 Dear Dr. Shashwati Sarkar Sen,\n\nThank you for your valuable comments about my case report. We respond to each suggestion as follows.\n\n1) Restrict the number of words in the title. Too many medical terms are used.\n\nAs suggested by the reviewer, we shorten the title to “A Case of Encephalopathy Presenting the Lentiform Fork Sign on MRI in a Diabetic Dialysis Patient”.\n\n2) Case Report: Correction - Arterial Blood Gas Analysis.\n\nThank you for pointing it out. We corrected “Atrial blood gas” to “Arterial blood gas analysis”. \n\n3) Mention the Glasgow Coma Score.\n\n We mentioned the Glasgow Coma Scale Score of E3V4M6 in the first line of the case report section.\n\n4) DUS may have a subacute presentation. Yoshiko Nishimura et al. have reported a case of Diabetic Uremic Syndrome where the clinical features developed over 3 months. In your case, ME seems to be the primary diagnosis and DUS may be considered as a differential diagnosis rather than a contributory factor.\n\nThank you for your comment. In our case, there was not enough evidence to diagnose ME. The first reason was the thiamin level was not decreased, even though metformin may induce thiamin deficiency. (We added serum thiamin value in the part of the case presentation.) Furthermore, thiamin deficiency can be caused by malnutrition and loss of water-soluble vitamins in the hemodialysis progression, but the patient did not have the symptoms of weight loss and seemed not to be undernourished. Secondly, the level of metabolic (lactic) acidosis on admission was also much mild not so high. Thirdly, as shown in Fig. 2, although the patient had had sluggish speaking and dysarthria and these findings had been gradually worsening six months before starting taking metformin, the relatively rapid-onset gait disturbance, severe dysarthria, and consciousness disturbance had appeared ten days before admission, which was a subacute progression. We could say that it was difficult to distinguish between ME and DUS, just considering the appearance of the findings. That is why we cannot necessarily diagnose ME, and we listed the two differential diagnoses, ME and/or DUS.\n\nWe added the following sentences in the Discussion section:\n\nAccording to the previous reports, hemodialysis patients are at risk for thiamin deficiency which is induced to encephalopathy, because they are in the condition of malnutrition and tend to lose water-soluble vitamins in the hemodialysis procedure [16, 17]. Furthermore, thiamin deficiency may be a possible mechanism in metformin-induced encephalopathy [18]. In our case, the thiamin level was not decreased and severe lactic acidosis was not observed. In addition to these, the occurrence of gait disturbance, severe dysarthria, and consciousness disturbance was subacute even though sluggish speaking and dysarthria had been gradually worsening six months before starting taking metformin as shown in Fig.2, and the patient was neither malnutrition nor weight loss. That is why it was not necessarily ME.\n\nReferences\n\nWe also read the two references which you indicated. According to Reference #1, thiamine must be a key to diagnose Metformin-induced encephalopathy. In the part of that we showed the thiamin level of our case, we quoted reference #1. On the other hand, we did not add reference #2 because it is written in Japanese and we thought that reader cannot understand it well.\n\nFurthermore, we quoted two more references to mention that our case is not necessarily ME in the perspective of thiamin level in hemodialysis patients (Szu-Chun H et al, AJKD, 2001).\n\nSincerely yours,\n\nYuri Ishizaki\n\nCompeting interests: No competing interests were disclosed.\n\nCompeting interests: No competing interests were disclosed.\n\nCompeting interests: None.\n\nCompeting interests: No competing interests were disclosed.\n\nCompeting interests: None\n==== Refs\n1 Akiyama H Matsuoka H Okuyama T : The acute encephalopathy induced by intake of sugihiratake mushroom in the patients with renal damage might be associated with the intoxication of cyanide and thiocyanate. Food Safety. 2015;3 (1 ):16–29. 10.14252/foodsafetyfscj.2014036\n2 Auxiliadora-Martins M Alkmin Teixeira GC da Silva GS : Severe encephalopathy after ingestion of star fruit juice in a patient with chronic renal failure admitted to the intensive care unit. Heart Lung. 2010;39 (5 ):448–452. 10.1016/j.hrtlng.2009.09.003 20561840\n3 Delluc A Mocquard Y Latour P : Encephalopathy and acute renal failure during acyclovir treatment. Rev Neurol (Paris). 2004;160 (6–7 ):704–706. 10.1016/s0035-3787(04)71022-x 15247861\n4 Wang HC Cheng SJ : The syndrome of acute bilateral basal ganglia lesions in diabetic uremic patients. J Neurol. 2003;250 (8 ):948‒955. 10.1007/s00415-003-1122-0 12928914\n5 Finelli PF Singh JU : A syndrome of bilateral symmetrical basal ganglia lesions in diabetic dialysis patients. Am J Kidney Dis. 2014;63 (2 ):286–288. 10.1053/j.ajkd.2013.08.030 24183109\n6 Kang YJ Bae EJ Seo JW : Two additional cases of metformin-associated encephalopathy in patients with end-stage renal disease undergoing hemodialysis. Hemodial Int. 2013;17 (1 ):111–115. 10.1111/j.1542-4758.2012.00698.x 22515914\n7 Simon SP Thomas J : Metformin-associated encephalopathy in hemodialysis. Indian J Nephrol. 2019;29 (3 ):194–196. 10.4103/ijn.IJN_257_17 31142967\n8 Kim DM Lee IH Song CJ : Uremic encephalopathy: MR imaging findings and clinical correlation. ANJR Am J Neuroradiol. 2016;37 (9 ):1604–1609. 10.3174/ajnr.A4776 27127003\n9 Abdel SC Carland JE Graham GG : Is the use of metformin in patients undergoing dialysis hazardous for life? A systematic review of the safety of metformin in patients undergoing dialysis. Br J Clin Pharmacol. 2019;85 (12 ):2772–2783. 10.1111/bcp.14107 31471973\n10 Vecchio S Giampreti A Petrolini VM : Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy. Clin Toxicol (Phila). 2014;52 (2 ):129–35. 10.3109/15563650.2013.860985 24283301\n11 Kumar G Goyal MK : Lentiform Fork sign: a unique MRI picture. Is metabolic acidosis responsible? Clin Neurol Neurosurg. 2010;112 (9 ):805–812. 10.1016/j.clineuro.2010.06.006 20615611\n12 Grasso D Borreggine C Perfetto F : Lentiform fork sign: a magnetic resonance finding in a case of acute metabolic acidosis. Neuroradiol J. 2014;27 (3 ):288–292. 10.15274/NRJ-2014-10041 24976195\n13 Saini AG Sreevilasan SK Singh P : Lentiform fork sign due to severe metabolic acidosis. BMJ Case Rep. 2017;2017 :bcr2017222871. 10.1136/bcr-2017-222871 29212873\n14 da Rocha AJ Maia AC Jr da Silva CJ : Lentiform fork sign in a child with dialysis disequilibrium syndrome: a transient MRI pattern which emphasizes neurologic consequence of metabolic acidosis. Clin Neurol Neurosurg. 2013;115 (6 ):790–792. 10.1016/j.clineuro.2012.07.013 22898090\n15 Beltz EE Mullins ME : Radiological reasoning: hyperintensity of the basal ganglia and cortex on FLAIR and diffusion-weighted imaging. AJR Am J Roentgenol. 2010;195 (3 Suppl ):S1–8(Quiz S9-11). 10.2214/AJR.07.7089 20729404\n16 Szu-Chun H Sze-Hung H Der-Cherng T : Chorea Induced by thiamin deficiency in hemodialysis patients. Am J Kidney Dis. 2001;37 (2 ):427–430. 10.1053/ajkd.2001.21337 11157387\n17 Szu-Chun H Sze-Hung H Der-Cherng T : Thiamin deficiency and unexpected encephalopathy in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis. 2001;38 (5 ):941–947. 10.1053/ajkd.2001.28578 11684545\n18 McGarvey C Franconi C Prentice D : Metformin-induced encephalopathy: the role of thiamine. Intern Med J. 2018;48 (2 ):194–197. 10.1111/imj.13693 29415360\n\n",
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"title": "Case Report: A Case of Encephalopathy Presenting the Lentiform Fork Sign on MRI in a Diabetic Dialysis Patient.",
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"abstract": "A prospective, randomised controlled trial compared the effects of two medications intended to reduce blood loss from total knee arthroplasty. Patients were randomised to one of the following three treatment groups: 10mg/kg tranexamic acid at given at induction of anaesthesia, 10 ml of fibrin spray administered topically during surgery, or to a control group receiving neither treatment. Sixty six patients underwent elective cemented total knee arthroplasty; computer navigation was used in all cases. There was no significant difference in blood loss between the tranexamic acid and fibrin spray groups (p=0.181). There was no significant difference in blood loss between the tranexamic acid and fibrin spray groups(p=0.181). The fibrin spray led to a significant reduction in blood loss compared to control (p=0.007). The effect of tranexamic acid did not reach significance (p=0.173). We conclude that fibrin spray was effective in reducing blood loss but that with a study of this power, we were unable to detect an effect of tranexamic acid in cemented navigated total knee replacement at the dose used.",
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"abstract": "BACKGROUND\nDifferentiation syndrome (DS) is a life-threatening complication that may be seen in patients with acute promyelocytic leukaemia undergoing induction therapy with all-trans retinoic acid or arsenic trioxide. It can lead to severe inflammatory response syndrome and shock if adequate measures are not taken immediately. The radiological features of lung nodules with changes in ground-glass opacity can represent DS. The principal unique feature of the case reported here is that the diagnosis of DS was based on imaging results in the absence of a low total leukocyte count.\n\n\nMETHODS\nA 14-year-old Indian girl diagnosed with acute promyelocytic leukaemia currently undergoing a chemotherapy regimen that included all-trans retinoic acid/arsenic trioxide was sent to the radiology department for investigation of respiratory distress which she had developed soon after the initiation of chemotherapy. Her chest radiograph showed bilateral lower zone lung infiltrates. Computed tomography (CT) revealed changes in ground-glass opacity in the lower lobes with multiple lung nodules. Differential diagnosis included bacterial, viral or fungal infections, leukemic infiltrates, drug toxicity, pulmonary haemorrhage or leukostasis. She was started on dexamethasone immediately after stopping the chemotherapy with all-trans retinoic acid/arsenic trioxide and given ventilatory support. Her condition subsequently improved and her follow-up chest radiograph and CT scan showed a significant reduction of abnormal lung findings. Based on the clinical improvement and the resolution of findings on imaging following the withdrawal of all-trans retinoic acid/arsenic trioxide, we made the diagnosis of DS.\n\n\nCONCLUSIONS\nThough a rather unusual possibility, the treatment history of the patient enabled a rather crucial diagnosis in the nick of time and imaging played a pivotal role. This case further iterates the importance of keeping DS in mind when dealing with similar patients in the future.",
"affiliations": "Department of Radiology, Tata Medical Center, 14 MAR (E-W), New Town, Rajarhat, Kolkata, 700160, West Bengal, India. sayansarkar08@gmail.com.;Department of Radiology, Tata Medical Center, 14 MAR (E-W), New Town, Rajarhat, Kolkata, 700160, West Bengal, India.;Department of Radiology, Tata Medical Center, 14 MAR (E-W), New Town, Rajarhat, Kolkata, 700160, West Bengal, India.;Department of Pediatric Haematology, Tata Medical Center, 14 MAR (E-W), New Town, Rajarhat, Kolkata, 700160, West Bengal, India.;Department of Pediatric ICU, Tata Medical Center, 14 MAR (E-W), New Town, Rajarhat, Kolkata, 700160, West Bengal, India.",
"authors": "Sarkar|Sayan|S|http://orcid.org/0000-0002-8818-0370;Ghosh|Priya|P|;Gehani|Anisha|A|;Ghara|Niharendu|N|;Bhattacharyya|Parthasarathi|P|",
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"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2790\n10.1186/s13256-021-02790-w\nCase Report\nMultidisciplinary corroboration in differentiation syndrome: a case report\nhttp://orcid.org/0000-0002-8818-0370\nSarkar Sayan sayansarkar08@gmail.com\n\n1\nGhosh Priya 1\nGehani Anisha 1\nGhara Niharendu 2\nBhattacharyya Parthasarathi 3\n1 grid.430884.3 0000 0004 1770 8996 Department of Radiology, Tata Medical Center, 14 MAR (E-W), New Town, Rajarhat, Kolkata, 700160 West Bengal India\n2 grid.430884.3 0000 0004 1770 8996 Department of Pediatric Haematology, Tata Medical Center, 14 MAR (E-W), New Town, Rajarhat, Kolkata, 700160 West Bengal India\n3 grid.430884.3 0000 0004 1770 8996 Department of Pediatric ICU, Tata Medical Center, 14 MAR (E-W), New Town, Rajarhat, Kolkata, 700160 West Bengal India\n5 5 2021\n5 5 2021\n2021\n15 22613 7 2020\n16 3 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nDifferentiation syndrome (DS) is a life-threatening complication that may be seen in patients with acute promyelocytic leukaemia undergoing induction therapy with all-trans retinoic acid or arsenic trioxide. It can lead to severe inflammatory response syndrome and shock if adequate measures are not taken immediately. The radiological features of lung nodules with changes in ground-glass opacity can represent DS. The principal unique feature of the case reported here is that the diagnosis of DS was based on imaging results in the absence of a low total leukocyte count.\n\nCase presentation\n\nA 14-year-old Indian girl diagnosed with acute promyelocytic leukaemia currently undergoing a chemotherapy regimen that included all-trans retinoic acid/arsenic trioxide was sent to the radiology department for investigation of respiratory distress which she had developed soon after the initiation of chemotherapy. Her chest radiograph showed bilateral lower zone lung infiltrates. Computed tomography (CT) revealed changes in ground-glass opacity in the lower lobes with multiple lung nodules. Differential diagnosis included bacterial, viral or fungal infections, leukemic infiltrates, drug toxicity, pulmonary haemorrhage or leukostasis. She was started on dexamethasone immediately after stopping the chemotherapy with all-trans retinoic acid/arsenic trioxide and given ventilatory support. Her condition subsequently improved and her follow-up chest radiograph and CT scan showed a significant reduction of abnormal lung findings. Based on the clinical improvement and the resolution of findings on imaging following the withdrawal of all-trans retinoic acid/arsenic trioxide, we made the diagnosis of DS.\n\nConclusions\n\nThough a rather unusual possibility, the treatment history of the patient enabled a rather crucial diagnosis in the nick of time and imaging played a pivotal role. This case further iterates the importance of keeping DS in mind when dealing with similar patients in the future.\n\nKeywords\n\nDifferentiation\nSyndrome\nLung\nLeukaemia\nATRA\nATO\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nAcute promyelocytic leukaemia (APML) is a subtype of acute myelocytic leukaemia (AML) that usually occurs in patients aged < 40 years; it accounts for approximately 10–15% of all AML cases [1]. APML is characterised by the specifc chromosomal translocation t(15;17). Differentiation syndrome (DS) is seen when patients with APML are treated with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO). Presenting symptoms are varied but frequently include dyspnoea, unexplained fever, unusual weight gain, unexplained hypotension, acute renal failure and a chest radiograph demonstrating pulmonary infiltrates or pleural or pericardial effusion [2].\n\nATRA belongs to a class of chemical compounds related to vitamin A that are also known as retinoids. These were first introduced in the treatment regimen of APML in the 1980s and have since revolutionised the concept of cancer treatment by not only destroying pathological cells but also supporting the completion of disrupted maturation. Treatment of APML with ATRA/ATO has improved remission rates to 90% and cure rates to approximately 80%, in comparison to rates of < 20% before its use [3]. The clinical picture of DS may be due to cellular migration, endothelial activation, release of interleukins and vascular factors responsible for tissue damage. Although a “cytokine storm” has been described to coincide with the differentiation of blasts, the exact underlying etiopathogenic mechanisms of DS remain partially unknown. The diagnosis of DS is mainly based on clinical and radiological features in the context of induction therapy of APML with differentiating agents, and it usually requires the exclusion of alternative causes that could explain the signs and symptoms of the syndrome [4].The radiological features are pulmonary nodules usually accompanied by changes in ground-glass opacity.\n\nThe radiological features can be easily mistaken for other causes if proper vigilance is not maintained. Laboratory evaluations frequently reveal leucocytosis [defined as a white blood cell count (WBC) > 10 × 109/l] and coagulopathy (prolongation of the partial thromboplastin time, prothrombin time and decreased fibrinogen) in patients with APML receiving differentiation therapy. About half of the patients treated with ATRA + ATO will develop leucocytosis compared to one-quarter of those receiving ATRA + chemotherapy [2]. Regarding the incidence of DS, most studies have reported that approximately 25% of patients with APML receiving ATRA as induction therapy develop this syndrome, but the incidence depends on the criteria employed and could be lower [2]. Our patient had a low total leucocyte count (TLC) (2.9 × 109/L) which made the diagnosis of DS all the more difficult. Imaging proved to be crucial in this regard.\n\nHere we discuss the case of a 14-year-old Indian girl who came to our hospital for treatment of APML and subsequently developed symptoms which later came to be diagnosed as DS based on the initial clinical presentation on starting induction with ATRA and ATO, subsequent stormy clinical course, quick response to withdrawal of ATRA and ATO, specific treatment with steroid and resolution of radiological findings.\n\nCase presentation\n\nA 14-year-old Indian girl presented with a history of sudden onset shortness of breath and was sent to the radiology department for a chest radiograph (CXR). The image showed bilateral middle and lower zone pulmonary alveolar infiltrates with relative sparing of the upper zones (Fig. 1). Her medical history indicated that she had been diagnosed with APML and had been started on chemotherapy as per the International Consortium for Childhood APML 02 protocol which included ATO and ATRA. Table 1 shows her initial laboratory results at admission. She developed worsening respiratory distress soon after the initiation of chemotherapy with increasing oxygen dependence and was transferred to the Pediatric Intensive Care Unit for ongoing care. ATRA and ATO were discontinued. Table 2 shows her laboratory test results after she became symptomatic.Fig.1 Chest radiograph showing bilateral middle and lower zone alveolar opacities with sparing of upper zones\n\nTable 1 Initial laboratory test results at admission\n\nParameter\tValues\t\nHaemoglobin\t6.5 g%\t\nTotal Leucocyte count\t6.7 x 109/L\t\nErythrocyte sedimentation rate)\t62 mm in 1st hour\t\nPlatelet count\t1.85 × 109/L\t\n\nTable 2 Laboratory results after patient became symptomatic\n\nParameter\tValue\t\nHaemoglobin\t3.7g%\t\nTotal leucocyte count\t2.9 × 109/L\t\nErythrocyte sedimentation rate\t62 mm in first hour\t\nPlatelet count\t0.07 × 109/L\t\n\nWithout any further testing to avoid wasting valuable time, systemic steroid (dexamethasone 10 mg/m2) therapy was initiated. Appropriate respiratory care in the form of bilevel positive airway pressure (BiPAP) was given. A computed tomography (CT) scan of thorax showed multiple bilateral lung nodules with surrounding changes in ground-glass opacity predominantly in the lower lobes (Fig. 2).The differential diagnosis based on her imaging findings included infective causes (bacterial, viral, fungal), leukemic infiltrates, acute respiratory distress syndrome (ARDS), leukostasis as part of hyperleukocytosis, drug toxicity, pulmonary oedema and pulmonary haemorrhage. Leukostasis was ruled out since the patient had a low TLC (2.9 × 109/L), and a requirement for leukostasis is a very high WBC count (> 100 × 109/L). Further, radiological studies revealed lung nodules with patchy changes in ground-glass opacity whereas leukostasis is characterised by more confluent opacities with interlobular septal thickening.Fig.2 a Axial computed tomography (CT) scan showing bilateral pulmonary parenchymal nodules and ground-glass changes in the middle lobe, lingular segment of left upper lobe and bilateral lower lobes. Upper lobes are less affected. b Coronal CT scan showing bilateral pulmonary parenchymal nodules and ground-glass changes in the middle lobe, lingular segment of left upper lobe and bilateral lower lobes. Upper lobes are less affected\n\nWith the treatment described above, her clinical, in particular her respiratory status, improved rapidly. A subsequent CT scan of the abdomen after 4 days of treatment showed a reduction in the lung changes at the visualised lung bases (Fig. 3). The changes in ground-glass opacity had almost disappeared with subsidence of the nodules. A CXR performed at around the same time also showed a reduction in the lung changes (Fig. 4), with bilateral reduction of the infiltrates in the middle and lower zones. Based on the clinical improvement and imaging changes following withdrawal of ATRA/ATO and starting of dexamethasone, the diagnosis that met all the features was that of differentiation syndrome. This was a rther unique diagnosis since most cases of DS reported in the literature are usually associated with high TLC (> 5 × 109/L). Thus, based on the radiological features and clinical correlation a difficult yet crucial diagnosis was possible which significantly affected the patient’s further treatment.Fig. 3 Follow-up axial computed tomography scan showing a significant reduction of pulmonary nodules and ground-glass changes in the middle lobe, lingular segment of left upper lobe, and bilateral lower lobes\n\nFig. 4 Follow-up chest radiograph showing a significant reduction of pulmonary alveolar opacities previously seen in bilateral middle and lower zones\n\nDiscussion and conclusions\n\nDifferentiation syndrome (originally called “retinoic acid syndrome”) is a potentially fatal complication that can arise during the treatment of APML with ATRA and/or ATO.\n\nThe reported incidence of DS in patients with APML treated with standard doses of ATRA ranges from 2 to 27%, compared to 7–31% in patients treated with ATO [4]. De Botton et al. [5] reported in a large series of patients with DS that respiratory signs and symptoms and fever were the most frequent clinical presentations of DS. These authors described 413 patients with newly diagnosed APML, 64 (15%) of whom developed DS (median at day 7), with nine (14%) patients dying from it [5].\n\nThe most common manifestations of DS are pulmonary infiltrate, pleural effusion and respiratory distress. Cardiac involvement is more commonly characterised by pericardial effusion, but it can also present as chest pain typical of coronary obstruction. Rarer clinical presentations, such as musculoskeletal symptoms, have also been reported. There is no pathognomonic clinical sign or laboratory test to diagnose DS. For this reason, DS can sometimes be misdiagnosed or confounded with other concurrent medical conditions, such as infection and heart failure. It has been suggested that DS be considered when at least three of the following signs, symptoms or imaging features are present: fever, weight gain, respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, hypotension and renal failure [3].\n\nThe pathogenesis of APML-linked DS is complex and not well understood. In essence, ATRA is thought to: (1) lead to a release of a variety of cytokines by differentiating blast cells and (2) induce a change in adhesive properties on blast cells. Pro-inflammatory cytokines, including interleukin 1 beta (IL1B), IL6, IL8 and tumour necrosis factor alpha are released, which leads to a systemic inflammatory response syndrome (SIRS). SIRS manifests as fever, tachycardia and tachypnoea and can progress into shock if left untreated. The release of cathepsin G increases vascular permeability and causes endothelial damage [2].\n\nUnivariate analysis identified a high WBC count at presentation, with 5 × 109/L as the most significant cutoff point, as a prognostic factor for severe DS [6]. This needs to be noted since in our case the TLC was much lower (2.9 × 109/L). Other prognostic factors for severe DS are abnormal levels of serum creatinine; FLT3-Internal Tandem Duplications (ITD) mutations; microgranular French American British (FAB) subtype; short promyelocytic leukaemia-retinoic acid receptor alpha (PML-RARA) isoform; and male sex [6]. As already stated, there are no clinical signs or laboratory tests to diagnose DS, nor is there a radiological finding pathognomonic for DS. Radiological features may be explained by the proposed hypotheses of pathophysiology of the DS. Most of the patients with DS show cardiomegaly, widening of the vascular pedicle width, increased pulmonary blood volume, peribronchial cuff, ground-glass opacity, septal lines and pleural effusion: these findings are similar to those of congestive heart failure with pulmonary oedema, but they can also probably be produced by leukemic lung infiltration and endothelial leakage [7]. In mild DS, lesions are prevalent in the lower lobes, while in severe DS, the lesions are diffuse, with no difference between peripheral or central regions [7]. Davis et al. [8] reported CT findings in three patients with DS, consisting of peripheral nodules, reticular and ground-glass opacity and pleural effusions. The CT scan showed similar findings in our case. These authors also reported the case of a patient with DS who developed pneumothorax [8]. Other reported histological findings in analyses of lungs are extensive interstitial and alveolar lung infiltration by maturing myeloid cells, endothelial cell damage, oedema, haemorrhage and fibrinous exudates that correspond to poorly defined centrilobular nodules and ground-glass opacity with or without interlobular septal thickening [7].\n\nPatients with APML and DS have a highly compromised immune system; therefore, it is not a rare event to find other concurrent pathologic conditions, such as pneumonia or fungal infections, which can confound the radiological picture of DS syndrome [7]. In our case also, the differential diagnosis was fungal infection. Hence, the treating physicians need to be aware of the clinical context to raise the possibility of DS when these findings are seen on CXR or CT, which our case further stressed. The low TLC makes our case different since most of the cases of DS reported to date had a high TLC.\n\nAs DS can have a subtle clinical picture at presentation but progress rapidly, it is of utmost importance to be aware of this complication and initiate therapy as soon as this syndrome is suspected. Dexamethasone is considered to be the mainstay of treatment of DS and should be administered at the first sign or symptom of this syndrome [3].\n\nThe same protocol was followed in our case after the withdrawal of ATRA/ATO. Gradually, once the patient responded to treatment, as was seen in our patient, the chemotherapy regimen could be restarted [3]. The strength of this report is that it paves the way for widening our range of differentials in the future for patients with APML who develop such symptoms. The main limitation is that the imaging features were not specific to the cause and there is no pathognomic test for clinching the diagnosis, as stated earlier.\n\nConclusion\n\nDifferentiation syndrome is a rare but severe complication of APML that can develop in patients treated with ATRA/ATO. The imaging features observed on CXR or CT scan of thorax have a wide range of differentials. Based on this case report, it is evident that DS should always be kept in mind. Early diagnosis can help expedite the treatment of the patient, thereby increasing chances of survival.\n\nAcknowledgements\n\nThere was no person involved in this case report who has not received mention among the list of authors. There was no technical help acquired from any third party.\n\nAuthors' contributions\n\nN. Ghara was the patient’s primary treating clinician. P. Bhattacharyya looked after the patient in the ICU. P. Ghosh reported the CT scans. A. Gehani reported the X-rays. S. Sarkar wrote the manuscript and was co-author of the CT report. All authors have read and approved the final manuscript.\n\nFunding\n\nNo funding was required.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval\n\nSince it was a case report concerning a single patient and there was no disclosure of the patient’s identity, neither was there any violation of the patient’s rights, the requirement for ethics approval was waived.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient’s legal guardians for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Eovaldi B Albaugh H Hyman J Greenwald D Diagnosis and management of acute promyelocytic leukemia in an active duty Air Force space operator J Mil Veteran Fam Health 2014 22 3 64\n2. Stahl M Tallman MS Differentiation syndrome in acute promyelocytic leukaemia Br J Haematol 2019 187 2 157 162 10.1111/bjh.16151 31410848\n3. Rego EM, De Santis GC. Differentiation syndrome in promyelocytic leukemia: clinical presentation, pathogenesis and treatment. Mediterr J Hematol Infect Dis. 2011;3(1):e2011048. 10.4084/mjhid.2011.048.\n4. Montesinos P, Sanz MA. The differentiation syndrome in patients with acute promyelocytic leukemia: experience of the pethema group and review of the literature. Mediterr J Hematol Infect Dis. 2011;3(1):e2011059. 10.4084/mjhid.2011.059.\n5. De Botton S Dombret H Sanz M Miguel JS Caillot D Zittoun R Incidence, clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia Blood 1998 92 8 2712 2718 10.1182/blood.V92.8.2712 9763554\n6. Montesinos P Bergua JM Vellenga E Rayón C Parody R de la Serna J Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors Blood 2009 113 4 775 783 10.1182/blood-2008-07-168617 18945964\n7. Cardinale L Asteggiano F Moretti F Torre F Ulisciani S Fava C Pathophysiology, clinical features and radiological findings of differentiation syndrome/all-trans-retinoic acid syndrome World journal of radiology. 2014 6 8 583 10.4329/wjr.v6.i8.583 25170395\n8. Davis BA Cervi P Amin Z Moshi G Shaw P Porter J Retinoic acid syndrome: pulmonary computed tomography (CT) findings Leuk Lymphoma 1996 23 1–2 113 117 10.3109/10428199609054809 9021693\n\n",
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"abstract": "OBJECTIVE\nThe aims of the present study, conducted in two regions of Italy, Calabria and Piedmont, were to assess the use of inappropriate drugs according to the Beers Criteria and to study the possible drug-drug interactions.\n\n\nMETHODS\nData were obtained retrospectively from 972 residential care patients between 2016 and 2018. Mean age was 82.4 ± 8.4 years, with a prevalence of women (64.8%). Activities of daily living, instrumental activities of daily living, Mini-Mental State Examination, Cumulative Illness Rating Scale, Neuropsychiatric Inventory Scale and number and kind of drugs were recorded. A classification of potential inappropriate drugs was made according to the Beers criteria. Data were collected through an Excel file able to gather the main information. In the case of suspected adverse event, Naranjo Scale was applied. The study of possible drug-drug interactions was made by Micromedex 2.0.\n\n\nRESULTS\nFunctional and cognitive impairments, comorbidities and number of drugs were assessed. The bivariate relationship between number of drugs and glomerular filtration rate assessed by CKD-EPI showed that the higher was the number of drugs used, the worst was kidney function assessment (p = 0.0001). The most frequent inappropriate drugs were anticholinergic drugs, tricyclics antidepressants, long-half-life benzodiazepines, antipsychotics and proton pump inhibitors.\n\n\nCONCLUSIONS\nThese data are very interesting and show the need for an accurate choice of drugs in elderly people and for starting a wise deprescribing procedure.",
"affiliations": "Center for Cognitive Disorders and Dementia (CDCD), Catanzaro Lido, ASP Catanzaro, Viale Crotone, Catanzaro, Italy. pietro.gareri@alice.it.;Geriatric Unit, Hospital Maria Vittoria and Territorial Facility, Turin, Italy.;RSA S. Francesco Hospital, Catanzaro, Italy.;Chair of Pharmacology, School of Medicine, University Magna Graecia, Catanzaro, Italy.;Chair of Pharmacology, School of Medicine, University Magna Graecia, Catanzaro, Italy.",
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"title": "The risk of polypharmacy and potentially inappropriate drugs in residential care dementia patients: tips from the PharE study.",
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"abstract": "The paper describes three case reports of changes in sexual behavior patterns in male patients who use stimulants (amphetamine and mephedrone). Two of them demonstrate that the consumption of stimulants may lead to hypersexuality and excessive masturbation. Case report three shows that mephedrone use results in such typical stimulant-related subjective effects as the intensification of sensory experiences and sexual arousal. It leads to the loss of interest in sex without mephedrone. In light of the popularity of sex under the influence of drugs, clinicians should be aware of this phenomenon, since it is associated with high-risk sexual behavior. The description of clinical cases on the link between sex and drugs expands our knowledge in this area, leading to more effective treatment interventions.",
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"title": "Changes in sexual behavior patterns due to stimulants use: three case reports.",
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... |
{
"abstract": "BACKGROUND\nIn resource-constrained settings where biologic agents are not widely available, there are limited therapeutic options for patients with rheumatoid arthritis (RA) refractory to other synthetic disease modifying antirheumatic (DMARD) therapies. The aim of this study is to evaluate the effectiveness and safety of leflunomide (LEF) with methotrexate (MTX) in refractory RA.\n\n\nMETHODS\nA retrospective record review of adult RA patients treated with LEF/MTX. Demographic details, adverse reactions, and the 3-variable 28 joint disease activity score (DAS28-3) were recorded at initiation of LEF/MTX therapy, and after 4 and 12 months of treatment.\n\n\nRESULTS\nOf 194 patients, most were middle-aged seropositive Black African females, with established disease [mean (standard deviation, SD) disease duration 9.4 (8.2) years] and time on previous DMARDs of 7.0 (5.5) years. Before adding LEF, the mean (SD) dose of MTX was 21.7 (3.5) mg/week, and 87.6% of patients used low dose oral corticosteroids. A good or moderate EULAR response was achieved by 44% and 42% of patients, and the retention rate was 71%. Major infections were seen in 6 patients: comprising 2 deaths, 3 cases of leucopaenia and septicaemia and 1 case of tuberculosis. Hepatotoxicity (n = 3), intolerable gastrointestinal symptoms (n = 3), and hypertension (n = 17) were the most common problems. Predictors of remission or low disease activity at 12 months was a baseline DAS28-3 ⩽ 5.5 [odds ratio (OR) = 2.7; 95% confidence interval (CI) 1.1-5.6; p = 0.01].\n\n\nCONCLUSIONS\nLEF/MTX was effective in the majority of patients in this cohort of mainly Black African women who failed other combination synthetic DMARDs, particularly in those with moderate disease activity at the time of addition of LEF. Infections and hypertension were important complications. In a setting where biologic DMARDs are not readily accessible, the combination of LEF/MTX is a cost-effective approach.",
"affiliations": "Division of Rheumatology, Chris Hani Baragwanath Academic Hospital, Faculty of Health Sciences and University of the Witwatersrand, Johannesburg, South Africa.;Division of Rheumatology, Department of Internal Medicine, Chris Hani Baragwanath Academic Hospital, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.;Division of Rheumatology, Department of Internal Medicine, Chris Hani Baragwanath Academic Hospital, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.",
"authors": "Hodkinson|Bridget|B|;Magomero|Kingsley Ross|KR|;Tikly|Mohammed|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1759720X16664324",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1759-720X",
"issue": "8(5)",
"journal": "Therapeutic advances in musculoskeletal disease",
"keywords": "leflunomide; rheumatoid arthritis; sDMARD",
"medline_ta": "Ther Adv Musculoskelet Dis",
"mesh_terms": null,
"nlm_unique_id": "101517322",
"other_id": null,
"pages": "172-179",
"pmc": null,
"pmid": "27721903",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": "19147616;24878863;23885741;21755815;15189743;12972472;20444750;25431484;12768933;16864918;18470473;21956233;16142705;10468411;3358796;23322457;10403258;12006342;12416946;8546736;23378555;17394230;11083289;22134750;24650220;12784387;17937473;20496042",
"title": "Combination leflunomide and methotrexate in refractory rheumatoid arthritis: a biologic sparing approach.",
"title_normalized": "combination leflunomide and methotrexate in refractory rheumatoid arthritis a biologic sparing approach"
} | [
{
"companynumb": "ZA-ACCORD-045224",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEFLUNOMIDE"
},
"drugadditional": null,
"dru... |
{
"abstract": "BACKGROUND\nHereditary angioedema (HAE) is an autosomal dominant hereditary disorder characterized by episodic swelling of many body regions (especially throat and abdomen), potentially triggered by medication. No data are available for HAE in patients with cancer assigned to standard chemotherapy. The aim of our study was to identify circulating mediators potentially predictive of acute HAE attacks during chemotherapy.\n\n\nMETHODS\nRepeated blood testing (approximately every week) for complement system members (C3, C4, CH50, C1 inhibitor, C1-inhibitor functional C1Q), D-dimers and for routine haematochemistry were performed in a 42-year-old male affected by type 2 HAE during standard adjuvant oxaliplatin/fluorouracil-based chemotherapy administered for stage III radically resected rectal cancer. Pre-medication with 1,000 U Berinert inhibitor C1 was administered every week throughout treatment. Mann-Whitney U-test was used to determine statistical differences in measures between the first 30 days of therapy and beyond day 30 of therapy.\n\n\nRESULTS\nPre-chemotherapy values of tested variables (day 0) were: C3: 101 mg/dl, C4: 5.71 mg/dl, CH50: 74%, C1 inhibitor: 43.4 mg/dl, C1-inhibitor functional: 18%, C1Q: 150 mg/dl, and D-dimers: 113 g/ml. A significant change in circulating values was observed for C3, D-dimers and C1-inhibitor functional. Four HAE attacks were observed, they started from the forth cycle of treatment and all were manageable. Changes in C3, D-dimers and C1-inhibitor functional preceded the attacks.\n\n\nCONCLUSIONS\nThe stress induced by chemotherapy such a standard oxaliplatin/fluorouracil increases the risk of attacks in patients with HAE. However, circulating biomarkers such as D-dimers, C3 and C1-inhibitor functional may serve as early predictors of acute HAE crisis.",
"affiliations": "Internal Medicine Department, Tor Vergata University Hospital, Medical Oncology Unit, Rome, Italy cristina.morelli89@gmail.com.;Internal Medicine Department, Tor Vergata University Hospital, Medical Oncology Unit, Rome, Italy.;Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy.;Medical Oncology Unit, INI Grottaferrata, Rome, Italy.;Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicinei, Tor Vergata University Hospital, Rome, Italy.;Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicinei, Tor Vergata University Hospital, Rome, Italy.;Internal Medicine Department, Tor Vergata University Hospital, Medical Oncology Unit, Rome, Italy.",
"authors": "Morelli|Cristina|C|;Formica|Vincenzo|V|;Pellicori|Stefania|S|;Menghi|Antonello|A|;Guarino|Maria Domenica|MD|;Perricone|Roberto|R|;Roselli|Mario|M|",
"chemical_list": "D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.13052",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "38(12)",
"journal": "Anticancer research",
"keywords": "Hereditary angioedema; chemotherapy; colon cancer; immunology",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D054179:Angioedemas, Hereditary; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D005338:Fibrin Fibrinogen Degradation Products; D006801:Humans; D008297:Male; D012004:Rectal Neoplasms",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "6801-6807",
"pmc": null,
"pmid": "30504393",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Chemotherapy in Patients with Hereditary Angioedema.",
"title_normalized": "chemotherapy in patients with hereditary angioedema"
} | [
{
"companynumb": "IT-FRESENIUS KABI-FK201601777",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,... |
{
"abstract": "One of the side-effects of ketamine abuse is genito-urinary damage. This report describes a case of a former ketamine user who presented with urinary symptoms associated with ketamine years after stopping consumption. This was a 26-year-old male with a history of ketamine abuse. He started treatment for alcohol dependence at age 19. He smoked marijuana daily and denied any other drug use. During the follow-up, urinary symptoms were evidenced (dysuria, frequency, urgency, incontinence, nocturia, hematuria, and suprapubic pain). Urinary symptoms started two years ago and worsened over time. The patient was referred to a urologist. A cystoscopy revealed lesions compatible with interstitial cystitis like the ones that appear in some ketamine abusers. Given the medical history, the urologist asked him about ketamine consumption and the patient declared a daily use of 50 milligrams intranasally from age 15 to age 17. Given these findings, not reported previously in the medical literature, future research should follow up patients who at some point in their life made an abusive consumption of ketamine in order to understand the pathogenesis and to be able to intervene before clinical disease manifests itself.",
"affiliations": "a Doctor and Researcher, Addiction and Dual Diagnosis Unit, Department of Psychiatry , Vall d'Hebron University Hospital-Public Health Agency, Barcelona (ASPB), CIBERSAM , Barcelona , Spain.;a Doctor and Researcher, Addiction and Dual Diagnosis Unit, Department of Psychiatry , Vall d'Hebron University Hospital-Public Health Agency, Barcelona (ASPB), CIBERSAM , Barcelona , Spain.;a Doctor and Researcher, Addiction and Dual Diagnosis Unit, Department of Psychiatry , Vall d'Hebron University Hospital-Public Health Agency, Barcelona (ASPB), CIBERSAM , Barcelona , Spain.;a Doctor and Researcher, Addiction and Dual Diagnosis Unit, Department of Psychiatry , Vall d'Hebron University Hospital-Public Health Agency, Barcelona (ASPB), CIBERSAM , Barcelona , Spain.;a Doctor and Researcher, Addiction and Dual Diagnosis Unit, Department of Psychiatry , Vall d'Hebron University Hospital-Public Health Agency, Barcelona (ASPB), CIBERSAM , Barcelona , Spain.;a Doctor and Researcher, Addiction and Dual Diagnosis Unit, Department of Psychiatry , Vall d'Hebron University Hospital-Public Health Agency, Barcelona (ASPB), CIBERSAM , Barcelona , Spain.",
"authors": "Robles-Martínez|María|M|0000-0003-0324-8354;Abad|Alfonso C|AC|;Pérez-Rodríguez|Violeta|V|;Ros-Cucurull|Elena|E|;Esojo|Abderraman|A|;Roncero|Carlos|C|0000-0003-1421-7385",
"chemical_list": "D007649:Ketamine",
"country": "United States",
"delete": false,
"doi": "10.1080/02791072.2017.1371364",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0279-1072",
"issue": "50(2)",
"journal": "Journal of psychoactive drugs",
"keywords": "Addiction; bladder; delayed; ketamine; side-effects; urinary",
"medline_ta": "J Psychoactive Drugs",
"mesh_terms": "D000328:Adult; D018856:Cystitis, Interstitial; D003558:Cystoscopy; D006801:Humans; D007649:Ketamine; D008297:Male; D019966:Substance-Related Disorders; D013997:Time Factors",
"nlm_unique_id": "8113536",
"other_id": null,
"pages": "129-132",
"pmc": null,
"pmid": "28934076",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delayed Urinary Symptoms Induced by Ketamine.",
"title_normalized": "delayed urinary symptoms induced by ketamine"
} | [
{
"companynumb": "ES-ENDO PHARMACEUTICALS INC-2017-005364",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "KETAMINE HYDROCHLORIDE"
},
"dru... |
{
"abstract": "We report a case of an 11-year-old female with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) overlap, most likely triggered by sulfamethoxazole-trimethoprim, who was treated with the combination of methylprednisolone, cyclosporine, and etanercept. Her condition stabilized and her skin involvement did not progress after the addition of etanercept. To our knowledge, this is the first report of etanercept for pediatric SJS/TEN.",
"affiliations": "1 Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.;1 Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.;1 Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.",
"authors": "Gavigan|Geneviève M|GM|;Kanigsberg|Nordau D|ND|;Ramien|Michele L|ML|https://orcid.org/0000-0001-9191-3611",
"chemical_list": "D007166:Immunosuppressive Agents; D000068800:Etanercept",
"country": "United States",
"delete": false,
"doi": "10.1177/1203475418758989",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1203-4754",
"issue": "22(5)",
"journal": "Journal of cutaneous medicine and surgery",
"keywords": "Stevens-Johnson syndrome; etanercept; pediatric; toxic epidermal necrolysis",
"medline_ta": "J Cutan Med Surg",
"mesh_terms": "D002648:Child; D000068800:Etanercept; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D012867:Skin; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "9614685",
"other_id": null,
"pages": "514-515",
"pmc": null,
"pmid": "29421925",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pediatric Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Halted by Etanercept.",
"title_normalized": "pediatric stevens johnson syndrome toxic epidermal necrolysis halted by etanercept"
} | [
{
"companynumb": "CA-TEVA-2019-CA-1004341",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditio... |
{
"abstract": "Background Available outcomes data for anticoagulation therapy in adults with congenital heart disease ( CHD ) provide assessment of global risk of this therapy for CHD patients (a heterogeneous population), but the risk of complications for the different CHD diagnoses is unknown. The purpose of the study was to describe the indications for anticoagulation, and the incidence and risk factors for major bleeding complication in adults with tetralogy of Fallot. Methods and Results We queried Mayo Adult Congenital Heart Disease (MACHD) database for tetralogy of Fallot patients (aged ≥18 years) that received anticoagulation, 1990-2017. Of 130 patients (42±14 years, 75 men [58%]), warfarin and direct oral anticoagulants were used in 125 (96%) and 5 (4%), respectively because atrial arrhythmias (n=109), mechanical prosthetic valve (n=29), intracardiac thrombus (n=4), pulmonary embolism (n=6), stroke (n=3), and perioperative anticoagulation (n=44). The median hypertension, abnormal renal or liver function; stroke; bleeding history or predisposition; labile international normalized ratio; elderly (>65 years); drug or alcohol use score for the entire cohort was 1 (0-2) and 27 (21%) had hypertension, abnormal renal or liver function; stroke; bleeding history or predisposition; labile international normalized ratio; elderly (>65 years); drug or alcohol use score ≥2. There were 14 minor bleeding events (1.6% per year) and 11 major bleeding events (1.3% per year) in 8 patients during median follow-up of 74 months (856 patient-years). Mechanical prosthesis (hazard ratio 1.78, CI 1.29-3.77, P=0.021) and hypertension, abnormal renal or liver function; stroke; bleeding history or predisposition; labile international normalized ratio; elderly (>65 years); drug or alcohol use score ≥2 (hazard ratio 1.41, CI 1.03-3.88, P=0.046) were risk factors for major bleeding events. All-cause mortality was higher in patients with major bleeding events (n=6, 75%) compared with patients without major bleeding events (n=25, 21%), P=0.001. Conclusions Considering the heterogeneity of the CHD population, data from the current study may be better suited for clinical decision-making in tetralogy of Fallot patients.",
"affiliations": "1 Department of Cardiovascular Medicine Mayo Clinic Rochester MN.;1 Department of Cardiovascular Medicine Mayo Clinic Rochester MN.;1 Department of Cardiovascular Medicine Mayo Clinic Rochester MN.;1 Department of Cardiovascular Medicine Mayo Clinic Rochester MN.;1 Department of Cardiovascular Medicine Mayo Clinic Rochester MN.;1 Department of Cardiovascular Medicine Mayo Clinic Rochester MN.;1 Department of Cardiovascular Medicine Mayo Clinic Rochester MN.;1 Department of Cardiovascular Medicine Mayo Clinic Rochester MN.",
"authors": "Egbe|Alexander C|AC|;Miranda|William R|WR|;Ammash|Naser M|NM|;Missula|Venkata R|VR|;Jadav|Raja|R|;Najam|Maria|M|;Kothapalli|Srikanth|S|;Connolly|Heidi M|HM|",
"chemical_list": "D000925:Anticoagulants",
"country": "England",
"delete": false,
"doi": "10.1161/JAHA.118.011474",
"fulltext": "\n==== Front\nJ Am Heart AssocJ Am Heart Assoc10.1002/(ISSN)2047-9980JAH3ahaoaJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-9980John Wiley and Sons Inc. Hoboken 3080328810.1161/JAHA.118.011474JAH33885Original ResearchOriginal ResearchCoronary Heart DiseaseOutcomes of Anticoagulation Therapy in Adults With Tetralogy of Fallot Egbe et alEgbe Alexander C. MD, MPH, FACCegbe.alexander@mayo.edu \n1\nMiranda William R. MD\n1\nAmmash Naser M. MD\n1\nMissula Venkata R. MD\n1\nJadav Raja MD\n1\nNajam Maria MD\n1\nKothapalli Srikanth MD\n1\nConnolly Heidi M. MD\n1\n\n1 \nDepartment of Cardiovascular Medicine\nMayo Clinic\nRochester\nMN\n* Correspondence to: Alexander C. Egbe, MD, MPH, FACC, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905. E‐mail: egbe.alexander@mayo.edu26 2 2019 05 3 2019 8 5 10.1002/jah3.2019.8.issue-5e01147414 11 2018 22 1 2019 © 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ 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.Background\nAvailable outcomes data for anticoagulation therapy in adults with congenital heart disease (CHD) provide assessment of global risk of this therapy for CHD patients (a heterogeneous population), but the risk of complications for the different CHD diagnoses is unknown. The purpose of the study was to describe the indications for anticoagulation, and the incidence and risk factors for major bleeding complication in adults with tetralogy of Fallot.\n\nMethods and Results\nWe queried Mayo Adult Congenital Heart Disease (MACHD) database for tetralogy of Fallot patients (aged ≥18 years) that received anticoagulation, 1990–2017. Of 130 patients (42±14 years, 75 men [58%]), warfarin and direct oral anticoagulants were used in 125 (96%) and 5 (4%), respectively because atrial arrhythmias (n=109), mechanical prosthetic valve (n=29), intracardiac thrombus (n=4), pulmonary embolism (n=6), stroke (n=3), and perioperative anticoagulation (n=44). The median hypertension, abnormal renal or liver function; stroke; bleeding history or predisposition; labile international normalized ratio; elderly (>65 years); drug or alcohol use score for the entire cohort was 1 (0–2) and 27 (21%) had hypertension, abnormal renal or liver function; stroke; bleeding history or predisposition; labile international normalized ratio; elderly (>65 years); drug or alcohol use score ≥2. There were 14 minor bleeding events (1.6% per year) and 11 major bleeding events (1.3% per year) in 8 patients during median follow‐up of 74 months (856 patient‐years). Mechanical prosthesis (hazard ratio 1.78, CI 1.29–3.77, P=0.021) and hypertension, abnormal renal or liver function; stroke; bleeding history or predisposition; labile international normalized ratio; elderly (>65 years); drug or alcohol use score ≥2 (hazard ratio 1.41, CI 1.03–3.88, P=0.046) were risk factors for major bleeding events. All‐cause mortality was higher in patients with major bleeding events (n=6, 75%) compared with patients without major bleeding events (n=25, 21%), P=0.001.\n\nConclusions\nConsidering the heterogeneity of the CHD population, data from the current study may be better suited for clinical decision‐making in tetralogy of Fallot patients.\n\nanticoagulationbleedingstroketetralogy of FallotthromboembolismSubject Categories\nCongenital Heart DiseaseNational Heart, Lung, and Blood InstituteK23 HL141448‐01 source-schema-version-number2.0component-idjah33885cover-date05 March 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.1 mode:remove_FC converted:05.03.2019\n(J Am Heart Assoc . 2019 ;8 :e011474 DOI: 10.1161/JAHA.118.011474 .)30803288\n==== Body\nClinical Perspective\nWhat Is New?\n\nThe incidence rate of major bleeding complication is 1.3% per year in patients with tetralogy of Fallot.\n\nIn patients with tetralogy of Fallot, having a mechanical prosthesis or a hypertension, abnormal renal or liver function; stroke; bleeding history or predisposition; labile international normalized ratio; elderly (>65 years); drug or alcohol use score ≥2 is a risk factor for major bleeding complications.\n\nHaving a major bleeding complication is associated with all‐cause mortality.\n\n\n\n\nWhat Are the Clinical Implications?\n\nPatients with tetralogy of Fallot who have risk factors for bleeding complications should have meticulous monitoring to prevent bleeding events and potentially reduce all‐cause mortality.\n\n\n\n\n\n\n\nIntroduction\nThe guidelines for management of adults with congenital heart disease (CHD) recommend anticoagulation with warfarin for patients with risk factors for thromboembolism such as atrial arrhythmia, mechanical valve prosthesis, and prior history of thromboembolism.1, 2, 3 In addition to these standard thromboembolic risk factors, the risk for thromboembolism also varies with certain CHD diagnoses and underlying physiology.4, 5, 6 Even within a specific diagnosis such as tetralogy of Fallot (TOF), the risk for thromboembolism will change over time as the patients become older and develop more comorbidities such as atrial arrhythmia, renal failure, ventricular dysfunction, and need for prosthetic valves.7, 8 There are limited data about outcomes of anticoagulation in adults with CHD,9, 10, 11, 12 and there are no studies specifically looking at outcomes of anticoagulation in adults with TOF. The purpose of the study was to describe the indications for anticoagulation and the incidence and risk factors for major bleeding complication in adults with TOF.\n\nMethods\nPatient Selection and Data Collection\nThe authors will make their data, analytic methods, and study materials available to other researchers on request.\n\nThe Mayo Adult Congenital Heart Disease (MACHD) database was queried for patients (aged ≥18 years) with repaired TOF that received anticoagulation therapy at Mayo Clinic Rochester, Minnesota from January 1, 1990 through December 31, 2017. The patients with pulmonary atresia were excluded. The Mayo Clinic institutional review board approved this study and waived informed consent for patients who provided research authorization. The electronic health records were extensively reviewed in these patients.\n\nStudy Terminologies\nA major bleeding event was defined as intracranial bleeding, intra‐thoracic or intra‐abdominal hematoma requiring drainage or arterial embolization, any bleeding event leading to a decrease in hemoglobin >2 g/dL and/or requiring transfusion of blood products.9, 13, 14 A minor bleeding event was defined as cutaneous bleeding, epistaxis, gastrointestinal bleeding, or any bleeding event that did not meet the criteria for major bleeding event. Hypertension, abnormal renal or liver function; stroke; bleeding history or predisposition; labile international normalized ratio [INR]; elderly [>65 years]; drug or alcohol use (HAS‐BLED) score was calculated for all patients as previously described.13\n\n\nStatistical Analysis\nData were presented as mean±SD, median (interquartile range) or counts (%). Unpaired t test, Wilcoxon rank sum test, χ2 or Fisher exact test (as appropriate) were used to compare between‐group differences. Freedom from major bleeding event was assessed using the Kaplan–Meier method, and the time of initiation of anticoagulation (or first presentation to Mayo Clinic for patients who were already on an anticoagulant) was used as “time zero”. In patients with >1 bleeding event, the first bleeding event was used as the index event in the assessment of time‐to‐event end point. Comparisons in between‐group freedom from major bleeding events were performed using the Wilcoxon test. Univariate and multivariate Cox proportional hazard models were constructed to determine the risk factors for major bleeding events, and association between variables and outcomes were expressed as hazard ratio and 95% CI. The variables included in the univariate model were chosen a priori on the basis of their previously demonstrated association with bleeding complications,9, 13 and only the variables with significant association with major bleeding complication in the univariate model (pre‐defined as P<0.20) were incorporated into the multivariate model. HAS‐BLED score showed significant association with major bleeding complications in the univariate model both as continuous variable and as categorical variable. We only used HAS‐BLED score as categorical variable (HAS‐BLED score <2 versus ≥2) in the multivariate model to avoid collinearity. All statistical analyses were performed with JMP software (version 13.0; SAS Institute Inc, Cary, NC) and P<0.05 (apart from the pre‐defined entry criterion for the multivariable model) was considered statistically significant.\n\nResults\nBaseline Characteristics\nOut of 465 TOF patients in the MACHD database, we selected 130 (28%) patients who met the study inclusion criteria. The average age at the beginning of the study was 42±14 years, the age at the time of TOF repair was 8 (5–18) years, and 75 (58%) were men. Table 1 shows the baseline clinical and echocardiographic data of the study cohort.\n\nTable 1 Baseline Characteristics\n\n\tAll (N=130)\tMajor Bleeding (n=8)\tNo Major Bleeding (n=122)\t\nP Value\t\nAge, y\t42±14\t37±19\t43±14\t0.456\t\nMale\t75 (58%)\t5 (53%)\t70 (57%)\t0.776\t\nBody mass index, kg/m2\n\t27±6\t27±6\t27±5\t0.843\t\nBody surface area, m2\n\t1.9±0.3\t1.9±0.2\t1.9±0.3\t0.632\t\nAge at TOF repair, y\t8 (5–18)\t11 (6–33)\t8 (4–19)\t0.437\t\nPrior palliative shunt\t61 (47%)\t4 (50%)\t57 (47%)\t0.857\t\nMechanical valve prosthesis\t29 (22%)\t3 (38%)\t26 (21%)\t0.090\t\nAntiplatelet therapy\t49 (38%)\t2 (25%)\t47 (39%)\t0.444\t\n% time in therapeutic range\t84%\t91%\t82%\t0.318\t\nComorbidities\t\nAtrial arrhythmia\t109 (84%)\t5 (63%)\t104 (85%)\t0.090\t\nHypertension\t56 (43%)\t1 (13%)\t55 (45%)\t0.071\t\nHyperlipidemia\t75 (58%)\t4 (50%)\t71 (58%)\t0.651\t\nCoronary artery disease\t32 (25%)\t4 (50%)\t28 (23%)\t0.083\t\nCurrent or prior smoker\t32 (25%)\t2 (25%)\t30 (25%)\t0.979\t\nDiabetes mellitus\t26 (20%)\t2 (25%)\t24 (20%)\t0.715\t\nSleep apnea\t54 (42%)\t4 (50%)\t50 (41%)\t0.616\t\nNYHA III/IV\t32 (25%)\t3 (38%)\t29 (24%)\t0.243\t\nHAS‐BLED score\t1 (0–2)\t2 (1–2)\t1 (0–2)\t0.064\t\nElevated ALT and/or ASTa\n\t1 (0.7%)\t0\t1 (0.8%)\t···\t\nLaboratory tests\t\nHemoglobin, g/dL\t14.1±1.8\t14.3±1.3\t14.0±14.9\t0.627\t\nCreatinine, mg/dL\t1.1±0.4\t1.1±0.3\t1.1±0.4\t0.732\t\nEchocardiography\t\n≥Moderate RV enlargementb\n\t95 (73%)\t7 (88%)\t88 (72%)\t0.307\t\n≥Moderate RV systolic dysfunctionb\n\t55 (42%)\t6 (75%)\t49 (40%)\t0.053\t\n≥Moderate RA enlargementb\n\t92 (11%)\t7 (88%)\t85 (70%)\t0.423\t\n≥Moderate LA enlargementb\n\t76 (59%)\t4 (50%)\t72 (59%)\t0.266\t\nLateral E/e′\t7±3\t8±2\t7±3\t0.656\t\nLV ejection fraction, %\t55±10\t57±6\t55±10\t0.379\t\nHAS‐BLED indicates hypertension, abnormal renal or liver function; stroke; bleeding history or predisposition; labile international normalized ratio; elderly (>65 years); drug or alcohol use; LA, left atrium; LV, left ventricle; NT‐proBNP, N‐terminal pro b‐type natriuretic peptide; NYHA, New York Heart Association; RA, right atrium; RAAS, renin angiotensin aldosterone system; RV, right ventricle; TOF, tetralogy of Fallot; AST, aspartate aminotransferase; ALT, alanine aminotransferase.\n\na Elevated ALT and/or AST defined as a level of alanine aminotransferase and/or aspartate aminotransferase >3 times the upper limit of normal.\n\nb Qualitative assessment of chamber size and/or function.\n\nThe indications for anticoagulation were atrial arrhythmia (n=109), mechanical prosthetic valve (n=29), intracardiac thrombus (n=4), pulmonary embolism (n=6), stroke (n=3), and perioperative anticoagulation for valve surgery and/or maze procedure (n=44). Of the 4 patients who had intracardiac thrombi, 3 patients had thrombi attached to pacemaker/defibrillator leads while 1 patient had a left atrial thrombus that was identified during transesophageal echocardiogram before direct current cardioversion. Among the 109 patients who receive anticoagulation because of atrial arrhythmia, the average CHA2DS2‐VASc score was 2±1 and 74 (68%) had CHA2DS2‐VASc score ≥2. The median HAS‐BLED score for the entire cohort was 1 (0–2) and 27 (21%) had HAS‐BLED score ≥2.\n\nOut of the 130 patients in the study, 26 (20%) patients were already on anticoagulation at the time of their first presentation to Mayo Clinic while anticoagulation was initiated in the other 104 (80%) patients in the course of follow‐up. Warfarin was used in 125 (96%) patients; direct oral anticoagulant was used in 5 (4%) patients, and 4 of the 5 patients who received direct oral anticoagulant had bioprosthetic pulmonary valves. Concomitant anti‐platelet therapy was used in 49 (38%) patients. Of the 125 patients who received warfarin, the target INR was 2.0 to 3.0 in 108 (83%) patients, 2.5 to 3.5 in 17 (13%) patients with mechanical mitral, tricuspid, or pulmonary valves. The average number of INR results reviewed was 11±7 per patient, and time within therapeutic range was 84% for the entire cohort.\n\nBleeding Complications\nThe median duration of follow‐up was 74 months (21–98) months, and the cumulative follow‐up for the entire cohort was 856 patient‐years. There were 14 minor bleeding events (1.6% per year [16 events per 1000 patient‐years]), and these events were epistaxis (n=5), gastrointestinal bleeding (n=8), and menorrhagia (n=1). Anticoagulation was discontinued in 2 of these patients because of the bleeding complication.\n\nThere were 11 major bleeding events (1.3% per year [13 events per 1000 patient‐years]), in 8 patients. The mean INR at the time of major bleeding event was 3.2±0.9, and 2 of these events occurred in the setting of INR above the therapeutic range for the indication. The freedom from major bleeding event was 89% in 10 years. There was no difference in the incidence of bleeding events, between the early era (1990–2003) and the late era (2004–2017); 1.3% versus 1.1%, P=0.788.\n\nOf the 11 major bleeding events, 2 events (retroperitoneal hemorrhage after catheter ablation and intracranial hemorrhage after a motor vehicle accident) were provoked. Excluding these 2 provoked events, major bleeding event rate was 0.9% per year (9 events per 1000 patient‐years). The freedom from major bleeding event was 93% at 10 years (Figure 1), and was significantly different in patients with HAS‐BLED scores ≥2 versus <2 (88% versus 96% at 10 years, P=0.038), and in patients with mechanical prostheses versus no mechanical prosthesis (83% versus 94% at 10 years, P=0.007), Figure 2.\n\nFigure 1 Kaplan–Meier curve showing the freedom from major bleeding complication.\n\nFigure 2 Kaplan–Meier curve comparing the freedom from major bleeding complication between patients with HAS‐BLED scores ≥2 vs <2 (A), and between patients with mechanical prostheses vs no mechanical prosthesis (B). HAS‐BLED indicates hypertension, abnormal renal or liver function; stroke; bleeding history or predisposition; labile international normalized ratio; elderly (>65 years); drug or alcohol use.\n\nThe multivariate risk factors for major bleeding event were mechanical prosthesis (hazard ratio 1.78, CI 1.29–3.77, P=0.021) and HAS‐BLED score ≥2 (hazard ratio 1.41, CI 1.03–3.88, P=0.046), Table 2. A subgroup analysis showed that major bleeding event rate in patients with mechanical valve prosthesis (n=29) was 2.1% per year (21 events per 1000 patient‐years), while major bleeding event rate in patients without mechanical valve prosthesis (n=101) was 0.9% per year (9 events per 1000 patient‐years). There were 31 deaths (all‐cause mortality), death was more common in patients with major bleeding events (n=6, 75%) compared with patients without major bleeding events (n=25, 21%), P=0.001. In addition to the 9 patients with embolic events before the initiation of anticoagulation (6 patients with history of pulmonary embolism and 3 patients with history of ischemic stroke), and 1 patient with a prior history of pulmonary embolism had another pulmonary embolism in the setting subtherapeutic INR of 1.3.\n\nTable 2 Risk Factors for Major Bleeding Complications\n\nBleeding Complications\tUnivariate\tMultivariate\t\nHR (95% CI)\t\nP Value\tHR (95% CI)\t\nP Value\t\nAge, y\t0.92 (0.61–2.04)\t0.105\t1.25 (0.21–3.14)\t0.611\t\nMale sex\t1.01 (0.22–4.12)\t0.872\t\t\t\nPercentage of time within therapeutic range\t0.86 (0.26–2.11)\t0.286\t\t\t\nAntiplatelet therapy\t1.34 (0.76–2.15)\t0.352\t\t\t\nHAS‐BLED score\t1.76 (0.98–3.06)\t0.076\t\t\t\nHAS‐BLED score ≥2\t1.85 (1.08–3.17)\t0.038\t1.41 (1.03–3.88)\t0.046\t\nMechanical prosthesis\t2.14 (1.85–3.34)\t0.007\t1.78 (1.29–3.77)\t0.021\t\nDirect oral anticoagulants\t1.71 (0.63–5.18)\t0.674\t\t\t\nHAS‐BLED indicates hypertension, abnormal renal or liver function; stroke; bleeding history or predisposition; labile international normalized ratio; elderly (>65 years); drug or alcohol use; HR, hazard ratio.\n\nThe clinical profiles of the 8 patients with major bleeding events are as follows:\n\nPatient #1: A male, aged 49 years, with Down syndrome and mechanical mitral valve prosthesis who was on warfarin and aspirin and had spontaneous subdural hematoma that was managed conservatively. He subsequently had a large hematoma in the right thigh (requiring percutaneous drainage) secondary to a mechanical fall at the age of 57 years. The patient died within 12 months from end‐stage heart failure.\n\n\nPatient #2: A male patient, aged 43 years, with mechanical aortic valve prosthesis who was on warfarin (without aspirin), and had iliopsoas hematoma (requiring surgical drainage) and a subsequent episode of massive gastrointestinal bleeding requiring multiple blood transfusions 3 months later.\n\n\nPatient #3: A male patient, aged 43 years, with mechanical aortic valve prosthesis that was on warfarin (without aspirin). He had an episode of massive gastrointestinal bleeding requiring multiple blood transfusions and died 3 days later from presumed sudden cardiac death.\n\n\nPatient #4: A female patient, aged 46 years, who was on warfarin (without aspirin) for atrial fibrillation/flutter. She had an episode of subarachnoid hemorrhage related to multiple intracranial aneurysms and required a neurosurgical intervention. Anticoagulation was discontinued after this event. The patient was followed for another 31 months after discontinuation of anticoagulation, and there were no other bleeding or embolic complications.\n\n\nPatient #5: A female, aged 63 years, who was on warfarin (without aspirin) for atrial flutter and left atrial thrombus. She had retroperitoneal bleeding after catheter ablation while anticoagulated. This was managed conservatively will multiple blood transfusions and discontinuation anticoagulation. She died at the age of 72 years from end‐stage heart failure.\n\n\nPatient #6: A male, aged 86 years, who was on warfarin (and aspirin) for persistent atrial fibrillation and had gastrointestinal bleeding requiring blood transfusions. Aspirin was discontinued and anticoagulation was switched from warfarin to a direct oral anticoagulant (dabigatran). The patient had another gastrointestinal bleeding 10 months later, and anticoagulation was discontinued completely. He died at the age of 91 years from a malignancy.\n\n\nPatient #7: A male, aged 43 years, with history of cirrhosis, renal failure, and prior banding of esophageal varices. He was on warfarin (without aspirin) for persistent atrial fibrillation and died from massive gastrointestinal bleeding.\n\n\nPatient #8: A male, aged 53 years, on warfarin for atrial flutter and pulmonary embolism. He died from bilateral subarachnoid and subdural hemorrhage after a motorcycle accident.\n\n\n\n\nDiscussion\nIn this review of the indications and outcomes of anticoagulation therapy in 130 adult TOF patients, the most common indications for anticoagulation were atrial arrhythmias, perioperative anticoagulation, and mechanical prosthetic valves. The annual risk of all major bleeding complications and unprovoked major bleeding complications was 1.2% and 0.9%, respectively, and mechanical valve prostheses and HAS‐BLED score ≥2 were risk factors for major bleeding complications.\n\nAnticoagulation with warfarin is routinely recommended in adults with CHD who have thromboembolic risk factors such as atrial arrhythmia, mechanical valve prosthesis, and history of thrombosis or thromboembolism.1, 2, 3 These anticoagulation indications are similar to those suggested for patients with acquired heart disease. We did not identify any additional indications for anticoagulation in our patient population.\n\nThe HAS‐BLED score was derived and validated in large cohorts of patients with acquired heart disease,13, 15 and prognostic data of the HAS‐BLED score in adults with CHD are limited.11, 12 The current study shows an association between HAS‐BLED score and annual bleeding risk in TOF patients, and this is consistent with the limited data from studies of other CHD patients.11, 12 Since the components of the HAS‐BLED score are based on information from history, physical exam, and routine laboratory blood tests, it can be assessed in all patients, and taken into account when deciding on anticoagulation therapy in the CHD population.\n\nIn contrast to patients with acquired heart disease where there are robust data to guide anticoagulation management,16, 17 outcomes data for anticoagulation in adults with CHD are limited.8, 9, 10, 11, 12 In a multicenter study of 229 adults with CHD from the CONCOR (Congenital Corvitia) registry, the annual risk of bleeding was 4.4%, and HAS‐BLED score was associated with major bleeding events.12 The annual bleeding risk from the CONCOR registry was much higher than reported in the current study, and we speculate that this difference may be related to the heterogeneous CHD diagnoses of the patients in the CONCOR registry. Of the 229 patients in the CONCOR study, patients with Fontan palliation and unrepaired single ventricle made up 12% of the cohort, and both of these diagnoses are known to have high bleeding risk,9, 10, 18, 19 while TOF patients only comprised 13% (30 of 220 patients) of that study. Since the current study was based entirely on TOF patients, we anticipate that the results of our study will be more applicable and generalizable to the adult TOF population.\n\nIn another multicenter study of outcomes of thromboprophylaxis for atrial arrhythmia in 482 adults with CHD, the annual risk of bleeding was 1.8%, and HAS‐BLED score was associated with a major bleeding event.11 The specific CHD diagnoses of the patients in the multicenter study were not specified, and thus diagnosis‐specific risk of bleeding complications could not be assessed. Prior data have demonstrated that certain CHD patient populations demonstrate excess bleeding risk on anticoagulation.9, 10, 18, 19 Despite the heterogeneity of CHD diagnosis in the multicenter study, the findings are consistent with our results. Our study provides outcomes data of anticoagulation in TOF patients, thereby bridging the knowledge gap of disease‐specific risk for the TOF population. The CHD patient populations, comorbid conditions, level and indications for anticoagulation vary between the 2 multicenter studies which likely accounts for the marked difference in bleeding risk.\n\nApart from patients with mechanical prosthetic valves in whom anticoagulation is mandatory, the decision to initiate anticoagulation therapy is based on a careful analysis of thromboembolic risk versus bleeding risk. Anticoagulation therapy, whether short‐term or long‐term, is indicated when thrombotic risk without anticoagulation exceeds bleeding risk with anticoagulation. While the current study did not perform a comparative analysis of thromboembolic events in TOF patients with and without anticoagulation, it provides important data about bleeding risk and factors that influence bleeding risk in patients on anticoagulation; this information will be helpful for risk stratification in clinical practice.\n\nAll‐cause mortality was higher in patients with major bleeding complications compared with the rest of the cohort even though there were no significant differences in the baseline clinical characteristics of both subgroups. Although the association between major bleeding events and mortality may be because of other confounders that the study was not powered to adjust for, this finding is consistent with prior data showing a relationship between bleeding complications and mortality in patients with acquired heart disease.20, 21, 22 If indeed such an association does exist, then meticulous risk stratification before initiating anticoagulation and clearly defining the duration and level of anticoagulation become even more important in the CHD population.\n\nDirect oral anticoagulant is now the preferred anticoagulation therapy for non‐valvular atrial fibrillation in selected patients with acquired heart disease because of a lower risk of bleeding compared with warfarin.16, 17, 23 Unfortunately there are limited data about safety and efficacy of direct oral anticoagulants in patients with CHD.24 Only 6 patients received direct oral anticoagulants in the current study, thereby limiting our ability to perform any meaningful comparative analysis of bleeding risk in this subgroup. This is an important knowledge gap that should be addressed as we strive towards improving long‐term outcomes of adults with CHD.\n\nThe current study was limited by the retrospective study design, referral bias, and small sample size. However, it provides data about the incidence and risk factors for bleeding complications in TOF patients. In contrast to previous studies that reported outcomes of anticoagulation in adults with CHD (a heterogeneous population), data from the current study may be better suited for clinical decision‐making in TOF patients. In addition to being a retrospective single center study, another limitation of the current study is the difference in the demographics of the patients included in this study and previously published TOF cohorts from other studies. Our patients were older (median age 42 years) and underwent TOF repair at an older age (median age 8 years). This will potentially affect the generalizability of the results.\n\nIn summary, the current study reported a 1.2% annual risk of major bleeding complication (0.9% annual risk of unprovoked major bleeding complication), identified mechanical valve prostheses and HAS‐BLED score as risk factors for major bleeding complications, and highlighted a potential association between major bleeding complications and all‐cause mortality. This information is important for the risk stratification of TOF patients being considered for anticoagulation therapy. Additionally, it provides preliminary data to support future studies to further assess the relationship between bleeding complications and mortality, and the potential role of direct oral anticoagulants as a strategy to reduce bleeding complications.\n\nSources of Funding\nDr Egbe is supported by National Heart, Lung, and Blood Institute (NHLBI) grant K23 HL141448‐01.\n\nDisclosures\nNone.\n==== Refs\nReferences\n1 \n\nStout \nKK \n, \nDaniels \nCJ \n, \nAboulhosn \nJA \n, \nBozkurt \nB \n, \nBroberg \nCS \n, \nColman \nJM \n, \nCrumb \nSR \n, \nDearani \nJA \n, \nFuller \nS \n, \nGurvitz \nM \n, \nKhairy \nP \n, \nLandzberg \nMJ \n, \nSaidi \nA \n, \nValente \nAM \n, \nVan Hare \nGF \n. 2018 AHA/ACC guideline for the management of adults with congenital heart disease . 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Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS‐BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score . J Am Coll Cardiol . 2011 ;57 :173 –180 .21111555 \n16 \n\nJanuary \nCT \n, \nWann \nLS \n, \nAlpert \nJS \n, \nCalkins \nH \n, \nCigarroa \nJE \n, \nCleveland \nJC \nJr\n, \nConti \nJB \n, \nEllinor \nPT \n, \nEzekowitz \nMD \n, \nField \nME \n, \nMurray \nKT \n, \nSacco \nRL \n, \nStevenson \nWG \n, \nTchou \nPJ \n, \nTracy \nCM \n, \nYancy \nCW \n; American College of Cardiology/American Heart Association Task Force on Practice Guidelines \n. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society . J Am Coll Cardiol . 2014 ;64 :e1 –e76 .24685669 \n17 \n\nKirchhof \nP \n, \nBenussi \nS \n, \nKotecha \nD \n, \nAhlsson \nA \n, \nAtar \nD \n, \nCasadei \nB \n, \nCastella \nM \n, \nDiener \nHC \n, \nHeidbuchel \nH \n, \nHendriks \nJ \n, \nHindricks \nG \n, \nManolis \nAS \n, \nOldgren \nJ \n, \nPopescu \nBA \n, \nSchotten \nU \n, \nVan Putte \nB \n, \nVardas \nP \n; ESC Scientific Document Group \n. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS . Eur Heart J . 2016 ;37 :2893 –2962 .27567408 \n18 \n\nSandoval \nJ \n, \nSantos \nLE \n, \nCordova \nJ \n, \nPulido \nT \n, \nGutierrez \nG \n, \nBautista \nE \n, \nMartinez Guerra \nML \n, \nPena \nH \n, \nBroberg \nCS \n. Does anticoagulation in Eisenmenger syndrome impact long‐term survival? \nCongenit Heart Dis . 2012 ;7 :268 –276 .22360787 \n19 \n\nBeghetti \nM \n, \nGalie \nN \n. Eisenmenger syndrome a clinical perspective in a new therapeutic era of pulmonary arterial hypertension . J Am Coll Cardiol . 2009 ;53 :733 –740 .19245962 \n20 \n\nGallego \nP \n, \nRoldan \nV \n, \nTorregrosa \nJM \n, \nGalvez \nJ \n, \nValdes \nM \n, \nVicente \nV \n, \nMarin \nF \n, \nLip \nGY \n. Relation of the HAS‐BLED bleeding risk score to major bleeding, cardiovascular events, and mortality in anticoagulated patients with atrial fibrillation . Circ Arrhythm Electrophysiol . 2012 ;5 :312 –318 .22319005 \n21 \n\nLind \nM \n, \nBoman \nK \n, \nJohansson \nL \n, \nNilsson \nTK \n, \nJarvholm \nLS \n, \nJansson \nJH \n. D‐dimer predicts major bleeding, cardiovascular events and all‐cause mortality during warfarin treatment . Clin Biochem . 2014 ;47 :570 –573 .24636802 \n22 \n\nLabaf \nA \n, \nGrzymala‐Lubanski \nB \n, \nStagmo \nM \n, \nLovdahl \nS \n, \nWieloch \nM \n, \nSjalander \nA \n, \nSvensson \nPJ \n. Thromboembolism, major bleeding and mortality in patients with mechanical heart valves‐ a population‐based cohort study . Thromb Res . 2014 ;134 :354 –359 .24985036 \n23 \n\nLevy \nJH \n, \nSpyropoulos \nAC \n, \nSamama \nCM \n, \nDouketis \nJ \n. Direct oral anticoagulants: new drugs and new concepts . JACC Cardiovasc Interv . 2014 ;7 :1333 –1351 .25523529 \n24 \n\nPujol \nC \n, \nNiesert \nAC \n, \nEngelhardt \nA \n, \nSchoen \nP \n, \nKusmenkov \nE \n, \nPittrow \nD \n, \nEwert \nP \n, \nKaemmerer \nH \n. Usefulness of direct oral anticoagulants in adult congenital heart disease . Am J Cardiol . 2016 ;117 :450 –455 .26725103\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2047-9980",
"issue": "8(5)",
"journal": "Journal of the American Heart Association",
"keywords": "anticoagulation; bleeding; stroke; tetralogy of Fallot; thromboembolism",
"medline_ta": "J Am Heart Assoc",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000925:Anticoagulants; D002318:Cardiovascular Diseases; D002423:Cause of Death; D016208:Databases, Factual; D005260:Female; D006470:Hemorrhage; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D019990:Perioperative Care; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D017741:Survivors; D013771:Tetralogy of Fallot; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101580524",
"other_id": null,
"pages": "e011474",
"pmc": null,
"pmid": "30803288",
"pubdate": "2019-03-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "21111555;29066332;27634123;24636802;20352134;27573597;19245962;20801927;20713900;30803288;28209388;25523529;25281599;27979032;22360787;25838183;26725103;22319005;25564556;24985036;20299623;27567408;15842354;24685669",
"title": "Outcomes of Anticoagulation Therapy in Adults With Tetralogy of Fallot.",
"title_normalized": "outcomes of anticoagulation therapy in adults with tetralogy of fallot"
} | [
{
"companynumb": "US-TEVA-2020-US-1815207",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "3",
"... |
{
"abstract": "Although previously associated with secondary adrenal insufficiency and other autoimmune diseases, eosinophilic esophagitis has not been described in patients with primary adrenal insufficiency. In this case series, we describe three patients with eosinophilic esophagitis and primary adrenal insufficiency, including two patients with polyglandular autoimmune syndrome type 1. All patients experienced improvement in esophageal symptoms with treatment of eosinophilic esophagitis. The association between eosinophilic esophagitis and primary adrenal insufficiency is unclear, but may include underlying genetic predisposition and/or immune system dysregulation.",
"affiliations": "Division of Community Internal Medicine, Department of Internal Medicine, Mayo Clinic Jacksonville, FL, United States. Electronic address: kwon.joshua@mayo.edu.;Division of Gastroenterology, Department of Internal Medicine, Mayo Clinic Jacksonville, FL, United States. Electronic address: koop.andree@mayo.edu.;Division of Endocrinology, Department of Internal Medicine, Mayo Clinic Jacksonville, FL, United States. Electronic address: meek.shon@mayo.edu.;Division of Gastroenterology, Department of Internal Medicine, Mayo Clinic Jacksonville, FL, United States. Electronic address: francis.dawn@mayo.edu.",
"authors": "Kwon|Josh|J|;Koop|Andree|A|;Meek|Shon|S|;Francis|Dawn|D|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.clinre.2021.101699",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2210-7401",
"issue": "45(4)",
"journal": "Clinics and research in hepatology and gastroenterology",
"keywords": "Dysphagia; Eosinophilic esophagitis; Polyglandular autoimmune syndrome type 1; Primary adrenal insufficiency",
"medline_ta": "Clin Res Hepatol Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101553659",
"other_id": null,
"pages": "101699",
"pmc": null,
"pmid": "33892157",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A case series of eosinophilic esophagitis and primary adrenal insufficiency.",
"title_normalized": "a case series of eosinophilic esophagitis and primary adrenal insufficiency"
} | [
{
"companynumb": "US-TEVA-2021-US-1935977",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nCutaneous metastases occur in 0.6-10.4% of all patients with underlying malignancy. Among them, the site of origin remains unknown in 4.4-14.5% of all cases.\n\n\nMETHODS\nThe authors describe a 68-year-old man with widespread skin and soft tissue metastases appearing as the first and dominant clinical manifestation of oncologic disease. Physical examination and CT scans revealed multiple cutaneous and subcutaneous tumor nodules arising in the neck, chest, abdomen, lumbar region and right forearm, as well as in the gluteal and iliacus muscles and in the proximal part of the left thigh. Light microscopy confirmed a metastasis of adenocarcinoma exhibiting a tubuloglandular pattern and a slight mucin production. It was immunoreactive for cytokeratin 7 and carcinoembryonic antigen and negative for cytokeratin 20, CDX-2, TTF-1 and prostatic specific antigen. Based upon the histomorphology and immunophenotype, the pathologist suggested a primary tumor in the stomach or biliopancreatic tract. However, further clinical workup did not clearly identify a primary lesion.\n\n\nCONCLUSIONS\nDetermining the origin of cutaneous metastases might be a challenging issue for both clinicians and pathologists. The case we describe is uncommon because widespread skin and subcutaneous metastases appeared as the first and dominant clinical sign of adenocarcinoma, the origin of which has not been established. This unusual tumor behavior may suggest that a spreading and colonization of metastatic cancer cells in the skin and soft tissue may be a specific biologic process.Key words: skin metastases - malignancy of unknown origin - adenocarcinoma.",
"affiliations": null,
"authors": "Bartoš|Vladimír|V|;Hamarová|Kamila|K|",
"chemical_list": "D000970:Antineoplastic Agents; D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin",
"country": "Czech Republic",
"delete": false,
"doi": "10.14735/amko2018143",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0862-495X",
"issue": "31(2)",
"journal": "Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti",
"keywords": null,
"medline_ta": "Klin Onkol",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D003841:Deoxycytidine; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D009382:Neoplasms, Unknown Primary; D012878:Skin Neoplasms; D012983:Soft Tissue Neoplasms",
"nlm_unique_id": "9425213",
"other_id": null,
"pages": "143-147",
"pmc": null,
"pmid": "29708358",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cutaneous and Subcutaneous Metastases of Adenocarcinoma as a Dominant Clinical Manifestation of Malignancy of Unknown Origin - a Case Report.",
"title_normalized": "cutaneous and subcutaneous metastases of adenocarcinoma as a dominant clinical manifestation of malignancy of unknown origin a case report"
} | [
{
"companynumb": "SK-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-172194",
"fulfillexpeditecriteria": "1",
"occurcountry": "SK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
... |
{
"abstract": "Severe hepatotoxicity in people with human immunodeficiency virus (HIV) receiving efavirenz (EFV) has been reported. We assessed the incidence and risk factors of hepatotoxicity in women of childbearing age initiating EFV-containing regimens.\n\n\n\nIn the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, ART-naive pregnant women with HIV and CD4 count ≥ 350 cells/μL and alanine aminotransferase ≤ 2.5 the upper limit of normal were randomized during the antepartum and postpartum periods to antiretroviral therapy (ART) strategies to assess HIV vertical transmission, safety, and maternal disease progression. Hepatotoxicity was defined per the Division of AIDS Toxicity Tables. Cox proportional hazards models were constructed with covariates including participant characteristics, ART regimens, and timing of EFV initiation.\n\n\n\nAmong 3576 women, 2435 (68%) initiated EFV at a median 121.1 weeks post delivery. After EFV initiation, 2.5% (61/2435) had severe (grade 3 or higher) hepatotoxicity with an incidence of 2.3 (95% confidence interval [CI], 2.0-2.6) per 100 person-years. Events occurred between 1 and 132 weeks postpartum. Of those with severe hepatotoxicity, 8.2% (5/61) were symptomatic, and 3.3% (2/61) of those with severe hepatotoxicity died from EFV-related hepatotoxicity, 1 of whom was symptomatic. The incidence of liver-related mortality was 0.07 (95% CI, .06-.08) per 100 person-years. In multivariable analysis, older age was associated with severe hepatotoxicity (adjusted hazard ratio per 5 years, 1.35 [95% CI, 1.06-1.70]).\n\n\n\nSevere hepatotoxicity after EFV initiation occurred in 2.5% of women and liver-related mortality occurred in 3% of those with severe hepatotoxicity. The occurrence of fatal events underscores the need for safer treatments for women of childbearing age.",
"affiliations": "University of California, Los Angeles, Los Angeles, California, USA.;Johns Hopkins University, Baltimore, Maryland, USA.;Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.;Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.;University of California, San Francisco, San Francisco, California, USA.;University of Zimbabwe, Harare, Zimbabwe.;University of North Carolina Project-Malawi, Lilongwe, Malawi.;University of California, Los Angeles, Los Angeles, California, USA.;College of Medicine, Johns Hopkins Research Project, Blantyre, Malawi.;FHI 360, Durham, North Carolina, USA.;National Institutes of Health, Bethesda, Maryland, USA.;National Institutes of Health, Bethesda, Maryland, USA.;National Institutes of Health, Bethesda, Maryland, USA.;University of California, Los Angeles, Los Angeles, California, USA.;Johns Hopkins University, Baltimore, Maryland, USA.",
"authors": "Bhattacharya|Debika|D|;Gupta|Amita|A|;Tierney|Camlin|C|;Huang|Sharon|S|;Peters|Marion G|MG|;Chipato|Tsungai|T|;Martinson|Frances|F|;Mohtashemi|Neaka|N|;Dula|Dingase|D|;George|Kathy|K|;Chaktoura|Nahida|N|;Klingman|Karin L|KL|;Gnanashanmugam|Devasena|D|;Currier|Judith S|JS|;Fowler|Mary G|MG|",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C098320:efavirenz",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciaa244",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "72(8)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "HIV; hepatotoxicity; liver enzyme elevation; real-world",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D018791:CD4 Lymphocyte Count; D056486:Chemical and Drug Induced Liver Injury; D003521:Cyclopropanes; D005260:Female; D006678:HIV; D015658:HIV Infections; D006801:Humans; D007223:Infant; D011247:Pregnancy",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1342-1349",
"pmc": null,
"pmid": "32161944",
"pubdate": "2021-04-26",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "11786975;11830344;15717255;12671779;23343913;12089658;20723261;12407142;28489856;17133571;21572852;26192873;20070390;26959511;17559344;19164417;22808112;12738113;18290996;20486732;17545706;18057928;28762375;14986275;14562855;27806243;2495549",
"title": "Hepatotoxicity and Liver-Related Mortality in Women of Childbearing Potential Living With Human Immunodeficiency Virus and High CD4 Cell Counts Initiating Efavirenz-Containing Regimens.",
"title_normalized": "hepatotoxicity and liver related mortality in women of childbearing potential living with human immunodeficiency virus and high cd4 cell counts initiating efavirenz containing regimens"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-050670",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EFAVIRENZ"
},
"drugaddi... |
{
"abstract": "Intra-arterial chemotherapy (IAC), delivered directly to the globe via the internal carotid artery is now an established treatment for retinoblastoma. We report a case of anterior segment ischaemia following treatment with multiple intra-arterial chemotherapy (IAC) infusions.\nA 5 month old female presented with bilateral retinoblastoma and was treated with 12 infusions of IAC. Her right eye was enucleated at diagnosis. After her seventh IAC treatment, she developed ipsilateral sixth and third cranial nerve palsies. After the twelfth IAC, she developed an area of conjunctival and scleral ischaemia between 12 and 3 o'clock meridians in her left eye. However, she maintained visual acuity of LogMAR 0.34.\nThe median number of IAC treatments in large studies is three. It is possible that repeated doses of IAC have an accumulative negative effect on the ocular blood supply, risking anterior segment and neurologic sequelae. This case highlights the significant challenge of balancing the salvage of eyes and vision with the potentially significant morbidity associated with IAC.",
"affiliations": "Retinoblastoma Service, Royal London Hospital, Whitechapel Road, Whitechapel, London, E1 1BB, UK.;Retinoblastoma Service, Royal London Hospital, Whitechapel Road, Whitechapel, London, E1 1BB, UK.;Great Ormond Street Hospital for Children, London, UK.;Great Ormond Street Hospital for Children, London, UK.;Retinoblastoma Service, Royal London Hospital, Whitechapel Road, Whitechapel, London, E1 1BB, UK.;Retinoblastoma Service, Royal London Hospital, Whitechapel Road, Whitechapel, London, E1 1BB, UK.",
"authors": "McAnena|Lisa|L|;Naeem|Zishan|Z|;Duncan|Catriona|C|;Robertson|Fergus|F|;Sagoo|Mandeep S|MS|;Reddy|M Ashwin|MA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2020.100611",
"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(19)30029-510.1016/j.ajoc.2020.100611100611Case ReportSclero-conjunctival ischaemia secondary to intra-arterial chemotherapy for retinoblastoma McAnena Lisa lisa.mcanena@nhs.neta∗Naeem Zishan aDuncan Catriona bRobertson Fergus bSagoo Mandeep S. acdReddy M. Ashwin aca Retinoblastoma Service, Royal London Hospital, Whitechapel Road, Whitechapel, London, E1 1BB, UKb Great Ormond Street Hospital for Children, London, UKc National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, 162 City Road, London, EC1V 2PD, UKd UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK∗ Corresponding author. 11 Cashelmara, Salthill, Galway, Ireland. lisa.mcanena@nhs.net30 1 2020 6 2020 30 1 2020 18 10061130 1 2019 19 1 2020 27 1 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nIntra-arterial chemotherapy (IAC), delivered directly to the globe via the internal carotid artery is now an established treatment for retinoblastoma. We report a case of anterior segment ischaemia following treatment with multiple intra-arterial chemotherapy (IAC) infusions.\n\nObservations\nA 5 month old female presented with bilateral retinoblastoma and was treated with 12 infusions of IAC. Her right eye was enucleated at diagnosis. After her seventh IAC treatment, she developed ipsilateral sixth and third cranial nerve palsies. After the twelfth IAC, she developed an area of conjunctival and scleral ischaemia between 12 and 3 o'clock meridians in her left eye. However, she maintained visual acuity of LogMAR 0.34.\n\nConclusions and Importance\nThe median number of IAC treatments in large studies is three. It is possible that repeated doses of IAC have an accumulative negative effect on the ocular blood supply, risking anterior segment and neurologic sequelae. This case highlights the significant challenge of balancing the salvage of eyes and vision with the potentially significant morbidity associated with IAC.\n\nKeywords\nRetinoblastomaIntra-arterial chemotherapy\n==== Body\n1 Introduction\nWe report a case of anterior segment ischaemia following treatment with multiple intra-arterial chemotherapy (IAC) infusions.\n\n2 Case report\nA 5 month old white female presented with right leukocoria. She had no significant family history. She was diagnosed with bilateral retinoblastomas, Group E (right eye) and group B (left eye) according to International Intraocular Retinoblastoma Classification1, H1cT3c (Right Eye) H1cT1b (left eye)1 Genetic analysis revealed a heterozygous RB1 exon 17 mutation (c.1630delA) The right Group E eye2 was enucleated at presentation. Her left eye had five extra-foveal tumours for which she received six cycles of systemic chemotherapy with vincristine, etoposide and carboplatin.\n\nTumor #1 was close to the optic nerve and relapsed repeatedly despite judicious transpupillary therapy away from the nerve (Fig. 1). It was treated a total of 12 infusions of IAC (4 cycles of 3 injections each at 3 weeks apart). For her first round of treatment, she received 2 doses each of 3mg melphalan and 0.3mg Topotecan. The final dose was increased to 4mg and topotecan 0.3mg as we use age appropriate doses3,4 and she had turned 12 months. This was effective for 2 years and 5 months and there were no complications from the IAC. Tumor#1 relapsed again and this time 5mg melphalan and 1 mg topotecan was used for the 3 injections of the 2nd cycle. A slight ptosis and supratrochlear rash followed but no other complications ensued. There was a complete response following the second cycle. After 4 months, Tumor #1 relapsed again and as she was 4 years of age, the dose was increased to melphalan 7.5mg and topotecan 1.5mg for her 3rd cycle and she developed lid swelling. Our practice is to give steroid drops for 3 weeks and oral steroids for 5 days tds (100 μg/kg). After the swelling she developed a third and sixth nerve palsy with an increase in the ptosis. The sixth nerve palsy was severe causing a −7 limitation of movement (severe restriction past the midline). Again, a complete response was achieved. There was no neutropenia after chemotherapy. After 5 months, yet again Tumor #1 relapsed and as the maximum dose of melphalan had already been given (for our unit), we opted for carboplatin 30mg and topotecan 1.5mg. After the twelfth IAC, she developed an area of conjunctival and scleral ischaemia between 12 and 3 o'clock meridians in her left eye (Fig. 2). Fluorescein demonstrated conjunctival ischaemia in this region (Fig. 3). There was no corresponding corneal epithelial abnormality and at 14 months following the onset of this sign (5 years after her initial diagnosis), she is pain free with visual acuity of LogMAR 0.34 with an adjusted head posture to compensate for her ptosis and third and sixth cranial nerve palsies. Tumor #1 has regressed without further relapse. There was no corresponding area of choroidal ischaemia on fluorescein angiography. There has been no scleromalacia or anterior staphyloma. The sixth nerve palsy has improved over 24 months from −7 to −4.5 limitation but the upward limitation remains at −3.5 and downward limitation has improved from −3.5 to −2.5. There is restriction in all directions when forced duction tests were performed and the eye is enophthalmic. The ptosis has slightly improved but remains after 24 months. She had a dominant accessory supply from the middle meningeal artery and this was used for the first 9 treatments. Unfortunately, it stenosed off and the smaller ophthalmic artery was used for the last 3 injections.Fig. 1 Relapse of juxtapapillary tumor.\n\nFig. 1Fig. 2 Focal sclero-conjunctival ischaemia of the left eye.\n\nFig. 2Fig. 3 Anterior fluorescein angiography.\n\nFig. 3\n\n3 Discussion\nTreatment of retinoblastoma has undergone a dramatic evolution over the past three decades; from external beam radiation therapy, now known to cause increased mortality from secondary tumours in patients with germ-line mutations5,6 to systemic intravenous chemotherapy (IVC) with focal laser and/or cryotherapy as standard treatment in the 1990s.7,8 Intra-arterial chemotherapy, delivered directly to the globe via the internal carotid artery is now an established treatment, used as first-line treatment or second line after systemic chemotherapy3,4,9, 10, 11, 12, 13\n\nIAC, along with intravitreal chemotherapy, are now being used both to salvage more eyes as well as retain function, where previously enucleation would have been the only option. However, IAC carries the risk of significant complications. These may include systemic complications such as bradycardia, hypotension, myelosuppression or allergic reactions.3,15, 16, 17 Local ophthalmic complications are commonly vascular in nature and include retinal or vitreous haemorrhage and retinal or choroidal vascular occlusions, including vein occlusions.12,15,16,18, 19, 20, 21 Rates of complications secondary to IAC are decreasing, however, as catheterisation techniques are improved19 and chemotherapy doses are adjusted to patient age.4 A median of 3 treatments has been reported in large case series12,15,22 and at our own centre.4 Tsimpida et al.23 found a visual loss rate of 42% for refractory retinoblastoma that was treated with IAC. However, by using age-appropriate dosing of melphalan, Reddy et al.4 demonstrated no visual loss in patients with healthy foveolae. The potential for visual loss was a major concern as this child was dependent on her only remaining eye for vision and she had a cumulative dose of 47.5 mg of melphalan. Francis et al. determined that a reduction in ERG became statistically significant at a cutoff cumulative dose of 14mg of melphalan, suggesting cumulative doses can have a deleterious effect on the retina. By multivariate analysis, however, they found that neither topotecan nor carboplatin had an effect on the ERG.23 There have been few studies on the complications of topotecan and carboplatin. It has been shown that like melphalan, these drugs are toxic to the RPE.24 Gobin et al. have shown that 50mg carboplatin can cause massive edema of the peri-ocular structures and possible myositis.3 Our patient had 3 doses of 30mg carboplatin. Daniels et al. have used animal model evidence to show that the doses of melphalan and carboplatin are the most important factors related to complications not catheterisation technique25: indeed this corroborates Reddy et al.'s findings.4 As topotecan has rarely been given without agents such as melphalan or carboplatin, it is difficult to tease out the topotecan specific complications of IAC.\n\nWe have previously reported anterior segment invasion by the tumor in eyes receiving IAC as salvage.26 Anterior segment ischaemia is an unusual complication of IAC, and, to the best of our knowledge, this case of sclero-conjunctival ischaemia secondary to IAC is unique. This is most likely due to the high number of IAC treatments (12 to date) that have been necessary to salvage this patient's remaining eye. It is possible that repeated doses of IAC have a summative effect on the ocular blood supply, risking anterior segment and neurologic sequelae. .\n\nWe would like to highlight that it is very unusual to administer such a large number of IAC infusions and that the rationale in this case was salvage of residual function in an only eye. Despite the significant morbidity from the treatment, this 5 year-old girl has functional vision in her remaining eye, with disease quiescence at most recent follow up (17 months since last treatment aged 6). Close observation will be continued in order to detect any future scleromalacia or anterior staphyloma and possible relapse.\n\n4 Conclusion\nThis case highlights the significant challenge of balancing the salvage of eyes and vision with the potentially significant morbidity associated with IAC.\n\nPatient consent\nConsent to publish the case report was not obtained. This report does not contain any personal information that could lead to the identification of the patient.\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgements and Disclosures\nThere was no funding or grant support for this case report. The following authors have no financial disclosures: LM, MS, MR. All authors attest that they meet the current ICMJE criteria for Authorship. There are no further relevant acknowledgements.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajoc.2020.100611.\n==== Refs\nReferences\n1 Amin M.B. Greene F.L. Edge S.B. The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more \"personalized\" approach to cancer staging CA A Cancer J Clin 67 2 2017 93 99 \n2 Linn Murphree A. Intraocular retinoblastoma: the case for a new group classification Ophthalmol Clin North Am 18 1 2005 41 53 viii 15763190 \n3 Gobin Y.P. Dunkel I.J. Marr B.P. Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience Arch Ophthalmol 129 6 2011 732 737 21320950 \n4 Reddy M.A. Naeem Z. Duncan C. Reduction of severe visual loss and complications following intra-arterial chemotherapy (IAC) for refractory retinoblastoma Br J Ophthalmol 101 12 2017 1704 1708 28432112 \n5 Wong F.L. Boice J.D. Jr. Abramson D.H. Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk JAMA 278 15 1997 1262 1267 9333268 \n6 Eng C. Li F.P. Abramson D.H. Mortality from second tumors among long-term survivors of retinoblastoma J Natl Cancer Inst 85 14 1993 1121 1128 8320741 \n7 Chan H.S. Gallie B.L. Munier F.L. Chemotherapy for retinoblastoma Ophthalmol Clin North Am 18 1 2005 55 63 viii 15763191 \n8 Ferris F.L. 3rd Chew E.Y. A new era for the treatment of retinoblastoma Arch Ophthalmol 114 11 1996 1412 8906034 \n9 Peterson E.C. Elhammady M.S. Quintero-Wolfe S. Selective ophthalmic artery infusion of chemotherapy for advanced intraocular retinoblastoma: initial experience with 17 tumors J Neurosurg 114 6 2011 1603 1608 21294621 \n10 Muen W.J. Kingston J.E. Robertson F. Efficacy and complications of super-selective intra-ophthalmic artery melphalan for the treatment of refractory retinoblastoma Ophthalmology 119 3 2012 611 616 22197434 \n11 Venturi C. Bracco S. Cerase A. Superselective ophthalmic artery infusion of melphalan for intraocular retinoblastoma: preliminary results from 140 treatments Acta Ophthalmol 91 4 2013 335 342 22268993 \n12 Shields C.L. Manjandavida F.P. Lally S.E. Intra-arterial chemotherapy for retinoblastoma in 70 eyes: outcomes based on the international classification of retinoblastoma Ophthalmology 121 7 2014 1453 1460 24656794 \n13 Francis J.H. Brodie S.E. Marr B. Efficacy and toxicity of intravitreous chemotherapy for retinoblastoma: four-year experience Ophthalmology 124 4 2017 488 495 28089679 \n15 Wang L. Han M. Zhao J. Intra-arterial chemotherapy for unilateral advanced intraocular retinoblastoma: results and short-term complications Medicine (Baltim) 97 42 2018 e12676 \n16 Abramson D.H. Daniels A.B. Marr B.P. Intra-arterial chemotherapy (ophthalmic artery chemosurgery) for group D retinoblastoma PloS One 11 1 2016 e0146582 \n17 Requejo F. Marelli J. Ruiz Johnson A. The technique of superselective ophthalmic artery chemotherapy for retinoblastoma: the Garrahan Hospital experience Intervent Neuroradiol 24 1 2018 93 99 \n18 Ancona-Lezama D. Dalvin L.A. Lucio-Alvarez J.A. Ophthalmic vascular events after intra-arterial chemotherapy for retinoblastoma: real-world comparison between primary and secondary treatments Retina 2018 \n19 Dalvin L.A. Ancona-Lezama D. Lucio-Alvarez J.A. Ophthalmic vascular events after primary unilateral intra-arterial chemotherapy for retinoblastoma in early and recent eras Ophthalmology 125 11 2018 1803 1811 29921454 \n20 Tuncer S. Sencer S. Kebudi R. Superselective intra-arterial chemotherapy in the primary management of advanced intra-ocular retinoblastoma: first 4-year experience from a single institution in Turkey Acta Ophthalmol 94 7 2016 e644 e651 27214798 \n21 Hua J. Gang S. Yizhou J. Intra-arterial chemotherapy as second-line treatment for advanced retinoblastoma: a 2-year single-center study in China J Canc Res Therapeut 14 1 2018 106 110 \n22 Francis J.H. Levin A.M. Zabor E.C. Ten-year experience with ophthalmic artery chemosurgery: ocular and recurrence-free survival PloS One 13 5 2018 e0197081 \n23 Tsimpida M. Thompson D.A. Liasis A. Visual outcomes following intraophthalmic artery melphalan for patients with refractory retinoblastoma and age appropriate vision Br J Ophthalmol 97 11 2013 1464 1470 24037611 \n24 Susskind D. Hagemann U. Schrader M. Toxic effects of melphalan, topotecan and carboplatin on retinal pigment epithelial cells Acta Ophthalmol 94 5 2016 471 478 26893290 \n25 Daniels A.B. Froehler M.T. Nunnally A.H. Rabbit model of intra-arterial chemotherapy toxicity demonstrates retinopathy and vasculopathy related to drug and dose, not procedure or approach Invest Ophthalmol Vis Sci 60 4 2019 954 964 30882851 \n26 Pavlidou E. Burris C. Thaung C. Anterior segment seeding in eyes with retinoblastoma failing to respond to intraophthalmic artery chemotherapy JAMA Ophthalmol 133 12 2015 1455 1458 26334520\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "18()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Intra-arterial chemotherapy; Retinoblastoma",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
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"pmc": null,
"pmid": "32149200",
"pubdate": "2020-06",
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"references": "29791475;24656794;24037611;26334520;22268993;28432112;21294621;8906034;28094848;9333268;28089679;29516970;15763191;29119878;27214798;15763190;26756643;8320741;30334950;30882851;26893290;21320950;29921454;30204728;22197434",
"title": "Sclero-conjunctival ischaemia secondary to intra-arterial chemotherapy for retinoblastoma.",
"title_normalized": "sclero conjunctival ischaemia secondary to intra arterial chemotherapy for retinoblastoma"
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"companynumb": "GB-FRESENIUS KABI-FK202003389",
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"abstract": "We sought to evaluate the use of propofol (2,6-diisopropylphenol) for ED procedural sedation, particularly when administered in a routine fashion for a variety of indications.\n\n\nMETHODS\nThis was a prospective observational study conducted in an urban teaching ED. Propofol was administered by handheld syringe and combined with fentanyl. Measurements included propofol and fentanyl dose, serial vital signs, pulse oximetry, adverse events, and patient and physician satisfaction.\n\n\nRESULTS\nOne hundred thirty-six subjects (18 to 69 years) were enrolled. Procedures included 82 (60.3%) abscess incision and drainages and 47 (34.6%) orthopedic reductions. Adverse events occurred in 14 cases (10.3%; 95% confidence interval 5.2% to 15.4%), including hypotension in 5, hypoxemia in 7, and apnea in 5. One patient required intubation. Both patient and physician satisfaction were excellent.\n\n\nCONCLUSIONS\nED procedural sedation with propofol was effective and well accepted by patients and physicians. However, it produced a significant incidence of hypotension, hypoxemia, and apnea.",
"affiliations": "Department of Emergency Medicine, Alameda County Medical Center-Highland Campus, Oakland, CA 94602, USA.",
"authors": "Frazee|Bradley W|BW|;Park|Robert S|RS|;Lowery|Derrick|D|;Baire|Mark|M|",
"chemical_list": "D000701:Analgesics, Opioid; D004338:Drug Combinations; D006993:Hypnotics and Sedatives; D005283:Fentanyl; D015742:Propofol",
"country": "United States",
"delete": false,
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"issue": "23(2)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid; D001049:Apnea; D016292:Conscious Sedation; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004632:Emergency Medical Services; D005260:Female; D005283:Fentanyl; D006801:Humans; D006993:Hypnotics and Sedatives; D007022:Hypotension; D000860:Hypoxia; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D017060:Patient Satisfaction; D015742:Propofol; D011446:Prospective Studies",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "190-5",
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"pmid": "15765343",
"pubdate": "2005-03",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Propofol for deep procedural sedation in the ED.",
"title_normalized": "propofol for deep procedural sedation in the ed"
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"abstract": "Massachusetts state agencies received reports of 37 adverse events (AEs) involving cataract surgery from 2011 to 2015. Fifteen were anesthesia related, including 5 wrong eye blocks, 3 cases of hemodynamic instability, 2 retrobulbar hematoma/hemorrhages, and 5 globe perforations resulting in permanent loss of vision. While Massachusetts' reported AEs likely underrepresent the true number of AEs that occur during cataract surgery, they do offer useful signal data to indicate the types of patient harm occurring during these procedures.",
"affiliations": "From the Betsy Lehman Center for Patient Safety, Boston, Massachusetts.;Department of Anesthesia, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts.;From the Betsy Lehman Center for Patient Safety, Boston, Massachusetts.;Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.;Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard University, Boston, Massachusetts.",
"authors": "Roberto|Sarah A|SA|;Bayes|Joseph|J|;Karner|Paul E|PE|;Morley|Michael G|MG|;Nanji|Karen C|KC|",
"chemical_list": null,
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"delete": false,
"doi": "10.1213/ANE.0000000000002526",
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"issn_linking": "0003-2999",
"issue": "126(5)",
"journal": "Anesthesia and analgesia",
"keywords": null,
"medline_ta": "Anesth Analg",
"mesh_terms": "D002386:Cataract; D002387:Cataract Extraction; D006801:Humans; D008404:Massachusetts; D064406:Patient Harm; D011183:Postoperative Complications",
"nlm_unique_id": "1310650",
"other_id": null,
"pages": "1548-1550",
"pmc": null,
"pmid": "28991108",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": "26405103;21350567;11887410;20030430;23869100;26804760;28991115",
"title": "Patient Harm in Cataract Surgery: A Series of Adverse Events in Massachusetts.",
"title_normalized": "patient harm in cataract surgery a series of adverse events in massachusetts"
} | [
{
"companynumb": "US-PFIZER INC-2018424628",
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... |
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"abstract": "Lipoprotein(a) [Lp(a)] is acknowledged to be an independent atherothrombotic risk factor. Although genetic studies have highlighted the causal relationship between coronary disease and Lp(a), it is uncertain which strategies maximize the therapeutic benefit of patients with high Lp(a) levels. We report the challenging case of a young coronary heart disease (CHD) patient who underwent 10 percutaneous coronary interventions due to repeated acute coronary syndromes (2006-2009) despite an optimally controlled, traditional risk-factor profile. For the first time, we performed specific Lp(a) immunoadsorption in the presence of very low levels of low-density lipoprotein cholesterol (LDL-C) while the patient was on a high-dose statin regimen. There have been no previous reports of patients with high Lp(a) levels who achieved LDL-C goals when treated with an isolated Lp(a)-lowering method. Despite the very high risk of cardiovascular death, targeting Lp(a) resulted in dramatic improvement of the patient's clinical condition. Thus, we suggest that specific Lp(a) apheresis should be considered an effective new treatment strategy for patients with progressive CHD who have reached LDL-C goals but harbor elevated Lp(a) levels.",
"affiliations": "Atherosclerosis Department, Russian Cardiology Research and Production Center, Moscow, Russia.;Atherosclerosis Department, Russian Cardiology Research and Production Center, Moscow, Russia.;Atherosclerosis Department, Russian Cardiology Research and Production Center, Moscow, Russia.;Center of Extracorporeal Therapies, MEDSI Clinic, Moscow, Russia.;Atherosclerosis Department, Russian Cardiology Research and Production Center, Moscow, Russia.",
"authors": "Safarova|Maya S|MS|;Ezhov|Marat V|MV|;Afanasieva|Olga I|OI|;Konovalov|Gennady A|GA|;Pokrovsky|Sergei N|SN|",
"chemical_list": "D008078:Cholesterol, LDL; D017270:Lipoprotein(a)",
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"doi": "10.1002/jca.21356",
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"issue": "30(3)",
"journal": "Journal of clinical apheresis",
"keywords": "coronary heart disease; lipoprotein(a); prevention; residual risk; specific Lp(a) immunoadsorption",
"medline_ta": "J Clin Apher",
"mesh_terms": "D000328:Adult; D001781:Blood Component Removal; D008078:Cholesterol, LDL; D003327:Coronary Disease; D018450:Disease Progression; D006801:Humans; D017270:Lipoprotein(a); D008297:Male; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8216305",
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"references": null,
"title": "Dramatic fate of a young coronary heart disease patient rescued with specific lipoprotein(a) apheresis.",
"title_normalized": "dramatic fate of a young coronary heart disease patient rescued with specific lipoprotein a apheresis"
} | [
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"companynumb": "RU-LUPIN PHARMACEUTICALS INC.-2016-00069",
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"activesubstancename": "CLOPIDOGREL BISULFATE"
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{
"abstract": "Cytomegalovirus (CMV) is the most common viral infection affecting the posttransplantation course of organ recipients. However, CMV involvement of the prostate even in immunocompromised hosts is rare. We describe the first case in the heart transplant literature of a 59-year-old heart recipient with CMV prostatitis. An elevated PSA prompted a prostate biopsy revealing an adenocarinoma, chronic prostatitis as well as viral cytopathic effect consistent with CMV infection. CMV PCR in the blood was negative. A few months prior, the patient developed CMV viremia and was treated initially with ganciclovir intravenously and subsequently with valganciclovir and CMV immunoglobulins. The patient did well with brachytherapy and additional anti-CMV agents. We discuss the role of CMV in the prostate and management of CMV prostatitis. Relationships between CMV, prostate cancer and heart transplantation are also outlined.",
"affiliations": "Division of Infectious Diseases Center for Heart Failure and Heart Transplantation, Emory University School of Medicine, Atlanta, GA, USA. nroupha@emory.edu",
"authors": "Rouphael|N G|NG|;Laskar|S R|SR|;Smith|A|A|;Lyon|G M|GM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/j.1600-6143.2011.03519.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "11(6)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": null,
"medline_ta": "Am J Transplant",
"mesh_terms": "D003586:Cytomegalovirus Infections; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011472:Prostatitis",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "1330-3",
"pmc": null,
"pmid": "21486388",
"pubdate": "2011-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cytomegalovirus prostatitis in a heart transplant recipient.",
"title_normalized": "cytomegalovirus prostatitis in a heart transplant recipient"
} | [
{
"companynumb": "US-ROCHE-1920709",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
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"drugadditional": "3",
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{
"abstract": "OBJECTIVE\nThe purpose of this study was to understand patient treatment patterns, outcomes, and healthcare resource use in cases of metastatic and/or locally recurrent, unresectable gastric cancer (MGC) in South Korea.\n\n\nMETHODS\nThirty physicians reviewed charts of eligible patients to collect de-identified data. Patients must have received platinum/fluoropyrimidine first-line therapy followed by second-line therapy or best supportive care, had no other primary cancer, and not participated in a clinical trial following MGC diagnosis. Data were summarized using descriptive statistics. Kaplan-Meier analysis was used to describe survival.\n\n\nRESULTS\nOf 198 patients, 73.7% were male, 78.3% were diagnosed with MGC after age 55 (mean, 61.3 years), and 47.0% were current or former smokers. The majority of tumorswere located in the antrum/pylorus (51.5%). Metastatic sites most often occurred in the peritoneum (53.5%), lymph nodes (47.5%), and liver (38.9%). At diagnosis, the mean Charlson comorbidity indexwas 0.4 (standard deviation, 0.6). The most common comorbidities were chronic gastritis (22.7%) and cardiovascular disease (18.7%). Most patients (80.3%) received second-line treatment. Single-agent fluoropyrimidine was reported for 22.0% of patients, while 19.5% were treated with irinotecan and a fluoropyrimidine or platinum agent. The most common physician-reported symptoms during second-line treatment were nausea/vomiting (44.7%) and pain (11.3%), with antiemetics (44.7%), analgesics (36.5%), and nutritional support (11.3%) most often used as supportive care. Two-thirds of inpatient hospitalizations were for chemotherapy infusion. Outpatient hospitalization (31.6%) and visits to the oncologist (58.8%) were common among second-line patients.\n\n\nCONCLUSIONS\nMost patients received second-line treatment, although regimens varied. Understanding MGC patient characteristics and treatment patterns in South Korea will help address unmet needs.",
"affiliations": "Eli Lilly and Company, Indianapolis, IN, USA.;Analysis Group, New York, NY, USA.;Analysis Group, New York, NY, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Analysis Group, Boston, MA, USA.;Analysis Group, New York, NY, USA.;Eli Lilly and Company, Sydney, Australia.;Eli Lilly and Company, Taipei, Taiwan.;Analysis Group, Boston, MA, USA.;Eli Lilly and Company, Seoul, Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.",
"authors": "Carter|Gebra Cuyun|GC|;Kaltenboeck|Anna|A|;Ivanova|Jasmina|J|;Liepa|Astra M|AM|;San Roman|Alexandra|A|;Koh|Maria|M|;Rajan|Narayan|N|;Cheng|Rebecca|R|;Birnbaum|Howard G|HG|;Kim|Jong Seok|JS|;Bang|Yung-Jue|YJ|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4143/crt.2016.001",
"fulltext": "\n==== Front\nCancer Res TreatCancer Res TreatCRTCancer Research and Treatment : Official Journal of Korean Cancer Association1598-29982005-9256Korean Cancer Association 2761882010.4143/crt.2016.001crt-2016-001Original ArticleReal-World Treatment Patterns among Patients with Advanced Gastric Cancer in South Korea Carter Gebra Cuyun PhD1Kaltenboeck Anna MA2Ivanova Jasmina MA2Liepa Astra M. PharmD1San Roman Alexandra BA3Koh Maria MSc2Rajan Narayan MS4Cheng Rebecca MD5Birnbaum Howard G. PhD3Kim Jong Seok MD6Bang Yung-Jue MDPhD7\n1 Eli Lilly and Company, Indianapolis, IN, USA\n2 Analysis Group, New York, NY, USA\n3 Analysis Group, Boston, MA, USA\n4 Eli Lilly and Company, Sydney, Australia\n5 Eli Lilly and Company, Taipei, Taiwan\n6 Eli Lilly and Company, Seoul, Korea\n7 Department of Internal Medicine, Seoul National University Hospital, Seoul, KoreaCorrespondence: Gebra Cuyun Carter, PhD Eli Lilly and Company, Lilly Corporate Center, 307 E. McCarty Street, Indianapolis, IN 46285, USA Tel: 1-317-370-2937 Fax: 1-317-433-1304 E-mail: cuyun_carter_gebra@lilly.com7 2017 12 9 2016 49 3 578 587 15 1 2016 26 8 2016 Copyright © 2017 by the Korean Cancer Association2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nThe purpose of this study was to understand patient treatment patterns, outcomes, and healthcare resource use in cases of metastatic and/or locally recurrent, unresectable gastric cancer (MGC) in South Korea.\n\nMaterials and Methods\nThirty physicians reviewed charts of eligible patients to collect de-identified data. Patients must have received platinum/fluoropyrimidine first-line therapy followed by second-line therapy or best supportive care, had no other primary cancer, and not participated in a clinical trial following MGC diagnosis. Data were summarized using descriptive statistics. Kaplan-Meier analysis was used to describe survival.\n\nResults\nOf 198 patients, 73.7% were male, 78.3% were diagnosed with MGC after age 55 (mean, 61.3 years), and 47.0% were current or former smokers. The majority of tumorswere located in the antrum/pylorus (51.5%). Metastatic sites most often occurred in the peritoneum (53.5%), lymph nodes (47.5%), and liver (38.9%). At diagnosis, the mean Charlson comorbidity indexwas 0.4 (standard deviation, 0.6). The most common comorbidities were chronic gastritis (22.7%) and cardiovascular disease (18.7%). Most patients (80.3%) received second-line treatment. Single-agent fluoropyrimidine was reported for 22.0% of patients, while 19.5% were treated with irinotecan and a fluoropyrimidine or platinum agent. The most common physician-reported symptoms during second-line treatment were nausea/vomiting (44.7%) and pain (11.3%), with antiemetics (44.7%), analgesics (36.5%), and nutritional support (11.3%) most often used as supportive care. Two-thirds of inpatient hospitalizations were for chemotherapy infusion. Outpatient hospitalization (31.6%) and visits to the oncologist (58.8%) were common among second-line patients.\n\nConclusion\nMost patients received second-line treatment, although regimens varied. Understanding MGC patient characteristics and treatment patterns in South Korea will help address unmet needs.\n\nTreatment patternsStomach neoplasmsRepublic of KoreaResource useObservational study\n==== Body\nIntroduction\nGastric cancer is the fourth most common cancer worldwide and the second most common cause of cancer-related deaths [1,2]. The incidence of gastric cancer is highest in East Asian countries and in some parts of South America, while its occurrence is lower in North America and Africa [1,3]. South Korea has the highest incidence rate of gastric cancer (age standardized, male vs. female: 64.2 and 26.7 per 100,000). Globally, a high proportion of patients are diagnosed with late-stage disease, and 5-year survival rates are < 25% for these patients. Gastric cancer is the second most commonly diagnosed cancer in South Korea, with male and female mortality rates of 37.1 and 15.0 per 100,000, respectively. Risk increases with advancing age, history of Helicobacter pylori infection and cigarette smoking [2,3].\n\nThere is high unmet need in gastric cancer as there are few approved agents, and treatment practices vary widely among countries [1,2], particularly in the second-line treatment setting. There is also limited information available on gastric cancer patient characteristics, healthcare resource use and treatment patterns [1,2,4].\n\nTherefore, this study was conducted to understand treatment patterns, patient outcomes, and healthcare resource use in South Korean patients with metastatic and/or locally recurrent, unresectable gastric cancer (MGC), including cancer of the stomach and gastroesophageal junction with adenocarcinoma histology.\n\nMaterials and Methods\nThis study is a retrospective analysis of de-identified patient-level data from medical charts collected via a physician-administered online chart review or face-to-face interviews with physicians who treated gastric cancer patients. Physicians selected at random from a panel of oncologists and referrals to the study by local contacts and elected to participate in the study provided de-identified patient-level data from a random sample of patient charts.\n\nThis study received Investigational Review Board (IRB) exemption from the Seoul National University Hospital and from the Western Institutional Review Board.\n\n1. Data collection\nPer protocol, each physician could provide information from up to 10 patient charts. Inclusion in the study was limited to adult patients (≥ 18 years) diagnosed with MGC, including cancer of the stomach or gastroesophageal junction with adenocarcinoma histology, on or after January 1, 2009 (until data collection began in 2013). Patients could have been diagnosed with an earlier stage gastric cancer before January 1, 2009. Eligible patients had no other primary malignant tumors and completed platinum/fluoropyrimidine (P/F) first-line therapy (with or without other drugs; e.g., therapy with trastuzumab) after MGC diagnosis. Upon completion of first-line therapy, eligible patients either went on to (1) second-line therapy or (2) best supportive care (BSC) only. Patients were not eligible if they participated in any clinical trials after MGC diagnosis.\n\nThe chart abstraction instrument was designed to collect information on physician and patient characteristics, treatment patterns by line of therapy, patient outcomes, and health care resource use. Comorbidities were also collected to allow reporting of patients’ Charlson comorbidity index (CCI). The CCI is a validated tool based on 17 comorbidities that is used to predict the risk of 1-year mortality [5].\n\n2. Statistical analysis\nPatient characteristics were compared between patients who received second-line therapy and those who received only BSC after first-line therapy. Chi-squared tests were used for comparisons of proportions, and Wilcoxon rank sum tests were used for comparisons of continuous variables. p-values of < 0.05 were considered statistically significant. All data were evaluated descriptively with univariate analysis using SAS ver. 9.3 (SAS Institute Inc., Cary, NC).\n\nKaplan-Meier analysis was used to describe survival and disease progression. Survival time was calculated from (1) the date of MGC diagnosis to the date of death for all patients, and (2) from the date of initiation of second-line therapy to the date of death for the cohort that received second-line therapy. Patients surviving at the time of data collection were censored at the date of last contact. Patients who were reported to have died, but for whom no dates of death were available, were recorded as having died on the date of last contact.\n\nRates of disease progression defined as discontinuing any agent in that line of therapy due to disease progression were calculated for each line of therapy. Duration of each line of therapy was defined as the number of days from the first to the last administration of any agent in that line of therapy. Patients with ongoing second-line and third-line therapy were excluded from the calculations of mean duration of second-line and third-line therapy, respectively, but not from Kaplan-Meier analyses of survival and disease progression.\n\nHealthcare resource utilization, including inpatient and outpatient office visits, was calculated for each line of therapy. Observations were excluded from the calculation of each resource use category if it was unknown in what line of therapy they occurred.\n\nResults\n1. Physician characteristics\nThirty physicians that were selected at random from a panel of oncologists and referrals to the study by local contacts and elected to participate in the study provided de-identified patient-level data from 198 patient charts. Most physicians (27/30, 90%) specialized in gastric oncology, and the average time in practice was 11.5 years (standard deviation [SD], 5.5 years). Nine of 30 physicians reported affiliation with one of the major cancer centers in South Korea based on a limited set of centers noted in the survey instruments. Data were collected from February 20, 2013, to April 29, 2013. No data identifying the physicians were collected, and only physicians had access to the medical charts during the abstraction process.\n\n2. Patient and disease characteristics\nCharts were abstracted for 198 MGC patients. At MGC diagnosis, patients were 61.3 years old (SD, 9.8) on average, and 73.7% were male. Most patients (41.9%) had no history of smoking, while 19.2% and 27.8% were current or former smokers, respectively. Alcohol use was most frequently light to moderate (47.5%), although 9.1% of patients had a history of heavy alcohol consumption. A history of H. pylori infection or a family history of gastric cancer was observed in 4.0% and 6.6% of patients, respectively (Table 1).\n\nThe most commonly reported comorbidities were chronic atrophic gastritis (22.7%), cardiovascular disease (18.7%), intestinal metaplasia (14.1%), and diabetes without chronic complications (12.1%). Excluding malignancy and metastatic solid tumor diagnoses, the mean CCI was 0.4 (SD, 0.6) (Table 1).\n\n3. Disease and tumor characteristics\nUpon initial gastric cancer diagnosis, 76.8% of patients had stage IV disease according to the American Joint Committee on Cancer TNM (tumor size, lymph nodes affected, metastases) system [6]. At MGC diagnosis, 97.5% of patients had stage IV disease, with diffuse histology (by the Laurén system [7]) being the most frequently reported type (33.3%). There were no patients with stage III disease, and the staging for the remaining 2.5% of patients was unknown/other. Histology information was missing for 32.8% of patients. The antrum and pylorus were the primary tumor locations in the majority of patients (51.5%). The most frequently reported metastatic sites were the peritoneum (53.5%), lymph nodes (47.5%), and liver (38.9%) (Table 1). On average, MGC diagnosis occurred 4.5 months (SD, 14.3) after initial gastric cancer diagnosis.\n\nOnly 84 of the 198 patients were tested for HER2 positivity, of which 9.5% had positive status (Table 1). Variability in HER2 positivity rates of testing over a 5-year period including 2009 to 2013 ranged from 0% in 2009 to 52.0% in 2012, with an overall rate of testing of 42.4% for patients in this sample. A higher percentage of patients were tested for HER2 status at major cancer centers (68.0%) than patients treated in other centers (30.0%).\n\n4. Treatment patterns\n1) First-line therapy\nBy design, all patients in the study were required to have first-line therapy for MGC. At therapy initiation, most patients (76.3%) were symptomatic but completely ambulatory (Eastern Cooperative Oncology Group performance status [ECOG PS], 1), while some remained asymptomatic (ECOG PS, 0; 12.6%).\n\nIn this sample of 198 patient charts, the most frequent first-line regimen type was a fluoropyrimidine with a platinum agent (+/– leucovorin) (60.6%), which consisted primarily of 5-fluorouracil with a platinum agent (40.9%), capecitabine with a platinum agent (14.6%), or S-1 with a platinum agent (5.1%). Single-agent fluoropyrimidine (+/– leucovorin) was prescribed for 19.2% of patients, and in fewer patients, irinotecan plus platinum and/or fluoropyrimidine (+/– leucovorin) (4.5%) was prescribed (Table 2). For 88.9% of patients, physicians reported selecting first-line treatment based on national guidelines. For 22.7% of patients, physician experience was a factor in selection of the first-line treatment regimen.\n\nFirst-line treatment lasted a median of 84 days (interquartile range [IQR], 49 to 155 days). Response to treatment included stable disease (52.0%), partial response (25.3%), disease progression (18.2%), complete response (3.0%), and unknown (1.5%). In 75.8% of patients, first-line therapy was discontinued due to disease progression, while it was discontinued in 12.6% of patients because of an adverse event (AE) or toxicity. Other reasons for discontinuation included patient preference, completion of protocol, lack of benefit, and unknown.\n\n2) Second-line therapy and BSC\nIn this study, 39 patients (19.7%) received BSC only following first-line therapy, while 159 (80.3%) received second-line therapy.\n\nSecond-line therapy was initiated due to tumor progression in 95.6% of patients. When qualitatively compared with first-line regimens, second-line regimens were more heterogeneous. Physicians reported treating 22.0% of patients with a single agent fluoropyrimidine (+/– leucovorin), 19.5% with irinotecan with a platinum agent and/or fluoropyrimidine (+/– leucovorin), 13.2% with fluoropyrimidine with a platinum agent (+/– leucovorin), and 8.2% with single-agent taxane. Other types of regimens were used in 37.1% of patients (Table 2). For 80.5% of patients, physicians reported selecting second-line therapy based on national guidelines, while in 34.6%, selection was guided at least in part by experience.\n\nSecond-line treatment lasted a median of 64 days (IQR, 37 to 105 days). The most frequent best response to therapy was stable disease (45.9%). Partial response was observed in 15.1% of patients, complete response in 1.3%, progression occurred in 22.6%, and response was unknown for 15.1%. Second-line therapy was discontinued because of disease progression in 61.6% of patients, patient refusal in 17.6%, AEs or toxicity in 11.3%, lack of benefit in 2.5%, other in 1.3%, end of protocol in 0.6%, and for unknown reasons in 13.2% of patients. When we stratified patients between those who received BSC and those who received second-line therapy, we found differences only in age and ECOG PS. Patients who received second-line therapy after first-line treatment were younger and more likely to be asymptomatic (Table 3).\n\n3) Third-line therapy\nThird-line therapy was administered in 23.2% of patients (46 out of 198). Due to the small number of patients who received third-line therapy, treatment patterns were not evaluated in detail.\n\n5. Physician-reported patient symptoms, supportive care, and healthcare resource use\nFor each line of therapy, physicians reported symptoms in patients related to either cancer or cancer treatments. The most common cancer-related symptoms or complications reported were pain in 26.3%, 27.7%, and 30.4%, and nausea/vomiting in 13.6%, 10.7%, and 10.9% of patients during first-, second-, and third-line therapy, respectively. Gastric obstruction was recorded in 5.6%, 6.3%, and 13.0%, ascites in 3.5%, 6.3%, and 6.5%, and bleeding in 3.0%, 1.9%, and 0% of patients undergoing first-, second-, and third-line therapy, respectively (Fig. 1).\n\nSymptoms related to cancer treatment were similar to those recorded for cancer. Nausea/vomiting was reported in 43.9%, 44.7%, and 19.6%, pain in 10.6%, 11.3%, and 23.9%, and ascites in 0.5%, 2.5%, and 2.2% of patients undergoing first-, second-, and third-line therapies, respectively. Treatment-related symptoms were similar during second-line treatment, with nausea/vomiting (44.7%) and pain (11.3%) being the most common. Fewer than 1% of patients experienced gastric obstruction or bleeding during any line of treatment.\n\nSupportive care needs were common during first-, second-, and third-line therapies as well as BSC, and most frequently consisted of antiemetics (52.0%, 44.7% and 45.7%, 17.9%), analgesics (37.4%, 36.5% and 28.3%, 23.1%), and granulocyte colony-stimulating factors (5.6%, 8.2% and 6.5%, 0%). Nutritional support was provided to 13.6%, 11.3% and 8.7% of patients undergoing first-, second-, and third-line treatment and 4% of patients during BSC (Table 4). The most commonly performed procedure was endoscopy, which was conducted in 18.2%, 7.5%, and 4.3% of patients during first-, second-, and third-line treatment, respectively, and in 10.3% of patients in BSC.\n\nInpatient hospitalizations were reported in 35.9% of patients during first-line treatment, 33.3% of patients receiving BSC only, and 30.2% of patients during second-line treatment. Chemotherapy infusions and disease symptom management were the most commonly cited reasons for inpatient hospitalizations across all groups (Table 4).\n\nOutpatient hospitalizations, which were most frequently for disease symptom management or AE/toxicity, occurred in 64.1% of patients during first-line treatment, 31.6% of patients in second-line treatment, 33.3% of patients during third-line treatment, and 30.8% of patients receiving BSC. Visits to oncology clinics, which were most commonly associated with pain management, were reported in 67.7%, 58.8%, 35.7%, and 36.0% of patients receiving first-, second-, and third-line treatment, and BSC, respectively (Table 4).\n\n6. Survival and disease progression\nOverall, the median survival time was 26.8 months (IQR, 9.9 to 41.6 months) from MGC diagnosis with 72.7% of patients censored. Patients who received second-line therapy had a median survival of 28.1 months (IQR, 10.5 to 36.6 months) with 74.2% of patients censored. Patients who received BSC only following first-line therapy had a median survival of 20.1 months (IQR, 8.5 to 41.6 months), with 66.7% of patients censored.\n\nAmong patients who received second-line therapy, median survival from initiation of second-line treatment was 13.0 months (IQR, 4.5 to 24.7 months) with 59.6% of patients censored.\n\nDiscussion\nOur observational study supplements the information currently available regarding treatment of MGC in South Korea. We found variations in treatment patterns in both first- and second-line treatment regimens of patients with MGC. These findings are consistent with the results reported for a REGATE study in which 96% of patients received adjuvant chemotherapy consisting of varying agents, combinations and routes of administration [4]. Recently published guidelines for the diagnosis and treatment of gastric cancer in Korea [8] recommend fluoropyrimidines, platinums, taxanes, irinotecan, and anthracyclines as first-line chemotherapy and state no standard for second-line has been established, while these guidelines were published prior to recent approvals the second line [9-11]. In the present study, the selected patients were required to have P/F first-line therapy (with or without other drugs; i.e., therapy with trastuzumab) after MGC diagnosis, but these criteria were not strictly adhered to and impacted the treatment regimens observed during first-line therapy. Following first-line treatment, 80.3% of the studied patients received second-line treatment, while 19.7% of patients received BSC. The large proportion of patients receiving second-line treatment rather than BSC only may have been due to recent reports of the clinical benefits of second-line chemotherapy to overall survival and quality of life [12-14]. In the REAL-2 study, which was a randomized, controlled clinical trial, only 14% of patients received second-line treatment [15]. More recently, in the AVAGAST trial, 66% of Asian patients received second-line treatment [16]. Patients in our study were required to have had either second-line therapy or BSC after first-line therapy. These criteria may impact survival estimates following MGC diagnosis. Patients in our study who received second-line treatment were younger and had higher ECOG PS than those who received BSC. Performance status was reported to be a predictor of response to chemotherapy [17]. A recent meta-analysis suggests that patients with PS 0 have better survival after chemotherapy than those with PS 1 [18]. Among patients who received second-line therapy in the present study, 61.6% discontinued treatment because of disease progression and 46 patients (23.2%) received third-line treatment, highlighting the need for more clinical trials in advanced gastric cancer.\n\nOverall, 42% of patients in this sample were tested for HER2 positivity, with a larger proportion of patients tested annually during the more recent years of the study. Of those tested, 9.5% tested positive for HER2. This rate of HER2 expression is consistent with the 6%-35% rate reported for gastric cancers [12,19]. HER2 testing is recommended in Korean gastric cancer treatment guidelines and in the ESMO and National Comprehensive Cancer Network guidelines [8,20,21]. Current guidelines recommend the addition of trastuzumab to chemotherapy in HER2+ patients [22].\n\nPhysician recommendations for MGC first-line therapy were most influenced by national guidelines and publications in top clinical journals. While the majority of first-line regimens administered to patients in this study consisted of a platinum agent and fluoropyrimidine as per eligibility criteria, second-line therapies varied widely, and include regimens that consisted of various single-agent fluoropyrimidines, doublet and triplet regimens, and single-agent taxanes. In a large, international prospective study of gastric cancer treatment (REGATE I), the use of a taxane such as paclitaxel, docetaxel, or irinotecan was reportedly the suggested second-line treatment for gastric cancer in Asia, though fewer than 10% of patients in the present sample were prescribed a taxane [1]. Other recent studies have reported a survival advantage associated with treatment with a second-line taxane such as docetaxel, or with irinotecan for cancers refractory to fluoropyrimidine and platinum treatment when compared to BSC [13,14]. In addition, no single agent option has been shown to be better than another in the second-line setting [18,23]. In our data, there appeared to be a trend in the increased use of taxanes as second-line therapy in 2012 relative to earlier years of the study (2009-2011); however, taxanes were prescribed to less than 20% of patients.\n\nBest response to therapy and reasons for discontinuation of first- and second-line therapies revealed a significant unmet need in the treatment of MGC. Most patients achieved at most partial response or stable disease while on first-line therapy, and most discontinued this treatment due to disease progression. Similarly, the reason for initiating second-line therapy was tumor progression in 96% of patients. Responses to second-line therapy were less favorable than those to the first-line. In addition to disease progression, a major reason for discontinuing second-line therapy was patient refusal.\n\nHealthcare resource use was driven both by chemotherapy administration and symptom management. The most commonly reported cancer treatment-related symptoms experienced by patients were nausea/vomiting and pain, and the most commonly used supportive care agents were antiemetics and analgesics. In addition to inpatient hospitalization visits for chemotherapy administration, patients were often seen in outpatient hospitals and oncology clinics for management of disease symptoms, AEs, toxicities, and pain.\n\nIt should be noted that this study is subject to the limitations of physician-administered chart abstractions. The completeness and accuracy of collected patient-level information depended on the accuracy of the physician recording the medical history information and treatment information, as well as the availability of a complete medical history in patient charts. Automated quality control checks for survey questions helped minimize possible inconsistencies in the recording of information. Patient-reported information documented in medical records and abstracted in this study may have been subject to self-report bias, including histories of smoking and alcohol use. Moreover, physicians may not have had full access to records documenting medical care administered to the patients over the course of MGC treatment, or to medical history prior to MGC diagnosis. Because a physician agreement was needed to participate, selection bias may play a role and treatment pattern information may not be representative of the treatment practice of all physicians or the treatments for all MGC patients in South Korea. It is important to interpret these results in light of the fact that the timeframe of this study was prior to more recent evidence supporting new therapies to guide practice in this space [9-11]. In addition, more than 70% of the study population was censored for survival, which is relatively high and may limit interpretation of the survival data.\n\nConclusion\nThe present study documents the high disease burden of gastric cancer and the significant unmet need that exists, particularly in the second-line setting. This study may help inform clinical practice and future research to ultimately improve patient outcomes.\n\nThis study was supported by Eli Lilly and Company. The following authors are employees of Eli Lilly and Company and may own company stock: G.C.C., A.M.L., N.R., R.C., and J.S.K.\n\nThe authors wish to thank the physicians who participated in the data collection for this study.\n\nFig. 1. Physician-reported symptoms (% of patients) by line of therapy. a)Other symptoms or complications included bruises,\ndiarrhea, neuralgia, mucositis, weakness, fatigue, hand numbness, hand-foot reaction, dermatitis, varicella, weakness of whole body, and leukopenia.\n\nTable 1. Baseline patient and disease characteristics at diagnosis\n\nVariable\tNo. (%)\t\nMGC patient\t198 (100)\t\nAge at MGC diagnosis, mean±SD\t61.3±9.8\t\nAge group at MGC diagnosis (yr)\t\t\n 25-44\t12 (6.1)\t\n 45-54\t31 (15.7)\t\n 55-64\t73 (36.9)\t\n ≥ 65\t82 (41.4)\t\nMale\t146 (73.7)\t\nBody mass indexa), mean±SD (kg/m2)\t21.4±2.6\t\nSmoking history\t\t\n Non-smoker\t83 (41.9)\t\n Current smoker\t38 (19.2)\t\n Former smoker\t55 (27.8)\t\n Unknown\t22 (11.1)\t\nAlcohol consumption\t\t\n No alcohol use\t68 (34.3)\t\n Light to moderate\t94 (47.5)\t\n Heavy\t18 (9.1)\t\n Unknown\t18 (9.1)\t\nHistory of Helicobacter pylori infection\t8 (4.0)\t\nFamily history of gastric cancer\t13 (6.6)\t\nCharlson comorbidity index (CCI)b), mean±SD\t0.4±0.6\t\nCommon comorbidity\t\t\n Chronic atrophic gastritis\t45 (22.7)\t\n Cardiovascular disease\t37 (18.7)\t\n Intestinal metaplasia\t28 (14.1)\t\n Diabetes without chronic complicationsc)\t24 (12.1)\t\n Chronic obstructive pulmonary diseasec)\t16 (8.1)\t\n Peptic ulcer diseasec)\t15 (7.6)\t\nStage IV at MGC diagnosis\t193 (97.5)\t\nDisease classification at MGC diagnosis\t\t\n Intestinal\t48 (24.2)\t\n Diffuse\t72 (36.4)\t\n Mixed\t13 (6.6)\t\n Unknown\t65 (32.8)\t\nTumor location\t\t\n Antrum and pylorus\t102 (51.5)\t\n Fundus and corpus\t48 (24.2)\t\n Gastric cardia\t25 (12.6)\t\n Esophagogastric junction\t11 (5.6)\t\n Whole stomach\t7 (3.5)\t\n Other\t1 (0.5)\t\n Unknown\t4 (2)\t\nMetastatic site\t\t\n Peritoneum\t106 (53.5)\t\n Lymph nodes\t94 (47.5)\t\n Liver\t77 (38.9)\t\n Bone\t22 (11.1)\t\n Lung\t9 (4.5)\t\n Other\t9 (4.5)\t\nTested for HER2/neu gene expressiond)\t84 (42.4)\t\n HER2 positive\t8 (9.5)\t\n HER2 negative\t75 (89.3)\t\n HER2 status unknown\t1 (1.2)\t\nMGC, metastatic and/or locally recurrent, unresectable gastric cancer; SD, standard deviation; HER2, human epidermal growth factor receptor 2.\n\na) Patients with weight less than 20 kg (n=1) were assumed to have the population average weight of 58 kg,\n\nb) The CCI was calculated excluding any malignancy (including leukemia and lymphoma) and metastatic solid tumor,\n\nc) Comorbidities contributing to the CCI are marked,\n\nd) The proportions of patients with positive, negative, and unknown values for HER2/neu gene expression are only among the tested patients.\n\nTable 2. Patient status and treatment regimens by line of therapy\n\nVariable\tNo. (%)\t\nMGC patient\t198 (100)\t\n Patient who received first-line chemotherapy treatment\t198 (100)\t\n Patient who received second-line chemotherapy treatment\t159 (80.3)\t\n Patient who received third-line chemotherapy treatment\t46 (23.2)\t\n Patient who received BSC only after first-line\t39 (19.7)\t\nECOG PS score of first-line patientsa)\t\t\n 0: Asymptomatic\t25 (12.6)\t\n 1: Symptomatic but completely ambulatory\t151 (76.3)\t\n 2: Symptomatic, < 50% in bed during the day\t19 (9.6)\t\n 4: Bedbound\t2 (1.0)\t\n Unknown\t1 (0.5)\t\nFirst-line regimenb)\t\t\n Fluoropyrimidine+platinum (+/- leucovorin)\t120 (60.6)\t\n Capecitabine+platinum\t29 (14.6)\t\n Single-agent fluoropyrimidine (+/- leucovorin)\t38 (19.2)\t\nReason for initiating second-line therapy\t159 (100)\t\n Tumor progression\t152 (95.6)\t\n Toxicity of first-line therapy\t7 (4.4)\t\nECOG PS score of second-line patientsa)\t159 (100)\t\n 0: Asymptomatic\t16 (10.1)\t\n 1: Symptomatic but completely ambulatory\t105 (66.0)\t\n 2: Symptomatic, < 50% in bed during the day\t35 (22.0)\t\n Unknown\t3 (1.9)\t\nSecond-line regimenb)\t159 (100)\t\n Single agent fluoropyrimidine (+/- leucovorin)\t35 (22.0)\t\n S-1\t11 (6.9)\t\n Capecitabine\t9 (5.7)\t\n 5-FU\t7 (4.4)\t\n Irinotecan+platinum and/or fluoropyrimidine (+/- leucovorin)\t31 (19.5)\t\n Irinotecan, 5-FU, leucovorin\t15 (9.4)\t\n Irinotecan, 5-FU\t10 (6.3)\t\n Fluoropyrimidine+platinum agent (+/- leucovorin)\t21 (13.2)\t\n Capecitabine+platinum agent\t9 (5.7)\t\n 5-FU+platinum agent\t7 (4.4)\t\n S-1+platinum agent\t5 (3.1)\t\n Single-agent taxane\t13 (8.2)\t\n Docetaxel\t9 (5.7)\t\n Otherc)\t59 (37.1)\t\nECOG score of third-line patient\t46 (100)\t\n 0: Asymptomatic\t5 (10.9)\t\n 1: Symptomatic but completely ambulatory\t25 (54.3)\t\n 2: Symptomatic, < 50% in bed during the day\t16 (34.8)\t\n Unknown\t0\t\nThird-line regimen\t\t\n Single-agent fluoropyrimidine (+/- leucovorin)\t12 (26.1)\t\n Fluoropyrimidine+platinum agent (+/- leucovorin)\t11 (23.9)\t\n Single-agent taxane\t9 (19.6)\t\n Irinotecan+platinum and/or fluoropyrimidine (+/- leucovorin)\t7 (15.2)\t\n Other\t7 (15.2)\t\nMGC, metastatic and/or locally recurrent, unresectable gastric cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; 5-FU, 5-fluorouracil.\n\na) Karnofsky scores were converted to ECOG PS scores (100 [ECOG PS 0], 80-90 [ECOG PS 1], 60-70 [ECOG PS 2], 40-50 [ECOG PS 3], and 10-30 [ECOG PS 4]),\n\nb) A patient could have received a maximum of four therapeutic agents,\n\nc) Other regimens included: irinotecan or oxaliplatin (6.9%), leucovorin/irinotecan (6.3%), cisplatin (5.7%), cisplatin/docetaxel (3.1%), and various other agents received by fewer than 2% of patients.\n\nTable 3. Patient demographic characteristics stratified by BSC or second-line therapy after first-line therapy\n\nVariable\tFirst-line followed by BSC (n=39)\tFirst-line followed by second-line (n=159)\tp-valuea)\t\nAge at MGC diagnosis (yr)\t\t\t\t\n Years\t64.5±9.3\t60.5±9.8\t0.012*\t\n Median (Q1-Q3)\t66 (60-71)\t62 (55-67)\t\t\n Distribution (yr)\t\t\t\t\n 25-34\t1 (2.6)\t3 (1.9)\t> 0.990\t\n 35-44\t0\t8 (5.0)\t0.360\t\n 45-54\t5 (12.8)\t26 (16.4)\t0.587\t\n 55-64\t11 (28.2)\t62 (39.0)\t0.211\t\n ≥ 65\t22 (56.4)\t60 (37.7)\t0.034*\t\nMale\t31 (79.5)\t115 (72.3)\t0.363\t\nEthnicity\t\t\t\t\n East Asian\t39 (100)\t159 (100)\t> 0.990\t\nBMI (kg/m2)b)\t21.8±2.8\t21.3±2.5\t0.121\t\nSmoking history\t\t\t\t\n Non-smoker\t18 (46.2)\t65 (40.9)\t0.550\t\n Current smoker\t9 (23.1)\t29 (18.2)\t0.492\t\n Former smoker\t11 (28.2)\t44 (27.7)\t0.947\t\n Unknown\t1 (2.6)\t21 (13.2)\t0.084\t\nAlcohol consumption\t\t\t\t\n No alcohol use\t11 (28.2)\t57 (35.8)\t0.368\t\n Light to moderate\t19 (48.7)\t75 (47.2)\t0.862\t\n Heavy\t6 (15.4)\t12 (7.5)\t0.131\t\n Unknown\t3 (7.7)\t15 (9.4)\t> 0.990\t\nPerformance status (ECOG score)c)\t\t\t\t\n 0: Asymptomatic\t1 (2.6)\t24 (15.1)\t0.033*\t\n 1: Symptomatic but completely ambulatory\t31 (79.5)\t120 (75.5)\t0.597\t\n 2: Symptomatic, < 50% in bed during the day\t5 (12.8)\t14 (8.8)\t0.542\t\n 3: Symptomatic, > 50% in bed, but not bedbound\t0\t0\t-\t\n 4: Bedbound\t2 (5.1)\t0\t0.038*\t\n Unknown\t0\t1 (0.6)\t> 0.990\t\nValues are presented as mean±standard deviation or number (%) unless otherwise indicated. BSC, best supportive care; MGC, metastatic and/or locally recurrent, unresectable gastric cancer; BMI, body mass index; ECOG, Eastern Cooperative Oncology Group.\n\na) Chi-squared or Fisher exact tests for categorical variables, Wilcoxon rank sum tests for continuous variables. p-values of < 0.05 are indicated by an asterisk (*),\n\nb) Patients weighing less than 20 kg (n=1) were assumed to have a population average weight of 58 kg,\n\nc) Performance status was assessed at the beginning of first-line treatment.\n\nTable 4. Patient supportive care and hospitalization stratified by line of therapy\n\nVariable\tFirst-line (n=198)\tSecond-line (n=159)\tBSC, no second-linea) (n=39)\tThird-line (n=46)\t\nSupportive care\t\t\t\t\t\n Antiemetics\t103 (52.0)\t71 (44.7)\t7 (17.9)\t21 (45.7)\t\n Analgesics\t74 (37.4)\t58 (36.5)\t9 (23.1)\t13 (28.3)\t\n Granulocyte-colony stimulating factors\t11 (5.6)\t13 (8.2)\t0\t3 (6.5)\t\n Diuretics\t9 (4.5)\t6 (3.8)\t1 (2.6)\t1 (2.2)\t\n Antidepressants\t6 (3.0)\t4 (2.5)\t1 (2.6)\t0\t\n Erythropoiesis stimulating agents\t4 (2.0)\t2 (1.3)\t0\t0\t\n GM-colony stimulating factors\t2 (1.0)\t0\t0\t0\t\n Narcotics\t0\t1 (0.6)\t0\t0\t\nNutritional support\t27 (13.6)\t18 (11.3)\t4 (10.3)\t4 (8.7)\t\nInpatient hospitalization\t\t\t\t\t\n At least one stay\t71 (35.9)\t48 (30.2)\t13 (33.3)\t11 (23.9)\t\n No. of visits/patient\t3.5±3.4\t2.1±1.4\t2.5±2.5\t3.7±2.0\t\n Length of stay/hospitalization (day)\t8.2±9.4\t9.1±11.3\t14.3±15.6\t10.2±12.5\t\nMain reasons for visit\t\t\t\t\t\n Chemotherapy infusion\t182 (73.4)\t68 (68.7)\t17 (53.1)b)\t23 (56.1)\t\n Disease symptom management\t38 (15.3)\t21 (21.2)\t9 (28.1)\t11 (26.8)\t\n Adverse events/toxicity\t19 (7.7)\t6 (6.1)\t2 (6.3)\t4 (9.8)\t\n Pain management\t2 (0.8)\t2 (2.0)\t3 (9.4)\t3 (7.3)\t\n Gastric cancer–related surgery\t6 (2.4)\t0\t1 (3.1)\t0\t\n Regular monitoring\t0\t2 (2.0)\t0\t0\t\nOutpatient hospitalization (patients with information available)\t92\t79\t13\t21\t\n At least one visit\t59 (64.1)\t25 (31.6)\t4 (30.8)\t7 (33.3)\t\n Mean visits/patient\t3.2±4.3\t2.5±3.3\t1±0.0\t2.7±2.5\t\nHospice unit (patients with information available)\t34\t29\t5\t10\t\n At least one stay\t1 (2.9)\t0\t1 (20)\t2 (20.0)\t\nOncologist clinic (patients with information available)\t127\t102\t25\t28\t\n At least one visit\t86 (67.7)\t60 (58.8)\t9 (36)\t10 (35.7)\t\n No. of visits/patient\t3.9±3.3\t3.0±3.6\t5.1±5.2\t2.8±1.9\t\nValues are presented as number (%) or mean±standard deviation unless otherwise indicated. BSC, best supportive care; GM, granulocyte-macrophage.\n\na) BSC was defined as having received first-line therapy but not continuing to second-line therapy,\n\nb) Hospitalizations were classified as occurring in a particular line of therapy if there was overlap in the dates of hospitalization and the line of therapy. Hospitalizations for chemotherapy infusion that overlapped between first-line therapy and BSC were counted toward both lines of treatment.\n==== Refs\nReferences\n1 Bang YJ Yalcin S Roth A Hitier S Ter-Ovanesov M Wu CW Registry of gastric cancer treatment evaluation (REGATE): I baseline disease characteristics Asia Pac J Clin Oncol 2014 10 38 52 23937356 \n2 Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 Int J Cancer 2015 136 E359 86 25220842 \n3 Jung KW Won YJ Kong HJ Oh CM Cho H Lee DH Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2012 Cancer Res Treat 2015 47 127 41 25761484 \n4 Ter-Ovanesov M Yalcin S Zalcberg J Hitier S Bang YJ Wu CW Registry of gastric cancer treatment evaluation (REGATE): II treatment practice Asia Pac J Clin Oncol 2013 9 373 80 23909998 \n5 Charlson ME Pompei P Ales KL MacKenzie CR A new method of classifying prognostic comorbidity in longitudinal studies: development and validation J Chronic Dis 1987 40 373 83 3558716 \n6 Sobin LH Fleming ID TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer Cancer 1997 80 1803 4 9351551 \n7 Hu B El Hajj N Sittler S Lammert N Barnes R Meloni-Ehrig A Gastric cancer: classification, histology and application of molecular pathology J Gastrointest Oncol 2012 3 251 61 22943016 \n8 Lee JH Kim JG Jung HK Kim JH Jeong WK Jeon TJ Clinical practice guidelines for gastric cancer in Korea: an evidence-based approach J Gastric Cancer 2014 14 87 104 25061536 \n9 Wilke H Muro K Van Cutsem E Oh SC Bodoky G Shimada Y Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial Lancet Oncol 2014 15 1224 35 25240821 \n10 Fuchs CS Tomasek J Yong CJ Dumitru F Passalacqua R Goswami C Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial Lancet 2014 383 31 9 24094768 \n11 Ford HE Marshall A Bridgewater JA Janowitz T Coxon FY Wadsley J Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial Lancet Oncol 2014 15 78 86 24332238 \n12 Bang YJ Van Cutsem E Feyereislova A Chung HC Shen L Sawaki A Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial Lancet 2010 376 687 97 20728210 \n13 Kang JH Lee SI Lim DH Park KW Oh SY Kwon HC Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone J Clin Oncol 2012 30 1513 8 22412140 \n14 Thuss-Patience PC Kretzschmar A Bichev D Deist T Hinke A Breithaupt K Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer: a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO) Eur J Cancer 2011 47 2306 14 21742485 \n15 Cunningham D Starling N Rao S Iveson T Nicolson M Coxon F Capecitabine and oxaliplatin for advanced esophagogastric cancer N Engl J Med 2008 358 36 46 18172173 \n16 Ohtsu A Shah MA Van Cutsem E Rha SY Sawaki A Park SR Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study J Clin Oncol 2011 29 3968 76 21844504 \n17 Wilson D Hiller L Geh JI Review of second-line chemotherapy for advanced gastric adenocarcinoma Clin Oncol (R Coll Radiol) 2005 17 81 90 15830569 \n18 Iacovelli R Pietrantonio F Farcomeni A Maggi C Palazzo A Ricchini F Chemotherapy or targeted therapy as second-line treatment of advanced gastric cancer: a systematic review and meta-analysis of published studies PLoS One 2014 9 e108940 25268988 \n19 Bang YJ Advances in the management of HER2-positive advanced gastric and gastroesophageal junction cancer J Clin Gastroenterol 2012 46 637 48 22751336 \n20 Ajani JA Barthel JS Bekaii-Saab T Bentrem DJ D'Amico TA Das P Gastric cancer J Natl Compr Canc Netw 2010 8 378 409 20410333 \n21 National Comprehensive Cancer Network Gastric cancer (version 3.2015) [Internet] Fort Washington, PA National Comprehensive Cancer Network 2015 [cited 2015 Jun 3]. Available from: http://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf \n22 Elimova E Shiozaki H Wadhwa R Sudo K Chen Q Estrella JS Medical management of gastric cancer: a 2014 update World J Gastroenterol 2014 20 13637 47 25320502 \n23 Hironaka S Ueda S Yasui H Nishina T Tsuda M Tsumura T Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial J Clin Oncol 2013 31 4438 44 24190112\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1598-2998",
"issue": "49(3)",
"journal": "Cancer research and treatment",
"keywords": "Observational study; Republic of Korea; Resource use; Stomach neoplasms; Treatment patterns",
"medline_ta": "Cancer Res Treat",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003131:Combined Modality Therapy; D015897:Comorbidity; D019468:Disease Management; D018450:Disease Progression; D005260:Female; D006297:Health Services Accessibility; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010641:Phenotype; D010818:Practice Patterns, Physicians'; D056910:Republic of Korea; D019233:Retreatment; D012307:Risk Factors; D013274:Stomach Neoplasms",
"nlm_unique_id": "101155137",
"other_id": null,
"pages": "578-587",
"pmc": null,
"pmid": "27618820",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": "25220842;24190112;21742485;22412140;18172173;25761484;25240821;15830569;3558716;23937356;24332238;25061536;22751336;20410333;21844504;9351551;24094768;25268988;25320502;23909998;22943016;20728210",
"title": "Real-World Treatment Patterns among Patients with Advanced Gastric Cancer in South Korea.",
"title_normalized": "real world treatment patterns among patients with advanced gastric cancer in south korea"
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"abstract": "Diabetic ulcers are at risk of becoming chronic and infected, as diabetics have hampered vascular structures, limiting oxygen and nutrient supply. These wounds can lead to pain, malodor, functional problems, and amputation. The current rise in antibiotic resistance demands for complementary therapies. Medical-grade honey (MGH) forms an attractive option because of its antimicrobial and pro-healing properties. We aim to show the beneficial effects of MGH in infected diabetic ulcers. We present six patients with infected diabetic ulcers, of which some were at risk of (further) amputation. Previous treatments with antibiotics, silver and alginate dressings, surgical closure, and maggot therapy were ineffective; therefore, the treatment was switched to the application of MGH. MGH therapy typically reduced the malodor in a couple of days and controlled infection within 2-3 weeks. MGH also enhanced wound healing by promoting granulation tissue formation, angiogenesis, and re-epithelialization, by decreasing inflammatory and oxidative stress and providing nutrients. Together, wound healing was enhanced, and the patient's quality of life improved. MGH is safe and cost-effective for treating complicated diabetic wounds with (antibiotic-resistant) infections and at risk of amputation. MGH forms a promising alternative or complementary therapy to replace antibiotics for treating locally infected wounds.",
"affiliations": "Wound Care Unit, Department of Internal Medicine, 50586, Kuala Lumpur Hospital, Kuala Lumpur 50586, Malaysia.;General Practitioner Xanthi, 67100 Xanthi, Greece.;Hospital Na Pleši (Nemocnice Na Pleši s. r. o.), Complex Rehabilitation Center, 262 04 Nová Ves pod Pleší, Czech Republic.;Hospital Na Pleši (Nemocnice Na Pleši s. r. o.), Surgical clinic, 262 04 Nová Ves pod Pleší, Czech Republic.;Triticum Exploitatie BV, 6222NK Maastricht, The Netherlands.",
"authors": "Nair|Harikrishna K R|HKR|;Tatavilis|Nektarios|N|;Pospíšilová|Ivana|I|;Kučerová|Jana|J|;Cremers|Niels A J|NAJ|0000-0003-4042-8987",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.3390/antibiotics9090529",
"fulltext": "\n==== Front\nAntibiotics (Basel)\nAntibiotics (Basel)\nantibiotics\nAntibiotics\n2079-6382 MDPI \n\n10.3390/antibiotics9090529\nantibiotics-09-00529\nArticle\nMedical-Grade Honey Kills Antibiotic-Resistant Bacteria and Prevents Amputation in Diabetics with Infected Ulcers: A Prospective Case Series\nNair Harikrishna K. R. 1 Tatavilis Nektarios 2 Pospíšilová Ivana 3 Kučerová Jana 4 https://orcid.org/0000-0003-4042-8987Cremers Niels A. J. 5* 1 Wound Care Unit, Department of Internal Medicine, 50586, Kuala Lumpur Hospital, Kuala Lumpur 50586, Malaysia; hulk25@hotmail.com\n2 General Practitioner Xanthi, 67100 Xanthi, Greece; nektart@yahoo.com\n3 Hospital Na Pleši (Nemocnice Na Pleši s. r. o.), Complex Rehabilitation Center, 262 04 Nová Ves pod Pleší, Czech Republic; pospisilova@naplesi.cz\n4 Hospital Na Pleši (Nemocnice Na Pleši s. r. o.), Surgical clinic, 262 04 Nová Ves pod Pleší, Czech Republic; fastkucerka@seznam.cz\n5 Triticum Exploitatie BV, 6222NK Maastricht, The Netherlands\n* Correspondence: niels@mesitran.com; Tel.: +31-(0)43-325-1773\n19 8 2020 \n9 2020 \n9 9 52907 7 2020 17 8 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Diabetic ulcers are at risk of becoming chronic and infected, as diabetics have hampered vascular structures, limiting oxygen and nutrient supply. These wounds can lead to pain, malodor, functional problems, and amputation. The current rise in antibiotic resistance demands for complementary therapies. Medical-grade honey (MGH) forms an attractive option because of its antimicrobial and pro-healing properties. We aim to show the beneficial effects of MGH in infected diabetic ulcers. We present six patients with infected diabetic ulcers, of which some were at risk of (further) amputation. Previous treatments with antibiotics, silver and alginate dressings, surgical closure, and maggot therapy were ineffective; therefore, the treatment was switched to the application of MGH. MGH therapy typically reduced the malodor in a couple of days and controlled infection within 2–3 weeks. MGH also enhanced wound healing by promoting granulation tissue formation, angiogenesis, and re-epithelialization, by decreasing inflammatory and oxidative stress and providing nutrients. Together, wound healing was enhanced, and the patient’s quality of life improved. MGH is safe and cost-effective for treating complicated diabetic wounds with (antibiotic-resistant) infections and at risk of amputation. MGH forms a promising alternative or complementary therapy to replace antibiotics for treating locally infected wounds.\n\ndiabetic ulcersantibiotic resistanceinfectionsmedical-grade honeycomplementary therapies\n==== Body\n1. Introduction\nThe prevalence of diabetes mellitus (DM) strongly increased over the last few decades [1]. In 2000, the prevalence was estimated to be 171 million, while this number increased to 451 million in 2017 [1,2]. The latter number already exceeds the predictions from 2004, in which 336 million people were predicted to be affected by 2030 [2]. Recent estimations predict a prevalence of 693 million by 2045 [1]. The comorbidities accompanying DM are serious life-threatening health problems that contribute to higher healthcare costs, reduced quality of life for the patient, and higher mortality rates [3]. A common complication is diabetic foot ulcers (DFU), with one-quarter of all diabetics developing one or more DFUs during their life. The definition of a diabetic foot is an “infection, ulceration, or destruction of tissues of the foot associated with neuropathy and/or peripheral artery disease in the lower extremity of a person with (a history of) diabetes mellitus” [4]. DFUs can lead to pain, malodor, functional problems, and eventually amputation when not receiving good care. Especially in diabetics, these ulcers are at risk of becoming chronic and getting infected, as they have hampered vascular structures, limiting oxygen and nutrient supply and transport of leucocytes that are needed to promote wound repair. In addition, DM patients often suffer from neuropathy, which means they cannot feel pain and notice the wounds properly, subsequently resulting in inadequate wound care and exacerbation of the injury. DFUs precede 84% of all diabetes-related lower-leg amputations as they are often contaminated with persistent infections [5]. Forceful drug marketing, competence of medical personnel, and patient compliance are factors contributing to the rise in antimicrobial resistance. The current surge in antibiotic resistance worsens the global outcome of pathogen persistence in infected wounds. Novel therapies working independently of resistance profiles are invaluable. Fortunately, medical-grade honey (MGH) formulations may form a promising complementary therapy that can become more popular in the healthcare sector.\n\nHoney is used for wound healing since ancient times because of its broad-spectrum antimicrobial and wound-healing activities [6]. Antibiotics replaced the use of honey, but the development of antibiotic resistance returned its use [7]. To assure the safety and efficacy of honey for clinical application, strict guidelines are followed to introduce MGH [8]. MGH must be free of any form of contamination, such as herbicides, pesticides, heavy metals, and dormant endospores. MGH must be collected in organic regions and gamma-sterilized, in addition to following strict quality, processing, and storage standards and regulations, in order to ensure the safety of the honey [8,9]. MGH has multiple physicochemical properties that result in antimicrobial and healing activities.\n\nMGH consists of more than 200 different constituents, of which water (17–18%) and carbohydrates (about 80%), such as glucose, fructose, and sucrose, encompass the relative majority. The sugar-rich composition has a hygroscopic activity, attracting fluid from the surrounding environment. This process also leads to dehydration of present microorganisms, making them vulnerable. The acidic pH of MGH makes it even harder for bacteria to persist. The release of the known antimicrobial hydrogen peroxide subsequently kills almost all microorganisms, including those resistant to antibiotics. Hydrogen peroxide is formed by the enzyme glucose oxidase, which the bees add to the honey, and it catalyzes glucose in the presence of water and oxygen into gluconic acid and hydrogen peroxide (C6H12O6 + H2O + O2 → gluconic oxidase→ C6H12O7 + H2O2). Moreover, other molecules present in MGH also have a direct antimicrobial effect, such as phenolic compounds, flavonoids, methylglyoxal, and Bee defencin-1 [6]. Since the antimicrobial activity of MGH is based on multiple mechanisms, microorganisms are not capable of developing resistance toward MGH [10]. Interestingly, smart honey formulations have added supplements such as vitamins C and E to further enhance the antimicrobial activity of raw honey [11,12,13]. MGH decreases the bacterial load, while it additionally prevents the invasion of new pathogens by forming a physical barrier when applied to the wound. Together, MGH offers a potent alternative for antibiotics for the treatment of locally infected wounds.\n\nIn addition to antimicrobial activity, MGH possesses strong healing activity [7,14]. MGH enhances healing by providing a moist and more regenerative wound environment, being anti-inflammatory and anti-oxidative, and by stimulating autolytic debridement, angiogenesis, and re-epithelialization [7,14,15,16,17]. Moreover, quality of life is improved by reducing pain, minimizing scar formation, and deodorizing wounds [7,18].\n\nDespite all these beneficial effects, the use of MGH is reserved and often limited to later lines of therapy, because clinicians unfortunately tend to stick to conventional treatments such as povidone iodine and antibiotics. Therefore, we aim to raise awareness for MGH as an alternative antimicrobial chemotherapeutic by presenting a case series of infected diabetic ulcers treated with MGH. Most cases were ineffectively treated previously with other therapies, including antibiotics. The use of MGH as an earlier line of treatment can enhance healing and prevent exacerbation of the injuries and potential subsequent amputations. This case series demonstrates the efficacy of MGH against antibiotic-resistant infections and the ease of application that will favor patient and healthcare.\n\n2. Results\n2.1. Case 1\nA 78-year-old obese male patient with venous insufficiency and type 2 DM that is non-compliant to his diabetic diet presented to the wound care clinic with an infected leg ulcer. The wound was previously treated with different therapies, including silver sulfadiazine, collagen (Promogran), paraffin gauze (Jelonet), calcium alginate (Algisite), enzyme products (Fibrolan), and silicone sheets (Mepilex), without adequate response. The wound appeared to be infected with ciprofloxacin-resistant Pseudomonas aeruginosa and Streptococci bacteria (Figure 1a, day 0). At the start of MGH therapy, the legs were edematous, and the wound was painful. A couple of days later, the malodor disappeared, while the infection was resolved within four weeks. Within the same period, pain, edema, and the production of excessive exudate gradually disappeared. Granulation tissue was evident after four weeks, and the wound was completely healed after 52 weeks of MGH therapy (Figure 1b, week 49). The total material costs for L-Mesitran treatment were €159 (4 × 50 g Soft and 2 × 10 pcs Net).\n\n2.2. Case 2\nA 63-year-old obese male patient with type 2 DM presented to the wound clinic with a DFU at risk of amputation for another part of his right foot. Previously, one toe was already amputated because of a non-healing DFU. The current wound was at least one cm deep and produced a very bad malodor. The patient was hospitalized for four weeks and lost 50 kg in weight. Previous treatments with sharp debridement, maggot therapy, and systemic antibiotics were ineffective for 1.5 months, and MGH therapy was started (Figure 2a). The wound was infected with Pseudomonas aeruginosa. Within two days after MGH therapy was started, the malodor disappeared, while the infection was resolved within one week. Granulation tissue was evident after four weeks, and the wound was completely healed after 32 weeks of MGH therapy (Figure 2b). The total material costs for L-Mesitran treatment were €381 (11 × 50 g Ointment, 28 × 20 g Ointment; 5 × 15 g Soft).\n\n2.3. Case 3\nA 64-year-old male patient with type 2 DM presented to the wound clinic with a DFU on his right foot. The wound was previously treated with maggots without success for 15 days, and he subsequently received MGH therapy. The wound with dimensions of 7 × 3 cm after amputation of the fourth and fifth digit was painful, red, infected, and produced exudate and bad odor (Figure 3a, day 0). The wound was colonized with a polymicrobial infection (Escherichia coli, Enterococcus faecalis, Finegoldia magna, and Bacterroides thetaiotaomicron) resistant to ampicillin and penicillin. The malodor disappeared within one week after MGH therapy was started, while the infection was resolved within three weeks. After three weeks, granulation tissue was evident, and the wound size decreased to 6.5 × 2.5 cm (Figure 3b). After six weeks, wound healing further progressed, and the size was 5 × 1.5 cm, while it was completely healed after ten weeks of MGH therapy (Figure 3c, week 9). The total material costs for L-Mesitran treatment were €71 (1 × 50 g Ointment and 7 pcs Hydro; 1 × 15 g Soft and 4 pcs Tulle).\n\n2.4. Case 4\nA 52-year-old male patient with type 2 DM presented to the wound clinic with multiple wounds on his left foot. One DFU of 3 × 3 cm and one wound arose following amputation of his little toe three months ago. The patient was non-compliant with his diabetic medication and wound management, despite the foot being at risk of further amputation. The wound was ineffectively treated for three months with different wound care products, including hydrogel (Intrasite), silver dressings (Acticoat, Aquacel Ag), NaCl-gel (Hypergel), alginate dressings (Kaltostat), iodosorb powder, metronidazole (Flagyl), and papase. The wounds were infected with multi-resistant Pseudomonas aeruginosa bacteria (piperacillin/tazobactam and amoxicillin resistance). The malodor disappeared within a couple of days after MGH therapy was started, while the infection was resolved within three weeks. Granulation tissue was evident after three weeks, and, after five weeks, the wound size of the DFU decreased to 1.5 × 1.5 cm, a decrease of 50% (Figure 4b). Wound healing further progressed and was evident after 11 weeks of MGH therapy despite the patient being non-compliant to his therapies (Figure 4c). The total material costs for L-Mesitran treatment were €13 (1 × 50 g Ointment).\n\n2.5. Case 5\nA 45-year-old female patient with type 2 DM presented to the wound clinic with multiple wounds on the toes of her left foot. Due to the severity of the wound, there was a risk of amputation. Previous treatments included hydrogel (Intrasite), alginate (Kaltostat), film dressing (Melolin), and paraffin gauzes (Jelonet), all without success. The wounds were infected with multi-resistant (ampicillin and tetracycline) streptococci and E. coli bacteria (Figure 5a) and discharged pus. The malodor disappeared within a couple of days after MGH therapy started. After nine days, the damage of the toe was already so severe that an amputation of the gangrenous top part was unfortunately inevitable (Figure 5b). After three weeks of MGH therapy, the infection resolved, and granulation tissue was evident (Figure 5c), while the wound completely healed after six weeks (Figure 5d). The total material costs for L-Mesitran treatment were €13 (1 × 50 g Ointment).\n\n2.6. Case 6\nAn 80-year-old obese female patient with type 2 DM presented to the wound clinic with multiple feet and leg ulcers accompanied by swelling of the lower extremities. The wounds were previously treated for 15 days with povidone iodine (Betadin), neomycin sulfate (Pulvo 47), and no coverage, without success. The wounds were infected with a methicillin-resistant Staphylococcus aureus and subsequently treated with MGH therapy (Figure 6a, day 0). The malodor disappeared within a couple of days after the start of MGH therapy, while the infection resolved, and necrotic tissue was fully autolytic debrided within two weeks (Figure 6b, day 12). In week three, the wound showed healthy granulation tissue. After one month, edema and the wound size strongly reduced (Figure 6c). After seven weeks of MGH therapy, the diabetic ulcers were completely healed (Figure 6d). MGH treatment prevented a possible amputation and restored the quality of life for the patient. The total material costs for L-Mesitran treatment were €121 (1 × 50 g Ointment and 14 pcs Net; 1 × 50 g soft and 7 pcs Tulle).\n\nThe key observations of the presented cases are summarized in Table 1. On average, MGH controlled infection in 2.6 weeks. The formation of healthy granulation tissue occurred with an average of 3.5 weeks. Factors such as noncompliance, comorbid complications, and weight loss possibly compromised the healing trajectory in cases 3, 4, and 5. With time, all wounds, including these three, progressed toward healing, and amputation could be avoided in all cases.\n\n3. Discussion\nDiabetic patients with advanced wounds, such as presented in this case series, typically do not take good care of themselves and have bad hygiene. In addition, they have different comorbidities, such as obesity, hampered blood flow, atherosclerosis, neuropathy, and a bad nutritional diet, which attenuate the wound healing, making them even more prone to developing infections. Due to these comorbidities, these patients do not sense the pain at the beginning of a wound. When stayed unnoticed, wounds will worsen and get infected, especially with a lack of hygiene, such as walking in dirty bathrooms on bare feet and inadequate or no cleaning and wound care. Regular pedicure visits may prevent the development of wounds. However, when wounds are present, MGH may be a potent treatment strategy that should be considered more often as first-line therapy.\n\nAs presented in the current case series, whereas the previous therapies proved ineffective in treating DFUs, the application of MGH effectively enhanced wound repair. Within days, the malodor of the wounds neutralized, and inflammation and infection were controlled after a couple of weeks, including those with antibiotic-resistant bacteria. MGH holds multiple antimicrobial mechanisms that are very effective in resolving infections and, therefore, must be considered as a complementary treatment for antibiotics, especially since no resistance will be developed toward MGH. In addition to the antimicrobial activity, MGH also enhances wound healing. Here, MGH clearly enhanced autolytic debridement, leading to quick elimination of slough and the appearance of healthy granulation tissue within the following weeks. Due to the underlying pathologies, healing time ranged from 1.5–8 months.\n\nChronic wounds may be arrested in an inflammatory phase due to an ongoing infection or chronic inflammatory or oxidative stress in the wound bed. MGH can create a switch in the micro-environment of the wound by eradicating the bacterial load and changing the wound physiology due to its anti-inflammatory and anti-oxidative activities. Moreover, MGH accommodates a moist wound environment, has a low pH, and modulates oxygen levels, osmotic pressure, and proteinase activities that can cause non-healing wounds to suddenly start healing.\n\nEdema, such as experienced in cases 1 and 6, can increase pressure on the wound, and it often leads to pain and a decreased quality of life for the patients. Infected wounds typically produce a lot of exudate, being presented as wet wounds. MGH consists of about 80% sugars (glucose, fructose, and sucrose), and these have a hygroscopic activity, attracting fluid from their environment. In wounds, this helps to draw out lymph fluid and clean the wound, stimulates autolytic debridement to remove necrotic tissue and slough, and decreases edema, as demonstrated in cases 1 and 2. The osmotic activity of MGH can result in elevated production of exudate, which may sometimes be noticed during wound dressing changes, especially at the beginning of MGH therapy when the MGH switches the wound environment.\n\nVenous insufficiency will limit the transport of leucocytes and nutrition to the wound site, which is necessary to fight infections and promote healing. MGH will replace the task of leucocytes via its antimicrobial activity, and it can serve as an important nutrient source that is needed for proliferation and migration of epithelial cells during the re-epithelialization process [19,20].\n\nThe efficacy and the safety of MGH for the treatment of DFUs were often investigated. Observational studies demonstrated that MGH can be used safely [21]. Makhdoom et al. observed excellent results with natural honey in 14 diabetic wounds, and the disability of these patients was minimized by decreasing the rate of leg or foot amputations [22]. A larger study in 172 diabetic patients also showed that the use of honey significantly reduced the amputation rate and improved wound healing in chronic diabetic foot ulcers [23]. Moghazy et al. found that commercial clover honey is a clinical and cost-effective dressing for diabetic wounds in developing countries [24]. In the systematic review and meta-analysis of Wang et al., MGH treatment shortened the wound debridement time, wound healing time, and bacterial clearance time and increased the wound healing rate and bacterial clearance rate during the first 1–2 weeks of use [25]. Many different MGH formulations exist, andm since honey is a natural product, there is a difference in antimicrobial and healing activities.\n\nA direct in vitro comparison study of L-Mesitran Soft and Medihoney against multiple (antibiotic-resistant) strains of staphylococci and Pseudomonas spp. pathogens showed that L-Mesitran had a more robust antimicrobial activity, despite containing half the concentration of honey [11]. This may have been caused by the difference in the type of honey, as there can be a 100-fold difference in antimicrobial activity between honey types [26]; alternatively, it may have been caused by the supplements added to L-Mesitran Soft [11]. Other studies demonstrated that L-Mesitran Soft has a stronger antimicrobial activity than its raw honey, which supports that the supplements added to the formulation, such as vitamins C and E, enhance the antimicrobial activity [11,12,13].\n\nThe quality of life of patients with DFUs is negatively affected. The malodor is unpleasant and may limit people who want to visit; additionally, the wound may heavily exudate that may stain clothes and require extra care, or these wounds with or without edema may be excruciating. MGH will attenuate all these problems and improve the quality of life for patients suffering from (infected) DFUs. MGH offers an alternative nutrient source for the bacteria, which switch from catabolizing smelling tissue debris and proteins to the odorless consumption of glucose, which subsequently rapidly decreases malodor. The high sugar content of MGH attracts lymph fluid and wound exudate out of the tissue into the wound dressing. This process, together with the anti-inflammatory activity of MGH, will subsequently reduce edema and pain. Diabetic patients with advanced wounds typically do not take good care of themselves and have bad hygiene. In addition, they have different comorbidities, such as obesity, hampered blood flow, atherosclerosis, neuropathy, and a bad nutritional diet, which attenuate the wound healing, making them even more prone to developing infections. These patients do not sense the pain of a beginning wound because of their neuropathy and do not adequately clean their wounds. Regular pedicure visits may prevent the development of wounds. However, when wounds are present, MGH may be a potent treatment strategy. In line with previous conclusions, we agree that MGH with its antimicrobial activity, via decreasing wound healing time and amputations and, thus costs, is a cost-effective treatment for the treatment of DFUs [22,23,24,25]. To illustrate, hospitalization costs for DFU patients needing an amputation range from United States dollars (USD) $12,851 to USD $16,267 [27]. By reducing the number of chronic wounds, not only will the wound care and societal costs decrease, but the quality of life for the patients will also be substantially improved [27,28].\n\nIn this case series, the products were easy to apply and provided excellent patient comfort. MGH prevents the adherence of newly formed granulation tissue into the wound dressing and does not re-open the tissue after removal; therefore, dressings can be replaced without pain. The high sugar content of the honey did not influence the blood glucose levels of the patients.\n\n4. Materials and Methods\nDiabetic ulcers were treated with one or more MGH formulations of the product range of L-Mesitran (Soft, Ointment, Net, Tulle, or Hydro, manufactured by Triticum Exploitatie BV, Maastricht, the Netherlands).\n\n4.1. Subjects and therapeutic interventions\nFollowing a multicenter approach, we included six patients with infected diabetic ulcers, of which five were colonized with antibiotic-resistant bacteria. Three patients had previous amputations, and, in four cases, there was a risk of (further) amputation. A plethora of prior treatments, including antibiotics, silver and alginate dressings, surgical closure, and maggot therapy, were ineffective. Subsequently, the treatment was switched to the application of MGH as monotherapy in all cases except one in which systemic antibiotics had to be administered as part of the hospital regulations. Wounds were cleaned following the local cleaning protocol. Compression therapy was temporarily given in cases 1 and 6 until the edema decreased, and only one patient (case 1) received medication (lisinopril 20 mg/day) to lower blood pressure. Patients were advised to offload the DFU to minimize pain, e.g., by using crutches during walking. The decision to use the L-Mesitran wound care product was dependent on the wound, the patient, and the experience of the wound care specialist. The products were applied following the manufacturer’s instructions and covered with a suitable secondary dressing. The dressing changes were done at the clinic, or the patients were clearly instructed to perform the dressing changes at home. An overview of the exact treatment protocol can be found in Table 2. Photos of the wounds were frequently taken to monitor and demonstrate the progression. All patients received medication to control their diabetes, and glucose levels were constantly monitored. No effect of L-Mesitran on blood glucose levels was observed.\n\nThe patients were informed about the study, and they all gave written informed consent to participate in the study and publication of the data. The principles of the World Medical Association’s Declaration of Helsinki were followed.\n\n4.2. About L-Mesitran wound care products\nL-Mesitran was the first MGH-based product to obtain both Food and Drug Administration (FDA) and European Conformity (CE: Conformité Européenne) approval in 2002 [29]. At that time, the initial scientific literature reported good antimicrobial activity for honey and showed that it could be effective for wound healing [7,30,31]. L-Mesitran manufactures a wide range of MGH-based wound care products, which can be used for different types of wounds. L-Mesitran Ointment and L-Mesitran Soft are a cream and gel, respectively. In general, the Ointment is a little thicker and contains slightly more MGH (48% versus 40% in L-Mesitran Soft), making the Soft a little easier to apply in deeper wounds. The more advanced wound care products of L-Mesitran are L-Mesitran Net, L-Mesitran Tulle, L-Mesitran Hydro/Border/Active, and the recently launched L-Mesitran Foam. In some of the presented cases, multiple L-Mesitran products were combined. L-Mesitran Net is a hydrogel that contains 20% MGH and can be used on moderate to heavily exuding wounds. However, it can also serve as a contact layer that stays well in place and, when necessary, can be combined with the L-Mesitran Ointment or L-Mesitran Soft for deeper wounds, which need a secondary dressing. L-Mesitran Tulle is a synthetic sterile gauze impregnated with L-Mesitran Soft and can be used on different kinds of wounds, for example, on superficial wounds; however, since it is so conformable, it can be easily applied to deeper wounds as well. The L-Mesitran Hydro, Border, and Active are all hydrogels that differ in size and having a border. They all contain 30% MGH and can absorb and encapsulate about 10 times their weight in wound fluid and, hence, can be used on exuding wounds. In addition, the instant cooling effect also makes them ideal for treating burn wounds. The newest product is L-Mesitran Foam, a highly absorbable foam dressing impregnated with L-Mesitran Soft, indicated for heavily exuding wounds. The polyurethane foam forms a cushioning layer that protects the wound from mechanical stress and allows drainage to pass, while the L-Mesitran Soft layer fights infections and optimizes wound healing.\n\n5. Conclusions\nIn light of the rise in diabetes prevalence and complications related to DFUs, as well as increased antibiotic resistance, it is essential to explore novel wound treatment options. MGH forms a potent strategy to fight (antibiotic-resistant) infections and serves as a promising alternative antimicrobial chemotherapeutic without a risk of developing resistance. MGH is easy to apply in clinic and home care, and it is proven to be a safe and cost-effective treatment for chronic diabetic ulcers. The application of MGH resolves infections and enhances wound healing, and it forms a promising strategy as the first line of therapy in diabetic ulcers, as well as other type of wounds.\n\nAuthor Contributions\nH.K.R.N., N.T., I.P., and J.K. served responsible for the use of the MGH and considered MGH to be the best option for the treatment in the presented cases. H.K.R.N., N.T., I.P., and J.K. performed the clinical treatments and collected all the data. H.K.R.N., N.T., I.P., and J.K. wrote the case reports. N.A.J.C. provided the MGH products free of charge and helped in writing the rationale and the underlying mechanisms of the MGH product. H.K.R.N., N.T., I.P., J.K., and N.A.J.C. wrote and reviewed the paper. All authors read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nHarikrishna K.R. Nair, Nektarios Tatavilis, Ivana Pospíšilová, and Jana Kučerová are all independent wound care specialists, and they all declare no conflicts of interest. Niels A.J. Cremers is employed by Triticum. Triticum provided the L-Mesitran MGH-based wound care products used in this study free of charge. No other conflict of interest applies. Niels A.J. Cremers was not involved in the design, treatment, and presentation of the results.\n\nFigure 1 Case 1: (a) the wound at the start of medical-grade honey (MGH) therapy (day 0); (b) complete healing of the wound after 49 weeks of MGH therapy.\n\nFigure 2 Case 2: (a) the wound one week after the start of MGH therapy; (b) complete healing of the wound after 34 weeks of MGH therapy.\n\nFigure 3 Case 3: (a) the wound at the start of MGH therapy (day 0); (b) progressed wound healing with healthy granulation tissue after three weeks of MGH therapy; (c) advanced healing of the wound after nine weeks of MGH therapy.\n\nFigure 4 Case 4: (a) the wound at the start of MGH therapy (day 0); (b) resolution of infection and clear progression of wound healing after five weeks of treatment; (c) advanced healing of the wound after 11 weeks of MGH therapy.\n\nFigure 5 Case 5: (a) the wound at the start of MGH therapy (day 0); (b) gangrenous toe at day nine that needed amputation; (c) advanced healing of the wound after three weeks of MGH therapy; (d) wound closure after six weeks of MGH therapy.\n\nFigure 6 Case 6: (a) the wound at the start of MGH therapy (day 0); (b) MGH therapy led to autolytic debridement of necrotic tissue at day 12; (c) after one month, the edema was reduced and wound healing progressed; (d) complete healing of the wounds after seven weeks of MGH therapy.\n\nantibiotics-09-00529-t001_Table 1Table 1 Wound healing trajectory per case, including time to full healing, time to reduce inflammation, and infection control.\n\nCase\t1\t2\t3\t4\t5\t6\t\nt Infection\t4 weeks\t1 week\t3 weeks\t3 weeks\t3 weeks\t2 weeks\t\nt Granulation\t4 weeks\t4 weeks\t3 weeks\t3 weeks\t3 weeks\t3 weeks\t\nt Healing\t52 weeks\t32 weeks\t10 weeks\t12 weeks\t6 weeks\t7 weeks\t\nRisk Amputation\t\n\tYes\tYes\tYes\tYes\t\n\t\nantibiotics-09-00529-t002_Table 2Table 2 Wound management overview of each case and their respective L-Mesitran products. Ointment, a 48% MGH lanolin ointment; Soft, a 40% MGH wound gel; Net, a hydrocolloid net dressing containing 20% MGH; Hydro, a hydrogel containing 30% MGH.\n\nCase\tInitial 1° Dressing \tInitial 2° Dressing \tDuration and Dressing Regime \t1° Dressing Treatment Change \t2° Dressing Treatment Change \tDuration and Dressing Regime \t\n1\tSoft and Net\tSterile absorptive gauzes\t4 weeks of daily changes \tSoft \tSterile absorptive gauzes\t48 weeks of daily changes following weekly application \t\n2\tOintment and Net\tSterile absorptive gauzes\t2 months of two changes per day\tSoft\tSterile absorptive gauzes\t6 months of daily changes\t\n3\tOintment and Hydro\tFixative gauzes\t7 weeks of daily changes\tSoft and Tulle\tSterile absorptive gauzes\t3 weeks of daily changes\t\n4\tOintment\tFilm dressing\t2 weeks of daily changes\tOintment \tAlginate and film dressing\t10 weeks of daily changes\t\n5\tOintment \tFilm dressing\t6 weeks of daily changes\t\n\t\n\t\n\t\n6\tOintment and Net\tSterile absorptive gauzes\t3 weeks of daily changes\tSoft and Tulle\tSterile absorptive gauzes\t3 weeks of daily changes\n==== Refs\nReferences\n1. Cho N.H. Shaw J.E. Karuranga S. Huang Y. da Rocha Fernandes J.D. Ohlrogge A.W. Malanda B. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045 Diabetes Res. Clin. Pract. 2018 138 271 281 10.1016/j.diabres.2018.02.023 29496507 \n2. Wild S. Roglic G. Green A. Sicree R. King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030 Diabetes Care 2004 27 1047 1053 10.2337/diacare.27.5.1047 15111519 \n3. Baena-Diez J.M. Penafiel J. Subirana I. Ramos R. Elosua R. Marin-Ibanez A. Guembe M.J. Rigo F. Tormo-Diaz M.J. Moreno-Iribas C. Risk of Cause-Specific Death in Individuals With Diabetes: A Competing Risks Analysis Diabetes Care 2016 39 1987 1995 10.2337/dc16-0614 27493134 \n4. van Netten J.J. Bus S.A. Apelqvist J. Lipsky B.A. Hinchliffe R.J. Game F. Rayman G. Lazzarini P.A. Forsythe R.O. Peters E.J.G. Definitions and criteria for diabetic foot disease Diabetes Metab Res. Rev. 2020 36 Suppl. S1 e3268 10.1002/dmrr.3268 31943705 \n5. Brem H. Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes J. Clin. Investig. 2007 117 1219 1222 10.1172/JCI32169 17476353 \n6. Smaropoulos E. Cremers N.A.J. Treating severe wounds in pediatrics with medical grade honey: A case series Clin. Case Rep. 2020 8 469 476 10.1002/ccr3.2691 32185038 \n7. Molan P.C. Re-introducing honey in the management of wounds and ulcers – theory and practice Ostomy Wound Manage. 2002 48 28 40 \n8. Hermanns R. Mateescu C. Thrasyvoulou A. Tananaki C. Wagener F.A. Cremers N.A. Defining the standards for medical grade honey J. Apic. Res. 2020 59 125 135 10.1080/00218839.2019.1693713 \n9. Postmes T. van den Bogaard A.E. Hazen M. Honey for wounds, ulcers, and skin graft preservation Lancet 1993 341 756 757 10.1016/0140-6736(93)90527-N \n10. Maddocks S.E. Jenkins R.E. Honey: A sweet solution to the growing problem of antimicrobial resistance? Future Microbiol. 2013 8 1419 1429 10.2217/fmb.13.105 24199801 \n11. Cremers N. Belas A. Santos Costa S. Couto I. de Rooster H. Pomba C. In vitro antimicrobial efficacy of two medical grade honey formulations against common high-risk meticillin-resistant staphylococci and Pseudomonas spp. pathogens Vet. Dermatol. 2020 31 90 96 10.1111/vde.12811 31808237 \n12. Hermanns R. Cremers N.A.J. Leeming J.P. van der Werf E.T. Sweet Relief: Determining the Antimicrobial Activity of Medical Grade Honey Against Vaginal Isolates of Candida albicans J. Fungi (Basel) 2019 5 10.3390/jof5030085 31505796 \n13. Oliveira A.M.P. Devesa J.S.P. Hill P.B. In vitro efficacy of a honey-based gel against canine clinical isolates of Staphylococcus pseudintermedius and Malassezia pachydermatis Vet. Dermatol. 2018 29 180-e165 10.1111/vde.12533 29569291 \n14. Saikaly S.K. Khachemoune A. Honey and Wound Healing: An Update Am. J. Clin. Dermatol. 2017 18 237 251 10.1007/s40257-016-0247-8 28063093 \n15. Gottrup F. Oxygen in wound healing and infection World J. Surg. 2004 28 312 315 10.1007/s00268-003-7398-5 14961190 \n16. Rossiter K. Cooper A.J. Voegeli D. Lwaleed B.A. Honey promotes angiogeneic activity in the rat aortic ring assay J. Wound Care 2010 19 440 446 440, 442–446 10.12968/jowc.2010.19.10.79091 20948492 \n17. Winter G.D. Formation of the scab and the rate of epithelization of superficial wounds in the skin of the young domestic pig Nature 1962 193 293 294 10.1038/193293a0 14007593 \n18. Lukanc B. Potokar T. Erjavec V. Complete skin regeneration with medical honey after skin loss on the entire circumference of a leg in a cat J. Tissue Viability 2020 10.1016/j.jtv.2020.03.007 \n19. Du Toit D.F. Page B.J. An in vitro evaluation of the cell toxicity of honey and silver dressings J. Wound Care 2009 18 383 389 10.12968/jowc.2009.18.9.44307 19789475 \n20. Smaropoulos E. Cremers N.A. Medical grade honey for the treatment of paediatric abdominal wounds: A case series J. Wound Care 2020 29 94 99 10.12968/jowc.2020.29.2.94 32058849 \n21. Kateel R. Adhikari P. Augustine A.J. Ullal S. Topical honey for the treatment of diabetic foot ulcer: A systematic review Complement. Ther. Clin. Pract. 2016 24 130 133 10.1016/j.ctcp.2016.06.003 27502813 \n22. Makhdoom A. Khan M.S. Lagahari M.A. Rahopoto M.Q. Tahir S.M. Siddiqui K.A. Management of diabetic foot by natural honey J. Ayub Med. Coll Abbottabad 2009 21 103 105 20364754 \n23. Surahio A.R. Khan A.A. Farooq M. Fatima I. Role of honey in wound dressing in diabetic foot ulcer J. Ayub Med. Coll Abbottabad 2014 26 304 306 25671933 \n24. Moghazy A.M. Shams M.E. Adly O.A. Abbas A.H. El-Badawy M.A. Elsakka D.M. Hassan S.A. Abdelmohsen W.S. Ali O.S. Mohamed B.A. The clinical and cost effectiveness of bee honey dressing in the treatment of diabetic foot ulcers Diabetes Res. Clin. Pract. 2010 89 276 281 10.1016/j.diabres.2010.05.021 20646771 \n25. Wang C. Guo M. Zhang N. Wang G. Effectiveness of honey dressing in the treatment of diabetic foot ulcers: A systematic review and meta-analysis Complement. Ther. Clin. Pract. 2019 34 123 131 10.1016/j.ctcp.2018.09.004 30712715 \n26. Mandal M.D. Mandal S. Honey: Its medicinal property and antibacterial activity Asian Pac. J. Trop. Biomed. 2011 1 154 160 10.1016/S2221-1691(11)60016-6 23569748 \n27. Olsson M. Jarbrink K. Divakar U. Bajpai R. Upton Z. Schmidtchen A. Car J. The humanistic and economic burden of chronic wounds: A systematic review Wound Repair Regen. 2019 27 114 125 10.1111/wrr.12683 30362646 \n28. Jarbrink K. Ni G. Sonnergren H. Schmidtchen A. Pang C. Bajpai R. Car J. The humanistic and economic burden of chronic wounds: A protocol for a systematic review Syst. Rev. 2017 6 15 10.1186/s13643-016-0400-8 28118847 \n29. Zbuchea A. Honey, Food and Medicine: Scientific Rationale and Practical Efficiency in External Administration of Medicinal Honey for Wound Healing J. Agric. Sci. Technol. B 2017 7 206 219 10.17265/2161-6264/2017.03.008 \n30. Moore O.A. Smith L.A. Campbell F. Seers K. McQuay H.J. Moore R.A. Systematic review of the use of honey as a wound dressing BMC Complement. Altern. Med. 2001 1 2 10.1186/1472-6882-1-2 11405898 \n31. Lusby P.E. Coombes A. Wilkinson J.M. Honey: A potent agent for wound healing? J. Wound Ostomy Continence Nurs. 2002 29 295 300 10.1097/00152192-200211000-00008 12439453\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2079-6382",
"issue": "9(9)",
"journal": "Antibiotics (Basel, Switzerland)",
"keywords": "antibiotic resistance; complementary therapies; diabetic ulcers; infections; medical-grade honey",
"medline_ta": "Antibiotics (Basel)",
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"pubdate": "2020-08-19",
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"title": "Medical-Grade Honey Kills Antibiotic-Resistant Bacteria and Prevents Amputation in Diabetics with Infected Ulcers: A Prospective Case Series.",
"title_normalized": "medical grade honey kills antibiotic resistant bacteria and prevents amputation in diabetics with infected ulcers a prospective case series"
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"abstract": "Even though no increased recurrence rate seems to be reported in patients with brain tumors receiving recombinant human growth hormone (rhGH) replacement, in some patients multiple risk factors could put at higher risk for recurrence. In such cases, the decision to start rhGH therapy should be very cautious. A boy with neurofibromatosis type 1 developed an atypical teratoid/rhabdoid tumor (AT/RT) of right cerebellum, treated with surgery, radiotherapy, and chemotherapy. After 3 years of remission, he started rhGH for growth hormone deficiency, having a negative magnetic resonance imaging (MRI) scan. Ten weeks after starting therapy, the boy became symptomatic and MRI showed relapse of AT/RT in the right cerebellum and a new lesion in the brainstem. The boy died of progressive disease. In this case, the connection between AT/RT recurrence and the beginning of rhGH therapy, with a negative pretreatment MRI, cannot be excluded. Additional caution should be used for rhGH in patients with multiple risk factors.",
"affiliations": "Institute for Maternal and Child Health - IRCCS \"Burlo Garofolo\" - Trieste, Italy.;Institute for Maternal and Child Health - IRCCS \"Burlo Garofolo\" - Trieste, Italy.;University of Trieste, Italy.;University of Trieste, Italy.;Institute for Maternal and Child Health - IRCCS \"Burlo Garofolo\" - Trieste, Italy.;Institute for Maternal and Child Health - IRCCS \"Burlo Garofolo\" - Trieste, Italy.;Institute for Maternal and Child Health - IRCCS \"Burlo Garofolo\" - Trieste, Italy.;Institute for Maternal and Child Health - IRCCS \"Burlo Garofolo\" - Trieste, Italy.;Institute for Maternal and Child Health - IRCCS \"Burlo Garofolo\" - Trieste, Italy.",
"authors": "Tornese|Gianluca|G|;Faleschini|Elena|E|;Matarazzo|Lorenza|L|;Bibalo|Cristina|C|;Zanazzo|Giulio Andrea|GA|;Rabusin|Marco|M|;Tonini|Giorgio|G|;Zennaro|Floriana|F|;Ventura|Alessandro|A|",
"chemical_list": "D011994:Recombinant Proteins; D019382:Human Growth Hormone",
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"doi": "10.1055/s-0034-1393706",
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"issue": "46(2)",
"journal": "Neuropediatrics",
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"mesh_terms": "D020295:Brain Stem Neoplasms; D002528:Cerebellar Neoplasms; D002648:Child; D019382:Human Growth Hormone; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009456:Neurofibromatosis 1; D011994:Recombinant Proteins; D012008:Recurrence; D018335:Rhabdoid Tumor; D012307:Risk Factors; D013724:Teratoma",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Relapse and metastasis of atypical teratoid/rhabdoid tumor in a boy with neurofibromatosis type 1 treated with recombinant human growth hormone.",
"title_normalized": "relapse and metastasis of atypical teratoid rhabdoid tumor in a boy with neurofibromatosis type 1 treated with recombinant human growth hormone"
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"abstract": "A 63-year-old woman on flecainide, furosemide, and triamterene-hydrochlorothiazide presented with weakness and diarrhoea. She had profound hyponatraemia, hypokalaemia and a pre-renal acute kidney injury (AKI). Her ECG showed a regular wide complex tachycardia concerning for monomorphic ventricular tachycardia. She was haemodynamically stable and treated with aggressive electrolyte repletion and amiodarone. Flecainide toxicity can present as a variety of arrhythmias and early recognition is crucial. This case focuses on flecainide toxicity from multiple concomitant insults: diuretic use, diarrhoea, hypokalaemia, hyponatraemia and pre-renal AKI. We emphasise the importance of close outpatient monitoring of electrolytes in a patient on diuretics and flecainide to prevent life-threatening arrhythmias. We discourage use of multiple diuretics in patients taking flecainide.",
"affiliations": "Inova Fairfax Medical Campus, Falls Church, Virginia, USA nisha.donthi@gmail.com.;Inova Fairfax Medical Campus, Falls Church, Virginia, USA.;Inova Heart and Vascular Institute, Falls Church, Virginia, USA.;Inova Heart and Vascular Institute, Falls Church, Virginia, USA.",
"authors": "Donthi|Nisha|N|http://orcid.org/0000-0002-2718-2663;Chandrabhatla|Tejasri|T|;Genovese|Leonard|L|;deFilippi|Christopher|C|",
"chemical_list": "D061567:Voltage-Gated Sodium Channel Blockers; D005424:Flecainide; D000638:Amiodarone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236932",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(12)",
"journal": "BMJ case reports",
"keywords": "arrhythmias; safety",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000638:Amiodarone; D004562:Electrocardiography; D005260:Female; D005424:Flecainide; D006801:Humans; D008875:Middle Aged; D017180:Tachycardia, Ventricular; D061567:Voltage-Gated Sodium Channel Blockers",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33318242",
"pubdate": "2020-12-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fast and furious: flecainide toxicity presenting as monomorphic ventricular tachycardia.",
"title_normalized": "fast and furious flecainide toxicity presenting as monomorphic ventricular tachycardia"
} | [
{
"companynumb": "US-TEVA-2021-US-1869968",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DILTIAZEM"
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"drugadditional": null,
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"abstract": "We present a case of neuroleptic malignant syndrome (NMS) in a 46-year-old white female from a state psychiatric hospital who also tested positive for coronavirus-2019 (COVID-19) (severe acute respiratory syndrome coronavirus, SARS-CoV-2) infection after re-introduction of her home antipsychotics medication. She presented with confusion and altered mental status likely secondary to delirium from COVID-19 infection. Clozapine and risperidone were initially held on admission and restarted after continuing agitation on day two. She began to have increased restlessness with rising creatinine kinase (CK) levels, peaking on day seven with sudden fever, hypertension, and tachycardia. The diagnosis of NMS was confirmed, antipsychotic medication was held, and appropriate treatment was administered. The mechanism explaining the occurrence of NMS in COVID-19 patients is still unclear, but COVID-19 infection may be a risk factor for this presentation. The mechanism of SARS-CoV-2 as a risk factor for NMS is still uncertain and needs to be investigated further. However, if their infection status is known, patients should be given neuroleptics with caution and carefully considered for the development of this rare condition.",
"affiliations": "Psychiatry, Drexel University College of Medicine, Philadelphia, USA.;Medicine, Drexel University College of Medicine, Philadelphia, USA.;Medical Critical Care, Boston Children's Hospital, Boston, USA.",
"authors": "Espiridion|Eduardo D|ED|;Mani|Valli|V|;Oladunjoye|Adeolu O|AO|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.13428",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.13428\nPsychiatry\nInfectious Disease\nNeuroleptic Malignant Syndrome After Re-introduction of Atypical Antipsychotics in a COVID-19 Patient\nMuacevic Alexander\nAdler John R\nEspiridion Eduardo D 12345\nMani Valli 6\nOladunjoye Adeolu O 75\n1 Psychiatry, Drexel University College of Medicine, Philadelphia, USA\n2 Psychiatry, West Virginia School of Osteopathic Medicine, Lewisburg, USA\n3 Psychiatry, West Virginia University School of Medicine, Martinsburg, USA\n4 Psychiatry, Philadelphia College of Osteopathic Medicine, Philadelphia, USA\n5 Psychiatry, Reading Hospital Tower Health, West Reading, USA\n6 Medicine, Drexel University College of Medicine, Philadelphia, USA\n7 Medical Critical Care, Boston Children's Hospital, Boston, USA\nEduardo D. Espiridion edjen19meg@gmail.com\n18 2 2021\n2 2021\n13 2 e1342818 2 2021\nCopyright © 2021, Espiridion et al.\n2021\nEspiridion et al.\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/52252-neuroleptic-malignant-syndrome-after-re-introduction-of-atypical-antipsychotics-in-a-covid-19-patient\nWe present a case of neuroleptic malignant syndrome (NMS) in a 46-year-old white female from a state psychiatric hospital who also tested positive for coronavirus-2019 (COVID-19) (severe acute respiratory syndrome coronavirus, SARS-CoV-2) infection after re-introduction of her home antipsychotics medication. She presented with confusion and altered mental status likely secondary to delirium from COVID-19 infection. Clozapine and risperidone were initially held on admission and restarted after continuing agitation on day two. She began to have increased restlessness with rising creatinine kinase (CK) levels, peaking on day seven with sudden fever, hypertension, and tachycardia. The diagnosis of NMS was confirmed, antipsychotic medication was held, and appropriate treatment was administered. The mechanism explaining the occurrence of NMS in COVID-19 patients is still unclear, but COVID-19 infection may be a risk factor for this presentation. The mechanism of SARS-CoV-2 as a risk factor for NMS is still uncertain and needs to be investigated further. However, if their infection status is known, patients should be given neuroleptics with caution and carefully considered for the development of this rare condition.\n\ncovid 19\nantipsychotic medication\naltered mental state\nneuroleptic medications\nneuroleptic malignant syndrome\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nNeuroleptic malignant syndrome (NMS) is a rare life-threatening neurological emergency associated with the use of antipsychotic agents, commonly first-generation or typical neuroleptics [1]. It is characterized by altered mental status, rigidity, fever, and autonomic instability. Coronavirus-2019 (COVID-19), on the other hand, causes flu-like symptoms and acute respiratory distress syndrome but it is now recognized to have a variety of neurological manifestations including altered mental status, impaired consciousness, delirium, encephalopathy, and seizures [2]. Our patient who was infected with COVID-19 was also susceptible to NMS, given her history of antipsychotic use. There are two established case reports of NMS in patients with COVID-19 infection [3-4]. However, our patient was diagnosed with COVID-19 infection while in the state psychiatric hospital, where they do weekly testing to their residents. She initially had fever, chills, fatigue, anosmia, and headaches. There were no initial complaints of rigidity. However, because she is on antipsychotics, an NMS diagnosis was considered in the differential diagnoses. This patient has a long psychiatric history and multiple prior psychiatric hospitalizations. She was diagnosed with schizoaffective disorder when she was 19 and has been stable on the combination of clozapine and risperidone for more than a decade. Her antipsychotics were initially held then restarted after continuous agitation. Over the next couple of days, the patient’s mental status worsened and she developed NMS. \n\nCase presentation\n\nHistory of present illness\n\nA 46-year-old white female with a past medical history of schizoaffective disorder, seizures, hypertension and hypothyroidism, presented to the ED from a state psychiatric hospital with altered mental status. She presented with a one-day history of a head injury after hitting her head against a wall status post manic episode. The staff described the manic episode as restlessness, not sleeping, irritable, impulsive, and internal preoccupation. Those symptoms have been observed for years and she had hit her head against the wall on several other occasions in the past five years. The patient was discharged after CT of the head/neck was negative for acute abnormalities. All the previous CT scans of the brain, which were ordered because of her head banging, showed no abnormalities. At this time, she was tested for a COVID-19 infection and found to be positive. She was afebrile with an oxygen saturation of 97% and no respiratory symptoms, so she was discharged back to the state hospital. The state hospital has a unit dedicated to psychiatric patients who tested positive for the COVID-19 infection. On the day of admission, the patient presented with altered mental status, as well as worsening restlessness and agitation. She also presented with autonomic instability, with hypotension and tachycardia, as well as palpitations. Lead-pipe rigidity was not observed on presentation. Notable home medications were clozapine, divalproex, escitalopram, lithium, and risperidone. After arriving at the ED, she received lorazepam 2 mg and ziprasidone 10 mg stat for sedation. At this time, risperidone 4 mg twice daily and clozapine 300 mg daily were held and the patient was admitted for encephalopathy.\n\nExamination\n\nAfter admission, the patient continued to be confused, disrobing, and unable to respond to commands. She was not responding to verbal redirections. Clozapine 300 mg daily and risperidone 4 mg twice daily were restarted as her home dose because of these symptoms. Over the next few days, she had intermittent periods of restlessness and thrashing of her extremities with disorientation. Prior to this admission, the patient was eating and drinking water but the oral intake became lesser than usual. In addition, the patient was still communicating with staff and her peers. Catalepsy was not observed. Unfortunately, her oral intake became worse and she was combative whenever assessed by the medical team so sedation was required throughout her hospitalization. On hospital day six, she exhibited abnormal vital signs: febrile temperature 103.8°F (reference range: 97-99°F), hypertension 180/89 mmHg (reference range: <120/80 mmHg), tachycardia 138 bpm (reference range: 60-100 bpm), and hypoxemia 91% (reference range: 95%-100%). On physical examination, the patient did not have typical “lead pipe” rigidity; however, her extremities were rigid with passive movement. In addition, she appeared to be responding to internal stimuli with no awareness of her surroundings. That evening, the patient’s fever spiked to 105.9°F and declined to 103.6°F after receiving acetaminophen 650 mg and lorazepam 1 mg. \n\nInvestigation\n\nWhen the patient tested positive for COVID-19, her chest X-ray showed bilateral basal infiltrates which was thought to be atelectasis. On initial assessment, laboratory findings were only significant for a creatinine kinase (CK) of 303 U/L (reference range: 30-200 U/L), which was attributed to agitation. Creatinine and vital signs were normal. Her CK continued to increase to 550 U/L and then later to 668 U/L. By day six, significant laboratory findings included CK of 1096 U/L, along with creatinine 1.44 mg/dL (reference range: 0.84-1.21 mg/dL) and white blood cell count 13.5 x 109 /L (reference range: 4.5-11 x 109 /L). Other significant laboratory values included hypernatremia 159 mmol/L (reference range: 136-145 mmol/L) and hyperchloremia 122 mmol/L (reference range 96-106 mmol/L). On day seven, CK peaked at 4,842 U/L. Autonomic instability, rigidity, rhabdomyolysis, and leukocytosis, along with altered mental status, in the setting of administration of multiple antipsychotic medications, raised suspicion for NMS. Both clozapine and risperidone were held. Other conditions were considered in the differential diagnoses. Catatonia was ruled out because her detailed psychiatric history did not reveal any episodes of catatonia while she was taking neuroleptics. The absence of mutism and the high levels of CK pointed to NMS. Traumatic brain injury was also considered because of the history of repeated head banging, but the CT scan of her brain showed no acute abnormalities. Serotonin syndrome presents the same way but the elevated CK levels do not occur in this condition. Malignant hyperthermia is another condition ruled out because there was no exposure to halogenated inhalational anesthetics or depolarizing muscle relaxants.\n\nTreatment\n\nAll antipsychotic medications were held and the patient was given lorazepam 1 mg as needed. She was transferred to the ICU and intubated for airway protection and to facilitate sedation. Another reason for the intubation was the presence of tachypnea, with a respiratory rate of 20, and labored breathing. At the ICU, she was treated with bromocriptine 2.5 mg per nasogastric tube every 12 hours and dantrolene 100 mg intravenously every six hours for the next five days. Empiric cefepime was started, as sepsis and meningitis were also considered as differentials, but discontinued when lumbar puncture and blood cultures eventually returned negative. Fever, tachycardia, and hypertension had resolved upon supportive care and intubation. CK and creatinine began to downtrend over the next week. Around this time, the CK went down to 242 U/L and her creatinine went down to 0.36 mg/dL. The patient was extubated two weeks later; however, repeat blood cultures were positive for methicillin-susceptible Staphylococcus aureus (MSSA). She remained in the hospital for treatment with cefazolin. Patient was re-evaluated by the psychiatrist, who documented her delirium had improved. Her mood and psychotic symptoms did not exacerbate and remained stable. She was observed to be eating and drinking fluids and she engaged during the evaluations. After completion of her treatment, she was then transferred to the state psychiatric hospital for long-term care.\n\nDiscussion\n\nEvidence shows that in the progression of symptoms for NMS, altered mental status appears first before hyperthermia and autonomic dysfunction in over 80% of cases [5]. This is shown through the patient’s worsening mental status after day two of hospitalization when clozapine and risperidone were re-introduced to her medication regimen. The keys to her diagnosis of NMS were hyperpyrexia and rhabdomyolysis, exhibited by elevated CK and creatinine. She also presented with rigidity and autonomic instability. Hypernatremia and hyperchloremia were secondary to dehydration from spiking fevers. CT scan of the brain did not show any acute abnormalities. This patient had been treated with antipsychotics in a state psychiatric facility for over 20 years and had no prior history of NMS. Patients at the highest risk of NMS are elderly males on typical antipsychotics, such as haloperidol and fluphenazine, due to their potent dopamine antagonism or those who switch to a higher dose of antipsychotic [1].\n\nSome COVID-19 patients without typical symptoms (fever, cough, diarrhea) present only with neurological symptoms [2]. In this case, the patient did not have any respiratory symptoms with only mild atelectasis on chest X-ray on initial presentation. Subsequently, she presented with altered mental status, agitation, and restlessness after infection with COVID-19. Reports of nonspecific central nervous system manifestations of COVID-19 are increasing, including headache, impaired consciousness, delirium, encephalopathy, seizures, and loss of taste and smell due to direct viral infection or inflammation of the CNS [6]. On a cellular level, it has been proposed that severe acute respiratory syndrome coronavirus (SARS-CoV-2) utilizes ACE2 receptors on host cells for its internalization [6]. These receptors are encoded in astrocytes, oligodendrocytes, and neurons, as well as other neurological structures in the brain, leading to the speculation that COVID-19 has the potential to infect neurons and glial cells [6]. It is possible that COVID-19 infection increases the susceptibility of patients prescribed antipsychotics to NMS as an additional risk factor. However, the exact mechanism is still unknown.\n\nAll antipsychotics may trigger NMS regardless of the patient's age, gender, or ethnicity. It is a potential side effect of second-generation antipsychotics which includes both clozapine and risperidone [7]. Atypical antipsychotics were assumed to be free from risks of NMS. It should be considered and ruled out if hyperpyrexia occurs during the course of antipsychotic treatment. This patient contracted COVID-19 sometime before she was admitted and her antipsychotics were initially held when first seen but later resumed when she continued to be agitated. Because of the emergence of other issues including elevated CK levels, autonomic instability, rigidity, and severe altered mental state, NMS was considered and her antipsychotics were held. \n\nConclusions\n\nThe mechanism explaining the occurrence of NMS in COVID-19 patients is still unclear, but this infection may be a risk factor for the presentation of NMS in this patient. The mechanism of SARS-CoV-2 as a risk factor for NMS needs to be investigated further. However, if their infection status is known, psychiatric patients should be given neuroleptics with caution and carefully considered for the development of this rare condition.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Neuroleptic malignant syndrome: a review for neurohospitalists Neurohospitalist Berman BD 41 47 1 2011 23983836\n2 Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China JAMA Neurol Mao L Jin H Wang M 683 690 77 2020 32275288\n3 Neuroleptic malignant syndrome in a COVID-19 patient Brain Behav Immun Kajani R Apramian A Vega A Ubhayakar N Xu P Liu A 28 29 88 2020 32425332\n4 Neuroleptic malignant syndrome in patients with COVID-19 Am J Emerg Med Soh M Hifumi T Isokawa S Shimizu M Otani N Ishimatsu S 2243 2241 38 2020\n5 Progression of symptoms in neuroleptic malignant syndrome J Nerv Ment Dis Velamoor VR Norman RM Caroff SN Mann SC Sullivan KA Antelo RE 168 173 182 1994 7906709\n6 Central nervous system manifestations associated with COVID-19 Curr Neurol Neurosci Rep Divani AA Andalib S Biller J 1 20 20 2020 32020300\n7 Second-generation antipsychotics and neuroleptic malignant syndrome: a systematic review and case report analysis Drugs RD Belvederi Murri M Guaglianone A Bugliani M 45 62 15 2015\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(2)",
"journal": "Cureus",
"keywords": "altered mental state; antipsychotic medication; covid 19; neuroleptic malignant syndrome; neuroleptic medications",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e13428",
"pmc": null,
"pmid": "33763319",
"pubdate": "2021-02-18",
"publication_types": "D002363:Case Reports",
"references": "23983836;25578944;32425332;32473756;7906709;32275288",
"title": "Neuroleptic Malignant Syndrome After Re-introduction of Atypical Antipsychotics in a COVID-19 Patient.",
"title_normalized": "neuroleptic malignant syndrome after re introduction of atypical antipsychotics in a covid 19 patient"
} | [
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"companynumb": "US-ACCORD-222361",
"fulfillexpeditecriteria": "1",
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"actiondrug": "1",
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"activesubstancename": "ESCITALOPRAM OXALATE"
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"drugadditional": null,
... |
{
"abstract": "The objective was to summarize pregnancy and fetal/postnatal outcomes following maternal perampanel exposure using preclinical and clinical data, and to use physiologically based pharmacokinetic (PBPK) modeling to improve understanding of perampanel pharmacokinetics (PK) during pregnancy.\n\n\n\nPreclinical developmental studies with perampanel were conducted in pregnant rats and rabbits. Clinical data were collated from the Eisai global perampanel safety database, comprising reports of perampanel exposure during pregnancy from routine clinical settings, interventional studies, and non-interventional post-marketing studies, searched for events coded to Medical Dictionary for Regulatory Activities (MedDRA) high-level group terms of Pregnancy, Labor, Delivery, and Postpartum Conditions and/or the Standardized MedDRA Query terms of Congenital, Familiar, and Genetic Disorders. A PBPK model was used to predict clinical perampanel PK throughout pregnancy.\n\n\n\nPreclinical studies indicated that perampanel may be linked with post-implantation loss and/or some specific physical development delays but not fertility and early embryonic development. As of August 31, 2018, 96 pregnancies in 90 women receiving perampanel had been reported. No concomitant medications were reported in 26 (28.9%) women taking perampanel. Overall, 43 pregnancies reached full term (all normal live births), 28 did not reach term (induced abortion, n = 18; spontaneous miscarriage, n = 6; incomplete spontaneous miscarriage, n = 2; premature delivery, n = 1; stillbirth [Fallot's tetralogy], n = 1), 18 were lost to follow-up, and seven were ongoing at data cut-off. Adverse events were reported in five full-term neonates (low Apgar score, n = 2; fatal neonatal aspiration, n = 1; cystic fibrosis and congenital deafness, n = 1; poor sucking reflex and shallow breathing, n = 1). PK simulations predicted perampanel exposure decreases throughout pregnancy and is up to four- and three-fold lower towards the end of pregnancy compared with non-pregnant women for total and unbound perampanel, respectively.\n\n\n\nThese data provide preliminary information on perampanel use during pregnancy and should be interpreted with caution. Further outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure.",
"affiliations": "NYU Langone Comprehensive Epilepsy Center, New York, New York, USA.;Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.;Eisai Inc., Woodcliff Lake, New Jersey, USA.;Eisai Inc., Woodcliff Lake, New Jersey, USA.;Department of Neuroscience, Central Clinical School, The Alfred Hospital, Monash University, Melbourne, Victoria, Australia.",
"authors": "Vazquez|Blanca|B|0000-0002-1151-6681;Tomson|Torbjörn|T|0000-0003-0554-5352;Dobrinsky|Cindy|C|;Schuck|Edgar|E|;O'Brien|Terence J|TJ|0000-0002-7198-8621",
"chemical_list": "D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; C551441:perampanel",
"country": "United States",
"delete": false,
"doi": "10.1111/epi.16821",
"fulltext": "\n==== Front\nEpilepsia\nEpilepsia\n10.1111/(ISSN)1528-1167\nEPI\nEpilepsia\n0013-9580\n1528-1167\nJohn Wiley and Sons Inc. Hoboken\n\n33666943\n10.1111/epi.16821\nEPI16821\nFull‐length Original Research\nFull‐length Original Research\nPerampanel and pregnancy\nVAZQUEZ et al.\nVazquez Blanca https://orcid.org/0000-0002-1151-6681\n1 Blanca.Vazquez@nyulangone.org\n\nTomson Torbjörn https://orcid.org/0000-0003-0554-5352\n2\nDobrinsky Cindy 3\nSchuck Edgar 3\nO’Brien Terence J. https://orcid.org/0000-0002-7198-8621\n4 5\n1 NYU Langone Comprehensive Epilepsy Center New York New York USA\n2 Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden\n3 Eisai Inc. Woodcliff Lake New Jersey USA\n4 Department of Neuroscience, Central Clinical School The Alfred Hospital, Monash University Melbourne Victoria Australia\n5 Department of Medicine The Royal Melbourne Hospital, The University of Melbourne Parkville Victoria Australia\n* Correspondence\nBlanca Vazquez, NYU Langone Comprehensive Epilepsy Center, 223 East 34th Street, New York, NY 10016, USA.\n\n05 3 2021\n3 2021\n62 3 10.1111/epi.v62.3 698708\n15 12 2020\n15 7 2020\n31 12 2020\n© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.\nThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ 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.\n\nAbstract\n\nObjective\n\nThe objective was to summarize pregnancy and fetal/postnatal outcomes following maternal perampanel exposure using preclinical and clinical data, and to use physiologically based pharmacokinetic (PBPK) modeling to improve understanding of perampanel pharmacokinetics (PK) during pregnancy.\n\nMethods\n\nPreclinical developmental studies with perampanel were conducted in pregnant rats and rabbits. Clinical data were collated from the Eisai global perampanel safety database, comprising reports of perampanel exposure during pregnancy from routine clinical settings, interventional studies, and non‐interventional post‐marketing studies, searched for events coded to Medical Dictionary for Regulatory Activities (MedDRA) high‐level group terms of Pregnancy, Labor, Delivery, and Postpartum Conditions and/or the Standardized MedDRA Query terms of Congenital, Familiar, and Genetic Disorders. A PBPK model was used to predict clinical perampanel PK throughout pregnancy.\n\nResults\n\nPreclinical studies indicated that perampanel may be linked with post‐implantation loss and/or some specific physical development delays but not fertility and early embryonic development. As of August 31, 2018, 96 pregnancies in 90 women receiving perampanel had been reported. No concomitant medications were reported in 26 (28.9%) women taking perampanel. Overall, 43 pregnancies reached full term (all normal live births), 28 did not reach term (induced abortion, n = 18; spontaneous miscarriage, n = 6; incomplete spontaneous miscarriage, n = 2; premature delivery, n = 1; stillbirth [Fallot’s tetralogy], n = 1), 18 were lost to follow‐up, and seven were ongoing at data cut‐off. Adverse events were reported in five full‐term neonates (low Apgar score, n = 2; fatal neonatal aspiration, n = 1; cystic fibrosis and congenital deafness, n = 1; poor sucking reflex and shallow breathing, n = 1). PK simulations predicted perampanel exposure decreases throughout pregnancy and is up to four‐ and three‐fold lower towards the end of pregnancy compared with non‐pregnant women for total and unbound perampanel, respectively.\n\nSignificance\n\nThese data provide preliminary information on perampanel use during pregnancy and should be interpreted with caution. Further outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure.\n\nadverse events\nepilepsy\nperampanel\nphysiologically based pharmacokinetics\npregnancy\nEisai Inc. source-schema-version-number2.0\ncover-dateMarch 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.0 mode:remove_FC converted:23.03.2021\n==== Body\nKey Points\n\nPreclinical data indicated that perampanel may be associated with post‐implantation loss and/or some specific physical development delays\n\nOf 96 pregnancies evaluated in 90 women exposed to perampanel, 43 reached full term; 26 (28.9%) women reported no concomitant ASM use\n\nOf 71 pregnancies with a known outcome, there was one report of stillbirth with Fallot’s tetralogy (concomitant levetiracetam reported)\n\nPharmacokinetic simulations suggested a possible three‐ to four‐fold decrease in perampanel exposure over the course of a pregnancy\n\nThe small size and 19% lost to follow‐up in this preliminary sample require more data to estimate prevalence of adverse pregnancy outcomes\n\n1 INTRODUCTION\n\nWomen with epilepsy have been estimated to account for up to 0.7% of pregnant women. 1 Due to the likelihood of seizures and associated risks therewith, and an increased risk of pregnancy‐related complications compared with women without epilepsy, 2 , 3 women with epilepsy frequently take anti‐seizure medication (ASM) during pregnancy. 4 , 5 , 6 Therefore, it is important to assess the safety of exposure to ASMs in utero, so that treatment with ASMs during pregnancy can balance adequate seizure control with the potential risk of adverse effects on the exposed fetus. 2 Pharmacokinetic (PK) changes of ASMs during pregnancy, such as enhanced drug elimination and decreased drug exposure compared with non‐pregnant women, are important to consider, as they may impact both fetal exposure and maternal seizure control. 5 , 7 However, there is limited information about PK changes of many of the newer ASMs during pregnancy. 5 , 7 , 8\n\nMoreover, use of ASMs in pregnant women is increasing, with a five‐fold increase in the use of newer ASMs (i.e., those approved in the United States since 1993) by pregnant women during the early‐to‐mid 2000s, whereas use of older ASMs has remained generally stable. 6 Additionally, some ASMs may also be used to treat non‐epilepsy indications, including bipolar disorder, neuropathic pain, and fibromyalgia, 9 and a substantial increase in the frequency of ASM use in pregnant women for non‐epilepsy indications, including psychiatric diagnoses and pain disorders, has been observed during the past 2 decades. 6 , 10 The prospective European Registry of Antiepileptic Drugs and Pregnancy (EURAP) registry noted marked changes in the use of different ASMs over a 14‐year period (2000–2013), with increased use of lamotrigine and levetiracetam and a decrease in the use of valproate and carbamazepine. 11 A 27% decrease in the prevalence of major congenital malformations was observed in parallel with this shift in ASM utilization, and there was no indication of an increase in the proportion of pregnancies with poor seizure control. 11 An analysis of data from the Australian Register of Antiepileptic Drugs in Pregnancy revealed that approximately half of women with epilepsy who received ASMs throughout pregnancy still experienced at least one seizure during their pregnancy. 12\n\nPerampanel is a once‐daily ASM that has been licensed for clinical use in the United States since 2012 for focal‐onset seizures (previously known as partial‐onset seizures) with or without focal to bilateral tonic–clonic seizures (previously known as secondarily generalized seizures), and generalized tonic–clonic seizures (previously known as primary generalized tonic–clonic seizures). 13 , 14 Perampanel is eliminated primarily via cytochrome P450 3A (CYP3A) metabolism, and concomitant enzyme‐inducing ASMs reduce exposure by ~50%–67%. 14 In vitro studies have shown that at clinically relevant concentrations (20–2000 ng/ml), perampanel is ~95%–96% bound to plasma proteins. 14\n\nThere are no adequate studies specifically in pregnant women treated with perampanel to assess outcomes of pregnancies that are exposed to perampanel. 14 Additionally, unknown effects of pregnancy on perampanel PK limit our understanding of whether dose adjustments may be necessary to maintain seizure control during pregnancy and/or reduce the likelihood of fetal adverse events (AEs). The aim of the analyses presented here is to summarize pregnancy and fetal/postnatal outcomes following maternal exposure to perampanel using preclinical and clinical data, and to gain a greater understanding of how perampanel PK may be affected by pregnancy through the use of physiologically based PK (PBPK) modeling.\n\n2 MATERIALS AND METHODS\n\n2.1 Preclinical data in pregnancy\n\nPreclinical studies were performed in accordance with Japanese guidelines in place at the time of study initiation. 15 , 16\n\nDevelopmental studies of perampanel were conducted in pregnant animals in line with licensing requirements. Dose‐ranging (0, 10, 30, and 60 mg/kg/day) and pivotal (0, 1, 3, and 10 mg/kg/day) embryo‐fetal development studies were performed in Sprague–Dawley rats (n = 7 and n = 20 per group, respectively) and New Zealand white rabbits (n = 5 and n = 20 per group, respectively), with perampanel administered orally on gestation Days 6–17 and Days 6–18 for rats and rabbits, respectively.\n\nDose‐ranging and pivotal pre‐ and postnatal development studies were performed in Sprague–Dawley rats (0, 1, 3, and 10 mg/kg/day). Perampanel was administered orally from gestation Day 6 to postnatal Day 6 in the dose‐ranging study (n = 8 per group) and from gestation Day 6 to postnatal Day 20 (weaning) in the pivotal study (n = 20 per group).\n\n2.2 Safety review in pregnancy\n\nA search of the Eisai global safety database for perampanel was performed for events coded to the Medical Dictionary for Regulatory Activities (MedDRA) high‐level group terms of Pregnancy, Labor, Delivery, and Postpartum Conditions, and/or the Standardized MedDRA Query terms of Congenital, Familiar, and Genetic Disorders. This analysis included all reports of exposure to perampanel during pregnancy from spontaneous sources (routine clinical settings) as well as solicited reports from interventional clinical studies and non‐interventional post‐marketing studies, up until the cut‐off date of August 31, 2018. Pregnancies from interventional clinical studies where the woman was reported to be exposed to placebo rather than perampanel, or where exposure only occurred post‐partum (e.g., during breastfeeding), and unpublished reports received from EURAP were excluded (no other registry data were included in the database). Pregnancies where perampanel exposure occurred via the father were evaluated separately from those with maternal perampanel exposure. Reported pregnancies were followed up every trimester and with a form requesting details of the final pregnancy outcome (including selection of category from the following: normal, abnormal baby, congenital abnormality, and died during perinatal period). There was no specific protocol for classification of congenital malformations, nor was there a requirement for assessment by a teratologist in cases of suspected abnormal outcomes. Any additional investigation was at the discretion of the treating physician, who was also responsible for reporting the pregnancy outcome. Outcomes for pregnancies reported before August 31, 2018 were updated in line with any follow‐up reports received by May 27, 2019 (additional information related to exposure in one woman during breastfeeding was received on June 17, 2019). In cases where no outcome was recorded by May 27, 2019, these pregnancies were either considered ongoing (if last reported as ongoing any time from January 2018 onwards) or lost to follow‐up (if last reported as ongoing any time prior to January 2018, or where dates of the pregnancy were unknown).\n\nThe clinical studies with perampanel in the global safety database included data from patients with or without epilepsy (focal‐onset or generalized tonic–clonic seizures), and healthy volunteers from Phase 1 studies. Pregnancy was an exclusion criterion for all these studies. The protocols for each study required patients to be abstinent or to use at least one medically acceptable method of contraception starting at Visit 1, throughout the entire study period, and for 2 months after the last dose of study drug. Pregnancy was captured as a treatment‐emergent AE, and confirmed with urine and serum pregnancy tests.\n\n2.3 PK modeling predictions in pregnancy\n\nA PBPK model for perampanel was developed using Simcyp® version 15.1. A previous model developed with Simcyp® version 11 17 was used as the starting point. The previous model predicted a slightly longer half‐life for perampanel than that observed clinically; thus, the following modifications were made to correct this discrepancy: (1) a middle‐out approach was used, where clinical total drug clearance values from clinical trial data (Study 005 17 ) were escalated to intrinsic hepatic drug clearance values using the retrograde calculator, (2) the scalar for tissue‐to‐plasma partition coefficients (Kps scalar) was manually adjusted from 1.0 to 0.75 to improve fit to the clinical data, (3) active uptake into hepatocytes was changed from 1.0 to 1.5, and (4) the absorption model was changed from the advanced dissolution absorption and metabolism model 18 to a first‐order absorption model with predicted inputs. The effective permeability in vivo (Peff = 7.73 × 10−4 cm/s), the absorption rate constant (ka = 3.38 h−1), and fraction absorbed (F = 0.999) were predicted by Simcyp® with the mechanistic permeability model (MechPeff 19 , 20 ) based on perampanel's partition co‐efficient, logPoctanol:water, of 2.86. 17 The model was evaluated by simulating clinical PK of single and multiple doses of perampanel in 100 healthy volunteers (10 trials each with 10 virtual subjects aged 20–50 years; 1:1 ratio of males to females). These predictions were compared with PK profiles for single oral doses of perampanel administered at 1, 2, 4, 6, or 8 mg and once‐daily doses of oral perampanel administered at 1, 2, 4, or 6 mg for 14 days that were observed in several clinical studies.\n\nSimcyp® supports modeling and simulations to assess potential PK‐related effects of pregnancy. The in‐built Simcyp® Pregnancy population file, with an updated CYP3A4 ontogeny (Figure S1), 21 was used to predict clinical PK in 25 pregnant women (five trials each with five virtual subjects aged 20–45 years) for single oral doses of perampanel 8 mg administered during pregnancy at Weeks 0, 10, 19, 28, and 36, and once‐daily doses of oral perampanel 8 mg administered over a 270‐day pregnancy.\n\n3 RESULTS\n\n3.1 Preclinical data of perampanel in pregnancy\n\nIn reproductive toxicology and developmental preclinical studies, perampanel induced developmental toxicity in pregnant rats and rabbits at clinically relevant doses, where 1 mg/kg/day is similar to 8 mg/day in humans. 14 No drug‐related effects of perampanel on fertility and early embryonic development were noted with doses of 1, 10, or 30 mg/kg/day. Dose‐dependent increases in rates of post‐implantation loss were observed with perampanel exposure following 30 and 60 mg/kg in rats and 10, 30, and 60 mg/kg in rabbits. In the pivotal embryo‐fetal development study in rats, perampanel was associated with increased rates of diverticulum of the intestine at all doses tested (1, 3, or 10 mg/kg/day).\n\nIn the dose‐ranging pre‐ and postnatal development study in rats, no developmental toxicity was observed. In the pivotal study, stillbirths were increased and the viability index was decreased for the mid‐ and high‐level doses (3 and 10 mg/kg/day). Behavioral and reproductive development of the offspring were not affected, but some parameters of physical development showed some delay (preputial separation in males and vaginal opening in females) in offspring born to mothers who received 10/mg/kg/day, which are probably secondary to the pharmacology‐based central nervous system effects of perampanel.\n\n3.2 Clinical data of pregnancy events and outcomes with perampanel\n\nAt the data cutoff of August 31, 2018, 96 pregnancies had been reported in 90 women aged 17–48 (age was unknown in 21 women) exposed to perampanel globally, including six women who had two pregnancies each. These pregnancies included 33 from patients enrolled in clinical studies or from other solicited reports, and 63 spontaneous reports from routine clinical settings. Perampanel dosing was discontinued or modified according to clinical need during the pregnancy in some women. The demographic characteristics and sources of clinical data for the women included in this analysis are shown in Table 1. Excluding three instances of perampanel exposure via a partner, perampanel was reported to have been taken by 26 of 90 (28.9%) women with no concomitant ASM use recorded (due to limited information provided in most cases, these women cannot be confirmed as receiving monotherapy). Perampanel administered with one concomitant ASM was reported for 24 of 90 (26.7%) women, and with ≥2 concomitant ASMs for 38 of 90 (42.2%) women; concomitant ASM use was unknown in two (2.2%) women, as only the neonatal records were available. The majority of patients from clinical trials included in this analysis were from trials that enrolled patients with focal‐onset seizures. For spontaneously reported pregnancies, the seizure types that patients had were not usually recorded. An additional three pregnancies were identified following paternal exposure to perampanel.\n\nTABLE 1 Demographic characteristics and sources of clinical data for women exposed to perampanel during pregnancy\n\nCharacteristic\tFrom clinical studies or solicited reports, n = 30\tFrom spontaneous reports, n = 60 a\tTotal, n = 90\t\nCountry of origin, n (%)\t\nJapan\t3 (10.0)\t9 (15.0)\t12 (13.3)\t\nSpain\t0 (0)\t12 (20.0)\t12 (13.3)\t\nFrance\t0 (0)\t8 (13.3)\t8 (8.9)\t\nUnited Kingdom\t1 (3.3)\t7 (11.7)\t8 (8.9)\t\nRussia\t1 (3.3)\t6 (10.0)\t7 (7.8)\t\nUnited States of America\t4 (13.3)\t3 (5.0)\t7 (7.8)\t\nChina\t4 (13.3)\t0 (0)\t4 (4.4)\t\nGermany\t0 (0)\t4 (6.7)\t4 (4.4)\t\nAustralia\t2 (6.7)\t1 (1.7)\t3 (3.3)\t\nAustria\t0 (0)\t3 (5.0)\t3 (3.3)\t\nSouth Korea\t3 (10.0)\t0 (0)\t3 (3.3)\t\nLatvia\t3 (10.0)\t0 (0)\t3 (3.3)\t\nOther b\t9 (30.0)\t7 (11.7)\t16 (17.8)\t\nAge group at time of pregnancy, n (%) c\t\n<20 years\t2 (6.7)\t5 (8.3)\t7 (7.8)\t\n20–24 years\t7 (23.3)\t6 (10.0)\t13 (14.4)\t\n25–29 years\t5 (16.7)\t12 (20.0)\t17 (18.9)\t\n30–34 years\t5 (16.7)\t8 (13.3)\t13 (14.4)\t\n35–39 years\t6 (20.0)\t10 (16.7)\t16 (17.8)\t\n≥40 years\t3 (10.0)\t0 (0)\t3 (3.3)\t\nUnknown\t2 (6.7)\t19 (31.7)\t21 (23.3)\t\nNumber of reported concomitant ASMs, n (%)\t\n0\t5 (16.7)\t21 (35.0) d\t26 (28.9)\t\n1\t6 (20.0)\t18 (30.0)\t24 (26.7)\t\n2\t9 (30.0) e\t11 (18.3)\t20 (22.2)\t\n≥3\t10 (33.3)\t8 (13.3)\t18 (20.0)\t\nUnknown\t0 (0)\t2 (3.3)\t2 (2.2)\t\nClinical data source, n (%)\t\nClinical studies f\t30 (100.0)\t0 (0)\t30 (33.3)\t\nSpontaneous reports\t0 (0)\t60 (100.0)\t60 (66.7)\t\nAbbreviations: ASM, anti‐seizure medication; n, number of women with pregnancies exposed to perampanel.\n\na Spontaneous reports of pregnancies in routine clinical practice.\n\nb Fewer than three patients each were from the following countries: Argentina, Belgium, Canada, Denmark, Estonia, India, Ireland, Israel, Lithuania, Mexico, and Slovakia.\n\nc For women with multiple pregnancies, age is recorded as age during the first perampanel‐exposed pregnancy.\n\nd No concomitant ASMs were reported; however, due to limited information being provided in most cases, monotherapy cannot be confirmed.\n\ne Includes one woman who received two ASMs during her first pregnancy and one ASM during a second pregnancy.\n\nf Studies 048 (NCT02279485), 207 (NCT00368472), 210 (NCT00154063), 304 (NCT00699972), 307 (NCT00735397), 332 (NCT01393743), 335 (NCT01618695), 342 (NCT03201900), 401 (NCT01871233), 402 (NCT02033902), 502 (NCT03059329), 505 (NCT02722590), and others.\n\nJohn Wiley & Sons, Ltd\n\nOf the 96 pregnancies reported in women receiving perampanel, 43 reached full term, 28 did not go to term, 18 were lost to follow‐up, and seven were ongoing at data cutoff (Table 2). Of the pregnancies that went to full term, all 43 resulted in normal live births. Of the pregnancies that did not go to term, 18 cases were induced abortions, six cases were spontaneous miscarriages, two cases were incomplete spontaneous miscarriages, one case resulted in premature delivery, and one resulted in stillbirth due to Fallot’s tetralogy (Table 2). The reasons for the decision to have an induced abortion were not usually known, but most were considered by the investigator or treating physician to be not related to perampanel; causality in two spontaneous reports was not reported by the treating physician, and the cases were therefore assumed to be possibly related to perampanel. Of the six women who had two perampanel‐exposed pregnancies, one woman had two full‐term normal births. Three women had one full‐term birth each, plus a spontaneous abortion, incomplete spontaneous abortion, or an unknown outcome, and two women had both an induced abortion and a spontaneous abortion. Of the three pregnancies with paternal exposure to perampanel, two resulted in normal live births; the outcome of the third pregnancy was unknown (Table 2).\n\nTABLE 2 Pregnancy outcomes in the global safety database\n\nOutcome\tFrom clinical studies or solicited reports\tFrom spontaneous reports a\tTotal\t\nMaternal exposure to perampanel\tn = 33\tn = 63\tn = 96\t\nReached full term\t8\t35\t43\t\nNormal live birth\t8\t35 b\t43\t\nDid not reach full term\t22\t6\t28\t\nInduced abortion\t15 c\t3\t18\t\nSpontaneous miscarriage\t5\t1\t6\t\nIncomplete spontaneous miscarriage\t2\t0\t2\t\nPremature delivery\t0\t1\t1\t\nStillbirth (Fallot’s tetralogy)\t0\t1\t1\t\nLost to follow‐up d\t2\t16\t18\t\nOngoing pregnancy e\t1\t6\t7\t\nPaternal exposure to perampanel\tn = 2\tn = 1\tn = 3\t\nReached full term\t2\t0\t2\t\nNormal live birth\t2\t0\t2\t\nLost to follow‐up e\t0\t1\t1\t\na Spontaneous reports of pregnancies in routine clinical practice.\n\nb Includes two cases where babies were exposed to perampanel during pregnancy and via breastfeeding.\n\nc Includes one case of benign hydatidiform mole and one case of ectopic pregnancy.\n\nd Cases that were last reported as ongoing any time prior to January 2018, and where no subsequent updates have been received, or where dates of pregnancy were unknown.\n\ne Cases that were last reported as ongoing any time from January 2018 onward, and where no subsequent updates have been received.\n\nJohn Wiley & Sons, Ltd\n\nAEs were reported in five of the 43 babies whose mothers received perampanel that reached full term: low Apgar score in two babies, fatal neonatal aspiration in one baby, cystic fibrosis and congenital deafness in one baby, and poor sucking reflex and shallow breathing in one baby (Table 3). In the cases where the relationship of AEs to perampanel was reported, poor sucking reflex and shallow breathing (reported in one baby who was also exposed to perampanel via breastfeeding) were considered possibly related to perampanel by the treating physician, whereas fatal neonatal aspiration, congenital deafness, and cystic fibrosis were not considered by the treating physician to be related to perampanel. In the case of fatal neonatal aspiration, the mother discontinued perampanel at ~2 months of gestation following the positive pregnancy test; the baby was born by Caesarian section at 39 of weeks' gestation, and the investigator considered that “the death was probably due to aspiration of fluid during birth.\" The baby with cystic fibrosis and congenital deafness was born to parents with congenital deafness who were carriers of the gene for cystic fibrosis. The relationship between perampanel exposure and low Apgar score in both babies was not reported, and therefore assumed to be possibly related to perampanel. Concomitant ASM use was reported for the mothers of the babies with fatal neonatal aspiration (carbamazepine and clobazam), poor sucking reflex and shallow breathing (clonazepam), and cystic fibrosis and congenital deafness (two unspecified ASMs). No concomitant ASMs were reported for the mothers of either baby with low Apgar score. No other birth defects or fetal malformations were reported in babies who reached full term.\n\nTABLE 3 Adverse events in babies from pregnancies with maternal exposure to perampanel that reached full term (n = 43)\n\nBaby\tOutcome\tCausality a\tPerampanel dose\tSource b\tConcomitant ASMs taken by mother\t\n1\tLow Apgar score\tNot reported c\t6 mg daily\tSpontaneous\tNone reported\t\n2\tLow Apgar score\tNot reported c\t8 mg daily\tSpontaneous\tNone reported\t\n3\tNeonatal aspiration (fatal)\tNot related to perampanel\t12 mg daily d\tClinical study\tCarbamazepine, clobazam\t\n4 e\tCystic fibrosis\tNot related to perampanel\tUnknown\tSpontaneous\tTwo unspecified ASMs\t\n\tCongenital deafness\tNot related to perampanel\t\t\t\t\n5 f\tPoor sucking reflex\tPossibly related to perampanel\t2 to >12 mg daily g\tSpontaneous\tClonazepam\t\n\tShallow breathing\tPossibly related to perampanel\t\t\t\t\nAbbreviation: ASM, antiseizure medication.\n\na As considered by the investigator/reporting physician.\n\nb Solicited reports of pregnancies from clinical studies/other solicited sources or spontaneous reports of pregnancies in routine clinical practice.\n\nc Not reported and therefore assumed to be possibly related.\n\nd Perampanel was discontinued at the time of positive pregnancy test (7 months prior to full‐term delivery by Caesarian section).\n\ne Both parents had congenital deafness and were carriers of the gene for cystic fibrosis.\n\nf This baby was also exposed to perampanel via breastfeeding.\n\ng Perampanel dose was increased to 6 mg/day following positive pregnancy test, to 10 mg/day approximately 1 month before birth, and at the mother's own discretion exceeded 12 mg/day prior to labor before reducing to 10 mg/day after the birth. Maternal perampanel plasma concentration was increased at the time of birth (2510 ng/ml).\n\nJohn Wiley & Sons, Ltd\n\nThe AEs related to pregnancies that did not reach full term were benign hydatidiform mole and ectopic pregnancy (one woman each, both of whom had an induced abortion; perampanel 6 mg daily and 2–4 mg daily, respectively), and stillbirth with Fallot’s tetralogy at the 30th week of pregnancy in one baby (perampanel 2–6 mg daily until the 11th week of pregnancy). None of these AEs, nor their associated induced abortions, was considered by the investigator or reporting physician to be related to perampanel, although no further explanation was provided. Use of concomitant ASM(s) was reported for all three of these mothers (benign hydatidiform mole: carbamazepine, clobazam, lamotrigine; ectopic pregnancy: lorazepam, levetiracetam, lacosamide, clonazepam; Fallot’s tetralogy: levetiracetam).\n\nThere were two cases of babies who were exposed to perampanel via breastfeeding in addition to in utero exposure to perampanel. As mentioned, poor sucking reflex and shallow breathing were reported in one of these babies. This baby was suspected to have withdrawal syndrome of perampanel and had a perampanel plasma concentration of 264 ng/ml 4 h after birth; the perampanel plasma concentration in the mother was 2510 ng/ml. Maternal concomitant clonazepam use was also reported for this pregnancy, and the baby had a clonazepam concentration of 2 mg/ml 4 h after birth. The plasma perampanel concentration in the baby decreased to 224 ng/ml 7 days after birth and to 124 ng/ml 14 days after birth; maternal plasma perampanel concentration had decreased to 845 ng/ml within approximately 2 months of the birth. No AEs were reported for the other baby who was exposed to perampanel via breastfeeding, and no information was recorded on the plasma concentrations of perampanel in that baby or its mother. No concomitant medication use was reported for the mother of this baby.\n\n3.3 PK modeling of perampanel in pregnancy\n\nDuring model evaluation, the PBPK model for perampanel generally predicted the PK profiles of perampanel well in single‐ and multiple‐dose studies in healthy volunteers (Figure S2). Single‐dose simulations of total and unbound plasma perampanel concentrations at timepoints throughout pregnancy are shown in Figure 1. These simulations predicted that total perampanel exposure is 2.5‐fold lower at the end of pregnancy (Week 36) compared with non‐pregnant women, whereas exposure for unbound (free) perampanel was predicted to be two‐fold lower (Table 4). Multiple‐dose simulations predicted that total perampanel exposure decreases over time during pregnancy, and is up to four‐fold lower toward the end of pregnancy (Week 36) compared with non‐pregnant women (Table 4 and Figure 2). Exposure for unbound perampanel was predicted to be three‐fold lower (Table 4).\n\nFIGURE 1 Single oral dose simulations of perampanel 8 mg administered during pregnancy at Weeks 0, 10, 19, 28, and 36. (A) Mean predicted total plasma concentrations of perampanel. (B) Mean predicted unbound plasma concentrations of perampanel\n\nTABLE 4 Total and free exposure parameters in physiologically based pharmacokinetic simulations in pregnant and non‐pregnant women\n\nGestational age at dosing\tCmax, mg/L\tAUC, mg/L/h\tCmax ratio\tAUC ratio\t\nTotal perampanel exposure for single 8‐mg doses\t\nNot pregnant\t0.180\t12.83\t1.00\t1.00\t\n10 weeks\t0.166\t10.78\t0.92\t0.84\t\n19 weeks\t0.152\t8.12\t0.84\t0.63\t\n28 weeks\t0.139\t6.16\t0.77\t0.48\t\n36 weeks\t0.128\t5.07\t0.71\t0.40\t\nFree perampanel exposure for single 8‐mg doses\t\nNot pregnant\t0.0090\t0.657\t1.00\t1.00\t\n10 weeks\t0.0089\t0.577\t0.99\t0.88\t\n19 weeks\t0.0087\t0.459\t0.97\t0.70\t\n28 weeks\t0.0085\t0.374\t0.94\t0.57\t\n36 weeks\t.0084\t0.333\t0.94\t0.51\t\nPregnancy status\tCmax, mg/L\tAUC, mg/L/h\tCmax ratio\tAUC ratio\t\nTotal perampanel exposure for multiple 8‐mg doses after 270 days of simulations\t\nNot pregnant\t0.53\t55.51\t1.00\t1.00\t\nPregnant\t0.26\t14.01\t0.49\t0.25\t\nFree perampanel exposure for multiple 8‐mg doses after 270 days of simulations\t\nNot pregnant\t0.027\t2.84\t1.00\t1.00\t\nPregnant\t0.017\t0.94\t0.63\t0.33\t\nAbbreviations: AUC, area under the curve; Cmax, maximum concentration.\n\nJohn Wiley & Sons, Ltd\n\nFIGURE 2 Predicted steady‐state pharmacokinetic profiles of perampanel 8 mg administered once daily for 240 days (5760 h) plus post‐dosing follow‐up period in pregnant and non‐pregnant women\n\n4 DISCUSSION\n\nIn the absence of any previously published systematic summary of pregnancy outcomes with perampanel, 14 the preclinical and clinical data presented here may offer some valuable information on the effects of in utero exposure to perampanel, supplemented by PK simulations of perampanel during pregnancy.\n\nThe preclinical studies indicate that perampanel may be linked with post‐implantation loss in pregnant rats and rabbits, and with diverticulum of the intestine and specific delays in physical development when administered to pregnant rats. Preclinical data for carbamazepine, phenytoin, topiramate, and valproate, which are ASMs associated with an increased risk of congenital malformations, reveal similar types of teratogenic effects to those observed clinically, 2 , 22 , 23 , 24 , 25 highlighting the possible relevance of preclinical data for determining potential adverse pregnancy outcomes in humans. Although the risks of congenital malformations are generally considered lower in lamotrigine, levetiracetam, and oxcarbazepine (vs. carbamazepine, phenytoin, topiramate, and valproate), 2 , 26 teratogenic effects have still been observed in preclinical data for these ASMs. 27 , 28 , 29 Thus, there is an unmet need for clinical data to confirm any teratogenic effects of perampanel in human babies.\n\nOf 71 pregnancies with a known outcome following maternal exposure to perampanel, there was one report of stillbirth with Fallot’s tetralogy and one report of fatal neonatal aspiration. Other AEs in babies included low Apgar scores in two babies, and poor sucking reflex and shallow breathing in one baby (all full‐term births). In the case of the baby with poor sucking reflex and shallow breathing, both mother and baby had elevated plasma perampanel concentrations following increased dosing of perampanel (>12 mg/day) at the mother's discretion prior to labor (concomitant clonazepam was also being taken by the mother). Additional AEs related to pregnancies that did not reach full term were benign hydatidiform mole and ectopic pregnancy (one woman each).\n\nThe conclusions that can be drawn from this safety review are limited by the low number of pregnancies included in the analysis. For example, there was a lack of information available in many of the pregnancy reports despite follow‐up at every trimester and until delivery or other outcome; this was particularly true for the reasons for induced abortions and in general for spontaneously reported pregnancies. In addition, causality with perampanel was as noted by the reporting physician, meaning that some AEs such as Fallot’s tetralogy were not attributed as related to perampanel although no alternate explanation was provided. Conversely, some AEs may have been incorrectly attributed as possibly related to perampanel due to expected effects of the drug (observer bias). A sizeable proportion of reported pregnancies (18.8%) were lost to follow‐up, which further reduces the number of pregnancy outcomes collated in this analysis. This highlights a need for the systematic collection of safety data related to epilepsy drug use during pregnancy via pregnancy registries. Finally, the mixed nature of the clinical trial and real‐world settings of perampanel administration for the patients included in this analysis meant that many patients received adjunctive perampanel rather than perampanel monotherapy. As a result, concomitant medications were administered in many, but not all, patients and some of the concomitant ASMs may have reduced perampanel exposure due to PK interactions.\n\nThe PK modeling of perampanel in pregnancy predicted that perampanel exposure may decline by two‐ to four‐fold during pregnancy, not taking into consideration any known effects of concomitant enzyme‐inducing ASMs. These differences predicted in pregnancy are a reflection of several physiological changes that are expected to occur during pregnancy, namely the two‐fold increase in CYP3A activity and an approximate 30% reduction in plasma albumin, which lead to higher free fractions in plasma and higher drug clearance. 5 , 30 Because perampanel is a low‐extraction drug, steady‐state unbound drug concentrations are independent of changes in protein binding, 31 which could explain why the predicted decrease in free perampanel exposure was smaller than that of total perampanel exposure during pregnancy.\n\nPregnancy can result in considerable changes to the PK of ASMs, which may have implications for seizure control and/or exposure of the fetus to ASMs. 7 Decreased serum concentrations for several ASMs, including carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, phenobarbital, and zonisamide, have been observed during pregnancy. 7 For example, total concentration of carbamazepine, which is ~75% protein bound and metabolized similarly to perampanel (mainly via CYP3A4), 32 is reported to decrease over the course of a pregnancy, with a more limited decrease of up to 28% in unbound carbamazepine. However, reported decreases have varied widely between studies (0%–42%), 7 and some studies have reported limited or no clinically significant change in total and free carbamazepine concentrations during pregnancy. 32 , 33 Lamotrigine serum concentration is suppressed during pregnancy by 50%–60% on average, although inter‐patient variability may result in greater decreases. 7 Although total valproate concentrations are reported to fall by up to 40% during late pregnancy compared with pre‐pregnancy, the PK of valproate, an ASM that is highly protein bound (~90%), are somewhat variable, 7 , 34 and data are limited due to the known teratogenic and possible cognitive effects of valproate. 35 , 36 Based on the information presented for the PK modeling of perampanel in pregnancy, the predicted changes appear to exceed those of other ASMs. However, it should be noted that the effect of perampanel in pregnancy has not been investigated in a clinical trial and PK modeling has not been validated against observed perampanel concentrations in pregnant women. PBPK modeling has been used previously to predict the PK of other types of drugs, including dexamethasone, betamethasone, caffeine, midazolam, metoprolol, and rilpivirine, during pregnancy, and in general, the values were found to be comparable with observed PK. 21 , 37 , 38\n\n5 CONCLUSIONS\n\nUnderstanding the implications of ASM use during pregnancy is important due to an increased use in pregnant women. Although the perampanel data reported here are limited, they summarize available information on perampanel use during pregnancy and provide some insights regarding the effects of in utero exposure to perampanel. These preliminary data should be interpreted with caution, as the sample size is limited, and 18.8% of the pregnancies were lost to follow‐up. More outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure. Physicians are encouraged to enroll pregnant women taking perampanel in a pregnancy registry, such as the North American Antiepileptic Drug Pregnancy Registry, EURAP, the UK and Irish Epilepsy & Pregnancy Registers, or the Australian Pregnancy Register, to allow more data to be collected on perampanel exposure during pregnancy. Pregnant women should also be carefully monitored, including drug‐level monitoring, where available, whilst taking perampanel as dose adjustments may be needed in order to maintain a similar level of exposure relative to a non‐pregnancy condition and to prevent the occurrence of breakthrough seizures.\n\nCONFLICT OF INTEREST\n\nB.V. has received research support from Biogen MA Inc., Cavion LLC, Engage Therapeutics Inc., Neurelis, Ovid Therapeutics, SK Life Science Inc., UCB Biopharma SPRL, and UCB Biosciences Inc. T.T. has received speaker's honoraria to his institution from Eisai, Sandoz, Sanofi, Sun Pharmaceutical Industries Ltd, and UCB, and research support from Bial, CURE, Eisai, the European Union (ESBACE), GlaxoSmithKline, Stockholm County Council, Teva, and UCB. C.D. and E.S. are employees of Eisai Inc. T.J.O. has received research and speaker honoraria from Eisai and UCB Pharma.\n\nAUTHOR CONTRIBUTIONS\n\nC.D. was involved in collating and reviewing the data relating to pregnancy events with exposure to perampanel. E.S. was responsible for developing the PBPK model for perampanel and running the pregnancy simulations. All authors were involved in the interpretation of the results, the reviewing and approval of the manuscript, and the decision to submit the article for publication. All authors also confirm accountability for the accuracy and integrity of the work.\n\nSupporting information\n\nFig S1‐S2\n\nClick here for additional data file.\n\nACKNOWLEDGMENTS\n\nFunding for these analyses was provided by Eisai Inc. Rick Dabagian is thanked for assistance with review of the data. Medical writing support, under the direction of the authors, was provided by Rebekah Waters, PhD, and Kirsty Muirhead, PhD, of CMC AFFINITY, McCann Health Medical Communications, funded by, Eisai Inc., in accordance with Good Publication Practice 3 (GPP3) guidelines.\n==== Refs\nREFERENCES\n\n1 Wang M , Li W , Tao Y , Zhao L . Emerging trends and knowledge structure of epilepsy during pregnancy research for 2000–2018: a bibliometric analysis. PeerJ. 2019;7 :e7115.31211023\n2 Veroniki AA , Cogo E , Rios P , Straus SE , Finkelstein Y , Kealey R , et al. Comparative safety of anti‐epileptic drugs during pregnancy: a systematic review and network meta‐analysis of congenital malformations and prenatal outcomes. BMC Med. 2017;15 :95.28472982\n3 MacDonald SC , Bateman BT , McElrath TF , Hernandez‐Diaz S . Mortality and morbidity during delivery hospitalization among pregnant women with epilepsy in the United States. JAMA Neurol. 2015;72 :981–8.26147878\n4 Andrade SE , Gurwitz JH , Davis RL , Chan KA , Finkelstein JA , Fortman K , et al. Prescription drug use in pregnancy. Am J Obstet Gynecol. 2004;191 :398–407.15343213\n5 Pariente G , Leibson T , Carls A , Adams‐Webber T , Ito S , Koren G . Pregnancy‐associated changes in pharmacokinetics: a systematic review. PLoS Med. 2016;13 :e1002160.27802281\n6 Bobo WV , Davis RL , Toh S , Li D‐K , Andrade SE , Cheetham TC , et al. Trends in the use of antiepileptic drugs among pregnant women in the US, 2001–2007: a medication exposure in pregnancy risk evaluation program study. Paediatr Perinat Epidemiol. 2012;26 :578–88.23061694\n7 Tomson T , Landmark CJ , Battino D . Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications. Epilepsia. 2013;54 :405–14.23360413\n8 Reimers A . New antiepileptic drugs and women. Seizure. 2014;23 :585–91.24908139\n9 Bialer M . Why are antiepileptic drugs used for nonepileptic conditions? Epilepsia. 2012;53 (Suppl 7 ):26–33.\n10 Leong C , Mamdani MM , Gomes T , Juurlink DN , Macdonald EM , Yogendran M . Antiepileptic use for epilepsy and nonepilepsy disorders: a population‐based study (1998–2013). Neurology. 2016;86 :939–46.26850976\n11 Tomson T , Battino D , Bonizzoni E , Craig J , Lindhout D , Perucca E , et al. Declining malformation rates with changed antiepileptic drug prescribing: an observational study. Neurology. 2019;93 :e831–40.31391249\n12 Vajda FJ , Hitchcock A , Graham J , O'Brien T , Lander C , Eadie M . Seizure control in antiepileptic drug‐treated pregnancy. Epilepsia. 2008;49 :172–6.18031551\n13 European Medicines Agency . Fycompa®. Annex I: Summary of Product Characteristics, 2017. https://www.ema.europa.eu/en/documents/product‐information/fycompa‐epar‐product‐information_en.pdf. Accessed 1 Oct 2020.\n14 Food and Drug Administration . FYCOMPA®. Prescribing information. September 2020. https://www.fycompa.com/‐/media/Files/Fycompa/Fycompa_Prescribing_Information.pdf. Accessed 1 Oct 2020.\n15 Ministry of the Environment (Japan) . Standards relating to the care and keeping and reducing pain of laboratory animals. https://www.env.go.jp/nature/dobutsu/aigo/2_data/laws/nt_h25_84_en.pdf. Accessed 2 July 2020.\n16 Ministry of the Environment (Japan ). Act on Welfare and Management of Animals (Act No. 105 of October 1, 1973). https://www.env.go.jp/nature/dobutsu/aigo/1_law/files/aigo_kanri_1973_105_en.pdf. Accessed 2 July 2020.\n17 Gidal BE , Maganti R , Laurenza A , Yang H , Verbel DA , Schuck E , et al. Effect of enzyme inhibition on perampanel pharmacokinetics: why study design matters. Epilepsy Res. 2017;134 :41–8.28535410\n18 Jamei M , Turner D , Yang J , Neuhoff S , Polak S , Rostami‐Hodjegan A , et al. Population‐based mechanistic prediction of oral drug absorption. AAPS J. 2009;11 :225–37.19381840\n19 Pade D , Jamei M , Rostami‐Hodjegan A , Turner DB . Application of the MechPeff model to predict passive effective intestinal permeability in the different regions of the rodent small intestine and colon. Biopharm Drug Dispos. 2017;38 :94–114.28214380\n20 Food and Drug Administration . Certara®. FDA workshop. https://www.fda.gov/downloads/drugs/newsevents/ucm503765.pdf. Accessed 19 May 2020.\n21 Ke AB , Milad MA . Evaluation of maternal drug exposure following the administration of antenatal corticosteroids during late pregnancy using physiologically‐based pharmacokinetic modeling. Clin Pharmacol Ther. 2019;106 :164–73.30924921\n22 Food and Drug Administration . Tegretol® and Tegretol®‐XR. Prescribing information. March 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016608s115_018281_s058_018927s055_020234_s047.pdf. Accessed 19 May 2020.\n23 Food and Drug Administration .Dilantin®. Prescribing information. October 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/084349s085lbl.pdf. Accessed 19 May 2020.\n24 Food and Drug Administration . Topamax®. Prescribing information. May 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020505s060,020844s051lbl.pdf. Accessed 19 May 2020.\n25 Food and Drug Administration . Depakene®. Prescribing information. February 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018081s069,018082s052lbl.pdf. Accessed 19 May 2020.\n26 Tomson T , Battino D , Perucca E . Teratogenicity of antiepileptic drugs. Curr Opin Neurol. 2019;32 :246–52.30664067\n27 Food and Drug Administration . Lamictal®. Prescribing information. July 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020241s056,020764s049,022251s020lbl.pdf. Accessed 19 May 2020.\n28 Food and Drug Administration . KEPPRA®. Prescribing information. October 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021035s100,021505s040lbl.pdf. Accessed 19 May 2020.\n29 Food and Drug Administration . Trileptal®. Prescribing information. January 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021014s043lbl.pdf. Accessed 19 May 2020.\n30 Hebert MF , Easterling TR , Kirby B , Carr DB , Buchanan ML , Rutherford T , et al. Effects of pregnancy on CYP3A and P‐glycoprotein activities as measured by disposition of midazolam and digoxin: a University of Washington specialized center of research study. Clin Pharmacol Ther. 2008;84 :248–53.18288078\n31 Gibaldi M , Perrier D . Pharmacokinetics. New York, NY: Marcel Dekker; 1982.\n32 Johnson EL , Stowe ZN , Ritchie JC , Newport DJ , Newman ML , Knight B , et al. Carbamazepine clearance and seizure stability during pregnancy. Epilepsy Behav. 2014;33 :49–53.24632353\n33 Tomson T , Lindbom U , Ekqvist B , Sundqvist A . Epilepsy and pregnancy: a prospective study of seizure control in relation to free and total plasma concentrations of carbamazepine and phenytoin. Epilepsia. 1994;35 :122–30.8112234\n34 Johannessen Landmark C , Farmen AH , Burns ML , Baftiu A , Lossius MI , Johannessen SI , et al. Pharmacokinetic variability of valproate during pregnancy—implications for the use of therapeutic drug monitoring. Epilepsy Res. 2018;141 :31–7.29453075\n35 Tomson T , Marson A , Boon P , Canevini MP , Covanis A , Gaily E , et al. Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia. 2015;56 :1006–19.25851171\n36 European Medicines Agency . PRAC recommends strengthening the restrictions on the use of valproate in women and girls. https://www.ema.europa.eu/en/documents/press‐release/prac‐recommends‐strengthening‐restrictions‐use‐valproate‐women‐girls_en.pdf. Accessed 10 Oct 2014.\n37 Gaohua L , Abduljalil K , Jamei M , Johnson TN , Rostami‐Hodjegan A . A pregnancy physiologically based pharmacokinetic (p‐PBPK) model for disposition of drugs metabolized by CYP1A2, CYP2D6 and CYP3A4. Br J Clin Pharmacol. 2012;74 :873–85.22725721\n38 Gockenbach M . Physiologically‐based pharmacokinetic modeling of rilpivirine during pregnancy. 2019. http://regist2.virology-education.com/presentations/2019/20AntiviralPK/33_Gockenbach.pdf. Accessed 27 Jan 2021.\n\n",
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"issn_linking": "0013-9580",
"issue": "62(3)",
"journal": "Epilepsia",
"keywords": "adverse events; epilepsy; perampanel; physiologically based pharmacokinetics; pregnancy",
"medline_ta": "Epilepsia",
"mesh_terms": "D000328:Adult; D000818:Animals; D000927:Anticonvulsants; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy; D005260:Female; D006801:Humans; D008875:Middle Aged; D009570:Nitriles; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011728:Pyridones; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D055815:Young Adult",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "698-708",
"pmc": null,
"pmid": "33666943",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "30664067;18031551;30924921;31211023;25851171;24632353;22725721;26147878;18288078;8112234;24908139;31391249;23360413;28472982;28535410;28214380;26850976;19381840;23061694;15343213;27802281;23153207;29453075",
"title": "Perampanel and pregnancy.",
"title_normalized": "perampanel and pregnancy"
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"abstract": "BACKGROUND\nStatins have recently been reported to cause a rare autoimmune inflammatory and/or necrotic myopathy that begins or persists after drug cessation.\n\n\nMETHODS\nWe report on 26 patients seen at a neuromuscular centre between 2005 and 2011 who demonstrated muscle weakness/myalgias and creatine kinase elevations during or after statin treatment with continuation of signs and symptoms despite statin withdrawal.\n\n\nRESULTS\nAll patients were treated with immunosuppressive therapy with good response; all improved biochemically and 86% improved clinically. Sixty-five percent of patients who attempted to taper off immunosuppressive therapy relapsed. We report on a novel finding whereby five of the seven patients who underwent multiple biopsies throughout their disease demonstrated a transformation of their histological diagnosis, with four progressing from having myofibre necrosis with minimal or no inflammation to a diagnosis of polymyositis.\n\n\nCONCLUSIONS\nThis study offers preliminary evidence that statin-associated necrotizing myopathy and statin-associated polymyositis may not be separate entities but are part of the same pathophysiological spectrum. Both entities respond well to immunosuppression.",
"affiliations": "1Stanford University School of Medicine,Stanford,California 94305,USA.;2Department of Pathology and Molecular Medicine,McMaster University,Hamilton General Site,Hamilton,Ontario L8L 2X2,Canada.;2Department of Pathology and Molecular Medicine,McMaster University,Hamilton General Site,Hamilton,Ontario L8L 2X2,Canada.;3Department of Pediatrics,McMaster Children's Hospital,Hamilton,Ontario L8N 3Z5,Canada.;4Department of Medicine,McMaster Children's Hospital,Hamilton,Ontario L8N 3Z5,Canada.",
"authors": "Wu|Yufan|Y|;Lach|Boleslaw|B|;Provias|John P|JP|;Tarnopolsky|Mark A|MA|;Baker|Steven K|SK|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1017/cjn.2014.22",
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"issue": "41(5)",
"journal": "The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques",
"keywords": null,
"medline_ta": "Can J Neurol Sci",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001327:Autoimmune Diseases; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases; D012189:Retrospective Studies",
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"other_id": null,
"pages": "638-47",
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"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Statin-associated Autoimmune Myopathies: A Pathophysiologic Spectrum.",
"title_normalized": "statin associated autoimmune myopathies a pathophysiologic spectrum"
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"companynumb": "US-MYLANLABS-2015M1039676",
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"abstract": "OBJECTIVE\nTo investigate the clinical characteristics of intraocular lymphoma and to evaluate two protocols of intravitreal methotrexate injection.\n\n\nMETHODS\nA retrospective chart review was conducted of newly-diagnosed intraocular lymphoma patients between January 2013 and January 2018 at National Taiwan University Hospital. Patients were divided into two groups. In Group A, intravitreal methotrexate was administered weekly for the initial 8 weeks, every 2 weeks for the following 12 weeks, and then monthly for 7 months. In Group B, intravitreal methotrexate was administered twice a week for the initial 2 weeks, weekly for the subsequent 2 weeks, once every 2 weeks for the next 1 month, and monthly for the last 10 months.\n\n\nRESULTS\nA total of 12 patients were analyzed in the study; seven of these patients were allocated to Group A. Differences in the overall survival and progression-free survival between the two groups did not yield statistical significance. The median visual acuity was improved from LogMAR 0.46 to LogMAR 0.30 with borderline significance in Group A (p = 0.053). Two of seven patients in Group A and five of five patients in Group B developed punctate keratitis during intravitreal methotrexate injection treatment.\n\n\nCONCLUSIONS\nIntravitreal methotrexate is an effective and repeatable treatment for intraocular lymphoma. A new protocol with reduced frequency of intravitreal injections as shown in this study could potentially produce similar results without a worse prognosis, along with a decrease in the incidence of keratitis.",
"affiliations": "Department of Ophthalmology, National Cheng Kung University Hospital, Tainan, Taiwan.;Division of Haematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan.;Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan.;Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan.;Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan; Department of Ophthalmology, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan. Electronic address: ptyeh67@ntu.edu.tw.",
"authors": "Hsu|Chiung-Ju|CJ|;Hou|Hsin-An|HA|;Lin|Chang-Ping|CP|;Lee|Yi-Jui|YJ|;Hsu|Wen-Fang|WF|;Yeh|Po-Ting|PT|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1016/j.jfma.2021.05.027",
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"issn_linking": "0929-6646",
"issue": null,
"journal": "Journal of the Formosan Medical Association = Taiwan yi zhi",
"keywords": "Intraocular lymphoma; Intravitreal injection; Keratitis; Methotrexate",
"medline_ta": "J Formos Med Assoc",
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"nlm_unique_id": "9214933",
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"pmid": "34112589",
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"publication_types": "D016428:Journal Article",
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"title": "Clinical outcomes of intravitreal methotrexate injection protocol with a reduced initial frequency for intraocular lymphoma.",
"title_normalized": "clinical outcomes of intravitreal methotrexate injection protocol with a reduced initial frequency for intraocular lymphoma"
} | [
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"companynumb": "TW-PFIZER INC-202200044680",
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"abstract": "A 57-year-old woman presented with swelling and thickening of the skin of the lower extremities. Three months prior to presentation, patient had MRI with gadolinium as part of an evaluation for suspected pancreatic malignancy. Creatinine levels at the time of gadolinium exposure were 0.9-1.2 mg/dL, with a corresponding estimated glomerular filtration rate of 64 mL/min/1.73m2 by modification of diet in renal disease equation. Twenty-four-hour urine creatinine clearance was performed as an outpatient following development of symptoms. This revealed a creatinine clearance of 23 mL/min, suggestive of advanced chronic kidney disease despite an estimated glomerular filtration rate of 64 mL/min/1.73m2 Skin biopsy was positive for sclerosing dermopathy. These findings, in addition to the temporal association with gadolinium exposure, led to the diagnosis of nephrogenic systemic fibrosis.",
"affiliations": "Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan, USA.;Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan, USA.;Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan, USA.;Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan, USA.",
"authors": "Lohani|Sadichhya|S|http://orcid.org/0000-0001-9769-1706;Golenbiewski|Jon|J|;Swami|Abhishek|A|;Halalau|Alexandra|A|http://orcid.org/0000-0002-1805-992X",
"chemical_list": "D003287:Contrast Media; D005682:Gadolinium; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-221016",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "contraindications and precautions; dermatology; renal system",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003287:Contrast Media; D066246:ErbB Receptors; D005260:Female; D005682:Gadolinium; D005919:Glomerular Filtration Rate; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D054989:Nephrogenic Fibrosing Dermopathy; D026741:Physical Therapy Modalities; D012017:Referral and Consultation; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29025775",
"pubdate": "2017-10-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19841406;17905680;24334413;26017739;15118390;16431890;25330850;2520314;26017458;18226000;23426620;18688172;22250974;18226008;19414839;19836645;20115955;20099361",
"title": "A unique case of nephrogenic systemic fibrosis from gadolinium exposure in a patient with normal eGFR.",
"title_normalized": "a unique case of nephrogenic systemic fibrosis from gadolinium exposure in a patient with normal egfr"
} | [
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"activesubstance": {
"activesubstancename": "GADOBENATE DIMEGLUMINE"
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"abstract": "BACKGROUND\nAlthough several consolidation strategies to prolong treatment-free survival (TFS) in chronic lymphocytic leukaemia have been investigated, most have proven either ineffective or toxic. Ofatumumab is a human type I anti-CD20 antibody approved by the US Food and Drug Administration as maintenance treatment of patients with recurrent or progressive chronic lymphocytic leukaemia who are in complete or partial response after at least two lines of treatment; higher efficacy might be observed if used as consolidation strategy than without consolidation in previously untreated patients.\n\n\nMETHODS\nWe recruited patients with previously untreated progressive chronic lymphocytic leukaemia who had an Eastern Cooperative Oncology Group performance status of 0-2 and adequate renal and hepatic function from centres in the USA. Patients with recent myocardial infarction; class III or IV heart failure; uncontrolled, HIV, or active hepatitis B or C infection; or active haemolytic anaemia were excluded. In the first arm of this study, which has been previously reported, patients were treated with six cycles of induction with pentostatin (2 mg/m(2) on day 1), cyclophosphamide (600 mg/m(2) on day 1), and ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg/m(2) on day 2; cycles 2-6: 1000 mg/m(2) on day 1) given intravenously every 21 days. Here were report the second arm, where patients received the same regimen as the first arm, with the addition of six cycles of consolidation with ofatumumab (1000 mg once every 4 weeks), also given intravenously. The primary endpoint was TFS at 18 months, assessed in those who began consolidation. We estimated the distribution of TFS using the Kaplan-Meier method, assessing between-group differences with log-rank statistics. The phase 2 trial, which is completed, is registered at ClinicalTrials.gov, number NCT01024010.\n\n\nRESULTS\nBetween Sept 21, 2011, and Nov 7, 2012, 34 patients were recruited to this second arm of the trial. Among the 31 (91%) patients who completed induction treatment and started consolidation, 26 (84%) completed the planned six cycles of ofatumumab consolidation. TFS at 18 months was 94·1% (95% CI 78·5-98·5). Grade 3 or worse adverse events deemed at least possibly related to treatment were neutropenia (14 [41%] patients), infection (2 [6%]), and one (3%) each with anaemia, haemolysis, fatigue, and a neurological, metabolic, respiratory, and vascular complication.\n\n\nCONCLUSIONS\nOfatumumab-based consolidation appears to be a well tolerated and effective consolidation strategy in patients with chronic lymphocytic leukaemia, which could improve survival.\n\n\nBACKGROUND\nGlaxoSmithKline.",
"affiliations": "Mayo Clinic College of Medicine, Rochester, MN, USA.;Duke University Medical Center, Durham, NC, USA.;Mayo Clinic College of Medicine, Rochester, MN, USA.;Mayo Clinic College of Medicine, Scottsdale, AZ, USA.;Duke University Medical Center, Durham, NC, USA.;Mayo Clinic College of Medicine, Rochester, MN, USA.;Mayo Clinic College of Medicine, Rochester, MN, USA.;Mayo Clinic College of Medicine, Rochester, MN, USA.;Mayo Clinic College of Medicine, Rochester, MN, USA.;Mayo Clinic College of Medicine, Rochester, MN, USA.;Mayo Clinic College of Medicine, Jacksonville, FL, USA.;Mayo Clinic College of Medicine, Rochester, MN, USA.;Mayo Clinic College of Medicine, Rochester, MN, USA.;Mayo Clinic College of Medicine, Rochester, MN, USA.;Mayo Clinic College of Medicine, Rochester, MN, USA. Electronic address: shanafelt.tait@mayo.edu.",
"authors": "Strati|Paolo|P|;Lanasa|Mark|M|;Call|Timothy G|TG|;Leis|Jose F|JF|;Brander|Danielle M|DM|;LaPlant|Betsy R|BR|;Pettinger|Adam M|AM|;Ding|Wei|W|;Parikh|Sameer A|SA|;Hanson|Curtis A|CA|;Chanan-Khan|Asher A|AA|;Bowen|Deborah A|DA|;Conte|Michael|M|;Kay|Neil E|NE|;Shanafelt|Tait D|TD|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015649:Pentostatin; D003520:Cyclophosphamide; C527517:ofatumumab",
"country": "England",
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"issn_linking": "2352-3026",
"issue": "3(9)",
"journal": "The Lancet. Haematology",
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"medline_ta": "Lancet Haematol",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D015649:Pentostatin; D011379:Prognosis; D015996:Survival Rate",
"nlm_unique_id": "101643584",
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"pubdate": "2016-09",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial.",
"title_normalized": "ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia a phase 2 trial"
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"abstract": "Lamotrigine is an important anticonvulsant drug. Its use, however, has been limited by the risk of potentially life-threatening dermatological reactions, such as a drug reaction with eosinophilia and systemic symptoms (DRESS). Here, we report the case of a 7-year-6-month-old girl with a history of epilepsy who developed a skin rash with dyspnoea after 2 weeks of lamotrigine treatment, with DRESS ultimately being diagnosed. After discontinuation of the offending drug and the initiation of systemic glucocorticosteroids, the DRESS symptoms were relieved and the patient was discharged in a stable condition. Anticonvulsant drugs such as lamotrigine are among the factors that induce DRESS in children. When a patient displays skin rash and systemic organ involvement following the initiation of an anticonvulsant drug, DRESS should not be overlooked as a diagnosis, and immunosuppressant drugs should be considered as an option for treating DRESS patients.",
"affiliations": "Division of Pediatric Pulmonology, China Medical University Children's Hospital, Taichung 404327, Taiwan.;Division of Pediatric Neurology, China Medical University Children's Hospital, Taichung 404327, Taiwan.;Division of Pediatric Neurology, China Medical University Children's Hospital, Taichung 404327, Taiwan.;Division of Pediatric Pulmonology, China Medical University Children's Hospital, Taichung 404327, Taiwan.;Division of Pediatric Neurology, China Medical University Children's Hospital, Taichung 404327, Taiwan.",
"authors": "Lin|Chien-Heng|CH|0000-0002-9278-5911;Lin|Sheng-Shing|SS|;Hong|Syuan-Yu|SY|;Chen|Chieh-Ho|CH|;Chou|I-Ching|IC|",
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"doi": "10.3390/children8111063",
"fulltext": "\n==== Front\nChildren (Basel)\nChildren (Basel)\nchildren\nChildren\n2227-9067\nMDPI\n\n10.3390/children8111063\nchildren-08-01063\nCase Report\nLamotrigine Induced DRESS Syndrome in a Child: A Case Report and Literature Review\nhttps://orcid.org/0000-0002-9278-5911\nLin Chien-Heng 12\nLin Sheng-Shing 3\nHong Syuan-Yu 3\nChen Chieh-Ho 1\nChou I-Ching 34*\nKanazawa Nobuo Academic Editor\n1 Division of Pediatric Pulmonology, China Medical University Children’s Hospital, Taichung 404327, Taiwan; lch227@ms39.hinet.net (C.-H.L.); d30270@mail.cmuh.org.tw (C.-H.C.)\n2 Department of Biomedical Imaging and Radiological Science, College of Medicine, China Medical University, Taichung 404328, Taiwan\n3 Division of Pediatric Neurology, China Medical University Children’s Hospital, Taichung 404327, Taiwan; d3900@mail.cmuh.org.tw (S.-S.L.); dazingdog@hotmail.com (S.-Y.H.)\n4 Graduate Institute of Integrated Medicine, China Medical University, Taichung 404328, Taiwan\n* Correspondence: iching@mail.cmu.edu.tw\n19 11 2021\n11 2021\n8 11 106316 9 2021\n15 11 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nLamotrigine is an important anticonvulsant drug. Its use, however, has been limited by the risk of potentially life-threatening dermatological reactions, such as a drug reaction with eosinophilia and systemic symptoms (DRESS). Here, we report the case of a 7-year-6-month-old girl with a history of epilepsy who developed a skin rash with dyspnoea after 2 weeks of lamotrigine treatment, with DRESS ultimately being diagnosed. After discontinuation of the offending drug and the initiation of systemic glucocorticosteroids, the DRESS symptoms were relieved and the patient was discharged in a stable condition. Anticonvulsant drugs such as lamotrigine are among the factors that induce DRESS in children. When a patient displays skin rash and systemic organ involvement following the initiation of an anticonvulsant drug, DRESS should not be overlooked as a diagnosis, and immunosuppressant drugs should be considered as an option for treating DRESS patients.\n\nDRESS syndrome\nlamotrigine\ndyspnea\n==== Body\npmc1. Introduction\n\nAnticonvulsant drugs can cause adverse cutaneous reactions, such as drug-induced hypersensitivity syndrome (DIHS), which is characterized by a skin rash, fever, and the involvement of internal organs, mainly the liver, kidneys, and lungs. The symptoms of DIHS usually develop 2–6 weeks after starting the offending drug but may occur at any time.\n\nBocquet et al. extended the definition of DIHS and introduced the term DRESS (drug reaction with eosinophilia and systemic symptoms) [1]. The drugs most commonly responsible for inducing DRESS include anticonvulsant drugs (carbamazepine, phenobarbital, phenytoin, and lamotrigine), antibiotics (minocycline, ß-lactams, and sulfonamides), antiviral agents, dapsone, sulfasalazine, and allopurinol [2,3]. The incidence of DRESS has been estimated to be between 1/1000 and 1/10,000 exposures to anticonvulsant drugs [4]. Furthermore, DRESS has previously been reported to be associated with herpesviruses, although existing explanations of how viral infections contribute to the pathogenesis of DRESS remain speculative [5].\n\nThere are two sets of diagnostic criteria for the diagnosis of DRESS; one set consists of the RegiSCAR criteria and the other consists of the SCAR-J criteria developed by Japanese investigators [6,7,8]. The treatment for DRESS consists of immediate withdrawal of the culprit drug followed by the initiation of systemic steroids.\n\n2. Case Presentation\n\nA 7-year-6-month-old girl was brought to our emergency room (ER) after experiencing a fever and dyspnea for 3 days. In the ER, a physical examination revealed lymphadenopathy, mild injected throat with coarse breathing sound, and a maculopapular skin rash on her face, trunk, and limbs (Figure 1). There were no specific findings upon neurological examination.\n\nLab data for the patient showed leukocytosis (white blood cell count: 18,100/uL) with an elevated level of eosinophils (10%, 1810/uL), with 49.4% neutrophils, 29.2% lymphocytes, and 11% monocytes. The patient’s C-reactive protein level was 5.3 mg/dL (normal: <0.8 mg/dL), while her aspartate transaminase (AST) level and alanine aminotransferase (ALT) level were 253 U/L and 93 U/L, respectively. A mycoplasma rapid test was positive, and a chest X-ray showed bilateral perihilar lung bronchitis infiltrates. Therefore, bronchopneumonia was suspected initially. After admission, the patient suffered from progressive dyspnea, and then was transferred to the pediatric intensive care unit for non-invasive ventilator support with bi-level positive airway pressure support. The laboratory data obtained after admission revealed that EB VCA and EBVA IgG were both positive, but the adenovirus rapid tests, HSV I/II IgM, EB VCA IgM, and mycoplasma IgM were all negative, and the mycoplasma pneumonia IgG test was equivocal.\n\nIn tracing back her past history, it was discovered that she had a history of epilepsy, which was kept under control with an anticonvulsant drug (Depakine, at an initial dose of 250 mg qhs). However, her electroencephalography (EEG) results showed generalized epileptiform discharge, and the dose of Depakine was increased to q12h one year ago, at which time her seizures went into remission. However, her body weight changed from 35 kg to 42.5 kg, resulting in her being overweight (body mass index > 24). Therefore, the anticonvulsant drug was changed to lamotrigine 25 mg and then 50 mg q12h one month prior to her arrival at the ER. The patient reported experiencing a maculopapular skin rash accompanied by an itchy sensation one week prior to her arrival in the ER, which was untreated because it was not obvious at the time.\n\nBecause of her clinical presentation of an erythematous rash spread all over her body about 2 weeks after starting lamotrigine, lamotrigine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) was suspected, and pulse therapy with high-dose intravenous methylprednisolone (30 mg/day) was prescribed for 3 days and then 1 mg/kg/day. In addition, the anticonvulsant drug was changed to levetiracetam 50 mg bid.\n\nHer respiratory condition subsequently improved, and she was then transferred back to a regular ward. However, on her 8th day of hospitalization, her eye became icteric, and her direct/total bilirubin increased to 1.8 mg/dL/2.8 mg/dL, before increasing even further to 20.4 mg/dL/31.6 mg/dL. Furthermore, her ALT/AST levels increased to 249 U/L/225 U/L. Meanwhile, an abdominal echo showed mild hepatomegaly. Pulse therapy was then prescribed again, and the patient was also treated with ursodeoxycholic acid and silymarin. She was discharged from the hospital day on the 26th day after her arrival with prescriptions of mycophenolate 2# (180 mg/tab) q12h, tacolimus 1# (1 mg/cap), and prednisolone 2# (5 mg/tab) bid to be taken orally.\n\n3. Discussion\n\nDRESS syndrome is an acute, severe, and life-threatening disease with a mortality rate of about 10%. It is more common in adults and only rarely seen in children, in whom it is frequently associated with systemic organ involvement, such as liver dysfunction, renal impairment, and interstitial pneumonitis. Myocarditis, thyroiditis, encephalitis, and type 1 diabetes mellitus have also been reported as manifestations of this syndrome. Other gastrointestinal organs are less frequently affected, but esophagitis, gastritis, enteritis, colitis, and pancreatitis have been reported in recent literature [6].\n\nDRESS usually starts abruptly with maculopapular morbilliform exanthema with a fever of >38 °C as of 2–3 weeks after the introduction of the culprit drug. Pulmonary manifestations are less common and are typically associated with more severe cases [7]. Therefore, when a patient with DRESS initially presents with pulmonary manifestations, a misdiagnosis of pneumonia can occur. Mycoplasma pneumoniae infection may induce a DRESS eruption [8], or an upper-airway infection-like prodrome may be detected, suggesting that viral infections may serve as possible triggers for this syndrome [9]. The differential diagnosis between respiratory infections and lung involvement in DRESS is important in these cases. The mycoplasma rapid test in our patient was positive in the ER, resulting in the initial consideration of mycoplasma pneumonia. However, after admission, laboratory tests for mycoplasma IgG and IgM were equivocal and negative, respectively; therefore, mycoplasma infection was able to be excluded. Our patient reported a skin rash 1 week before arrival in the ER, followed by the development of fever and the worsening of the skin rash. We speculate that a viral infection may have triggered the DRESS eruption observed in this patient.\n\nA diagnosis of DRESS can be made based on the diagnostic criteria established by the RegiSCAR group or those established by the Japanese Research Committee on Severe Cutaneous Adverse Reaction, respectively [9,10,11]. Leukocytosis with atypical lymphocytes and eosinophilia of various degrees are unique features of the early phase of DRESS, although leukocytopenia can occasionally precede leukocytosis. Our patient presented with fever and skin rash, and her lab data showed leukocytosis; therefore, mycoplasma pneumonia was suspected initially. However, in tracing back our patient’s past history, it was found that she had a history of epilepsy that been controlled initially under treatment with the anticonvulsant drug sodium valproate, which had subsequently been replaced with lamotrigine 2 weeks after the initiation of which her skin rash first appeared. The patient’s skin rash and drug history were very important clues for diagnosing DRESS.\n\nAccording to a review article by Shiohara et al. [3], lamotrigine is the fourth most common culprit among anticonvulsant drugs in terms of inducing DRESS. In another study, Newell et al. [12] reported that among 32 children diagnosed with anticonvulsant hypersensitivity syndrome, 12 of them (37.5%) were taking carbamazepine, 11 of them (34.5%) were taking phenytoin, 5 of them (6.25%) were taking phenobarbital, and 5 of them (6.25%) were taking lamotrigine. In still another study, Wang et al. [13] reported that of 57 patients with DRESS induced by lamotrigine, 14 of them (24.6%) were children. This study found a greater predominance of women with lamotrigine-induced DRESS, but in children, we found a greater predominance of lamotrigine-induced DRESS among boys (with a boy-to-girl ratio = 9:7), and we have summarized the characteristics of 16 published cases of pediatric patients with lamotrigine-induced DIHS/DRESS in Table 1. Four of them had DRESS when lamotrigine was given concurrently with sodium valproate.\n\nAbout 50 to 60% of cases of DRESS with organ involvement occur in the liver, and such DRESS may progress into fulminant hepatitis or hepatomegaly, with hepatic failure being a common cause of death [14].\n\nSystemic corticosteroids have been accepted as the gold standard treatment for ameliorating the clinical symptoms of DRESS. However, they need to be tapered over 6–8 weeks to prevent the relapse of various symptoms [3]. The usage of intravenous immunoglobulin (IVIG) for patients with life-threatening signs such as renal failure or respiratory failure has also been recommended [13,14,15,16]. Meanwhile, some authors have reported the beneficial effects of the concomitant use of N-acetyl cysteine because of its detoxifying capabilities [13]. Alexander et al. reported a dramatic, sustained clinical response to therapeutic plasma exchange after a steroid treatment failed in a pediatric case of DRESS associated with either lamotrigine or bupropion, leading to multiorgan involvement and life-threatening complications of respiratory failure and cardiac arrest [14]. Our patient presented fever and dyspnea initially, and her symptoms progressed to pulmonary insufficiency requiring non-invasive positive pressure ventilator support. Furthermore, our patient developed jaundice with severe liver dysfunction, and the immunosuppressant drugs of mycophenolate and tacolimus were even prescribed after steroid therapy due to hepatic failure. The use of immunosuppressant drugs for DRESS has never previously been reported in the literature. Our patient may thus be the first patient with a case of DRESS treated with immunosuppressant drugs.\n\nThe pathogenesis of DRESS remains a matter of speculation, but several theories have been proposed. One theory is that the anticonvulsants are converted into toxic arene oxide metabolites, which are then metabolized by enzymes within the body [17]. Another neoantigen theory speculates that toxic arene oxide reactive metabolites may also alter the cytochrome P450 enzymes, such as those in the liver, skin, kidneys, stomach, intestinal tract, and lungs [18]. In short, it is generally regarded, like other severe drug eruptions, as a T-cell mediated hypersensitivity reaction. Therefore, the clinical resolution of DRESS is associated with a shift away from Tregs to Th 17 cell differentiation [3].\n\n4. Conclusions\n\nDRESS should be considered in patients with skin rash and liver function impairment occurring several weeks after the initiation of an anticonvulsant drug. Relatedly, the early recognition and early withdrawal of allergenic drugs is a very important aspect of the management of DRESS. Glucocorticoid therapy is the first-choice treatment, and plasma exchange, IVIG, and immunosuppressant drugs should be considered for multiorgan involvement and life-threatening complications.\n\nAcknowledgments\n\nThe authors would like to thank the patient’s family members for their assistance throughout the study period and China Medical University Hospital Medical Research Department (DMR-110-069) for providing support and assistance for this work.\n\nAuthor Contributions\n\nConceptualization, C.-H.L. and I.-C.C.; methodology, C.-H.L.; validation, C.-H.L. and S.-S.L.; formal analysis, S.-Y.H. and C.-H.C.; investigation, S.-Y.H. and C.-H.C.; writing—original draft preparation, C.-H.L. and C.-H.C.; writing—review and editing, C.-H.C., S.-Y.H., and C.-H.C.; supervision, I.-C.C. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis study was supported by a research grant from China Medical University Hospital, Taiwan (grant number DMR-110-069).\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of China Medical University.\n\nInformed Consent Statement\n\nWritten informed consent was obtained from the patients’ parents to publish this paper.\n\nData Availability Statement\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Scattered red maculopapular rash on the trunk and limbs, partially pressed to fade and partially fused into patches.\n\nchildren-08-01063-t001_Table 1 Table 1 Characteristics of children (<18 year-old) with lamotrigine-induced DIHS/DRESS in published case studies [12,13,14].\n\nCase\tAge/Sex\tInitial Dose (mg/Day)\tFinal Dose (mg/Day)\tLatency Time (Days)\tConcurrent Drugs\tTreatment\tOutcome\t\n1\t11/F\tNA\tNA\tNA\tNA\tSteroid + IVIG\tCured\t\n2\t6/M\tNA\tNA\t10\tVPA\tNo steroid\tCured\t\n3\t14/M\tNA\tNA\t52\tNA\tNo steroid\tCured\t\n4\t8/M\tNA\tNA\t21\tNone\tSteroid\tNA\t\n5\t16/F\tNA\tNA\twithin 56\tNA\tNA\tNA\t\n6\t17/F\t50\t50\t21\tNone\tSteroid\tCured\t\n7\t4/F\tNA\tNA\tNA\tNA\tNA\tNA\t\n8\t2/F\tNA\tNA\tNA\tNA\tNA\tNA\t\n9\t3/M\tNA\tNA\tNA\tNA\tNA\tNA\t\n10\t7/M\tNA\tNA\tNA\tNA\tNA\tNA\t\n11\t12/M\tNA\tNA\tNA\tNA\tNA\tNA\t\n12\t6/M\tNA\tNA\tNA\tVPA\tNo steroid\tCured\t\n13\t15/F\t50\t75\t30\tVPA 2000 mg/d\tNA\tNA\t\n14\t12/M\t25\t50\t18\tVPA\tSteroid\tCured\t\n15\t4/M\tNA\tNA\t30\tNA\tIVIG + plasma exchange\tCured\t\n16 *\t7/F\t50\t100\t14\tNA\tSteroid + mycophenolate + tacolimus\tCured\t\n* Our patient. VPA = valproic acid, IVIG = intravenous immunoglobulin, NA = not available.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Bocquet H. Bagot M. Roujeau J.C. Drug induced pseudolymphoma and drug hypersensitivity syndrome (drug rush with eosinophilia and systemic symptoms-DRESS) Semin. Cutan. Med. Surg. 1996 15 250 257 10.1016/S1085-5629(96)80038-1 9069593\n2. Saida S. Yoshida A. Tanaka R. Abe J. Hamahata K. Okumura M. Momoi T. A case of drug-induced hypersensitivity syndrome-like symptoms following HHV-6 encephalopathy Allergol. Int. 2015 59 83 86 10.2332/allergolint.09-CR-0090 19946201\n3. Shiohara T. Mizukawa Y. Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): An update in 2019 Allergol. Int. 2019 68 301 308 10.1016/j.alit.2019.03.006 31000444\n4. Knowles S.R. Shapiro L. Shear N.H. Anticonvulsant hypersensitivity syndrome: Incidence prevention and management Drug Saf. 1999 21 489 501 10.2165/00002018-199921060-00005 10612272\n5. Hagiya H. Iwamuro M. Tanaka T. Hasegawa K. Hanayama Y. Kimura M. Otsuka F. Reactivation of human herpes virus-6 in the renal tissue of a patient with drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms (DIHS/DRESS) Intern. Med. 2016 55 1769 1774 10.2169/internalmedicine.55.6287 27374681\n6. Jevtic D. Dumic I. Nordin T. Singh A. Sulovic N. Radovanovic M. Jecmenica M. Milovanovic T. Less Known Gastrointestinal Manifestations of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome: A Systematic Review of the Literature J. Clin. Med. 2021 10 4287 10.3390/jcm10184287 34575398\n7. Taweesedt P.T. Nordstrom C.W. Stoeckel J. Dumic I. Pulmonary Manifestations of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome: A Systematic Review BioMed Res. Int. 2019 2019 7863815 10.1155/2019/7863815 31662996\n8. Shalom G. Khoury R. Horev A. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Associated with Mycoplasma pneumoniae Infection Case Rep. Dermatol. 2020 12 225 230 10.1159/000510706 33362508\n9. Kardaun S.H. Sidoroff A. Valeyrie-Allanore L. Halevy S. Davidovici B.B. Mockenhaupt M. Roujeau J.C. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: Does a DRESS syndrome really exist? Br. J. Dermotol. 2007 156 609 611 10.1111/j.1365-2133.2006.07704.x 17300272\n10. Hung S.I. Chung W.H. Liou L.B. Chu C.C. Lin M. Huang H.P. Lin Y.L. Lan J.L. Yang L.C. Hong H.S. HLA-B*5801 alleles as a genetic marker for severe cutaneous adverse reactions caused by allopurinol Proc. Natl. Acad. Sci. USA 2005 102 4134 4139 10.1073/pnas.0409500102 15743917\n11. Mizukawa Y. Hirahara K. Kano Y. Shiohara T. Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) severity score: A useful tool for assessing disease severity and predicting fatal cytomegalovirus disease J. Am. Acad. Dermatol. 2019 80 670 678 10.1016/j.jaad.2018.08.052 30240780\n12. Newell B.D. Moinfar M. Mancini A.J. Nopper A.J. Retrospective analysis of 32 pediatric patients with anticonvulsant hypersensitivity syndrome (ACHSS) Pediatr. Dermatol. 2009 26 536 546 10.1111/j.1525-1470.2009.00870.x 19840307\n13. Wang X.Q. Lv B. Wang H.F. Zhang X. Yu S.Y. Huang X.S. Zhang J.T. Tian C.L. Lang S.Y. Lamotrigine induced DIHS/DRESS: Manifestations, treatment, and outcome in 57 patients Clin. Neurol. Neurosurg. 2015 138 1 7 10.1016/j.clineuro.2015.07.008 26209753\n14. Roujeau J.C. Treatment of severe drug eruptions J. Dermatol. 1999 26 718 722 10.1111/j.1346-8138.1999.tb02082.x 10635613\n15. Moling O. Tappeiner L. Piccin A. Pagani E. Rossi P. Treatment of DIHSDRESS with comined N-acetylcysteine, prednisone and valganciclovir-a hypothesis Med. Sci. Moni. 2012 18 57 62\n16. Alexander T. Iglesia E. Park Y. Duncan D. Pedan D. Shiekh S. Ferris M. Severe DRESS syndrome managed with therapeutic plasma exchange Pediatrics 2013 131 e945 e949 10.1542/peds.2012-2117 23420918\n17. Spielberg S.P. Gordon G.E. Blake D.A. Mellits E.D. Bross D.S. Anticonvulsant toxicity in vitro: Possible role of arene oxides J. Pharmcol. Exper. Therapy 1981 217 386 389\n18. Tas S. Simonart T. Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): An update Dermatology 2003 206 353 356 10.1159/000069956 12771485\n\n",
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},
"drugadditional": "1... |
{
"abstract": "We report a very high factor V inhibitor affecting the measurement of all coagulation factors besides fibrinogen, all these factors being dramatically decreased. This inhibitor could be linked to antibiotic use. The patient died of massive hemorrhage before a plasma exchange could be initiated.",
"affiliations": "CHRU Brest - Laboratoire d'Hématologie, Brest, France.;HYPHEN BioMed, Neuville sur Oise, France.;CHRU Brest - Service de Maladies Infectieuses, Brest, France.;CHRU BREST - Laboratoire de Biochimie, Brest, France.;CHRU BREST - Pharmacovigilance, Brest, France.;CHRU Brest - Service de Médecine Interne, Brest, France.;CHRU Brest - Laboratoire d'Hématologie, Brest, France.;CHRU Brest - Laboratoire d'Hématologie, Brest, France.;CHRU Brest - Laboratoire d'Hématologie, Brest, France.;CHRU BREST - Service d'Hématologie Clinique, Brest, France.;CHRU BREST - Service d'Hématologie Clinique, Brest, France.;CHRU Brest - Laboratoire d'Hématologie, Brest, France.;CHRU Brest - Laboratoire d'Hématologie, Brest, France.",
"authors": "Hoffmann|Claire|C|;Amiral|Jean|J|;Rezig|Schéhérazade|S|;Kerspern|Hélène|H|;Jantzem|Hélène|H|;Robin|Sara|S|;Collins|Adam|A|;Mornet|Clelia|C|;Mingant|Fanny|F|;Pan Petesch|Brigitte|B|;Ianotto|Jean-Christophe|JC|;Lippert|Eric|E|;Galinat|Hubert|H|https://orcid.org/0000-0001-7102-5078",
"chemical_list": "D015415:Biomarkers; D019774:Blood Coagulation Factor Inhibitors; D005165:Factor V",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13249",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "103(2)",
"journal": "European journal of haematology",
"keywords": "coagulation factors; factor V inhibitor; factor inhibitor",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000369:Aged, 80 and over; D015415:Biomarkers; D001777:Blood Coagulation; D019774:Blood Coagulation Factor Inhibitors; D001780:Blood Coagulation Tests; D004198:Disease Susceptibility; D005165:Factor V; D017809:Fatal Outcome; D005260:Female; D006470:Hemorrhage; D006801:Humans",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "137-139",
"pmc": null,
"pmid": "31102471",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A very potent factor V inhibitor interferes with the levels of all coagulation factors and causes a fatal hemorrhagic syndrome.",
"title_normalized": "a very potent factor v inhibitor interferes with the levels of all coagulation factors and causes a fatal hemorrhagic syndrome"
} | [
{
"companynumb": "FR-PFIZER INC-2019238946",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLINDAMYCIN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nTo investigate the clinical and macular spectral-domain optical coherence tomography (SD-OCT) findings after intravitreal ranibizumab treatment for type 1 retinopathy of prematurity (ROP).\n\n\nMETHODS\nEighteen eyes of 10 premature infants with type 1 ROP were retrospectively studied. All eyes were treated with intravitreal ranibizumab as monotherapy. Macular SD-OCT was performed before and after intravitreal ranibizumab therapy using a portable SD-OCT machine; the follow-up images were taken 1 day, 1 week, 1 month, and 2 months after therapy.\n\n\nRESULTS\nAmong the 10 infants, there were six males and four females. Mean central foveal thickness before and 2 months after intravitreal ranibizumab was 292.5 ± 61.4 and 171.6 ± 21.7 µm, respectively. Differences were statistically significant (P = .01). Sixteen eyes of eight patients had macular edema before treatment. Two eyes of two patients developed a crack in the outer hyperreflective line on SD-OCT corresponding with retinal pigment epithelium with serous retinal detachment 1 day after treatment. Macular edema regressed in all patients 2 months after intravitreal ranibizumab therapy. Mean follow-up time was 11.4 ± 1.5 months. No recurrence was seen except in both eyes of one patient treated with intravitreal ranibizumab monotherapy.\n\n\nCONCLUSIONS\nIntravitreal ranibizumab injection is effective for the treatment of type 1 ROP as a monotherapy agent; however, macular changes not seen with indirect ophthalmoscope may develop.",
"affiliations": null,
"authors": "Erol|Muhammet Kazim|MK|;Coban|Deniz Turgut|DT|;Özdemir|Özdemir|Ö|;Tunay|Zuhal Özen|ZÖ|;Bilgin|Ahmet Burak|AB|;Dogan|Berna|B|",
"chemical_list": "D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab",
"country": "United States",
"delete": false,
"doi": "10.3928/01913913-20150326-12",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0191-3913",
"issue": "52(3)",
"journal": "Journal of pediatric ophthalmology and strabismus",
"keywords": null,
"medline_ta": "J Pediatr Ophthalmol Strabismus",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D005260:Female; D005865:Gestational Age; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D019102:Infant, Very Low Birth Weight; D058449:Intravitreal Injections; D008266:Macula Lutea; D008269:Macular Edema; D008297:Male; D000069579:Ranibizumab; D012178:Retinopathy of Prematurity; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity",
"nlm_unique_id": "7901143",
"other_id": null,
"pages": "152-8",
"pmc": null,
"pmid": "25859685",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spectral-Domain OCT Analyses of Macular Changes After Ranibizumab Therapy for Type 1 Retinopathy of Prematurity.",
"title_normalized": "spectral domain oct analyses of macular changes after ranibizumab therapy for type 1 retinopathy of prematurity"
} | [
{
"companynumb": "TR-ROCHE-1684161",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": null,
"dr... |
{
"abstract": "There have been increasing reports of food-borne zoonotic transmission of hepatitis E virus (HEV) genotype 3, which causes chronic infections in immunosuppressed patients. We performed phylogenetic analyses of the HEV sequence (partial and full-length) from 1 patient from the Middle East who underwent liver transplantation, and compared it with other orthohepevirus A sequences. We found the patient to be infected by camelid HEV. This patient regularly consumed camel meat and milk, therefore camelid HEV, which is genotype 7, might infect human beings. Our finding links consumption of camel-derived food products to post-transplantation hepatitis E, which, if detected at early stages, can be cured with antiviral therapy and reduced administration of immunosuppressive agents.",
"affiliations": "Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Medicine, National University Health System, Singapore; National University Centre for Organ Transplantation, National University Hospital, Singapore. Electronic address: mdcleegh@nus.edu.sg.;Saw Swee Hock School of Public Health, National University of Singapore, Singapore.;Department of Hematology, Singapore General Hospital, Singapore.;Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Medicine, National University Health System, Singapore; National University Centre for Organ Transplantation, National University Hospital, Singapore.;Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Medicine, National University Health System, Singapore; National University Centre for Organ Transplantation, National University Hospital, Singapore.;Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Pathology, National University Health System, Singapore.;Genome Institute of Singapore, Singapore.;Genome Institute of Singapore, Singapore.;Genome Institute of Singapore, Singapore; London School of Hygiene and Tropical Medicine, London, United Kingdom.;Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore.;Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia.;Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia.",
"authors": "Lee|Guan-Huei|GH|;Tan|Boon-Huan|BH|;Teo|Esmeralda Chi-Yuan|EC|;Lim|Seng-Gee|SG|;Dan|Yock-Young|YY|;Wee|Aileen|A|;Aw|Pauline Poh Kim|PP|;Zhu|Yuan|Y|;Hibberd|Martin Lloyd|ML|;Tan|Chee-Kiat|CK|;Purdy|Michael A|MA|;Teo|Chong-Gee|CG|",
"chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5085",
"issue": "150(2)",
"journal": "Gastroenterology",
"keywords": "Case Study; Liver Disease; Viral Infection; Zoonosis",
"medline_ta": "Gastroenterology",
"mesh_terms": "D000818:Animals; D000998:Antiviral Agents; D002162:Camelus; D005506:Food Contamination; D005838:Genotype; D016751:Hepatitis E; D016752:Hepatitis E virus; D006521:Hepatitis, Chronic; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D008297:Male; D008460:Meat; D008875:Middle Aged; D008892:Milk; D010802:Phylogeny; D013997:Time Factors; D016896:Treatment Outcome; D015047:Zoonoses",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "355-7.e3",
"pmc": null,
"pmid": "26551551",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Chronic Infection With Camelid Hepatitis E Virus in a Liver Transplant Recipient Who Regularly Consumes Camel Meat and Milk.",
"title_normalized": "chronic infection with camelid hepatitis e virus in a liver transplant recipient who regularly consumes camel meat and milk"
} | [
{
"companynumb": "SG-CONCORDIA PHARMACEUTICALS INC.-GSH201808-003118",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EZETIMIBE"
},
"druga... |
{
"abstract": "Tissue plasminogen activator (t-PA) is an effective therapy for acute ischemic stroke, but some patients still have poor clinical outcome. In this study, we investigated clinical characteristics of stroke patients and determined predictors for poor clinical outcome in response to t-PA treatment.\n\n\n\nClinical data from 247 patients were retrospectively reviewed. Clinical parameters that were associated with survival of patients were analyzed. Areas under receiver operating characteristic curves (ROC) were used to determine the feasibility of using various combinations of the clinical parameters to predict poor clinical response. The clinical outcome was defined according to the changes in Modified Rankin Scale.\n\n\n\nOverall, 145 patients had improved/complete recovery, 73 had no change, and 29 had worsening conditions or died during the in-clinic period. A univariate analysis showed that baseline characteristics including age, CRP, blood glucose level, systolic blood pressure, and admission NIHSS were significantly different (p < 0.05) among patients with different clinical outcome. A further multivariate analysis was then performed. Variables associated with poor clinical outcome (worsening/death) (p < 0.1) were included in the logistic regression model. Four parameters were retained in the model: Age, CRP, Blood glucose level, and Systolic blood pressure (ACBS). To allow a convenient usage of the ACBS classifier, the parameters were put into a scoring system, and the score at 7.7 was chosen as a cut-off. The ROC curve of this ACBS classifier has an area under the curve (AUC) of 0.7788, higher than other individual parameters. The ACBS classifier provided enhanced sensitivity of 69.2% and specificity of 74.3%.\n\n\n\nThe ACBS classifier provided a satisfactory power in estimating the patients' clinical outcome. After further validating, the classifier may provide important information to clinicians for making clinical decisions.",
"affiliations": "Department of Neurology, Yangpu Hospital Tongji University School of Medicine, Shanghai, China.;Department of Neurology, Yangpu Hospital Tongji University School of Medicine, Shanghai, China.;Department of Neurology, Yangpu Hospital Tongji University School of Medicine, Shanghai, China.;Department of Neurology, Yangpu Hospital Tongji University School of Medicine, Shanghai, China.;Department of Neurology, Yangpu Hospital Tongji University School of Medicine, Shanghai, China.;Department of Neurology, Yangpu Hospital Tongji University School of Medicine, Shanghai, China.;Department of Neurology, Yangpu Hospital Tongji University School of Medicine, Shanghai, China.;Department of Neurology, Yangpu Hospital Tongji University School of Medicine, Shanghai, China.;Department of General Medicine, Yangpu Hospital Tongji University School of Medicine, Shanghai, Shanghai, China.",
"authors": "Yue|Yun-Hua|YH|0000-0001-8812-5745;Li|Zhi-Zhang|ZZ|;Hu|Liang|L|;Zhu|Xiao-Qiong|XQ|;Xu|Xu-Shen|XS|;Sun|Hong-Xian|HX|;Wan|Zhi-Wen|ZW|;Xue|Jie|J|;Yu|De-Hua|DH|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1002/brb3.1251",
"fulltext": "\n==== Front\nBrain BehavBrain Behav10.1002/(ISSN)2157-9032BRB3Brain and Behavior2162-3279John Wiley and Sons Inc. Hoboken 10.1002/brb3.1251BRB31251Original ResearchOriginal ResearchClinical characteristics and risk score for poor clinical outcome of acute ischemic stroke patients treated with intravenous thrombolysis therapy YUE et al.Yue Yun‐hua https://orcid.org/0000-0001-8812-5745\n1\nLi Zhi‐zhang \n1\nHu Liang \n1\nZhu Xiao‐qiong \n1\nXu Xu‐shen \n1\nSun Hong‐xian \n1\nWan Zhi‐wen \n1\nXue Jie \n1\nYu De‐hua yunhua.yue@tongji.edu.cn \n2\n\n1 \nDepartment of Neurology\nYangpu Hospital Tongji University School of Medicine\nShanghai\nChina\n\n2 \nDepartment of General Medicine\nYangpu Hospital Tongji University School of Medicine\nShanghai, Shanghai\nChina\n* Correspondence\n\nDe‐hua Yu, Department of General Medicine, Yangpu Hospital Tongji University School of Medicine, Shanghai, China.\n\nEmail: yunhua.yue@tongji.edu.cn\n11 3 2019 4 2019 9 4 10.1002/brb3.2019.9.issue-4e0125112 7 2018 25 1 2019 18 2 2019 © 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nBackground\nTissue plasminogen activator (t‐PA) is an effective therapy for acute ischemic stroke, but some patients still have poor clinical outcome. In this study, we investigated clinical characteristics of stroke patients and determined predictors for poor clinical outcome in response to t‐PA treatment.\n\nMethods\nClinical data from 247 patients were retrospectively reviewed. Clinical parameters that were associated with survival of patients were analyzed. Areas under receiver operating characteristic curves (ROC) were used to determine the feasibility of using various combinations of the clinical parameters to predict poor clinical response. The clinical outcome was defined according to the changes in Modified Rankin Scale.\n\nResults\nOverall, 145 patients had improved/complete recovery, 73 had no change, and 29 had worsening conditions or died during the in‐clinic period. A univariate analysis showed that baseline characteristics including age, CRP, blood glucose level, systolic blood pressure, and admission NIHSS were significantly different (p < 0.05) among patients with different clinical outcome. A further multivariate analysis was then performed. Variables associated with poor clinical outcome (worsening/death) (p < 0.1) were included in the logistic regression model. Four parameters were retained in the model: Age, CRP, Blood glucose level, and Systolic blood pressure (ACBS). To allow a convenient usage of the ACBS classifier, the parameters were put into a scoring system, and the score at 7.7 was chosen as a cut‐off. The ROC curve of this ACBS classifier has an area under the curve (AUC) of 0.7788, higher than other individual parameters. The ACBS classifier provided enhanced sensitivity of 69.2% and specificity of 74.3%.\n\nConclusion\nThe ACBS classifier provided a satisfactory power in estimating the patients’ clinical outcome. After further validating, the classifier may provide important information to clinicians for making clinical decisions.\n\noutcomestroketissue plasminogen activator source-schema-version-number2.0component-idbrb31251cover-dateApril 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:10.04.2019\n\n\nYue \nY \n, \nLi \nZ \n, \nHu \nL \n, et al. Clinical characteristics and risk score for poor clinical outcome of acute ischemic stroke patients treated with intravenous thrombolysis therapy . Brain Behav . 2019 ;9 :e01251\n10.1002/brb3.1251 \n\n\n\nYun‐hua Yue, Zhi‐zhang Li, and Liang Hu contribute equally to this work.\n==== Body\n1 INTRODUCTION\nStroke is the leading cause of disability among adults. It is caused by thrombotic or embolic occlusion of a cerebral artery. Each year, about 800,000 strokes occurred; and of all strokes, 87% are ischemic in origin (Roger et al., 2011). The risk of stroke is higher among elderly than youngsters (Rosamond et al., 1999). Many of the stroke survivors continue to experience functional deficits that diminished their quality of life. In Framingham study, almost half of all elderly stroke survivors had moderate to severe neurological deficits (Kelly‐Hayes et al., 2003). Because of an increase in life expectancy, the number of individuals at risk for ischemic stroke is expected to increase, making the management of stroke disability among elderly an important public health concern.\n\nTissue plasminogen activator (t‐PA) is a US Food and Drug Administration‐approved drug for treatment of ischemic stroke. It is a serine protease that enhances the conversion of inactive plasminogen to active plasmin. Plasmin acts on fibrin clots, resulting in dissolution and lysis. Studies suggested that the administration of t‐PA within 3 hr after the onset of stroke increases the probability of favorable clinical outcome (Wechsler, 2011). However, only a small fraction of potentially eligible stroke patients is receiving t‐PA therapy. In US, it is estimated that the rate of t‐PA use averages not more than 2% (Katzan et al., 2000). In China, the rate of t‐PA usage was only about 1.6% (Dong et al., 2017). The difficulty in predicting the clinical outcome of patients receiving t‐PA treatment is hampering the widespread usage of t‐PA by clinicians.\n\nA prognostic model that would allow an early estimation of clinical outcomes of patients receiving t‐PA treatment is in need. A handy prognostic model should contain variables that are readily available in clinical settings for all patients. To date, there have been limited prognostic models for stroke recovery, and the predictive power was not satisfactory (Counsell & Dennis, 2001). There were other models that relied on imaging variables, which may not be available for all patients (Baird et al., 2001; Johnston, Connors, Wagner, & Haley, 2003; Johnston et al., 2000). In the current study, we investigated different baseline clinical characteristics that may associate with the poor clinical outcome of stroke patients as assessed by Modified Rankin Scale (MRS). These patients likely would not benefit from the t‐PA therapy.\n\n2 PATIENTS AND METHODS\n2.1 Patient characteristics\nA total of 247 patients with acute ischemic stroke were included in this study, and their clinical data were retrospectively reviewed. These patients were admitted to the Department of Neurology, Yangpu Hospital, Tongji University School of Medicine between January 2016 and December 2017. On arrival in the emergency room, patients underwent standard neurological and cardiological examinations. Blood chemistry, vital signs, and CT scans of the brain were obtained before the start of treatment. The CT scans were reviewed by a neuroradiologist with extensive experience in acute stroke. Previous and concomitant diseases were recorded.\n\nAll of the patients were treated with t‐PA at a dose of 0.9 mg/kg. National Institute of Health Stroke Scale (NIHSS) score was assessed at various time points during the clinical stay. Patients with admission NIHSS ≥20 were considered as severe, 4–19 were moderate, and <4 represented mild or normal. MRS was assessed at admission and at discharge. We defined the clinical outcome according to the differences in admission MRS and discharge MRS. Patients with a lower MRS (or MRS = 0) at discharge were defined as “improved/complete cure,” those with the same MRS were defined as “no change,” and those with a higher MRS (or died after treatment) were defined as “worsening/death.” Adverse events of hemorrhage, including symptomatic intracerebral hemorrhage, were identified. The study was approved by the Hospital's ethics committee.\n\n2.2 Statistical analyses\nAll statistical analyses were carried out by SAS9.3. Continuous variables were expressed as mean ± SD, whereas categorical variables were expressed as numbers (percentages). A value of p < 0.05 was considered statistically significant. For comparisons of three or more groups with data normally distributed, one‐way analysis of variance was used; otherwise, Kruskal–Wallis test was used.\n\nA univariate analysis was performed to compare variables among the groups: Improved/complete cure, No change, and Worsening/death. Variables associated with poor clinical outcome (worsening/death) (p < 0.1) were included in the logistic regression model. In the meantime, variable selection was performed to balance the predictive power and complexity of the model. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to determine the feasibility of using clinical parameters as a classifier to predict treatment response of patients. Mann–Whitney test was used to compare the differences of AUC between various parameters. The Youden's Index was used to identify the optimal cut‐off point. Sensitivity, specificity, and confidence interval calculations were performed using standard procedures.\n\n3 RESULTS\nWe evaluated a total of 247 patients (145 males, 102 female) with acute ischemic stroke; all of them were treated with intravenous t‐PA. Demographic data, baseline clinical findings, and medical history were shown in Table 1. The mean age of the cohort was 69.78 ± 13.62 years. Patients arrived at the emergency department after stroke onset in 1.64 ± 2.21 hr. The time elapsed between symptom onset and t‐PA treatment was 2.72 ± 2.56 hr. Baseline clinical assessment revealed that 75.3% of the patients had hypertension. The median NIHSS score of the cohort at admission was 3.\n\nTable 1 Baseline characteristics of patients (n = 247) with acute ischemic stroke\n\nCharacteristics\tValues\tBaseline characteristics\tValues\t\nAge (year), mean ± SD\t69.78 ± 13.62\tMedical history\t \t\nMale, n (%)\t145 (58.70)\tHypertension, n (%)\t186 (75.30)\t\nCRP (mg/L), median (IQR)\t0 (0, 6)\tDiabetes, n (%)\t71 (28.74)\t\nCreatinine (μmol/L), median (IQR)\t73 (60,92)\tAtrial fibrillation, n (%)\t41 (16.60)\t\nUric acid (μmol/L), median (IQR)\t293 (211, 371)\tRenal insufficiency, n (%)\t11 (4.45)\t\nBlood glucose (mmol/L), median (IQR)\t6.76 (5.74, 8.68)\tCoronary heart Disease, n (%)\t20 (8.10)\t\nHomocysteine (μmol/L), median (IQR)\t16.05 (11.79, 21.00)\tLung infection, n (%)\t1 (0.40)\t\nSystolic blood pressure (mmHg), median (IQR)\t154 (142, 170)\tCancer, n (%)\t2 (0.81)\t\nDiastolic blood pressure (mmHg), median (IQR)\t86 (76, 95)\tCerebral infraction, n (%)\t12 (4.86)\t\nNIHSS, median (IQR)\t3 (2, 7)\tOther medical history, n (%)\t35 (14.17)\t\nJohn Wiley & Sons, LtdNIHSS data were completed at baseline in 247 (100%), at 2 hr in 246 (99.6%), at 24 hr in 232 (93.9%), at 2 days in 221 (89.5%), at 3 days in 211 (85.4%), at 7 days in 196 (79.4%), and at 14 days in 81 (32.8%) patients. MRS data were completed at baseline and at discharge. Higher number of patients had a mild severity (score 0–1) of MRS at discharge (n = 179) than at the baseline (n = 124). Overall, 145 patients had improved/complete recovery, 73 had no changes, and 29 had the outcome of worsening/died.\n\nIt has been known that the major complication of thrombolytic therapy for acute stroke is hemorrhage. In the current cohort, the reported treatment‐related hemorrhage included oral (n = 18), gastrointestinal (n = 2), and intracranial hemorrhage (n = 8). Most of the related adverse events (AEs) were mild (n = 14) or moderate (n = 12) in intensity. A total of eight related AEs were severe, including three events of deaths (these three patients had symptomatic hemorrhage).\n\nA univariate analysis was performed for the available variables, and the results showed that baseline characteristics including age, CRP, blood glucose level, systolic blood pressure, and admission NIHSS were significantly different (p < 0.05) among patients with different clinical outcome (Table 2). A further multivariate analysis was then performed. Variables associated with poor clinical outcome (worsening/death) (p < 0.1) were included in the logistic regression model. In the meantime, variable selection was performed. After balancing the predictive power and complexity of the model, four parameters were retained: Age, CRP, Blood glucose level, and Systolic blood pressure (ACBS). These parameters were statistically significant among groups, and their predictive power was high when used in combination. Also, these were objective parameters (when compared to NIHSS) and could be obtained easily in clinical setting. Recognizing the relatively wide 95% CI of the data, several models were established (Table 3).\n\nTable 2 Univariate analysis of baseline characteristics and clinical outcome\n\nBaseline characteristics\tImproved/complete cure, n = 145\tNo change, n = 73\tWorsening/death\t\np\n\t\nAge (year), mean ± SD\t69.17 ± 13.24\t68.05 ± 14.57\t77.14 ± 10.79\t0.001\t\n80 ≤ age\t38 (26.39)\t21 (28.77)\t15 (51.72)\t0.029\t\n70 ≤ age < 80\t27 (18.75)\t13 (17.81)\t5 (17.24)\t\n60 ≤ age < 70\t46 (31.94)\t16 (21.92)\t8 (27.59)\t\nAge <60\t33 (22.92)\t23 (31.51)\t1 (3.45)\t\nGender, n (%)\t\nMale\t86 (59.31)\t40 (54.79)\t19 (65.52)\t0.595\t\nFemale\t59 (40.69)\t33 (45.21)\t10 (34.48)\t\nHypertension, n (%)\t105 (72.41)\t59 (80.82)\t22 (75.86)\t0.396\t\nDiabetes, n (%)\t41 (28.28)\t19 (26.03)\t11 (37.93)\t0.479\t\nAtrial fibrillation, n (%)\t22 (15.17)\t16 (21.92)\t3 (10.34)\t0.283\t\nRenal insufficiency, n (%)\t5 (3.45)\t2 (2.74)\t4 (13.79)\t0.072\t\nCoronary heart disease, n (%)\t13 (8.97)\t5 (6.85)\t2 (6.90)\t0.837\t\nLung infection, n (%)\t0 (0.00)\t1 (1.37)\t0 (0.00)\t0.413\t\nCancer, n (%)\t0 (0.00)\t1 (1.37)\t1 (3.45)\t0.083\t\nCerebral Infraction, n (%)\t6 (4.14)\t4 (5.48)\t2 (6.90)\t0.753\t\nOther medical history, n (%)\t17 (11.72)\t10 (13.70)\t8 (27.59)\t0.081\t\nAdmission CRP, median, (IQR)\t0 (0,6)\t0 (0,6)\t5 (0,20.89)\t0.005\t\n16.5 ≤ CRP\t12 (8.45)\t6 (8.45)\t9 (31.03)\t0.030\t\n7 ≤ CRP < 16.5\t15 (10.56)\t8 (11.27)\t2 (6.90)\t\n0 ≤ CRP < 7\t115 (80.99)\t57 (80.28)\t18 (62.07)\t\nCreatinine (μmol/L), median (IQR)\t74 (62,95)\t72 (54,84)\t72.5 (58.5,89)\t0.206\t\nUric acid (μmol/L), median (IQR)\t290 (205,371)\t309 (236,381)\t305 (54.84,369)\t0.655\t\nBlood Glucose (mmol/L), median (IQR)\t6.47 (5.64,8.63)\t6.77 (5.65,8.23)\t8.36 (6.62,10.93)\t0.008\t\n9 ≤ glucose\t30 (21.58)\t13 (18.31)\t12 (44.44)\t0.054\t\n7.5 ≤ glucose < 9\t15 (10.79)\t9 (12.68)\t4 (14.81)\t\n0 < glucose < 7.5\t94 (67.63)\t49 (69.01)\t11 (40.74)\t\nHomocysteine (μmol/L), median (IQR)\t16.46 (11.64,21)\t14.6 (10.82,18.58)\t20 (14.43,26.98)\t0.058\t\nSystolic blood pressure (mmHg), median (IQR)\t151 (140,166)\t154.5 (143,170)\t166 (148,177.5)\t0.049\t\n165 ≤ systolic blood pressure\t37 (25.87)\t22 (31.43)\t16 (57.14)\t0.024\t\n155 ≤ systolic blood pressure < 165\t25 (17.48)\t13 (18.57)\t4 (14.29)\t\n0 < systolic blood pressure < 155\t81 (56.64)\t35 (50.00)\t8 (28.57)\t\nDiastolic blood pressure (mmHg), median (IQR)\t85 (76,93)\t88 (77,98)\t85.5 (75.5,95.5)\t0.337\t\nAdmission NIHSS, median (IQR)\t3 (2,7)\t3 (2,5)\t4 (3,9)\t0.032\t\n20 ≤ NIHSS\t8 (5.52)\t4 (5.48)\t4 (13.79)\t0.082\t\n4 ≤ NIHSS < 20\t58 (40.00)\t26 (35.62)\t16 (55.17)\t\n0 ≤ NIHSS < 4\t79 (54.48)\t43 (58.90)\t9 (31.03)\t\nJohn Wiley & Sons, LtdTable 3 Multivariate analysis of occurrence of worsening/death after treatment in patients with different clinical outcome\n\nModel\tIndependent variables\tLevels (risk factors)\tOdds ratio\t95% CI\t\np\n\t\nLower limit\tUpper limit\t\nModel 1\tGender\tMale versus female\t1.141\t0.400\t3.254\t0.805\t\nRenal insufficiency\tAbsence versus presence\t0.220\t0.035\t1.398\t0.109\t\nCancer\tAbsence versus presence\t0.507\t0.013\t19.172\t0.714\t\nAge\t80 ≤ age versus age <60\t5.772\t0.650\t51.238\t0.273\t\n70 ≤ age < 80 versus age <60\t5.014\t0.474\t53.045\t0.532\t\n60 ≤ age < 70 versus age <60\t5.662\t0.630\t50.909\t0.316\t\nCRP\t16.5 ≤ CRP versus 0 ≤ CRP < 7\t5.694\t1.649\t19.665\t0.008\t\n7 ≤ CRP < 16.5 versus 0 ≤ CRP < 7\t0.868\t0.166\t4.548\t0.227\t\nBlood glucose\t9 ≤ blood glucose versus 0 < blood glucose < 7.5\t2.309\t0.780\t6.835\t0.521\t\n7.5 ≤ blood glucose < 9 versus 0 < blood glucose < 7.5\t2.631\t0.660\t10.498\t0.411\t\nSBP\t165 ≤ SBP versus 0 < SBP < 155\t5.906\t1.869\t18.667\t0.006\t\n155 ≤ SBP < 165 versus 0 < SBP <155\t1.662\t0.393\t7.025\t0.570\t\nNIHSS\t20 ≤ NIHSS versus 0 ≤ NIHSS < 4\t1.867\t0.334\t10.445\t0.678\t\n4 ≤ NIHSS < 20 versus 0 ≤ NIHSS < 4\t1.770\t0.601\t5.211\t0.644\t\nModel 2\tAge\tUnit = 1\t1.044\t1.007\t1.082\t0.019\t\nCRP\tUnit = 1\t1.013\t0.999\t1.027\t0.068\t\nBlood glucose\tUnit = 1\t1.091\t0.967\t1.231\t0.158\t\nSBP\tUnit = 1\t1.024\t1.004\t1.044\t0.016\t\nModel 3\tAge\t80 ≤ age versus age <60\t6.039\t0.719\t50.746\t0.253\t\n70 ≤ age < 80 versus age <60\t6.207\t0.637\t60.431\t0.326\t\n60 ≤ age < 70 versus age <60\t5.536\t0.628\t48.843\t0.394\t\nCRP\t16.5 ≤ CRP versus 0 ≤ CRP < 7\t6.732\t2.108\t21.503\t0.002\t\n7 ≤ CRP < 16.5 versus 0 ≤ CRP < 7\t0.912\t0.179\t4.638\t0.200\t\nBlood glucose\t9 ≤ blood glucose versus 0 < blood glucose < 7.5\t2.512\t0.914\t6.902\t0.352\t\n7.5 ≤ blood glucose < 9 versus 0 < blood glucose < 7.5\t2.387\t0.620\t9.192\t0.531\t\nSBP\t165 ≤ SBP versus 0 < SBP < 155\t5.654\t1.888\t16.931\t0.006\t\n155 ≤ SBP < 165 versus 0 < SBP < 155\t1.783\t0.428\t7.422\t0.664\t\nNote\nModel 1, the characteristic variables of p < 0.1 in the univariate analysis were all used as independent variables, and the logistic regression model was established by using clinical outcome of worsening/death after treatment. Model 2: Age, CRP, blood glucose, SBP were selected as independent variables. Model 3: Age, CRP, blood glucose, and SBP were selected as an independent variable.\n\nJohn Wiley & Sons, LtdThe four variables, age, CRP, blood glucose, and SBP, were continuous variables and might not be convenient to use in a regression model. The parameters were thus put into a scoring system (Table 4). The levels were first assigned on the basis of the cut‐off of the single parameter, and then adjusted in combination with other parameters until the predictive power of the classifier became satisfactory (higher predictive value than the single parameter). The score at 7.7 was chosen as a cut‐off, as it has the highest Youden's Index. Risk of the poor clinical outcome increased with higher scores.\n\nTable 4 ACBS scoring system\n\nCharacteristics\tCriteria\tScore\t\nAge (year)\t<60\t0\t\n60–69\t1\t\n70–79\t2\t\n≥80\t3\t\nCRP (mg/L)\t<7\t1\t\n7–16.4\t2\t\n≥ 16.5\t3\t\nBlood glucose level (mmol/L)\t<7.5\t1\t\n7.5–8.9\t2\t\n≥9\t3\t\nSystolic blood pressure (mmHg)\t<155\t1\t\n155–164\t2\t\n≥165\t3\t\nJohn Wiley & Sons, LtdThe ROC curve of this ACBS classifier has an AUC of 0.7788, while other individual parameters had smaller AUC, including age (AUC = 0.6617), CRP (AUC = 0.6337), blood glucose grade (AUC = 0.6371), SBP grade (AUC = 0.6753), admission NIHH (AUC = 0.6510), and admission MRS (AUC = 0.6173) (Table 5 and Figure 1). The ACBS classifier provided enhanced sensitivity of 69.2% and specificity of 74.3%.\n\nTable 5 Comparisons of AUC between ACBS classifier and various parameters\n\nIndicators\tAUC\t95% CI\tDifference*\n\t\np\n*\n\t\nLower limit\tUpper limit\t\nACBS score\t0.7788\t0.6831\t0.8744\t–\t–\t\nAge\t0.6617\t0.5667\t0.7567\t−0.1451\t0.0020\t\nCRP\t0.6337\t0.5267\t0.7406\t−0.1417\t0.0182\t\nBlood glucose\t0.6371\t0.5306\t0.7435\t−0.1035\t0.0109\t\nSBP\t0.6753\t0.5702\t0.7803\t−0.1278\t0.0453\t\nNIHSS of admission\t0.6510\t0.5541\t0.7479\t−0.1615\t0.0358\t\nMRS of admission\t0.6173\t0.4991\t0.7355\t−0.2788\t0.0153\t\nReference line\t0.5000\t0.5000\t0.5000\t−0.1451\t<0.0001\t\n* The differences in AUC and p‐value compared to ACBS.\n\nJohn Wiley & Sons, LtdFigure 1 Receiver operating characteristic curves for age, CRP, blood glucose grade, SBP grade, baseline NIHSS, baseline MRS, and ACBS classifier with respect to clinical outcome\n\n4 DISCUSSION\nThe current study showed that the combination of age, CRP, baseline SBP, and blood glucose was a classifier that could predict patients with high risk of poor response to t‐PA treatment. Comparing to other predictive models (Baird et al., 2001; Johnston et al., 2003, 2000), the ACBS scoring system is simple to use. It is based on commonly assessed clinical parameters for stroke patients.\n\nSeveral analyses from observational studies as well as randomized clinical trials reported the predictive value of age (Fiorelli et al., 1995; Generalized efficacy of t‐PA for acute stroke, 1997; Johnston et al., 2003). In the current study, patients with worsening/death outcome after treatment were significantly older. Age was also a variable in the ACBS classifier predicting the clinical outcome. The DRAGON score, which includes age in the scoring system, predicts the functional outcome of patients as assessed by MRS as well (Kent, 2012). Indeed, age was also a variable in different models that predict the risk of hemorrhage after t‐PA (Lou et al., 2008; Lyden, 2012; Menon et al., 2012). Overall, the data suggested that age is an important characteristic that has to be considered for clinical decision.\n\nOur findings indicated that high blood glucose level was associated with poor clinical outcome of patients. Several studies also showed that hyperglycemia was related to poor outcome of acute ischemic stroke patients (Fuentes, 2010; Stead et al., 2009; Williams et al., 2002). The relationship between high blood glucose level and severity of ischemic stroke can be explained by the increase of lactate production in the ischemic region. The production lead to generation of hydrogen ions and disruption of intracellular pH homeostasis. As a result, some reactions and enzyme systems that are essential to cellular viability were interrupted (Lindsberg & Roine, 2004; Pulsinelli, Waldman, Rawlinson, & Plum, 1982; Rehncrona, Rosen, & Siesjo, 1981). In the current cohort, about 35% of patients had high blood glucose level (>7.5 mmol/L). Initiation of intensive insulin therapy has been suggested for stroke patients, but currently available data fail to identify the clinical benefits of the therapy, for example, the UK Glucose Insulin in Stroke Trial (GIST‐UK) showed no significant clinical benefit associated with insulin therapy in 933 patients with stroke (Gray et al., 2007).\n\nHigh blood pressure is common in acute stroke patients. Several studies suggested a U‐shaped relationship between baseline blood pressure and poor outcome of ischemic stroke (Leonardi‐Bee, Bath, Phillips, & Sandercock, 2002; Vemmos et al., 2004). Both high blood pressure and low blood pressure were prognostic for poor outcome. The analyses of data from the thrombolysis implementation and monitor of AIS in China (TIMS‐China) showed that a higher first 2 hr systolic blood pressure was related to symptomatic intracerebral hemorrhage. A proper control of systolic blood pressure for the first 2 hr was thus recommended to decrease the risk of hemorrhage (Wu, 2016). Our study also supported the notion that high systolic blood pressure at admission was related to poor clinical outcome among ischemic stroke subjects.\n\nSeveral studies have reported the predictive value of plasma CRP concentrations. Elevated CRP concentration predicted poor survival and poor functional outcome of patients with acute ischemic stroke (Mazaheri, Reisi, Poorolajal, & Ghiasian, 2018; Muir, Weir, Alwan, Squire, & Lees, 1999). It was suggested that CRP concentration may correlate with the degree of inflammation directly consequent to cerebral infraction. There were some studies, however, reported that baseline CRP failed to predict clinical outcomes (Karlinski et al., 2014; Topakian, Strasak, Nussbaumer, Haring, & Aichner, 2008). Our results supported the usefulness of baseline CRP as a predictive marker of poor clinical outcome.\n\nOur study has some limitations. The study populations of the current study represent hospital‐based cohorts; unselected patients in different clinical settings are needed for validating the model. Also, the number of patients is limited for establishing a prognostic model. This is a retrospective study, therefore our findings await replication in a prospective cohort to determine the best approach to manage patients with high score in the ACBS scoring system. The cut‐off criteria for the clinical variables will need to be further verified. In summary, we evaluated the baseline clinical characteristics of stroke patients associated with patient outcome as assessed by MRS. The ACBS classifier provided a satisfactory sensitivity and specificity in estimating the patients’ response to t‐PA treatment. After further validating, the classifier may provide important information to clinicians when discussing treatment options with patients and their families.\n\n5 CONCLUSION\nThe ACBS classifier provided a satisfactory power in estimating the patients’ clinical outcome. After further validating, the classifier may provide important information to clinicians for making clinical decisions.\n\nINFORMED CONSENT\nAll the patients gave their written information consent.\n\nETHICAL APPROVAL\nThe study was approved by the Hospital's ethics committee.\n\nCONFLICT OF INTEREST\nAll the authors declare that they have no conflict of interest.\n==== Refs\nREFERENCES\n\n\nBaird , A. E. \n, \nDambrosia , J. \n, \nJanket , S.‐J. \n, \nEichbaum , Q. \n, \nChaves , C. \n, \nSilver , B. \n, … \nWarach , S. \n (2001 ). A three‐item scale for the early prediction of stroke recovery . 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"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "9(4)",
"journal": "Brain and behavior",
"keywords": "outcome; stroke; tissue plasminogen activator",
"medline_ta": "Brain Behav",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D020521:Stroke; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "101570837",
"other_id": null,
"pages": "e01251",
"pmc": null,
"pmid": "30859753",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": "22811458;30859753;22508227;18484234;10229731;18357419;29664664;6890157;26828609;11445104;21160056;28989804;21631326;14757880;10187871;24571644;22529207;12105309;11641579;12511774;11988609;9368551;7872877;14746563;18955684;10703777;20724713;17434094;17903915;10657421;7328145",
"title": "Clinical characteristics and risk score for poor clinical outcome of acute ischemic stroke patients treated with intravenous thrombolysis therapy.",
"title_normalized": "clinical characteristics and risk score for poor clinical outcome of acute ischemic stroke patients treated with intravenous thrombolysis therapy"
} | [
{
"companynumb": "CN-ROCHE-2515638",
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{
"abstract": "We report a 21-year-old young male with Lemierre's syndrome presented as tonsillitis and Fusobacterium septicemia with respiratory failure and required intensive care. Lemierre's syndrome is the septic embolic complication of recent pharyngeal illness. Fusobacterium spp. accounts for the majority of cases. High index of suspicion is needed and prolonged antibiotic is advised. It is seldom seen in intensive care but should never be forgotten.",
"affiliations": "Department of Intensive Care, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China.;Department of Intensive Care, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China.;Department of Intensive Care, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China.;Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China.",
"authors": "Man|Man-Yee|MY|;Shum|Hoi-Ping|HP|;Yan|Wing-Wa|WW|;Lau|Susanna K P|SKP|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijccm.IJCCM_388_17",
"fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XMedknow Publications & Media Pvt Ltd India IJCCM-22-12210.4103/ijccm.IJCCM_388_17Case ReportA Case of Lemierre's Syndrome in Intensive Care Unit Man Man-Yee Shum Hoi-Ping Yan Wing-Wa Lau Susanna K. P. 1Department of Intensive Care, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China1 Department of Microbiology, The University of Hong Kong, Hong Kong SAR, ChinaAddress for correspondence: Dr. Man-Yee Man, Department of Intensive Care, Pamela Youde Nethersole Eastern Hospital, 3 Lok Man Road, Chai Wan, Hong Kong SAR, China. E-mail: mmy553@ha.org.hk2 2018 22 2 122 124 Copyright: © 2018 Indian Journal of Critical Care Medicine2018This 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.We report a 21-year-old young male with Lemierre's syndrome presented as tonsillitis and Fusobacterium septicemia with respiratory failure and required intensive care. Lemierre's syndrome is the septic embolic complication of recent pharyngeal illness. Fusobacterium spp. accounts for the majority of cases. High index of suspicion is needed and prolonged antibiotic is advised. It is seldom seen in intensive care but should never be forgotten.\n\nCritical careFusobacterium necrophorumLemierre's syndrome\n==== Body\nINTRODUCTION\nLemierre's syndrome is the septic embolic complication of recent pharyngeal illness. It is commonly caused by Fusobacterium spp. We present a case of young man with Lemierre's syndrome and provide literature review on management principles.\n\nCASE REPORT\nA 21-year-old male with unremarkable past health except was allergic to cefuroxime and metronidazole presented with sore throat and shortness of breath. He was initially seen by otorhinolaryngologist for left tonsillitis in the Emergency Department. Flexible laryngoscopy showed mobile bilateral vocal cords with patent upper airway. He was in septic shock and transferred to the Intensive Care Unit for acute tonsillitis complicated with septic shock on October 7, 2016.\n\nDetailed medical history reviewed a 4-day history of sore throat, fever, and poor oral intake. He was febrile with low-grade temperature of 37.6°C. Chest X-ray showed bilateral lower zone infiltrates. Ultrasound thorax showed bilateral pleural effusion around 4 cm without septation. He developed respiratory failure and intubated for respiratory support.\n\nHe was treated with doxycycline, clindamycin, and vancomycin empirically in view of the drug allergy history. Upon clinical deterioration, antibiotics were upgraded to meropenem and doxycycline.\n\nThroat swab, urine, and sputum culture were negative. Endotracheal aspirates for influenza and other viruses were negative and bacterial culture was negative. Blood culture on day 2 yielded Fusobacterium necrophorum, sensitive to metronidazole and minimal inhibitory concentration of clindamycin 0.12 μg/mL. Microbiologists were consulted and suggested to keep meropenem alone.\n\nIn view of persistent leukocytosis and neck pain, computed tomography (CT) of neck and thorax was performed on October 13, 2016, which showed no obvious abscess, but left internal jugular thrombophlebitis [Figure 1] and multiple cavitating lung nodules [Figure 2] compatible with distal thromboembolism and supported the diagnosis of Lemierre's syndrome. Right internal jugular vein, left brachiocephalic vein, and superior vena cava were patent. Otorhinolaryngologist suggested to continue antibiotics and not for internal jugular vein ligation. He was shortly discharged to general ward to continue intravenous amoxicillin-clavulanate following the antibiotic desensitization protocol. He made satisfactory progress and was discharged home with oral amoxicillin-clavulanate. No anticoagulation was given. Subsequent follow-up with chest X-ray showed resolution of lung infiltrates, and antibiotic was stopped after 6 weeks.\n\nFigure 1 Thrombosis of left internal jugular vein and its branches on contrast computed tomography\n\nFigure 2 Computed tomography thorax shows multiple cavitary lung lesions\n\nDISCUSSIONS\nLemierre's syndrome is the septic thrombophlebitis following an oropharyngeal infection.[1] It was first described by Lemierre et al. in 1936. Up to 60% of cases were caused F. necrophorum infection.[2] In a systematic review by Johannesen and Bodtger, other pathogens causing Lemierre's syndrome include Streptococcus, Staphylococcus aureus, Klebsiella spp., and Pseudomonas.[3] Septic emboli in the liver and lung were commonly identified,[4] but rarer complications including necrotizing fasciitis, mycotic aneurysms, and central nervous system infections have also been reported.[356] Lemierre's syndrome, often known as “the forgotten disease,” has a markedly reduced incidence since the 1940s, probably due to the widespread use of antimicrobials.\n\nThe disease tends to affect young adults who were otherwise healthy.[17] Men are two times more likely to be affected than women. More than two-third of the patients presented with tonsillitis, pharyngitis, or upper respiratory tract infections.[1] Increased incidence during late winter has been observed.[7]\n\nPatients suffering from Lemierre's syndrome infrequently require invasive organ supports. In our patient's case, he presented with septic shock and shortly intubated for mechanical ventilation. Prognosis is generally good with low mortality, but recurrence of abscess can sometimes happen.\n\nF. necrophorum is an obligate Gram-negative anaerobic bacterium. It is commonly found in oral cavity, and up to 20% of healthy teenagers are colonized with F. necrophorum. It may be the second most common bacterial cause of pharyngotonsillitis of adolescents.[7] Coinfection with virus and bacteria, i.e., Streptococcus has been reported.[7] Simultaneous Epstein–Barr virus infection was reported in up to 19% of cases.[7]\n\nF. necrophorum is difficult to culture and requires a longer incubation period. Identification of F. necrophorum to species level often relies on newer microbiological techniques, i.e., 16 s ribosomal RNA and matrix-assisted laser desorption/ionization time-of-flight.[7] In our patient, prolonged incubation of the blood culture yielded F. necrophorum.\n\nDifferent imaging modalities assist in the diagnosis of Lemierre's syndrome. Doppler ultrasound of the internal jugular veins allows a quick screening for thrombophlebitis and is especially helpful as a bedside tool in intensive care settings. Moreover, central venous cannulations in such affected vein should be avoided. CT scan confirms and delineates the extent of thrombophlebitis and also allows the identification of lung abscess in our patient. In fact, more than 95% of cases of internal jugular thrombophlebitis were diagnosed by CT.[3] Serial scans also allow disease monitoring and possibly guide antibiotics and anticoagulation treatments.\n\nManagement of Lemierre's syndrome lies on early adequate and prolonged course of antibiotics. The debate for anticoagulation is ongoing, yet it may seem reasonable to anticoagulate high-risk patients. Surgical interventions including abscess drainage may be helpful, but venous ligation is seldom indicated.\n\nVarieties of treatment durations have been suggested. In general, a prolonged course of antibiotics around 3–6 weeks is generally recommended. Metronidazole is often the recommended agent with adequate tissue penetration.[1] A combination of third-generation cephalosporin and metronidazole would provide a reasonable coverage for other coinfections with Streptococcus.[2] Erythromycin resistance is not uncommon and up to 20% has been reported. Antibiotics can be initially given intravenously for 2–3 weeks then orally up to 6 weeks.[8]\n\nThe role, duration, and targets of anticoagulation were uncertain. A retrospective analysis of 18 cases with or without anticoagulation showed no difference in thrombi resolution,[9] while another retrospective review of pediatric patients did not show major bleeding complications on anticoagulation.[10] A systematic review of 137 cases found that more than 60% were anticoagulated for 2 weeks to 6 months with only 2 patients suffered from complications. However, the severity and sites of thrombosis were not specified.[3] Some authors suggest to anticoagulate high-risk patients, in particular, those who had extensive thrombosis or cerebral sinus thrombosis. There was also a concern for surgical operation and prothrombotic workup before starting anticoagulation. However, high-quality studies on Lemierre's syndrome were limited due to its uncommon nature.\n\nSurgical drainage of sizable and accessible abscess might be beneficial to allow better control of infection.[38] As most of the cases can be treated successfully by antibiotics, ligation of the internal jugular vein is seldom needed. Detailed dental assessment and teeth extractions may be required to prevent further septic embolism.\n\nLemierre's syndrome is the septic embolic complication of recent pharyngeal illness. Fusobacterium spp. accounts for the majority of cases. A high index of suspicion is needed and prolonged antibiotic is advised. It is seldom seen in intensive care but should never be forgotten.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Kuppalli K Livorsi D Talati NJ Osborn M Lemierre's syndrome due to Fusobacterium necrophorum Lancet Infect Dis 2012 12 808 15 22633566 \n2 Karkos PD Asrani S Karkos CD Leong SC Theochari EG Alexopoulou TD Lemierre's syndrome: A systematic review Laryngoscope 2009 119 1552 9 19554637 \n3 Johannesen KM Bodtger U Lemierre's syndrome: Current perspectives on diagnosis and management Infect Drug Resist 2016 9 221 7 27695351 \n4 Takano Y Fukuda K Takayasu H Shinmura K Koizumi G Sasai M Liver abscessation and multiple septic pulmonary emboli associated with Lemierre's syndrome: A case report BMC Res Notes 2015 8 65 25889618 \n5 Suzuki K Hayashi Y Otsuka H Orita M Kuwana T Hashimoto K Case report; A case of Lemierre's syndrome associated with necrotizing fasciitis and septic embolization Nihon Naika Gakkai Zasshi 2016 105 99 104 27266049 \n6 Chamseddin KH Kirkwood ML Lemierre's syndrome associated mycotic aneurysm of the external carotid artery with primary internal carotid artery occlusion in a previously healthy 18-year-old female Ann Vasc Surg 2016 36 291.e 14 \n7 Holm K Bank S Nielsen H Kristensen LH Prag J Jensen A The role of Fusobacterium necrophorum in pharyngotonsillitis – A review Anaerobe 2016 42 89 97 27693542 \n8 Riordan T Human infection with Fusobacterium necrophorum (Necrobacillosis), with a focus on Lemierre's syndrome Clin Microbiol Rev 2007 20 622 59 17934077 \n9 Cupit-Link MC Nageswara Rao A Warad DM Rodriguez V Lemierre syndrome: A Retrospective study of the role of anticoagulation and thrombosis outcomes Acta Haematol 2017 137 59 65 28006761 \n10 Rebelo J Nayan S Choong K Fulford M Chan A Sommer DD To anticoagulate? Controversy in the management of thrombotic complications of head & neck infections Int J Pediatr Otorhinolaryngol 2016 88 129 35 27497400\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0972-5229",
"issue": "22(2)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Critical care; Fusobacterium necrophorum; Lemierre's syndrome",
"medline_ta": "Indian J Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "101208863",
"other_id": null,
"pages": "122-124",
"pmc": null,
"pmid": "29531456",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports",
"references": "27693542;28006761;27497400;27266049;19554637;27695351;22633566;27421193;25889618;17934077",
"title": "A Case of Lemierre's Syndrome in Intensive Care Unit.",
"title_normalized": "a case of lemierre s syndrome in intensive care unit"
} | [
{
"companynumb": "HK-ALKEM LABORATORIES LIMITED-HK-ALKEM-2018-01699",
"fulfillexpeditecriteria": "2",
"occurcountry": "HK",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFUROXIME AXETIL"
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... |
{
"abstract": "OBJECTIVE\nTo study the efficacy and incidence of treatment-related side effects of mycophenolate mofetil (MMF) therapy in patients with noninfectious inflammatory eye diseases.\n\n\nMETHODS\nRetrospective cohort study of 27 Chilean patients treated for noninfectious inflammatory eye diseases using MMF therapy over a 10-year period. Main outcome measures were: ability to control ocular inflammation and to taper prednisone to ≤10 mg daily (treatment success); incidence of treatment-related side effects.\n\n\nRESULTS\nThe proportion of patients with sustained control of inflammation was 81.48% at 6 months. Additionally 55.56% and 22.22% of patients succeeded in tapering their prednisone to 5-10 mg/day and <5 mg/day, at 6 months. Two patients developed a neoplasia during MMF therapy; however, this cohort is too small to interpret the significance of this relation to MMF treatment.\n\n\nCONCLUSIONS\nMMF seems to be an effective corticosteroid-sparing agent with an acceptable safety profile.",
"affiliations": "1 Department of Medicine, Clinical Hospital University of Chile , Santiago, Chile .;2 Ophthalmology Department, Clinical Hospital, Catholic University of Chile , Santiago, Chile .;3 Los Andes Ophthalmologic Foundation, Los Andes University , Santiago, Chile .;3 Los Andes Ophthalmologic Foundation, Los Andes University , Santiago, Chile .;3 Los Andes Ophthalmologic Foundation, Los Andes University , Santiago, Chile .;2 Ophthalmology Department, Clinical Hospital, Catholic University of Chile , Santiago, Chile .;3 Los Andes Ophthalmologic Foundation, Los Andes University , Santiago, Chile .;3 Los Andes Ophthalmologic Foundation, Los Andes University , Santiago, Chile .;3 Los Andes Ophthalmologic Foundation, Los Andes University , Santiago, Chile .",
"authors": "Cuchacovich|Miguel|M|;Solanes|Federica|F|;Perez|Claudio|C|;Verdaguer|Juan Ignacio|JI|;Verdaguer|Juan|J|;Castiglione|Enzo|E|;Carpentier|Cristian|C|;Traipe|Leonidas|L|;Villarroel|Francisco|F|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.1089/jop.2015.0044",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1080-7683",
"issue": "32(1)",
"journal": "Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics",
"keywords": null,
"medline_ta": "J Ocul Pharmacol Ther",
"mesh_terms": "D000328:Adult; D002677:Chile; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007249:Inflammation; D007634:Keratitis; D008297:Male; D009173:Mycophenolic Acid; D012189:Retrospective Studies; D015423:Scleritis; D016896:Treatment Outcome; D014605:Uveitis",
"nlm_unique_id": "9511091",
"other_id": null,
"pages": "55-61",
"pmc": null,
"pmid": "26562247",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Mycophenolate Mofetil Therapy in Refractory Inflammatory Eye Disease.",
"title_normalized": "mycophenolate mofetil therapy in refractory inflammatory eye disease"
} | [
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"companynumb": "CL-JUBILANT CADISTA PHARMACEUTICALS-2016JUB00073",
"fulfillexpeditecriteria": "1",
"occurcountry": "CL",
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"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
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{
"abstract": "Use of an anticoagulant after transcatheter aortic valve replacement (TAVR) has been increasing in practice after noted leaflet thrombosis on dual antiplatelet therapy. As the use of anticoagulation increases so does the number of poor warfarin candidates or warfarin intolerant patients. While direct oral anticoagulant (DOAC) use is increasing for other indications, there is a paucity of data for use after TAVR. The objective of this case series is to add to the available evidence for patients who may require a DOAC after TAVR.\n\n\n\nA single-center, retrospective observational case series was conducted including adults 18 years of age and older who received a DOAC after TAVR between November 2008 and June 2018 at Mayo Clinic Hospital-Rochester. All patients were identified as part of the Society of Thoracic Surgeons database.\n\n\n\nTwenty-one patients were identified as having received a DOAC after TAVR. Median age was 83.5 years (interquartile range 77-87), with 71% males. Within this cohort, 20 patients (95.2%) had an alternative indication for anticoagulation of either atrial fibrillation or atrial flutter. Apixaban was prescribed in 66.7% of patients, followed by rivaroxaban (14.3%), dabigatran (9.5%), and edoxaban (4.8%). No thromboembolic events were reported. Three patients experienced a bleeding event, of which only 2 occurred in the 3 months immediately after TAVR.\n\n\n\nDOAC therapy after TAVR was generally safe and well tolerated. Taken in context of other retrospective studies, these data suggest that the presence of valvular heart disease, specifically TAVR in this case, should not preclude the use of DOACs.",
"affiliations": "Departments of Pharmacy; and.;Departments of Pharmacy; and.;Cardiovascular Surgery, Mayo Clinic, Rochester, MN.;Departments of Pharmacy; and.",
"authors": "Hendricks|Abby K|AK|;Nei|Scott D|SD|;Greason|Kevin L|KL|;Scott|Rachael A|RA|",
"chemical_list": "D000991:Antithrombins; D065427:Factor Xa Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1097/FJC.0000000000000755",
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"issn_linking": "0160-2446",
"issue": "75(1)",
"journal": "Journal of cardiovascular pharmacology",
"keywords": null,
"medline_ta": "J Cardiovasc Pharmacol",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins; D001021:Aortic Valve; D001024:Aortic Valve Stenosis; D001281:Atrial Fibrillation; D001282:Atrial Flutter; D016208:Databases, Factual; D065427:Factor Xa Inhibitors; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008910:Minnesota; D012189:Retrospective Studies; D012307:Risk Factors; D013923:Thromboembolism; D013997:Time Factors; D065467:Transcatheter Aortic Valve Replacement; D016896:Treatment Outcome",
"nlm_unique_id": "7902492",
"other_id": null,
"pages": "41-44",
"pmc": null,
"pmid": "31633585",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Direct Oral Anticoagulant Use After Transcatheter Aortic Valve Replacement: A Case Series.",
"title_normalized": "direct oral anticoagulant use after transcatheter aortic valve replacement a case series"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-023546",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
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{
"abstract": "Disulfiram has been widely used for over six decades in the treatment of alcohol dependence, as an aversive therapeutic agent. Despite having very few side effects when taken without concurrent alcohol consumption, some of these may underlie serious clinical complications. Epileptic seizure induction is a rare adverse effect of disulfiram and its aetiological mechanism is unknown. We present a hospitalised 47-year-old male patient with two episodes of generalised tonic-clonic seizures during treatment with disulfiram while abstinent from alcohol.",
"affiliations": "Unidade de Alcoologia e Novas Dependências, Centro Hospitalar Psiquiatrico de Lisboa, Lisboa, Portugal violetanogueira@chpl.min-saude.pt.;Serviço de Psiquiatria, Centro Hospitalar Psiquiatrico de Lisboa, Lisboa, Portugal.;Serviço de Psiquiatria, Centro Hospitalar Psiquiatrico de Lisboa, Lisboa, Portugal.;Unidade de Alcoologia e Novas Dependências, Centro Hospitalar Psiquiatrico de Lisboa, Lisboa, Portugal.",
"authors": "Nogueira|Violeta|V|;Mendes|Mafalda Azevedo|MA|;Pereira|Inês|I|;Teixeira|Joana|J|",
"chemical_list": "D000927:Anticonvulsants; D002220:Carbamazepine; D004221:Disulfiram",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236296",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(3)",
"journal": "BMJ case reports",
"keywords": "drugs: psychiatry; epilepsy and seizures; safety",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000927:Anticonvulsants; D002220:Carbamazepine; D004221:Disulfiram; D004828:Epilepsies, Partial; D004829:Epilepsy, Generalized; D004830:Epilepsy, Tonic-Clonic; D006801:Humans; D008297:Male; D008875:Middle Aged; D012640:Seizures",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33731397",
"pubdate": "2021-03-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disulfiram-induced epileptic seizures.",
"title_normalized": "disulfiram induced epileptic seizures"
} | [
{
"companynumb": "PT-ENDO PHARMACEUTICALS INC-2021-002571",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXAZEPAM"
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{
"abstract": "OBJECTIVE\nPrimary: to investigate Italian rheumatology practice regarding latent tubercular infection (LTBI) detection and tuberculosis (TB) prevention in patients requiring anti-tumor necrosis factor (anti-TNF) therapy. Secondary: to assess the overall number of TB cases over 10 years and their distribution by drug.\n\n\nMETHODS\nAn anonymous, 24 multiple-response questionnaire was completed by 393/449 (87.5%) rheumatologists prescribing anti-TNF therapy. Six questions provided setting information, and 18 the compliance with recommendations and the recorded TB cases.\n\n\nRESULTS\nThe Italian recommendations were used by 323 (82%) and other sets by 60 (15%). TB specialists were always consulted by 81 (21%) and occasionally by 73 (19%). LTBI screening was made using chest radiograph (CR) by 5%, tuburculin skin test (TST) by 5.3%, CR + TST by 35.6%, interferon-gamma release assay (IGRA) by 7.4%, CR + IGRAs by 26% and CR + TST + IGRA by 20.6%. Isoniazid was initiated in the presence of positivity of TST by 97 (24.7%), TST + IGRA by 101 (25.7%) and IGRA by 195 (49.6%). Anti-TNF starting delay was 1 month in 63.1% of the cases, 3 months in 27.7%, concomitantly in 5.6%. Overall, 317 TB reactivation cases occurred in 39 353 patients, with an incidence rate of 80.5 cases/100 000/year (10 times higher than in the Italian general population). TB occurred during TB prophylaxis in 192 (60.6%). TB cases incidence rate divided by drug was: etanercept (ETN) 51 (16%), 28/100 000/year, adalimumab (ADA) 98 (31%), 89/100 000/year, infliximab (IFX) 137 (43.2%), 211/100 000/year, with a significantly lower frequency in the ETN group compared to ADA and IFX groups (χ(2) = P < 0.001).\n\n\nCONCLUSIONS\nItalian rheumatologists are highly aware of anti-TNF-related TB risk with variable LTBI screening and TB prevention strategies. TB outcome was significantly lower in the ETN group.",
"affiliations": "Division of Rheumatology, Misericordia e Dolce Hospital, Prato, Italy.;Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy.;Division of Rheumatology, Day Hospital Unit, Istituto Ortopedico G. Pini, Milano, Italy.;2nd Chair of Rheumatology, Department of Medical Sciences, University of Cagliari, Cagliari, Italy.;Rheumatology Department of Lucania, San Carlo Hospital of Potenza and Madonna delle Grazie Hospital of Matera, Potenza, Italy.;Rheumatology Unit, Department of Internal Medicine, Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy.;Rheumatology Research Unit, Department of Clinical and Experimental Medicine, University Federico II, Naples, Italy.;Department of Internal Medicine and Medical Specialties, Rheumatology Division - \"La Sapienza\", University of Rome, Rome, Italy.",
"authors": "Cantini|Fabrizio|F|;Lubrano|Ennio|E|;Marchesoni|Antonio|A|;Mathieu|Alessandro|A|;Olivieri|Ignazio|I|;Salvarani|Carlo|C|;Scarpa|Raffaele|R|;Spadaro|Antonio|A|",
"chemical_list": "D018501:Antirheumatic Agents; D000995:Antitubercular Agents; D001688:Biological Products; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept",
"country": "England",
"delete": false,
"doi": "10.1111/1756-185X.12708",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-1841",
"issue": "19(8)",
"journal": "International journal of rheumatic diseases",
"keywords": "anti-TNF; interferon-gamma release assays; latent tuberculosis infection; tuberculin skin test; tuberculosis",
"medline_ta": "Int J Rheum Dis",
"mesh_terms": "D000068879:Adalimumab; D018501:Antirheumatic Agents; D000995:Antitubercular Agents; D001688:Biological Products; D016009:Chi-Square Distribution; D000068800:Etanercept; D019983:Guideline Adherence; D019538:Health Care Surveys; D006801:Humans; D016867:Immunocompromised Host; D015994:Incidence; D000069285:Infliximab; D007558:Italy; D055985:Latent Tuberculosis; D009894:Opportunistic Infections; D017410:Practice Guidelines as Topic; D010818:Practice Patterns, Physicians'; D011237:Predictive Value of Tests; D011379:Prognosis; D012216:Rheumatic Diseases; D000072140:Rheumatologists; D012307:Risk Factors; D013997:Time Factors; D014376:Tuberculosis; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101474930",
"other_id": null,
"pages": "799-805",
"pmc": null,
"pmid": "26172207",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Latent tuberculosis infection detection and active tuberculosis prevention in patients receiving anti-TNF therapy: an Italian nationwide survey.",
"title_normalized": "latent tuberculosis infection detection and active tuberculosis prevention in patients receiving anti tnf therapy an italian nationwide survey"
} | [
{
"companynumb": "IT-UCBSA-2016038735",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CERTOLIZUMAB PEGOL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nOral mucositis is a common complication of cancer therapy. Animal models suggest that curcumin may prevent oral mucositis. To date, no clinical studies have been reported.\n\n\nOBJECTIVE\nThe primary aim of this pilot study was to assess the tolerability of a curcumin mouthwash. The secondary aim was to describe oral mucositis in pediatric patients undergoing doxorubicin-containing chemotherapy who were using the curcumin mouthwash.\n\n\nMETHODS\nThe research team had originally designed a placebo-controlled study, but gastrointestinal adverse events (nausea and vomiting) affected the compliance of the first three participants who entered the study. An independent researcher found that all three had received the placebo. Believing it unethical to continue using the study's original design, the research team discontinued the control group, and the resulting study is comparable to a case series.\n\n\nMETHODS\nThe research team performed the study at Hadassah University Medical Center in Jerusalem, Israel.\n\n\nMETHODS\nParticipants were seven pediatric and young-adult oncology patients.\n\n\nMETHODS\nIn addition to standard, preventive oral care (chlorhexidine 0.2% mouthwash for 30 s twice per day), participants also used 10 drops of Curcumall twice per day in a mouthwash during treatment with highdose chemotherapy.\n\n\nMETHODS\nOral mucositis was assessed on days 0, 7, 10, 14, and 21. The World Health Organization (WHO) scale, the Oral Mucositis Assessment Scale (OMAS), and a Visual Analog pain scale (VAS; patient reporting scale of 0-10) were used. Adverse events were tracked.\n\n\nRESULTS\nNo oral adverse events were documented. No systemic adverse events that possibly could be related to the use of the curcumin mouthwash were observed. In the four patients who fulfilled the compliance criteria, the WHO, OMAS and VAS scores were lower than the severity of oral mucositis previously reported in the literature. Four out of the five participants developed OM, but the values were low, reflecting a relatively mild case.\n\n\nCONCLUSIONS\nIn this study, the research team suggested that curcumin mouthwash was safe and well-tolerated. More research is warranted about the efficacy of topical curcumin in the prevention of oral mucositis.",
"affiliations": "University of Rochester Medical Center, Rochester, NY, USA. selad@urmc.rochester.edu",
"authors": "Elad|Sharon|S|;Meidan|Irit|I|;Sellam|Gila|G|;Simaan|Sohair|S|;Zeevi|Itai|I|;Waldman|Elisha|E|;Weintraub|Michael|M|;Revel-Vilk|Shoshana|S|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D003474:Curcumin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-6791",
"issue": "19(3)",
"journal": "Alternative therapies in health and medicine",
"keywords": null,
"medline_ta": "Altern Ther Health Med",
"mesh_terms": "D000287:Administration, Topical; D000293:Adolescent; D000903:Antibiotics, Antineoplastic; D002648:Child; D003474:Curcumin; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008297:Male; D009061:Mouth Mucosa; D010147:Pain Measurement; D010865:Pilot Projects; D012509:Sarcoma; D013280:Stomatitis; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9502013",
"other_id": null,
"pages": "21-4",
"pmc": null,
"pmid": "23709456",
"pubdate": "2013",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Topical curcumin for the prevention of oral mucositis in pediatric patients: case series.",
"title_normalized": "topical curcumin for the prevention of oral mucositis in pediatric patients case series"
} | [
{
"companynumb": "US-JNJFOC-20130603072",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "Hepatitis C (HCV) remains the single most common etiology of end-stage liver disease leading to simultaneous liver/kidney transplant (SLKT) and has worse post-transplant survival compared to non-HCV patients. We aim to assess the effectiveness and tolerance of the all-oral direct-acting antiviral (DAA) agents with or without ribavirin (RBV) in the treatment of HCV recurrence post-SLKT. Thirty-four patients were studied retrospectively, composed predominantly of treatment-naïve (73.5%) non-Caucasian (61.8%) males (82.4%) infected with genotype 1a (64.7%). 94.1% reached a sustained virologic response (SVR) after 24 weeks (32/34 patients), without difference between 12 and 24 weeks of therapy. 64.7% had no clinical side effects. Three deaths occurred, all unrelated to treatment. One patient had liver rejection; tacrolimus was increased and prednisone was initiated while HCV treatment was continued and the patient ultimately achieved SVR. No liver graft losses. No kidney rejection or losses. We demonstrated that DAA combinations with or without RBV result in a remarkable SVR rate and tolerated in the majority of the studied SLKT patients. It is safe to wait to treat until post-kidney transplant and therefore increase the donor pool for these patients. Our cohort is ethnically diverse, making our results generalizable.",
"affiliations": "MedStar Georgetown Transplant Institute, Washington, DC, USA.;Mount Sinai Hospital, New York, NY, USA.;Mount Sinai Hospital, New York, NY, USA.;University of Chicago Medicine, Chicago, IL, USA.;Oregon Health and Sciences University, Portland, OR, USA.;MedStar Georgetown Transplant Institute, Washington, DC, USA.;MedStar Georgetown Transplant Institute, Washington, DC, USA.;MedStar Georgetown Transplant Institute, Washington, DC, USA.;University of Minnesota, Minneapolis, MN, USA.;University of Minnesota, Minneapolis, MN, USA.;MedStar Georgetown Transplant Institute, Washington, DC, USA.",
"authors": "Nookala|Anupama U|AU|0000-0002-8262-4209;Crismale|James|J|;Schiano|Thomas|T|;Te|Helen|H|;Ahn|Joseph|J|;Robertazzi|Suzanne|S|;Rodigas|Colleen|C|;Satoskar|Rohit|R|;Kc|Mandip|M|;Hassan|Mohamed|M|;Smith|Coleman|C|",
"chemical_list": "D000998:Antiviral Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.13198",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "32(3)",
"journal": "Clinical transplantation",
"keywords": "direct-acting antiviral therapy; hepatitis C; liver/kidney transplantation",
"medline_ta": "Clin Transplant",
"mesh_terms": "D000998:Antiviral Agents; D005260:Female; D005500:Follow-Up Studies; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "e13198",
"pmc": null,
"pmid": "29323755",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Direct-acting antiviral regimens are safe and effective in the treatment of hepatitis C in simultaneous liver-kidney transplant recipients.",
"title_normalized": "direct acting antiviral regimens are safe and effective in the treatment of hepatitis c in simultaneous liver kidney transplant recipients"
} | [
{
"companynumb": "US-BAUSCH-BL-2018-011294",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
... |
{
"abstract": "HIV-associated lymphomas (HALs) have high rates of latent infection by gammaherpesviruses (GHVs). We hypothesized that proteasome inhibition would induce lytic activation of GHVs and inhibit HIV infectivity via preservation of cytidine deaminase APOBEC3G, improving lymphoma control. We tested this oncolytic and antiviral strategy by using bortezomib combined with ifosfamide, carboplatin, and etoposide (ICE) alone or with rituximab (ICE/R) in relapsed/refractory HAL. A 3+3 dose-escalation design was used with a 7-day lead-in period of single-agent bortezomib. Bortezomib was administered intravenously on days 1 and 8 of each cycle at 1 of 4 dose levels: 0.7, 1.0, 1.3, or 1.5 mg/m2 ICE began day 8 of cycle 1 and day 1 of subsequent cycles. Rituximab was included on day 1 of cycles 2 to 6 for CD20+ lymphomas. Twenty-three patients were enrolled. The maximum tolerated dose of bortezomib was not reached. Grade 4 toxicities attributable to bortezomib were limited to myelosuppression. Responses occurred in 17 (77%) of 22 patients receiving any protocol therapy. The 1-year overall survival was 57%. After bortezomib alone, both patients with Kaposi sarcoma herpesvirus (KSHV)-positive lymphoma had more than a 1-log increase in KSHV viral load. In 12 patients with Epstein-Barr virus (EBV)-positive lymphoma, median values of EBV viral load increased. Undetectable HIV viremia at baseline in the majority of patients limited evaluation of HIV inhibition. APOBEC3G levels increased in 75% of evaluable patients. Bortezomib combined with ICE/R in patients with relapsed/refractory HAL is feasible with response and survival comparing favorably against previously reported second-line therapies. Changes in GHV viral loads and APOBEC3G levels trended as hypothesized. This trial was registered at www.clinicaltrials.gov as #NCT00598169.",
"affiliations": "Moores Cancer Center, University of California, San Diego, La Jolla, CA.;Moores Cancer Center, University of California, San Diego, La Jolla, CA.;HIV Dynamics and Replication Program, National Cancer Institute, National Institutes of Health, Frederick, MD.;Memorial Sloan Kettering Cancer Center, New York, NY.;Pennsylvania Hospital, Philadelphia, PA.;Floyd and Delores Jones Cancer Institute at Virginia Mason Medical Center, Seattle, WA.;Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.;Montefiore Medical Center, Bronx, NY.;Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.;Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR.;Department of Pathology, Weill Cornell Medical College, New York, NY; and.;Department of Pathology, Weill Cornell Medical College, New York, NY; and.;Center for AIDS Research and Education, University of California, Los Angeles, Los Angeles, CA.;Moores Cancer Center, University of California, San Diego, La Jolla, CA.",
"authors": "Reid|Erin G|EG|0000-0003-4029-8641;Looney|David|D|;Maldarelli|Frank|F|0000-0002-3062-5250;Noy|Ariela|A|0000-0002-3001-4898;Henry|David|D|;Aboulafia|David|D|0000-0002-6752-3530;Ramos|Juan Carlos|JC|0000-0002-3769-6035;Sparano|Joseph|J|0000-0002-9031-2010;Ambinder|Richard F|RF|;Lee|Jeannette|J|;Cesarman|Ethel|E|;Yahyaei|Sara|S|;Mitsuyasu|Ronald|R|;Wachsman|William|W|0000-0001-8918-9687;|||",
"chemical_list": "D000069283:Rituximab; D000069286:Bortezomib; D005047:Etoposide; D016190:Carboplatin; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": "10.1182/bloodadvances.2018022095",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2473-9529",
"issue": "2(24)",
"journal": "Blood advances",
"keywords": null,
"medline_ta": "Blood Adv",
"mesh_terms": "D000071480:APOBEC-3G Deaminase; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D016190:Carboplatin; D005047:Etoposide; D005260:Female; D006678:HIV; D015658:HIV Infections; D006801:Humans; D007069:Ifosfamide; D007963:Leukocytes, Mononuclear; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D050130:Oncolytic Virotherapy; D012008:Recurrence; D000069283:Rituximab; D019562:Viral Load",
"nlm_unique_id": "101698425",
"other_id": null,
"pages": "3618-3626",
"pmc": null,
"pmid": "30573564",
"pubdate": "2018-12-26",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "12042983;9711914;20023215;14672928;11744828;17332288;15994147;28803888;19412164;23045581;28079515;21517809;17069461;25738670;15613699;22642936;17242396;25663691;27297790;8445433;29527667;20461118;24158828;25636338;12808466;8640681;22180164;14504078",
"title": "Safety and efficacy of an oncolytic viral strategy using bortezomib with ICE/R in relapsed/refractory HIV-positive lymphomas.",
"title_normalized": "safety and efficacy of an oncolytic viral strategy using bortezomib with ice r in relapsed refractory hiv positive lymphomas"
} | [
{
"companynumb": "US-TAKEDA-2019MPI000099",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
... |
{
"abstract": "We conducted a phase I-II study of transplantation conditioning with clofarabine-melphalan-alemtuzumab for patients with advanced hematologic malignancies. Ten patients were accrued to the phase I portion, which utilized an accelerated titration design. No dose-limiting toxicity was observed, and clofarabine 40 mg/m(2) × 5, melphalan 140 mg/m(2) × 1, and alemtuzumab 20 mg × 5 was adopted for the phase II study, which accrued 72 patients. Median age was 54 years. There were 44 patients with acute myelogenous leukemia or myelodysplastic syndromes, 27 with non-Hodgkin lymphoma, and nine patients with other hematologic malignancies. The largest subgroup of 35 patients had American Society for Blood and Marrow Transplantation high-risk, active disease. All evaluable patients engrafted with a median time to neutrophil and platelet recovery of 10 and 18 days, respectively. The cumulative incidence of treatment-related mortality was 26% at 1 year. Cumulative incidence of relapse was 29% at 1 year. Overall survival was 80% (95% confidence interval [CI], 71-89) at 100 days and 59% (95% CI, 47-71) at 1 year. Progression-free-survival was 45% (95% CI, 33-67) at 1 year. Rapid-onset renal failure was the main toxicity in the phase II study and more frequent in older patients and those with baseline decrease in glomerular filtration rate. Grade 3-5 renal toxicity was observed in 16 of 74 patients (21%) treated at the phase II doses. Clofarabine-melphalan-alemtuzumab conditioning yields promising response and duration of response, but renal toxicity poses a considerable risk particularly in older patients.",
"affiliations": "Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA. kvbesien@uchicago.edu",
"authors": "van Besien|Koen|K|;Stock|Wendy|W|;Rich|Elizabeth|E|;Odenike|Olatoyosi|O|;Godley|Lucy A|LA|;O'Donnell|Peter H|PH|;Kline|Justin|J|;Nguyen|Vu|V|;Del Cerro|Paula|P|;Larson|Richard A|RA|;Artz|Andrew S|AS|",
"chemical_list": "D000227:Adenine Nucleotides; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D000074323:Alemtuzumab; D000077866:Clofarabine; D008558:Melphalan",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2011.10.041",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "18(6)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": null,
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D058186:Acute Kidney Injury; D000227:Adenine Nucleotides; D000328:Adult; D000367:Age Factors; D000368:Aged; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D000077866:Clofarabine; D005260:Female; D005919:Glomerular Filtration Rate; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D012008:Recurrence; D012306:Risk; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "913-21",
"pmc": null,
"pmid": "22079470",
"pubdate": "2012-06",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "9262252;21425150;11071652;18565853;7581076;18215784;19361753;17562873;21467544;20801570;12791647;15073032;16009946;15737876;20946966;15543194;16338616;2702835;8674058;20399878;21142785;21252987;19652076;19139740;19064981;12637486;11157478;16622268;12942092;20919852;21801703;21749304;16400339;14551141;19821799;11753543;16403905;21441963;20062101;20208570",
"title": "Phase I-II study of clofarabine-melphalan-alemtuzumab conditioning for allogeneic hematopoietic cell transplantation.",
"title_normalized": "phase i ii study of clofarabine melphalan alemtuzumab conditioning for allogeneic hematopoietic cell transplantation"
} | [
{
"companynumb": "US-SA-2014SA124582",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": null,
"dr... |
{
"abstract": "The purpose of this study is to describe the effects and complications of photodynamic therapy (PDT) on Chinese patients with circumscribed choroidal hemangioma (CCH). In this retrospective study, 22 CCH patients who underwent PDT performed 15 min after the injection of intravenous verteporfin (6 mg/m2)with multiple 83-second laser spots at 689 nm (50 J/cm2) were studied. Fluorescein angiography and/or indocyanine green angiography, B-scan ultrasonography and optical coherence tomography were performed in all patients. Follow-up was performed until 12 months post-treatment. All patients were treated with one session, except 1 case with prior transpupillary thermotherapy history. At the 12-month follow-up, the mean of the best corrected visual acuity (BCVA) increased from 0.40 ± 0.38 to 0.56 ± 0.42 (p < 0.05), tumors became thinner (1.96 ± 2.65 mm vs. 4.31 ± 2.04 mm) (p < 0.05), and exudative detachment were diminished. The mean fovea center thickness (FCT) decreased from 540.1 ± 470.6 to 171.6 ± 79.3 μm at the 3-month follow-up. The 12-month BCVA was correlated with prior laser treatment, symptom duration, baseline CCH diameter and thickness, baseline FCT and cystoid macular edema. One patient developed a branch retinal artery occlusion. In conclusion, PDT is an effective and safe treatment for CCH. Specific PDT protocols for CCH should be standardized. The retinal arteriole should be spared during the treatment.",
"affiliations": "Department of Ophthalmology, the First Affiliated Hospital of China Medical University. No. 155 Nanjing Bei Street, Heping District, Shenyang City, Liaoning Province, 110001, People's Republic of China.;Department of Ophthalmology, Tacheng area people's Hospital, No. 22, Wenhua road Tacheng City, the Xinjiang Uygur Autonomous Region, People's Republic of China.;Department of Ophthalmology, the First Affiliated Hospital of China Medical University. No. 155 Nanjing Bei Street, Heping District, Shenyang City, Liaoning Province, 110001, People's Republic of China; Diabetic Eye Center of Liaoning province. No. 155 Nanjing Bei Street, Heping District, Shenyang City, Liaoning Province, 110001, People's Republic of China; The Key Laboratory of Endocrine diseases in Liaoning Province, The First Hospital of China Medical University, No. 155 Nanjing Bei Street, Heping District, Shenyang City, Liaoning Province, 110001, People's Republic of China.;Department of Ophthalmology, the First Affiliated Hospital of China Medical University. No. 155 Nanjing Bei Street, Heping District, Shenyang City, Liaoning Province, 110001, People's Republic of China; Department of Ophthalmology, Tacheng area people's Hospital, No. 22, Wenhua road Tacheng City, the Xinjiang Uygur Autonomous Region, People's Republic of China; Diabetic Eye Center of Liaoning province. No. 155 Nanjing Bei Street, Heping District, Shenyang City, Liaoning Province, 110001, People's Republic of China; The Key Laboratory of Endocrine diseases in Liaoning Province, The First Hospital of China Medical University, No. 155 Nanjing Bei Street, Heping District, Shenyang City, Liaoning Province, 110001, People's Republic of China. Electronic address: laser2005sy@126.com.",
"authors": "Liu|Limin|L|;Hu|Chunmei|C|;Chen|Lei|L|;Hu|Yuedong|Y|",
"chemical_list": "D017319:Photosensitizing Agents; D000077362:Verteporfin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.pdpdt.2018.10.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1572-1000",
"issue": "24()",
"journal": "Photodiagnosis and photodynamic therapy",
"keywords": "Best corrected visual acuity; Branch retinal artery occlusion; Circumscribed choroidal hemangioma; Cystoid macular edema; Optical coherence tomography; Photodynamic therapy; Verteporfin",
"medline_ta": "Photodiagnosis Photodyn Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D002681:China; D002830:Choroid Neoplasms; D005260:Female; D006391:Hemangioma; D006801:Humans; D008297:Male; D008875:Middle Aged; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D012189:Retrospective Studies; D012737:Sex Factors; D000077362:Verteporfin; D014792:Visual Acuity",
"nlm_unique_id": "101226123",
"other_id": null,
"pages": "372-376",
"pmc": null,
"pmid": "30381258",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Photodynamic therapy for symptomatic circumscribed choroidal hemangioma in 22 Chinese patients: A retrospective study.",
"title_normalized": "photodynamic therapy for symptomatic circumscribed choroidal hemangioma in 22 chinese patients a retrospective study"
} | [
{
"companynumb": "CN-BAUSCH-BL-2018-035642",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VERTEPORFIN"
},
"drugadditional": "3",
... |
{
"abstract": "Although prognosis in patients with localized osteosarcoma has been dramatically improved by the introduction of multiple chemotherapy agents known as combination chemotherapy, there is growing concern about the development of secondary malignant neoplasms. We report the case of a 13-year-old girl in whom the diagnosis of Ewing sarcoma of bone localized on the shaft of left femur was made 2 years after successful treatment without radiotherapy for osteosarcoma of right proximal femur. EWS-FLI1 fusion gene was detected by reverse transcriptase-polymerase chain reaction. To our knowledge, this is the first case with Ewing sarcoma of the bone as a secondary malignant neoplasm developed in osteosarcoma survivor. We collected 15 cases, included this case, with secondary Ewing sarcoma family of tumor by utilizing the PubMed search and might consider the causes of this secondary cancer.",
"affiliations": "Departments of *Pediatrics †Orthopaedic Surgery ‡Molecular and Laboratory Medicine, Mie University Graduate School of Medicine §Pathology Division, Mie University Hospital, Mie, Japan.",
"authors": "Yodoya|Noriko|N|;Iwamoto|Shotaro|S|;Matsumine|Akihiko|A|;Azuma|Eiichi|E|;Toyoda|Hidemi|H|;Miura|Yoshihiro|Y|;Nakatani|Kaname|K|;Imai|Hiroshi|H|;Hirayama|Masahiro|M|;Komada|Yoshihiro|Y|",
"chemical_list": "C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D016190:Carboplatin; C027260:pirarubicin; D002945:Cisplatin; D007069:Ifosfamide; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000721",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "39(1)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
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"abstract": "BACKGROUND\nAlthough FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS), pts > 75 yrs old were excluded from this study. The purpose of this study was to assess the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in this population.\n\n\nMETHODS\nWe retrospectively analyzed unresectable PC pts, age ≥ 75, treated with mFOLFIRINOX at MD Anderson from 2011 to 2017. Primary outcome was rate of grade 3 or 4 hematologic toxicity (HT).\n\n\nRESULTS\n24 pts were included. Grade 3 or 4 HT occurred in 11 pts 6 pts required hospitalization for any toxicity, and 10 stopped mFOLFIRINOX due to toxicity. The most frequently used starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m2, respectively. Median PFS was 3.7 months (95% CI: 3.0-5.7) with a median OS of 11.6 months (95% CI: 6.14-15.7). For first line pts, median PFS and OS were 5.1 (95% CI: 2.0-12.8) and 12.2 months (95% CI: 4.8-30.8), respectively.\n\n\nCONCLUSIONS\nIn this single-center retrospective analysis of unresectable PC pts age 75 or older given mFOLFIRINOX, toxicities and survival outcomes were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar toxicity and efficacy when compared to younger pts.",
"affiliations": "The University of Texas MD Anderson Cancer Center, USA. Electronic address: jdmizrahi@mdanderson.org.;The University of Texas MD Anderson Cancer Center, USA.;The University of Texas MD Anderson Cancer Center, USA.;The University of Texas MD Anderson Cancer Center, USA.;The University of Texas MD Anderson Cancer Center, USA.;The University of Texas MD Anderson Cancer Center, USA.;The University of Arizona Cancer Center, USA.;The University of Texas MD Anderson Cancer Center, USA.;The University of Texas MD Anderson Cancer Center, USA.;The University of Texas MD Anderson Cancer Center, USA.;The University of Texas MD Anderson Cancer Center, USA.;The University of Texas MD Anderson Cancer Center, USA.",
"authors": "Mizrahi|Jonathan D|JD|;Rogers|Jane E|JE|;Hess|Kenneth R|KR|;Wolff|Robert A|RA|;Varadhachary|Gauri R|GR|;Javle|Milind M|MM|;Shroff|Rachna T|RT|;Ho|Linus|L|;Fogelman|David R|DR|;Raghav|Kanwal P S|KPS|;Overman|Michael J|MJ|;Pant|Shubham|S|",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D002955:Leucovorin; D008297:Male; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome",
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"title": "Modified FOLFIRINOX in pancreatic cancer patients Age 75 or older.",
"title_normalized": "modified folfirinox in pancreatic cancer patients age 75 or older"
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"abstract": "It has been hypothesized that silent hypoxemia is the cause of rapid progressive respiratory failure with severe hypoxia that occurs in some COVID-19 patients without warning.\nA 60-year-old male presented cough without any breathing difficulty. Vital signs showed blood pressure 130/75 mmHg, pulse 84x/minute, respiratory rate (RR) 21x/minute, body temperature 36.5C, and oxygen saturation (SpO2) 75% on room air. RT-PCR for COVID-19 were positive. On third day, he complained of worsening of breath shortness, but his RR was still normal (22x/minute) with SpO2 of 98% on 3 L/minute oxygen via nasal cannula. On fifth day, he experienced severe shortness of breath with RR 38x/minute. He was then intubated using a synchronized intermittent mandatory ventilation. Blood gas analysis showed pH 7.54, PaO2 58.9 mmHg, PaCO2 31.1 mmHg, HCO3 26.9mEq/L, SaO2 94.7%, FiO2 30%, and P/F ratio 196 mmHg. On eighth day, his condition deteriorated with blood pressure 80/40 mmHg with norepinephrine support, pulse 109x/minute, and SpO2 72% with ventilator. He experienced cardiac arrest and underwent basic life support, then resumed strained breathing with return of spontaneous circulation. Blood gas analysis showed pH 7.07, PaO2 58.1 mmHg, PaCO2 108.9 mmHg, HCO3 32.1mEq/L, SaO2 78.7%, FiO2 90%, and P/F ratio 65 mmHg. Three hours later, he suffered cardiac arrest again and eventually died.\nPossible mechanisms of silent hypoxemia are V/Q mismatch, intrapulmonary shunting, and intravascular microthrombi.\nSilent hypoxemia might be considered as an early sign of deterioration of COVID-19 patients, thus, physician may be able to intervene early and decrease its morbidity and mortality.",
"affiliations": "Department of Physiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/UGM Academic Hospital, Yogyakarta, 55291, Indonesia.;Pulmonology Division, Department of Internal Medicine, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, 55281, Indonesia.;Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, 55281, Indonesia.;Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, 55281, Indonesia.;Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, 55281, Indonesia.;Panti Rapih Hospital, Yogyakarta, 55223, Indonesia.;Department of Physiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia.;Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, 55281, Indonesia.",
"authors": "Siswanto|||;Gani|Munawar|M|;Fauzi|Aditya Rifqi|AR|;Yuliyanti|Ririn Enggy|RE|;Inggriani|Maria Patricia|MP|;Nugroho|Bagus|B|;Agustiningsih|Denny|D|;Gunadi|||",
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"fulltext": "\n==== Front\nAnn Med Surg (Lond)\nAnn Med Surg (Lond)\nAnnals of Medicine and Surgery\n2049-0801\nElsevier\n\nS2049-0801(20)30480-5\n10.1016/j.amsu.2020.11.053\nCase Report\nPossible silent hypoxemia in a COVID-19 patient: A case report\nSiswanto sis12@ugm.ac.id\na∗\nGani Munawar munawargani.paru@gmail.com\nb\nFauzi Aditya Rifqi aditya.rifqi.f@mail.ugm.ac.id\nc\nYuliyanti Ririn Enggy enggy24@gmail.com\nc\nInggriani Maria Patricia maria.patricia.i@mail.ugm.ac.id\nc\nNugroho Bagus bagusnugroho400@gmail.com\nd\nAgustiningsih Denny denny_agustiningsih@ugm.ac.id\ne\nGunadi drgunadi@ugm.ac.id\nc∗∗\na Department of Physiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/UGM Academic Hospital, Yogyakarta, 55291, Indonesia\nb Pulmonology Division, Department of Internal Medicine, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, 55281, Indonesia\nc Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, 55281, Indonesia\nd Panti Rapih Hospital, Yogyakarta, 55223, Indonesia\ne Department of Physiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia\n∗ Corresponding author. Department of Physiology Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada UGM Academic Hospital, Jl. Kabupaten Yogyakarta, 55291, Indonesia. sis12@ugm.ac.id\n∗∗ Corresponding author. Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito Hospital, Jl. Kesehatan No. 1 Yogyakarta, 55281, Indonesia. drgunadi@ugm.ac.id\n24 11 2020\n12 2020\n24 11 2020\n60 583586\n15 10 2020\n14 11 2020\n17 11 2020\n© 2020 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.\n2020\n\nThis is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nIntroduction\n\nIt has been hypothesized that silent hypoxemia is the cause of rapid progressive respiratory failure with severe hypoxia that occurs in some COVID-19 patients without warning.\n\nPresentation of case\n\nA 60-year-old male presented cough without any breathing difficulty. Vital signs showed blood pressure 130/75 mmHg, pulse 84x/minute, respiratory rate (RR) 21x/minute, body temperature 36.5C, and oxygen saturation (SpO2) 75% on room air. RT-PCR for COVID-19 were positive. On third day, he complained of worsening of breath shortness, but his RR was still normal (22x/minute) with SpO2 of 98% on 3 L/minute oxygen via nasal cannula. On fifth day, he experienced severe shortness of breath with RR 38x/minute. He was then intubated using a synchronized intermittent mandatory ventilation. Blood gas analysis showed pH 7.54, PaO2 58.9 mmHg, PaCO2 31.1 mmHg, HCO3 26.9mEq/L, SaO2 94.7%, FiO2 30%, and P/F ratio 196 mmHg. On eighth day, his condition deteriorated with blood pressure 80/40 mmHg with norepinephrine support, pulse 109x/minute, and SpO2 72% with ventilator. He experienced cardiac arrest and underwent basic life support, then resumed strained breathing with return of spontaneous circulation. Blood gas analysis showed pH 7.07, PaO2 58.1 mmHg, PaCO2 108.9 mmHg, HCO3 32.1mEq/L, SaO2 78.7%, FiO2 90%, and P/F ratio 65 mmHg. Three hours later, he suffered cardiac arrest again and eventually died.\n\nDiscussion\n\nPossible mechanisms of silent hypoxemia are V/Q mismatch, intrapulmonary shunting, and intravascular microthrombi.\n\nConclusions\n\nSilent hypoxemia might be considered as an early sign of deterioration of COVID-19 patients, thus, physician may be able to intervene early and decrease its morbidity and mortality.\n\nHighlights\n\n• Some patients with COVID-19 might experience rapid deterioration without warning.\n\n• Silent hypoxemia might be considered as an early clinical sign of deterioration of patients with COVID-19.\n\n• Several hypotheses of silent hypoxemia have been proposed, including V/Q mismatch, intrapulmonary shunting and endothelial injury.\n\nKeywords\n\nARDS\nCOVID-19\nEarly sign of deterioration\nRespiratory failure with severe hypoxia\nSilent hypoxemia\n==== Body\n1 Introduction\n\nThe SARS-CoV-2 virus that causes Coronavirus Disease 2019 (COVID-19) was declared a pandemic since the World Health Organization (WHO) decree on March 11, 2020, and has infected more than 54 million people and caused more than 1.3 million deaths as of November 14, 2020 [1,2].\n\nThe early sign of severe disease of SARS-CoV-2 infection is pneumonia with respiratory failure, similar to Acute Respiratory Distress Syndrome (ARDS). Although hypoxic acute respiratory failure causes an increase in respiratory rate (RR), in some patients, a persistent normal RR was found and inconsistent with the severity of hypoxia. Some patients with COVID-19 reported experiencing rapid deterioration without warning. This reaction might be caused by ‘silent hypoxemia’. Research has shown that failure of pulmonary oxygen diffusion causes a gradual decrease in oxygen saturation [3,4]. Here, we reported one COVID-19 case with the possibility of silent hypoxemia.\n\n2 Presentation of case\n\nA 60-year-old Javanese male came to outpatient clinic in our hospital with complaints of cough that was felt for two weeks before admission without any breathing difficulty. Complaints were accompanied by fever, runny nose and sore throat. He had a comorbid condition of uncontrolled diabetes mellitus (DM). He was not a smoker and had no history of chronic pulmonary disease. His vital signs examination showed blood pressure 130/75 mmHg, pulse 84 times per minute, normal respiratory rate (RR) of 21 times per minute, body temperature 36.5C, 75% oxygen saturation on room air. His body mass index is 28.04, categorized as overweight. On physical examination, an increase in vesicular sounds and crackles in both lungs were identified. Laboratory tests showed an increase in C-reactive protein (CRP), neutrophil-lymphocyte ratio, aspartate transaminase (AST), and alanine aminotransferase (ALT) of 140 mg/L, 8.7, 88 μ/L, and 116 μ/L, respectively. Chest x-ray showed bilateral pneumonia (Fig. 1). Sputum and GeneXpert tests were performed, and the results were negative for tuberculosis infection. The nasopharyngeal and oropharyngeal swab real-time polymerase chain reaction tests for COVID-19 were positive. After admission, the patient received antibiotics and antiviral therapy based on the COVID-19 Prevention and Control guidelines by the Indonesian Ministry of Health [5], namely intravenous azithromycin 500mg once daily, oral lopinavir/ritonavir 400/100mg twice daily, oral chloroquine sulfate 150 mg twice a day, intravenous meropenem 1 gr thrice daily, and medications for his DM (Fig. 2). On the third day of treatment, the patient complained of worsening of shortness of breath, but his RR was still normal with 22 times per minute with SpO2 of 98% on 3 L/minute oxygen via nasal cannula. On the fifth day of treatment, the patient experienced severe shortness of breath with a RR of 38 times per minute. The patient was then intubated using a mechanical ventilator with synchronized intermittent mandatory ventilation. The patient was not in a prone position. Moreover, continuous positive airway pressure was not utilized in this patient as a bridging intervention to mechanical ventilation. His blood gas analysis showed respiratory alkalosis (pH 7.54, PaO2 58.9 mmHg, PaCO2 31.1 mmHg, HCO3 26.9 mEq/L, SaO2 94.7%, FiO2 30%, P/F ratio 196 mmHg, indicating moderate ARDS). On the following day, his blood gas analysis showed compensated respiratory alkalosis (pH 7.45, PaO2 64.6 mmHg, PaCO2 42.9, HCO3 29.9 mEq/L, SaO2 93.6%, FiO2 60%, P/F ratio of 111.5 mmHg, indicating moderate ARDS). On the eighth day of treatment, his condition deteriorated starting in the morning, with blood pressure 80/40 mmHg with norepinephrine support, pulse 109 times per minute, and 72% SpO2 with ventilator. In the afternoon, the patient experienced cardiac arrest and underwent basic life support, then resumed strained breathing with return of spontaneous circulation. His laboratory results showed leucocyte count of 21.33x103/μL, AST of 112 μ/L, ALT of 96 μ/L, blood urea nitrogen of 41.5 mg/dL, creatinine of 3.36 mg/dL, and CRP of 140 mg/L. Blood gas analysis showed severe respiratory acidosis (pH 7.07, PaO2 58.1 mmHg, PaCO2 108.9 mmHg, HCO3 32.1 mEq/L, SaO2 78.7%, FiO2 90%, P/F ratio of 65 mmHg, indicating severe ARDS) (Fig. 2). Three hours later, he suffered cardiac arrest again, but was unable to be resuscitated. The patient eventually died.Fig. 1 Chest x-rays: a) on the admission day indicated bilateral pneumonia, which is not compatible with the relatively slight clinical manifestations of patient, b) on the third day, and c) on the eight day also showed bilateral pneumonia.\n\nFig. 1\n\nFig. 2 Clinical picture and disease progression of case. ROSC, return of spontaneous circulation; iv, intravenous; †, died. Y-axis scale: SBP, systolic blood pressure (mmHg, violet triangle); HR, heart rate (times/min, red circle); RR, respiratory rate (times/min, green circle); T, temperature (°C, blue circle); SpO2, oxygen saturation (%, yellow circle). (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\n3 Discussion\n\nHere, we discuss a case with COVID-19 with the possibility of silent hypoxemia. Hypoxemia itself is defined as a potential life-threatening condition characterized by a decrease in arterial PO2 below the normal value. Hypoxemia documentation can be done by checking pulse oximetry and arterial blood gas analysis. Hypoxemia occurs when PaO2 is less than 80 mmHg, and severe hypoxemia is when it is less than 60 mmHg. There are four main factors that can impair pulmonary gas exchange and cause hypoxemia when breathing room water is at sea level: hypoventilation, diffusion limitation, shunt, and ventilation-perfusion (V/Q) mismatch [[7], [8], [9]].\n\nThis unusual ‘silent hypoxemia’ phenomenon showed it is possible that the virus has an idiosyncratic effect on the respiratory control system. Angiotensin-converting-enzyme 2 (ACE2) receptors are highly expressed in the carotid bodies, which are also the same sites where chemoreceptors sense oxygen. ACE2 receptors are also widely expressed in the nasal mucosa. Symptoms of anosmia-hyposmia are experienced by a third of patients with COVID-19, and the olfactory bulb can be the entrance of the virus to the brain and may also play a role in depressed dyspnea response [10,11].\n\nMoreover, ACE2 counteracts the physiological functions of ACE and results in the activation of the renin-angiotensin-aldosterone system (RAAS) related to blood pressure regulation through the conversion of Angiotensin I to Angiotensin II and the electrolyte homeostasis. During the hypoxia condition, Angiotensin II induces vasoconstriction to improve the V/Q mismatch, however, at the same time, it also stimulates the pro-fibrotic effect, and both effects are aggravated by the concomitant upregulation of ACE2 [[10], [11], [12]].\n\nGattinoni et al. [13] suggested two primary phenotypes of hypoxemia in patients with COVID-19: type L and type H. Type L is caused by loss of respiratory regulation and loss of hypoxic vasoconstriction. The condition of hypoxemia is due to an increase in minute ventilation, mainly by increasing the tidal volume (up to 15–20 ml/kg). Meanwhile, type H is a transition from type L, which is associated with a more negative intrathoracic inspiratory pressure. Diffuse pulmonary microvascular thrombosis is also believed to be the cause of hypoxemia in patients with COVID-19 [14].\n\nPneumonia analysis of COVID-19 shows that the air sacs in the lungs of patients are not filled with fluid or pus as in pneumonia infections in general but instead the virus causes the water sacs to collapse, thereby reducing the oxygen level and causing hypoxia in the patient, but the reaction still enhances the normal lung ability to expel carbon dioxide. Since carbon dioxide removal is still effective, patients do not feel shortness of breath [15]. Another mechanism proposed is intrapulmonary shunting. Infection causes interstitial edema, loss of surfactant and superimposed pressure, which induces alveolar collapse and substantial fraction of cardiac output perfusing non-aerated lung tissue. Over time, increased edema will increase lung weight, alveolar collapse, and dependent atelectasis, leading to increased shunting [16].\n\nEndothelial injury as a central hallmark in the pathogenesis of COVID-19 is thought to also play a role in the mechanism of silent hypoxemia. SARS-CoV-2 can directly infect lung capillary endothelial cells expressing ACE2. Endothelial injury and acute inflammation provoke the formation of intravascular microthrombi. Lung autopsies in patients after severe disease have shown diffuse alveolar damage, thickening of the vascular walls, and formation of microthrombi that clog capillaries. Hypercoagulable conditions accelerate the worsening of V/Q mismatch and lung tissue damage [16].\n\nRisk factors for silent hypoxemia are old age and having diabetes [9] and these factors are known to blunt the body's regulatory response to hypoxia [17], as in our case: a 60-year-old-male with comorbidity of diabetes mellitus. Therefore, early detection of silent hypoxemia such as by using prehospital pulse oximetry [5], or radiology imaging [18,19] might provide some red flag signs of impending danger of eminent cardiac arrest or sudden respiratory failure.\n\n4 Conclusions\n\nSilent hypoxemia might be considered as an early clinical sign of deterioration of patients with COVID-19, thus, the physician may be able to intervene early and decrease its morbidity and mortality.\n\nConsent of patient\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nProvenance and peer review\n\nNot commissioned, externally peer reviewed.\n\nList of Abbreviations\n\nSARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2\n\nCOVID-19 Coronavirus Disease 2019\n\nRR Respiratory rate\n\nACE2 Angiotensin-converting-enzyme 2\n\nRAAS renin-angiotensin-aldosterone system\n\nAppendix A Supplementary data\n\nThe following is the Supplementary data to this article:Multimedia component 1\n\nMultimedia component 1\n\nAcknowledgement\n\nThis study was funded by Indonesia Ministry of Research and Technology/National Agency for Research and Innovation.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2020.11.053.\n==== Refs\nReferences\n\n1 World Health Organization https://www.who.int/news-room/detail/27-04-2020-who-timeline---covid-19\n2 World Health Organization Coronavirus Disease 2019 (COVID-19) Weekly Epidemiological Update – 12 October 2020 2020 WHO Geneva\n3 Ottestad W. Seim M. Mæhlen J.O. COVID-19 with silent hypoxemia 2020 Tidsskrift for Den Norske Legeforening\n4 Jouffroy R. Jost D. Prunet B. Prehospital pulse oximetry: a red flag for early detection of silent hypoxemia in COVID-19 patients Crit. Care 24 2020 1 2 31898531\n5 Isbaniah F. Saputro D.D. Sitompul P.A. Susilo A. Wihastuti R. Manalu R. Pedoman Pencegahan Dan Pengendalian Coronavirus Disease (Covid-19) 2020 Kementerian Kesehatan RI Jakarta\n7 Lai C.C. Jou M.J. Huang S.Y. Li S.W. Wan L. Tsai F.J. Lin C.W. Proteomic analysis of up‐regulated proteins in human promonocyte cells expressing severe acute respiratory syndrome coronavirus 3C‐like protease Proteomics 7 2007 1446 1460 17407183\n8 Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. Liu L. Shan H. Lei C.L. Hui D.S. Du B. Clinical characteristics of coronavirus disease 2019 in China N. Engl. J. Med. 382 2020 1708 1720 32109013\n9 Tobin M.J. Laghi F. Jubran A. Why COVID-19 silent hypoxemia is baffling to physicians Am. J. Respir. Crit. Care Med. 202 3 2020 356 360 32539537\n10 Bourgonje A.R. Abdulle A.E. Timens W. Hillebrands J.L. Navis G.J. Gordijn S.J. Bolling M.C. Dijkstra G. Voors A.A. Osterhaus A.D. van der Voort P.H. Angiotensin‐converting enzyme‐2 (ACE2), SARS‐CoV‐2 and pathophysiology of coronavirus disease 2019 (COVID‐19) J. Pathol. 251 3 2020 228 248 32418199\n11 Bach J. A quick reference on hypoxemia Vet. Clin. Small Anim. Pract. 47 2017 175 179\n12 Archer S.L. Sharp W.W. Weir E.K. Differentiating COVID-19 pneumonia from acute respiratory distress syndrome (ARDS) and high altitude pulmonary edema (HAPE): therapeutic implications Circulation 142 2 2020 101 104 32369390\n13 Gattinoni L. Coppola S. Cressoni M. Busana M. Rossi S. Chiumello D. COVID-19 does not lead to a \"typical\" Acute Respiratory Distress Syndrome Am. J. Respir. Crit. Care Med. 201 2020 1299 1300 32228035\n14 Bhatia P. Mohammed S. Severe hypoxemia in early COVID-19 pneumonia Am. J. Respir. Crit. Care Med. 202 4 2020 621 622 32579023\n15 Teo J. Early detection of silent hypoxia in COVID-19 pneumonia using Smartphone pulse oximetry J. Med. Syst. 44 2020 1 2\n16 Dhont S. Derom E. Van Braeckel E. Depuydt P. Lambrecht B.N. The pathophysiology of ‘happy’ hypoxemia in COVID-19 Respir. Res. 21 2020 1 9 31898493\n17 Chandra A. Chakraborty U. Pal J. Karmakar P. Silent hypoxia: a frequently overlooked clinical entity in patients with COVID-19 BMJ Case Rep. 13 2020 e237207\n18 Ozturk T. Talo M. Yildirim E.A. Baloglu U.B. Yildirim O. Acharya U.R. Automated detection of COVID-19 cases using deep neural networks with X-ray images Comput. Biol. Med. 2020 103792 32568675\n19 Yang W. Sirajuddin A. Zhang X. Liu G. Teng Z. Zhao S. Lu M. The role of imaging in 2019 novel coronavirus pneumonia (COVID-19) Eur. Radiol. 2020 1 9 31278580\n\n",
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"abstract": "RET rearrangements are observed in 1-2% of non-small-cell lung cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. In NSCLC patients, RET rearrangements have been associated with a history of non-smoking, a higher rate of brain metastasis at initial diagnosis and a low immune infiltrate. Traditionally, RET fusions are considered mutually exclusive with other oncogenic drivers, even though a co-occurrence with EGFR mutations and MET amplifications has been observed. Cabozantinib, vandetanib and lenvatinib are the first multi-kinase inhibitors tested in RET-rearranged NSCLC patients with contrasting results. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy rates and good tolerability and they were approved for the treatment of patients with metastatic RET fusion-positive NSCLC on the bases of the results of phase II studies. Two ongoing phase III clinical trials are currently comparing selpercatinib or pralsetinib to standard first line treatments and will definitively establish their efficacy in RET-positive NSCLC patients.",
"affiliations": "Thoracic Medical Oncology, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.;Thoracic Medical Oncology, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.;Thoracic Medical Oncology, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.;Department of Oncology and Hematology, Azienda Ospedaliera Pugliese-Ciaccio, 88100 Catanzaro, Italy.;Thoracic Medical Oncology, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.;Thoracic Medical Oncology, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.;Thoracic Medical Oncology, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.;Thoracic Medical Oncology, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.;Thoracic Medical Oncology, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.;Department of Pathology, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.;Clinical Trials Unit, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.;Thoracic Surgery, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.;Department of Radiotherapy, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.;Department of Radiotherapy, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.;Department of Radiology, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.;Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, 80131 Napoli, Italy.;Cellular Biology and Biotherapy and Scientific Directorate, Istituto Nazionale Tumori, \"Fondazione G.Pascale\" IRCCS, 80131 Napoli, Italy.;Thoracic Medical Oncology, Istituto Nazionale Tumori IRCCS \"Fondazione G. Pascale\", 80131 Napoli, Italy.",
"authors": "Cascetta|Priscilla|P|;Sforza|Vincenzo|V|0000-0001-7828-3854;Manzo|Anna|A|;Carillio|Guido|G|0000-0002-7652-9432;Palumbo|Giuliano|G|;Esposito|Giovanna|G|;Montanino|Agnese|A|;Costanzo|Raffaele|R|;Sandomenico|Claudia|C|;De Cecio|Rossella|R|;Piccirillo|Maria Carmela|MC|;La Manna|Carmine|C|;Totaro|Giuseppe|G|;Muto|Paolo|P|;Picone|Carmine|C|;Bianco|Roberto|R|;Normanno|Nicola|N|0000-0002-7158-2605;Morabito|Alessandro|A|0000-0002-1319-9608",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/cancers13174415",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694\nMDPI\n\n10.3390/cancers13174415\ncancers-13-04415\nReview\nRET Inhibitors in Non-Small-Cell Lung Cancer\nCascetta Priscilla 1\nhttps://orcid.org/0000-0001-7828-3854\nSforza Vincenzo 1\nManzo Anna 1\nhttps://orcid.org/0000-0002-7652-9432\nCarillio Guido 2\nPalumbo Giuliano 1\nEsposito Giovanna 1\nMontanino Agnese 1\nCostanzo Raffaele 1\nSandomenico Claudia 1\nDe Cecio Rossella 3\nPiccirillo Maria Carmela 4\nLa Manna Carmine 5\nTotaro Giuseppe 6\nMuto Paolo 6\nPicone Carmine 7\nBianco Roberto 8\nhttps://orcid.org/0000-0002-7158-2605\nNormanno Nicola 9\nhttps://orcid.org/0000-0002-1319-9608\nMorabito Alessandro 1*\nInamura Kentaro Academic Editor\n1 Thoracic Medical Oncology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Napoli, Italy; priscillacascetta@gmail.com (P.C.); v.sforza@istitutotumori.na.it (V.S.); anna.manzo@istitutotumori.na.it (A.M.); giuliano.palumbo@yahoo.it (G.P.); espositogiovanna87@gmail.com (G.E.); a.montanino@istitutotumori.na.it (A.M.); r.costanzo@istitutotumori.na.it (R.C.); c.sandomenico@istitutotumori.na.it (C.S.)\n2 Department of Oncology and Hematology, Azienda Ospedaliera Pugliese-Ciaccio, 88100 Catanzaro, Italy; guidocarillio@gmail.com\n3 Department of Pathology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Napoli, Italy; r.dececio@istitutotumori.na.it\n4 Clinical Trials Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Napoli, Italy; m.piccirillo@istitutotumori.na.it\n5 Thoracic Surgery, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Napoli, Italy; c.lamanna@istitutotumori.na.it\n6 Department of Radiotherapy, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Napoli, Italy; g.totaro@istitutotumori.na.it (G.T.); p.muto@istitutotumori.na.it (P.M.)\n7 Department of Radiology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Napoli, Italy; c.picone@istitutotumori.na.it\n8 Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, 80131 Napoli, Italy; robianco@unina.it\n9 Cellular Biology and Biotherapy and Scientific Directorate, Istituto Nazionale Tumori, “Fondazione G.Pascale” IRCCS, 80131 Napoli, Italy; n.normanno@istitutotumori.na.it\n* Correspondence: a.morabito@istitutotumori.na.it or alessandromorabito1@virgilio.it; Tel.: +39-0815903522; Fax: +39-0817702938\n01 9 2021\n9 2021\n13 17 441523 7 2021\n30 8 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nSimple Summary\n\nNon-small cell lung cancer (NSCLC) remains a significant cause of death worldwide, despite the significant progresses to date. Multiple molecular alterations have been identified in NSCLC, leading to the development of target-based agents that have shown significant clinical benefits. Rearranged during Transfection (RET) fusions have recently emerged as a new potential target and a number of non-selective and selective RET inhibitors have been tested in RET positive NSCLC. In this review we analyse and summarise the characteristics of RET functions and its alterations in NSCLC. We then present the state of the art RET inhibitors in the treatment of NSCLC, discussing the ongoing trials and the future perspectives for RET positive (RET+) NSCLC patients.\n\nAbstract\n\nRET rearrangements are observed in 1–2% of non-small-cell lung cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. In NSCLC patients, RET rearrangements have been associated with a history of non-smoking, a higher rate of brain metastasis at initial diagnosis and a low immune infiltrate. Traditionally, RET fusions are considered mutually exclusive with other oncogenic drivers, even though a co-occurrence with EGFR mutations and MET amplifications has been observed. Cabozantinib, vandetanib and lenvatinib are the first multi-kinase inhibitors tested in RET-rearranged NSCLC patients with contrasting results. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy rates and good tolerability and they were approved for the treatment of patients with metastatic RET fusion-positive NSCLC on the bases of the results of phase II studies. Two ongoing phase III clinical trials are currently comparing selpercatinib or pralsetinib to standard first line treatments and will definitively establish their efficacy in RET-positive NSCLC patients.\n\nNSCLC\nRET\nselpercatinib\npralsetinib\ncabozantinib\nvandetanib\nlenvatinib\n==== Body\npmc1. Introduction\n\nThe RET (Rearranged during Transfection) gene encodes a single-pass transmembrane receptor tyrosine kinase (RTK) physiologically involved in renal morphogenesis, neural and neuroendocrine tissue development as well as spermatogonial stem cell maintenance. The RET protein consists of an extracellular, a transmembrane and an intracellular region. The N-terminal extracellular region contains four highly repeated domains (cadherin-like domains) as well as a cysteine-rich domain and each domain is implied in both normal protein conformation and the construction of active ternary complexes [1]. The transmembrane domain links the extracellular cysteine-rich domain with the intracellular tyrosine kinase (TKI) domain, which ends with isoform-specific tails. In order to be activated, the RET protein requires the constitution of a heterogeneous ternary complex, which usually includes the glial cell line-derived neurotrophic factor (GDNF) family ligands and GDNF family co-receptors (GFRα1-4) (Figure 1). Once assembled, newly formed ternary complexes lead to the auto-phosphorylation of the RET TKI domains, resulting in the activation of downstream signalling pathways normally implied in cell proliferation, growth, differentiation and survival, such as RAS/MAPK, PI3K/AKT, PKC and JAK-STAT [2]. RET gain-of-function alterations have been identified in multiple solid tumours. By sequencing more than 10,000 different metastatic tumours, RET alterations have been found in 2.4% of all cases, primarily in thyroid cancers and NSCLC. Oncogenic RET gain-of-function alterations mainly occur via either germline/somatic mutations or chromosomal rearrangements. Point mutations represent the main RET alteration in medullary thyroid cancer and may occur in either the extracellular domain or the intracellular TKI domain, resulting in a ligand-independent RET activation. Instead, RET fusions are frequently found in NSCLC as well as in papillary thyroid cancer and could result in either ligand-independent activation or aberrant RET expression [3]. Based on previous data, both selective and non-selective RET inhibitors have been explored in NSCLC in multiple clinical trials.\n\nIn this review we present the state of the art RET inhibitors in the treatment of NSCLC, discuss the ongoing trials and the future perspectives for RET positive (RET+) NSCLC patients and provide an updated panorama of this topic, especially on selective RET inhibitors.\n\nRET Rearrangements in NSCLC\n\nRET rearrangements are rarely found in NSCLC patients (1–2%). In most cases, patients harboring RET alterations do not display any concurrent oncogenic driver. However, some small retrospective studies have reported MET amplification and EGFR mutations in this subset of patients [4,5]. Moreover, a large study also confirmed the co-existence of other genetic alterations in RET+ patients. By analysing 4871 different tumour samples, the co-occurrence of genetic abnormalities has been found in the majority of RET- altered patients (81.8%, 72/88 patients), the most common being TP-53 associated genes (59.1%, 52/88 patients), cell cycle-associated genes (39.8%, 35/88 patients), the PI3K signalling pathway (30.7%, 27/88 patients), MAPK effectors (22.7%, 20/88 patients) or other tyrosine kinase families (21.6%, 19/88 patients) such as FGFR families, EGFR, ALK, HER2, PDGFRα and PDGFRβ [6]. Finally, de novo RET fusions are a well described acquired mechanism of resistance to first, second and third generation anti-EGFR TKIs in EGFR mutant NSCLC patients [7,8]. To date, at least 12 fusion RET partner genes have been identified, the most common being KIF5B and CCDC6 (70–90% and 10–25% of all cases, respectively). Despite the breakpoints and fusion partners, a newly formed fusion gene occurs when a 5′ sequence encoding for a coiled coil domain of a RET fusion partner juxtaposes with the 3′ RET sequence encoding for the intracellular tyrosine kinase domain of RET, which usually preserves its functions. Coiled coil domains of these neo-constituted proteins induce ligand-independent homodimerization and the activation of the RET TKI domain by autophosphorylation, resulting in the constitutive stimulation of downstream signalling pathways [9]. RET rearrangements have been identified in tumour specimens via classic techniques, such as FISH and RT-PCR. Both these techniques, however, display some limits, namely their inability to detect de novo or unknown RET fusion partners. By analysing multiple genes at the same time, these limitations have been overcome by innovative techniques such as next generation sequencing (NGS). Moreover, NGS can also be used to investigate both RNA and DNA tumours and may therefore amplify the RET fusion detection rate [2]. Furthermore, NGS can be performed in both tumour specimens and in liquid biopsies, with obvious benefits in terms of invasiveness [10]. On the contrary, due to variable staining patterns as well as weak reactivity, immunohistochemistry (IHC) has been largely exceeded by the aforementioned techniques [11].\n\nTraditionally, RET fusions have been related to young females with a history of non- smoking, although these clinical characteristics are still controversial and may differ between Asian and non-Asian populations [4,5,12,13,14]. Due to a higher percentage of RET fusions in NSCLC patients with a previous history of radiation (5.4% versus 0.4% of cases), gamma rays have been implied as a putative causal factor and these data were also validated in preclinical settings [15]. As previously mentioned, RET fusions are often present in NSCLC patients without other oncogenic drivers. Thus, the clinical and pathological characteristics of RET+ patients may differ from what has been observed for those with other oncogenic drivers. In 2012, Wang et al. analysed 936 tumour specimens obtained from Chinese patients who underwent surgery for mainly early-stage NSCLC. Although no statistical significance was achieved, RET+ patients tended to be younger than those harbouring EGFR mutations (RET+ vs. EGFR+ patients with <60 years: 72.7 % vs. 47.8%, p = 0.131). Likewise, RET+ tumours were poorly differentiated compared to what was observed for ALK positive, EGFR positive or RET negative (RET−) disease (poor differentiation in RET+ vs. ALK+: 63.6% vs. 25%, p = 0.029, poor differentiation in RET+ vs EGFR+: 63.6% vs. 23.8%, p = 0.007, poor differentiation in RET+ vs. RET−: 63.6% vs. 33.9%, p = 0.054). Interestingly, all RET+ patients had a small primary lesion (<3 cm) with a significantly higher percentage of N2 disease (54.5% for RET+ vs. 22.6% for other adenocarcinoma patients, p = 0.024) [12]. Nonetheless, these characteristics did not translate into worse clinical outcomes as no differences were seen in terms of either relapse free survival (RFS) or overall survival (OS) in RET+ versus RET-patients. Further data also confirmed the absence of prognostic impact in terms of PFS and OS for RET status both in Caucasian and in Asian NSCLC patients [4,14]. According to several studies, however, RET+ patients displayed a more advanced disease at the time of the initial diagnosis with up to 77% of patients presenting with stage III/IV versus 22% of patients presenting with stage I and II [5,13]. Furthermore, RET rearranged tumours have been linked to certain subtypes of adenocarcinoma, notably lepidic, solid and papillary, both in Asians and in non-Asians [4,13,16]. Interestingly, some initial reports showed that lymphangitic spread and psammoma bodies were frequently reported in a small series of RET-rearranged NSCLC, suggesting that RET assessment should be encouraged in those cases [17]. In an additional and larger retrospective study, however, no difference in the incidence of lymphangitic carcinomatosis was seen among RET+, ALK+ or ROS1+ advanced NSCLC patients. Compared with these other molecular subtypes, RET+ patients had a higher frequency of neuroendocrine histology (RET+ versus ALK+: 12% vs. 2%, p = 0.025; RET+ vs. ROS1+: 12% vs. 0%, p = 0.010) as well as peripheral primary tumours (RET+ vs. ALK+: 69% vs. 47%, p = 0.029; RET+ vs. ROS1: 69% vs. 36%, p = 0.003). Moreover, brain metastases were more likely to present at initial diagnosis in RET+ patients than in ROS1+ patients (RET+ vs. ROS1+: 32% vs. 10%; p = 0.039), whereas no differences were observed in RET+ and ALK+ patients (RET+ vs. ALK+: 32% vs. 25%; p = 0.592) [18]. Subsequent data also identified RET fusions as an independent risk factor for brain metastases in advanced NSCLC patients [19]. Finally, RET fusions have been related to a low response to immune checkpoint inhibitors due to a low TMB (tumour mutational burden) as well as a low level of PD-L1 expression [20].\n\n2. Non-Selective RET Inhibitors\n\nA number of multi-kinase inhibitors have been evaluated in RET-rearranged NSCLC, including cabozantinib, vandetanib and lenvatinib, with contrasting results (Table 1).\n\n2.1. Cabozantinib\n\nCabozantinib is an oral multi-kinase inhibitor that is active against VEGFR2, MET, ROS1, AXL, KIT and TIE2, with decreased activity against RET (IC50 = 5.2 nM) [21]. Several clinical studies have demonstrated the efficacy of this drug in specific NSCLC cohorts, in particular in RET-rearranged lung cancer. After the identification of RET fusion in NSCLC by Ju et al. [22], Drilon et al. first reported the clinical activity of cabozantinib (60 mg/day) in three chemo-pretreated NSCLC patients harboring RET fusion [23]. Among them, two patients showed a partial response and a third patient had prolonged stable disease. Each patient who exhibited adverse events (AEs) required dose reduction thereafter (grade 3 proteinuria and hypertension). However, these toxicities were manageable with dose modifications and all patients manifested a prolonged response (responses or stable disease). Based on this evidence, an open-label single arm phase II trial was conducted to evaluate cabozantinib in both pretreated and naive RET+ NSCLC patients [24]. A total of 26 patients were enrolled and treated with cabozantinib (60 mg/day). Although no complete responses were observed, 28% of patients responded to cabozantinib. Moreover, responses to treatment were seen early, with a high percentage rate of tumour shrinkage (≥30% tumour reduction in 70% of patients). The median duration of the response was 7.0 months. The median PFS was 5.5 months (95% CI: 3.8–8.4) and the median OS was 9.9 months (95% CI: 8.1–not reached), respectively. Almost all patients (96.4%) experienced AEs, mainly with low grade toxicities (grade 1–2). The most common AEs were grade 3 elevated lipase, increased hepatic enzymes, a decreased platelet count and hypophosphataemia. The onset of grade 2 and 3 AEs required dose reduction in 73% of patients, the most common being palmar-plantar erythrodysaesthesia, fatigue and diarrhoea.\n\nPreclinical studies have suggested that EGFR signalling could play a central role in reducing RET inhibitors’ efficacy in NSCLC cell lines, thus providing a rationale for co-targeting both EGFR and RET in order to reduce the onset of drug resistances. By using NSCLC cell lines harbouring ALK, ROS1, RET and NTRK1 fusions, Vaishnavi et al. also confirmed that EGFR signalling was involved at different levels in determining the resistance to multi-kinase inhibitors so that treatment with gefitinib was able to abrogate EGFR contributions [25]. For this reason, a combination of erlotinib and cabozantinib was evaluated in a phase I–II trial [26]. This trial enrolled 54 pretreated NSCLC patients who received daily doses of cabozantinib plus erlotinib in a 3 + 3 design using combination doses across 5 cohorts in 2 parallel arms (A and B). Across all dose levels, 12 patients experienced at least 1 dose limiting toxicity (DLT): diarrhoea, elevated Aspartate Transaminase (AST), palmar-plantar erythrodysesthesia, mucositis, hypertension, hypokalemia, elevated lipase and fatigue. The most frequent grade 3–4 AEs were diarrhoea (26%), fatigue (15%), dyspnea (12%) and hypoxia (9%). The combination of these drugs was safe and encouraging clinical activity was observed in a largely erlotinib pretreated population, including patients with EGFR T790M and MET amplification. Based on these data, cabozantinib alone or with erlotinib was tested in a phase II trial to assess the improvement in PFS for cabozatinib over erlotinib in patients with EGFR wild-type NSCLC [27]. A total of 125 pretreated NSCLC patients without mutations in EGFR were enrolled and randomly assigned to one of the three treatment arms (cabozantinib alone 60 mg/day, cabozantinib 40 mg/day plus erlotinib 150 mg/day, erlotinib alone 150 mg/day). The primary endpoint was PFS. Secondary endpoints included OS, ORR and the toxicity associated with each regimen. Cabozantinib alone significantly increased PFS (median PFS 4.3 months, 95% CI: 3.6–7.4) compared to erlotinib (1.8 months, 95% CI: 1.7–2.2; HR 0.39, 80% CI: 0.27–0.55; p = 0.0003) and even the combination of cabozantinib plus erlotinib had a longer PFS (4.7 months; 95% CI: 2.4–7.4) compared to erlotinib alone (HR 0.37, 95% CI: 0.25–0.53; p = 0.0003). OS was also better with cabozantinib than with erlotinib (HR 0.68, 80% CI: 0.49–0.95; p = 0.071) and with cabozantinib plus erlotinib than with erlotinib alone (HR 0.51, 80% CI: 0.35–0.74; p = 0.011). The estimated median OS was 5.1 months (95% CI: 3.3–9.3) with erlotinib, 9.2 months (95% CI: 5.1–15.0) with cabozantinib and 13.3 months (95% CI: 7.6–not reached) with erlotinib plus cabozantinib. No differences were recorded in ORR between these three groups. Cabozantinib alone or with erlotinib was more toxic and was associated with an increased occurrence of grade 3 or worse AEs compared to erlotinib alone. Consistent with the literature, the most common grade 3 or 4 AEs were diarrhoea, hypertension, fatigue, oral mucositis and a thromboembolic event. Since testing for RET rearrangements was not mandatory in either of these two trials, the real efficacy of combining cabozantinib with anti-EGFR TKIs in RET+ NSCLC patients needs to be further elucidated.\n\n2.2. Vandetanib\n\nVandetanib is an oral multi-kinase inhibitor that selectively targets RET, VEGFR and EGFR signalling [28]. Phase I and phase II trials in various advanced tumours demonstrated that single agent vandetanib was well tolerated at a daily dose up to 300 mg.\n\nThe efficacy of vandetanib was tested in four phase III trials as single agents or in combination with chemotherapy for patients with advanced NSCLC unselected for RET rearrangements [29,30,31,32]. In the ZEST study, 1240 chemo-pretreated NSCLC patients were randomly assigned to either vandetanib (300 mg daily) or erlotinb (150 mg daily) as second or third line treatment [29]. No significant improvement in PFS was observed for vandetanib over erlotinib (HR 0.98; 95.22% CI: 0.87–1.10; p = 0.721). No significant differences were seen in terms of OS (HR 1.01; p = 0.830), ORR (12% for both arms) and time to deterioration of symptoms. The most frequent AEs with vandetanib were diarrhoea (50% vs. 38%) and hypertension (16% vs. 2%). Grade ≥ 3 toxicities were more frequent with vandetanib than with erlotinib (50% vs. 40%). Moreover, the ZEPHYR trial aimed to compare vandetanib (300mg/day) with a placebo in patients whose disease progressed after at least two lines of treatment, including an EGFR TKI inhibitor [30]. Vandetanib performed better than the placebos in terms of PFS (HR 0.63, p < 0.001) and ORR (2.6% vs. 0.7%, respectively). However, vandetanib did not significantly increase OS compared with the placebo (8.5 vs. 7.8 months; HR 0.95; 95.2% CI: 0.81–1.11; p = 0.527). Common adverse events in the vandetanib arm were diarrhoea (46% vs. 11%), rash (42% vs. 11%) and hypertension (26% vs. 3%). In the ZODIAC study, 1391 patients with advanced NSCLC progression after first line chemotherapy were enrolled to receive second line docetaxel plus vandetanib (100 mg/day) or docetaxel plus the placebo [31]. The median PFS was significantly improved by adding vandetanib to docetaxel (4.0 vs. 3.2 months; HR (hazard ratio) 0.79; 97.58% CI: 0.70–0.90; p < 0.0001). The advantage was seen across all subgroups, including women (PFS 4.6 vs. 4.2 months, HR 0.79; 97.58% CI: 0.62–1.00, p = 0.024). However, there was no significant difference in OS (10.3 vs. 9.9 months; HR 0.95, 95% CI: 0.84–1.07; p = 0.371). Rash (9% vs. 1%), neutropenia (29% vs. 24%), leukopenia (14% vs. 11%) and febrile neutropenia (9% vs. 7%) were the most common grade ≥3 AEs in the docetaxel plus vandetanib arm. Similarly, the ZEAL trial compared pemetrexed plus vandetanib (100 mg/day) with pemetrexed plus placebo as a second line treatment for 534 NSCLC patients, 21% of whom had squamous histology [32]. No significant advantage in terms of PFS was noted by adding vandetanib to chemotherapy. However, a trend towards a better PFS (HR 0.86; 97.58% CI: 0.69–1.06; p = 0.108) and OS (HR 0.86; 97.54% CI: 0.65–1.13; p = 0.219) was noted, with a similar advantage observed for females. There was a statistically significant improvement in ORR (19.1% vs. 7.9%, p < 0.001) and time to deterioration of symptoms (HR 0.61, p = 0.004). Common AEs were rash (38% vs. 26%), diarrhoea (26% vs. 18%) and hypertension (12% vs. 3%). The evidence suggested that adding vandetanib to pemetrexed results in a lower rate of chemo-induced toxicities: anaemia 8% vs. 22%, nausea 29% vs. 37%, vomiting 15% vs. 22%, fatigue 37% v.s 45% and asthenia 11% vs. 17%. The incidence of QT prolongation was <1%. There was no increase in bleeding or thrombotic events in the vandetanib arm. As previously highlighted, however, patients included in these trials were not selected for RET rearrangements. Thus, no data regarding this subgroup of patients can be extrapolated. Indeed, further trials tested vandetanib in specifically selected RET+ patients. In an open-label phase II trial by Lee SH et al., 18 patients with metastatic or recurrent NSCLC harbouring RET rearrangements confirmed by fluorescence in situ hybridization were enrolled [33]. Most of the patients received two or more chemotherapy regimens. ORR was observed in 18% of patients and a stable disease was seen in 47% of the population, with a disease control rate (DCR) of 65%. Moreover, vandetanib showed a PFS of 4.5 months and an OS of 11.6 months after a median follow up of 14 months. The safety profile was consistent with the previous studies. Another phase II trial by Yoh K et al. (LURET) screened 1536 patients with EGFR mutation-negative NSCLC and discovered 34 (2%) RET-rearranged cases [34]. Among 19 patients receiving 300 mg/day of vandetanib, 47% achieved an objective response and the median PFS was 4.7 months. The most common grade 3 or grade 4 AEs were hypertension (58%), diarrhoea (11%), rash (16%), dry skin (5%) and QT prolongation (11%).\n\n2.3. Lenvatinib\n\nLenvatinib is a multi-kinase inhibitor of RET, KIT, VEGFR1–3, PDGFRα and FGFR1–4. It is currently used for radioactive iodine-refractory differentiated thyroid cancer in combination with everolimus for patients with advanced renal cell carcinoma, for the first line treatment of patients with unresectable hepatocellular carcinoma and in combination with pembrolizumab for the treatment of patients with advanced endometrial carcinoma [35]. In a double-blind, placebo-controlled, randomised phase II study that enrolled 134 non-squamous, heavily pretreated (≥3 lines) NSCLC patients unselected for RET rearrangements, lenvatinib (24 mg once daily) plus best supportive care (BSC) improved OS (38.4 vs. 24.1 weeks, p = 0.065), PFS (20.9 vs. 7.9 weeks, p < 0.001) and ORR (10.1% vs. 2.2%) compared with BSC [36]. In a phase II trial conducted in 25 pretreated patients with RET+ lung adenocarcinoma, lenvatinib (24 mg once daily) showed 16% in ORR (95% CI: 4.5–36.1), with no significant differences between patients with the KIF5B–RET fusion variant and the CCDC6–RET fusion variant [37]. The median PFS was 7.3 months (95% CI: 3.6–10.2) and it was longer in patients with the KIF5B–RET fusion variant versus the CCDC6–RET fusion (9.1 months vs. 3.6 months, respectively). The safety profile of Lenvatinib was manageable with hypertension, nausea, diarrhoea and proteinuria being the most common AEs. A phase Ib/II trial was conducted with lenvatinib (20 mg/day) plus pembrolizumab (200 mg every 3 weeks) in pretreated patients with different tumour types (21 patients with advanced NSCLC) who were not previously selected for PDL1 or other biomarkers. In NSCLC patients, the overall ORR was from 14.6% to 57.0% and the median PFS was 5.9 months (95% CI, 2.3 to 13.8 months) [38]. cancers-13-04415-t001_Table 1 Table 1 Non-selective RET inhibitors in RET+ NSCLC patients.\n\nAuthor\tRegimen\tSetting\tPts\tORR (%)\tMedian PFS (Months)\tMedian OS (Months)\t\nDrilon, A. et al., 2016 [24]\tCabozantinib\n60 mg/day\tPretreated or\nuntreated\t26\t28\t5.5\t9.9\t\nNeal, J.W. et al., 2016 [27]\tCabozantinib 60 mg/day\nvs. cabozantinib 40 mg/day + erlotinib\n150 mg/day\nVs. erlotinib 150 mg/day\tPretreated\t125\t11 vs. 3 vs. 3\t4.3 vs. 4.7 vs. 1.8\t9.2 vs. 13.3 vs. 5.1\t\nLee, S.H. et al., 2017 [33]\tVandetanib\n300 mg/day\tPretreated\t18\n(17 evaluable)\t18\t4.5\t11.6\t\nYoh, K, et al., 2017 [34]\tVandetanib\n300 mg/day\tPretreated\t19\t47\t4.7\t11.1\t\nHida, T, et al., 2019 [37]\tLenvatinib\n24 mg/day\tPretreated\t25\t16%\t7.3\t-\t\nORR: objective response rate; PFS: progression-free survival; OS: overall survival; Pts: patients.\n\n3. Selective RET Inhibitors\n\nSmall, highly selective RET inhibitors have been developed with the aim of overcoming treatment-related toxicities commonly seen with non-selective RET inhibitors [39,40]. Among these, selpercatinib and pralsetinib received FDA approval for the treatment of NSCLC harbouring RET alterations (Table 2).\n\n3.1. Selpercatinib\n\nSelpercatinib (LOXO-292) is an oral TKI inhibitor with potent and specific activity against the RET kinase domain, including multiple RET alterations such as fusions, activating point mutations and predicted acquired resistance mutations. Its activity on kinases other than RET is negligible. As one of the most selective RET inhibitors, selpercatinib represents a step forward for the management of RET+ lung cancer patients who have been traditionally treated with standard of care therapies [39,40]. The clinical safety of selpercatinib and its activity profile have been tested in the phase I–II open-label, first-in-human, clinical trial LIBRETTO-001. The study enrolled, in separate cohorts, patients with advanced or metastatic RET+ NSCLC who had disease progression after platinum-based chemotherapy and patients with the same biological characteristics but who were treatment naïve [41]. In the phase I dose escalation, nine dose levels ranging from 20 mg once daily (QD) to 240 mg twice a day (BID) were investigated. At the 240 mg BID dose level, two DLTs were reported: one grade 3 tumour lysis syndrome and one grade 3 thrombocytopenia [42]. The recommended phase II dose established at 160 mg BID demonstrated a favorable safety profile and durable antitumour activity. In phase II, 105 patients were enrolled with RET+ NSCLC who were pretreated with platinum chemotherapy. The median age was 61 years (range, 23–81) and the ECOG performance status was 0–1 (98%) or 2 (2%). Although many of these patients were heavily pretreated, with a median of three prior lines of systemic therapies (including immunotherapy and multitargeted kinase inhibitors with anti-RET activity), an ORR of 64% (95% CI: 54%–73%) was observed, with a median duration of response of 17.5 months (95% CI: 12–NE months; NE, not estimable) as determined by the independent review committee. The responses were observed regardless of the RET fusion partner. At one year, 66% (95% CI: 55 to 74) of all patients were progression-free and the median PFS was 16.5 months (95% CI: 13.7 to NE). It is important to note that 55% of patients received a previous treatment with anti-PD-1/PD-L1 either sequentially or concurrently with platinum-based chemotherapy, achieving an ORR of 66% (95% CI: 52%–78%) with a median duration of response of 12.5 months (95% CI: 8.3-NE). Given the high risk for patients with RET-alterations of developing brain metastasis [43], selpercatinib was also designed to achieve a significant central nervous system (CNS) penetration and activity; thus, 11 patients with measurable brain metastasis were enrolled and responses in the intracranial lesions were observed in 10 of them, with a duration of response of 10.1 months (95% CI: 6.7-NE). The major benefit was observed in the cohort of 39 treatment-naive patients: the ORR was 85% (95% CI: 70–94%) and, to date, the median duration of response and PFS have not been reached. Regarding the safety profile, selpercatinib was well-tolerated and clinically manageable, with lower rates (2%) of study drug discontinuation due to AEs, such as an increase in the alanine aminotransferase level (in 2 patients) and drug hypersensitivity (in 2 patients). Grade 3 or 4 treatment-related adverse events observed in ≥5% of cases were hypertension (in 14% of the patients), increased blood levels of transaminases (alanine aminotransferase in 13%), (aspartate aminotransferase in 10%), hyponatremia and lymphopenia (6%, both). A total of 6 grade 5 adverse events were reported and considered unrelated to the study treatment by the investigators, including sepsis and cardiac arrest, multiple organ dysfunction syndrome, pneumonia and respiratory failure. Dose reduction was necessary in 30% of patients because of treatment-related adverse events. On the basis of these data, on May 8th of 2020, the US Food and Drug Administration (FDA) granted an accelerated approval of selpercatinib for the treatment of adult patients with metastatic RET+ NSCLC regardless of the line of therapy.\n\n3.2. Pralsetinib\n\nPralsetinib (BLU-667) is a small molecule that strongly inhibits the RET kinase domain. In vitro studies demonstrated that, compared with cabozantinib and vandetanib, this molecule is 8 to 28-fold more potent against the wild-type RET kinase domain. Moreover, pralsetinib also displays a strong activity against common oncogenic RET alterations, such as RET M918T, KIF5B–RET and CCDC6–RET fusions. Pralsetinib also has an 88-fold higher selectivity against RET over VEGFR2 compared to what was observed with other multi-kinase inhibitors [44]. Furthermore, pralsetinib is also able to overcome acquired resistance to multi-kinases inhibitors as well as to third generation anti-EGFR TKIs such as osimertinib [7,44]. Pralsetinib is currently being evaluated in the multicenter phase I-II ARROW trial. This trial consists of a dose escalation phase and a subsequent dose expansion phase. In the dose escalation phase, patients with advanced RET-altered solid tumours have been enrolled in order to find the recommended dosage of the drug (400 mg daily). Instead, the currently ongoing dose expansion phase aims to assess the efficacy of pralsetinib in seven different cohorts, including patients with advanced RET+ NSCLC either as first line or in subsequent lines of treatment. Significant key eligibility criteria include no other additional driver mutations as well as ECOG PS 0–1. Importantly, patients with asymptomatic brain metastasis were allowed to enter the trial. The primary endpoints are safety and ORR evaluated by a blinded independent central review as per the RECIST 1.1 criteria. The first results regarding the RET+ NSCLC cohort were presented at the 2019 ASCO Annual Meeting. A total of 79 patients were enrolled, the majority of whom were highly pretreated with two prior therapies as a median number, primarily chemotherapy (76%), immunotherapy (41%) and multi kinase inhibitors (27%). Brain metastasis at the baseline occurred in 39% of patients. The most common RET -fusion partner was KIF5B (44/79 of cases), followed by CCDC6 (16/79 cases). In 19 patients, the RET fusion partner remained unknown. The efficacy population included 57 patients, all with at least one follow-up assessment. The ORR was observed in 56% of cases and 6 patients manifested controlled disease for more than 6 months. DCR was observed in 91% of patients (52/57 patients). Responses occurred regardless of the number and type of prior therapies as well as RET fusion partners, although patients previously treated with platinum agents displayed a more significant ORR (60%). It was also demonstrated that pralsetinib had significant intracranial activity. In terms of side effects, pralsetinib has been well tolerated with mainly low grade toxicities (28% had ≥ grade 3 events). The most commonly observed adverse events were AST and ALT increase (22% and 17%, respectively), hypertension (18%), constipation (17%), neutropenia (15%) and fatigue (15%) [45]. More importantly, after 8 weeks of treatment, patients treated with pralsetinib experimented a major clearance in RET ctDNA. This phenomenon corresponded to either a partial response or stable disease at subsequent assessments [46]. The updated results were presented at the 2020 ASCO Annual Meeting, substantially confirming the efficacy and safety of pralsetinib. In 116 NSCLC patients, ORR overall was 65%. Interestingly, pralsetinib performed better in naïve patients than in platinum pretreated patients in terms of response rate, with an ORR of 73% versus 61%, respectively. On the contrary, DCR was higher in platinum pretreated patients than in naïve patients (DCR 95% versus 88% in platinum pretreated versus naïve patients, respectively). After a follow-up of 8.8 months, the median time to response was 1.8 months and the median duration of response was not reached. Indeed, no data on PFS are currently available [47]. Among eight patients with measurable central nervous system metastases at the baseline, an intracranial response was observed in four patients (complete response in two). Intracranial responses were long lasting, without progression after 6 months. The pharmacokinetic proprieties of pralsetinib suggest that this drug is primarily metabolised by cytochromes (mainly CYP3A4) and largely excreted in feces. No differences in the pharmacokinetic proprieties have been found according to age, sex or mild or moderate renal or hepatic impairment. Since food intake may alter drug absorption, the recommended dosage of pralsetinib is 400 mg orally taken once daily on an empty stomach [48]. Even in the absence of larger studies and given the promising efficacy data from the ARROW trial, the FDA recently approved pralsetinib for the treatment of RET+ advanced NSCLC patients. cancers-13-04415-t002_Table 2 Table 2 Selective RET inhibitors in RET+ NSCLC patients.\n\nAuthor\tPhase\tRegimen\tSetting\tPts\tORR (%)\tMedian PFS (Months)\t\nDrilon, A. et al., 2020 [41]\tI–II\tSelpercatinib\n160 mg twice daily\tPlatinum pretreated\t105\t64 (95% CI: 54–73%)\t16.5 (95% CI: 17.7–n.r.)\t\nII\tSelpercatinib\n160 mg twice daily\tUntreated\t39\t85 (95% CI: 70–94%)\tn.r. (95% CI: 13.8–n.r.)\t\nGainor, J.F. et al., 2020 [47]\tI–II\tPralsetinib\n400 mg daily\tPretreated\t80\t61 (95% CI: 50–72)\t-\t\nII\tPralsetinib\n400 mg daily\tUntreated\t26\t73 (95% CI: 52–88)\t-\t\nn.r.: not reached; ORR: objective response rate; PFS: progression-free survival; OS: overall survival; IC: interval confidence; Pts: patients.\n\n4. Discussion\n\nRET fusions were recently identified in lung cancer and to date several phase II trials have investigated the role of RET non-selective multi-kinase inhibitors in RET+ lung cancer patients, with unsatisfactory clinical results. The weaknesses of these drugs was essentially due to their poor anti-RET potency and to their off-target side-effects, resulting in limited clinical activity burdened by excessive toxicities [39]. On the contrary, promising results have been reported to date in phase I–II studies with two selective RET inhibitors, selpercatinib and pralsetinib, with ORR in 56–85% patients, pretreated or not with multiple lines of chemotherapy and a good safety profile. Based on the aforementioned results, the FDA have granted an accelerated approval of selpercatinib and pralsetinib for the treatment of adult patients with metastatic RET+ NSCLC. However, the clinical research on RET inhibitors in NSCLC is just beginning and a number of relevant questions remain to be addressed: what is the best RET inhibitor for patients with advanced NSCLC and what will be their impact on overall survival? Are there alternative strategies to improve these results, such as combining anti-RET TKI with chemotherapy, immunotherapy or other TKIs? How is it possible to face the resistance mechanisms for RET inhibitors?\n\nFor the first question, there are currently two ongoing phase III clinical trials that are comparing selpercatinib or pralsetinib to platinum-based chemotherapy with or without pembrolizumab as an initial treatment for advanced or metastatic RET+ NSCLC patients (Table 3). The LIBRETTO-431 trial is a phase III trial involving metastatic or stage IIIB–C naive patients not suitable for radical surgery or radiation therapy [49]; patients must have a RET gene fusion found from a tumour biopsy or in blood samples. In this trial, patients will be randomised to receive selpercatinib or pemetrexed plus carboplatin or cisplatin with or without pembrolizumab. The primary outcome measure is PFS. The results are expected in August 2025. The AcceleRET trial is a phase III trial involving metastatic or stage IIIB–C naive patients not suitable for radical surgery or radiation therapy with a RET gene fusion [50]. Patients will be randomised to receive pralsetinib or, if they are non-squamous patients, platinum plus pemetrexed with or without pembrolizumab, while if they are squamous patients, platinum plus gemcitabine. The primary outcome measure is PFS. The estimated enrollment is 250 patients. The results are expected in December of 2024. Overall, both these studies share a similar design and will clarify whether upfront anti-RET treatments should be preferred over chemotherapy alone or combined with pembrolizumab. Instead, no direct comparison between the efficacy of pralsetinib and selpercatinib could be made.\n\nPrecision medicine could also be a helpful tool to further assess which is the best upfront RET inhibitor and how to improve its efficacy. Other RET inhibitors in clinical development are alectinib and brigatinib. Alectinib is under evaluation in the first line setting in the B-FAST trial, a multi-cohort phase II/III trial with an innovative diagnostic strategy based on a liquid biopsy to define different cohorts of treatment [51]. Cohort B is devoted to RET+ patients treated with alectinib at the dose of 1200 mg BID. The primary end point is the objective response rate. The results are expected in the last quarter of 2021. In the second line setting, the ROME trial is a proof-of-concept phase II trial which is trying to assess the efficacy of a treatment based on the genomic profile evidenced through Foundation One. This trial involves patients with different solid tumours, including NSCLC [52]. Enrolled patients must have progressed after at least one prior line of therapy. Next, the Foundation One profiling is performed and patients are therefore treated according to the mutation eventually found, independently from their type of cancers. For RET-mutated patients, the drugs that are allowed are alectinib and brigatinib. The primary end point is ORR. The estimated enrollment is 384 patients. The results are expected in August 2024. A section of the LUNG-MAP clinical trial is dedicated to patients with RET fusion. LUNG-MAP is an umbrella trial that has enrolled stage IV or unresectable lung cancer patients who have undergone at least first line treatment with platinum or, if they have received a treatment with platinum while in stage I–III, then progression must have happened in less than one year [53]. In the prescreening phase, patients are tested with Foundation One to assess or confirm the presence of the RET mutation and then they are treated with selpercatinib. The primary outcome measure is the response rate. The estimated enrollment is 124 participants. The results are expected in March 2023. A number of phase II trials are exploring the activity of other RET inhibitors in pretreated patients, including cabozantinib in the Creta trial and alectinib in the Alert-lung trial [54,55]. Even though these trials are designed to assess the efficacy of anti-RET TKIs in a selected population, they will also demonstrate to what extent precision medicine techniques should be considered helpful in case of doubts. Despite the high reliability, some discrepancies might arise when comparing liquid and tissue biopsies, mainly due to high intra-tumour heterogeneity. A possible implication of this concept that could represent a further investigational area would be the analysis of the tumour heterogeneity among upfront non-responsive patients.\n\nFor the second question, multiple ongoing trials are currently evaluating whether combined treatment strategies could lead to better results. Indeed, a phase II trial is exploring the activity of cabozantinib alone, cabozantinib plus nivolumab or cabozantinib plus nivolumab and ipilimumab in recurring stage IV NSCLC [56]. In this trial, arm T is devoted to patients with ROS1, MET and also RET fusions: in this arm, all patients will receive intravenous nivolumab every 28 days plus cabozantinib daily per os. Patients may have been treated with multiple lines, including biological therapy. The primary end point is PFS. The estimated enrollment in the whole trial is 169 patients. The results are expected in 2022. A phase III trial is ongoing to assess the efficacy of a novel multi-targeting tyrosine kinase inhibitor, anlotinib, in combination with chemotherapy in squamous NSCLC unselected patients for RET fusions. Patients can be enrolled only if disease progression has occurred for more than 12 months after the end of the last treatment and they will be randomised to receive anlotinib plus carboplatin and taxol or placebo plus carboplatin and taxol [57]. The primary outcome measure is PFS. The estimated enrollment is 386 patients. The results are expected in July 2022. Moreover, another phase III trial is assessing the efficacy of the combination of lenvatinib plus pembrolizumab versus pembrolizumab alone in the first line in patients with advanced NSCLC, a PDL-1 greater than or equal to 1%, but who have been selected for RET positivity [58]. As previously described, concurrent genetic alterations have been identified in tumour samples of RET-rearranged NSCLC patients, mainly in TP-53 associated genes, cell-cycle associated genes and PI3K signalling pathway [6]. Furthermore, both in vitro and in vivo models of RET+ NSCLC cell lines demonstrated a strong synergistic effect when non-selective anti-RET TKIs were combined with either CDK 4/6 inhibitors or PI3K/mTOR inhibitors [59]. In this scenario, available preclinical data have highlighted a potential role of multi-targeted agents in the treatment of RET-rearranged NSCLC, which is also going to be further verified in clinic. In an ongoing phase I trial including 13 RET+ NSCLC patients, vandetanib plus everolimus led to 54% of ORR with important responses also seen in brain metastases. The median PFS was 4.4 months. The major toxicities included diarrhoea (21%), thrombocytopenia (16%), QTc prolongation (5%) and rash (5%) and 17/19 patients required dose reduction because of toxicities [60].\n\nTaken together, all these data seem to demonstrate a possible crosstalk between different pathways both in vivo and in vitro. However, given the predominant role of new selective anti-RET molecules, all these data might now be considered outdated. Thus, an interesting future field of investigation would be the further exploration of an upfront combination strategy using either pralsetinib or selpercatinib.\n\nFor the third question, despite the encouraging preliminary results obtained, the benefit from RET-selective inhibitors might be limited by the development of acquired resistance; hence, understanding and developing therapeutic strategies to overcome them is of primary interest. Solomon et al. firstly described a RET G810 solvent front mutation as a mechanism of resistance to selpercatinib in five patients with RET fusion-positive NSCLC and RET-mutant medullary thyroid cancer [61]. Thereafter, Lin and co. reported a multi-institutional analysis of repeat tumour or plasma biopsies from RET+ NSCLC patients treated selpercatinib or pralsetinib, highlighting the role of RET solvent front mutations G810C and G810S as on-target mechanisms of resistance and MET and KRAS amplification as an RET-independent mechanism of escape [62]. Finally, in a recently published paper, Rosen et al. demonstrated through single patient protocols that combination treatment with selpercatinib and crizotinib is safe and clinically active to overcome MET-amplification as a mechanism of resistance during treatment with selpercatinib [63]. A phase I-II trial is investigating the role of TPX-0046, a new potent RET inhibitor, that has shown activity even in tumour models with Solvent Front Mutations [64]. This trial enrolls patients with solid tumours harboring RET fusions in progression after previous therapy or who are ineligible or unlikely to benefit from standard treatment. Cohorts one and two are dedicated to NSCLC patients, for naive and pre-treated patients respectively. All patients will receive TPX-0046. ORR is the primary end point of phase II. The estimated enrollment is 362 patients. The results are expected in March 2025. To date, however, less is known about acquired resistance mechanisms to anti-RET TKIs and how to treat patient who progressed after these molecules. Therefore, this research area needs to be better characterised.\n\nCurrently, RET rearrangements in NSCLC represent an evolving topic with a growing number of manuscripts becoming available. In a similar review published by Choudhury and Drilon in 2020, the authors explained RET protein structure and its activation, but the topic of RET diagnostic techniques and concurrent mutations was not discussed. Furthermore, Choudhury et al. discussed the characteristics of RET+ NSCLC patients, but we tried to highlight the differences in terms of clinical and pathological presentation at diagnosis for this subgroup of patients. Despite similar trials cited in both these papers, our review provides an updated panorama of this topic, especially if considered selective RET inhibitors [65]. cancers-13-04415-t003_Table 3 Table 3 Ongoing trials with RET inhibitors in RET positive NSCLC patients.\n\nTrial\tPhase\tSetting\tStage\tPts\tTreatment\tPrimary End Points\t\nNCT04194944 (LIBRETTO-431) [49]\tPhase III\tFirst line\tStage IV or IIIB-C *\t250\tSelpercatinib vs. platinum + pemetrexed with or without pembrolizumab\tPFS\t\nNCT04222972(ACCELE-RET) [50]\tPhase III\tFirst line\tStage IV or IIIB-C *\t250\tPralsetinib vs. platinum + pemetrexed with or without pembrolizumab (if non squamous) or platinum + gemcitabine\tPFS\t\nNCT03178552\n(B-FAST) [51]\tPhase I/II\tFirst line\tStage IV or stage III *\t50\tAlectinib\tORR\t\nNCT04591431ROME [52]\tPhase II\tSecond line\tStage IV\t384\tAlectinib or brigatinib\tORR\t\nNCT04268550 (LUNG-MAP) [53]\tPhase II\tSecond or subsequent lines\tStage IV or stage III *\t124\tSelpercetinib\tORR\t\nNCT04131543 (CRETA) [54]\tPhase II\tSecond or subsequent lines\tStage IV or stage III *\t25\tCabozantinib\tORR\t\nNCT03445000 (ALERT-LUNG) [55]\tPhase II\tSecond or subsequent lines\tStage IV or stage III *\t44\tAlectinib\tORR\t\nNCT03468985 [56]\tPhase II\tPretreated\tStage IV\t169\tNivolumab + cabozantinib\tPFS\t\nNCT04161391 [64]\tPhase I-II\tNaive or pretreated\tStage IV\t362\tTPX-0046\tORR\t\n* not suitable for radical surgery or radiation therapy; PFS: progression-free survival; ORR: objective response rate.\n\n5. Conclusions\n\nSelective RET inhibitors including selpercatinib and pralsetinib have been recently approved by the FDA for the treatment of RET+ advanced NSCLC patients on the basis of the positive results of phase II studies. Two ongoing randomised phase III studies are currently comparing these two drugs with standard first line treatment of patients with advanced NSCLC harbouring RET rearrangements and should better define their role in the first line setting. Open issues are the evaluation of the role of combining RET inhibitors with chemotherapy or immunotherapy to improve activity and to face resistance mechanisms of RET inhibitors.\n\nAcknowledgments\n\nThe authors are grateful to Maura Tracey RN for her English revision and to Alessandra Trocino, the Librarian at IRCCS “G. Pascale” of Naples, Italy, for the bibliographic assistance.\n\nAuthor Contributions\n\nConceptualization, A.M. (Alessandro Morabito) and P.C.; writing, P.C., V.S., A.M. (Anna Manzo), G.C., G.P., G.E., A.M. (Agnese Montanino), R.C., C.S., R.D.C., M.C.P., C.L.M., G.T., P.M., C.P., R.B., N.N., A.M. (Alessandro Morabito), review and editing, P.C. and A.M. (Alessandro Morabito); visualization, P.C. and A.M. (Alessandro Morabito); supervision, A.M. (Alessandro Morabito) All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nNot applicable.\n\nConflicts of Interest\n\nAlessandro Morabito declares the following conflicts of interest: Speaker’s fee: MSD, BMS, Boehringer, Pfizer, Roche, AstraZeneca, Novartis; Advisory Board: Takeda, Eli-Lilly. Nicola Normanno declares the following personal financial interests (speaker’s fee and/or advisory boards): MSD, Qiagen, Bayer, Biocartis, Incyte, Roche, BMS, MERCK, Thermofisher, Boehringer Ingelheim, Astrazeneca, Sanofi, Eli Lilly; Institutional financial interests (financial support to research projets): MERCK, Sysmex, Thermofisher, QIAGEN, Roche, Astrazeneca, Biocartis. Non-financial interests: President, International Quality Network for Pathology (IQN Path); President, Italian Cancer Society (SIC). All the other Authors declare no conflict of interest.\n\nFigure 1 RET structure and its activation. The RET protein includes an extracellular, a transmembrane and an intracellular region. The RET extracellular region consists of four highly repeated domains (cadherin-like domains) as well as a cysteine-rich domain. The transmembrane domain links the extracellular region to the intracellular tyrosine kinase domain (TKI), which ends with isoform specific tails (on the left). Glial cell line-derived neurotrophic factor (GDNF) family ligands and GDNF family co-receptors (GFR α1-4) play a central role in RET activation. The binding of the GDNF ligand to the GFR co-receptor determines the construction of a ternary complex which includes RET, the GDNF ligand and the GFR co-receptors. The newly formed ternary complex leads to RET TKI domain phosphorylation. Phosphorylated RET TKI domains then activate the downstream signalling pathways implied in cell proliferation, growth, differentiation and survival such as RAS/MAPK, PI3K/AKT, PKC and JAK-STAT (on the right).\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Amoresano A. Incoronato M. Monti G. Pucci P. de Franciscis V. Cerchia L. 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Clinicopathological Characteristics of RET Rearranged Lung Cancer in European Patients J. Thorac. Oncol. 2016 11 122 127 10.1016/j.jtho.2015.09.016 26762747\n6. Kato S. Subbiah V. Marchlik E. Elkin S.K. Carter J.L. Kurzrock R. RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients Clin. Cancer Res. 2017 23 1988 1997 10.1158/1078-0432.CCR-16-1679 27683183\n7. Piotrowska Z. Isozaki H. Lennerz J.K. Gainor J.F. Lennes I.T. Zhu V.W. Marcoux N. Banwait M.K. Digumarthy S.R. Su W. Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion Cancer Discov. 2018 8 1529 1539 10.1158/2159-8290.CD-18-1022 30257958\n8. Klempner S.J. Bazhenova L.A. Braiteh F.S. Nikolinakos P.G. Gowen K. Cervantes C.M. Chmielecki J. Greenbowe J.R. Ross J.S. Stephens P.J. Emergence of RET Rearrangement Co-Existing with Activated EGFR Mutation in EGFR-Mutated NSCLC Patients Who Had Progressed on First- or Second-Generation EGFR TKI Lung Cancer 2015 89 357 359 10.1016/j.lungcan.2015.06.021 26187428\n9. Ferrara R. Auger N. Auclin E. Besse B. Clinical and Translational Implications of RET Rearrangements in Non–Small Cell Lung Cancer J. Thorac. Oncol. 2018 13 27 45 10.1016/j.jtho.2017.10.021 29128428\n10. Esagian S.M. Grigoriadou G.I. Nikas I.P. Boikou V. Sadow P.M. Won J.-K. Economopoulos K.P. Comparison of Liquid-Based to Tissue-Based Biopsy Analysis by Targeted next Generation Sequencing in Advanced Non-Small Cell Lung Cancer: A Comprehensive Systematic Review J. Cancer Res. Clin. Oncol. 2020 146 2051 2066 10.1007/s00432-020-03267-x 32462295\n11. Go H. Jung Y.J. Kang H.W. Park I.-K. Kang C.-H. Lee J.W. Ju Y.S. Seo J.-S. Chung D.H. Kim Y.T. Diagnostic Method for the Detection of KIF5B-RET Transformation in Lung Adenocarcinoma Lung Cancer 2013 82 44 50 10.1016/j.lungcan.2013.07.009 23932363\n12. Wang R. Hu H. Pan Y. Li Y. Ye T. Li C. Luo X. Wang L. Li H. Zhang Y. RET Fusions Define a Unique Molecular and Clinicopathologic Subtype of Non-Small-Cell Lung Cancer J. Clin. Oncol. 2012 30 4352 4359 10.1200/JCO.2012.44.1477 23150706\n13. Dugay F. Llamas-Gutierrez F. Gournay M. Medane S. Mazet F. Chiforeanu D.C. Becker E. Lamy R. Léna H. Rioux-Leclercq N. Clinicopathological Characteristics of ROS1 - and RET -Rearranged NSCLC in Caucasian Patients: Data from a Cohort of 713 Non-Squamous NSCLC Lacking KRAS/EGFR/HER2/BRAF/PIK3CA/ALK Alterations Oncotarget 2017 8 53336 53351 10.18632/oncotarget.18408 28881815\n14. Hess L.M. Han Y. Zhu Y.E. Bhandari N.R. Sireci A. Characteristics and Outcomes of Patients with RET-Fusion Positive Non-Small Lung Cancer in Real-World Practice in the United States BMC Cancer 2021 21 28 10.1186/s12885-020-07714-3 33402119\n15. Dacic S. Luvison A. Evdokimova V. Kelly L. Siegfried J.M. Villaruz L.C. Socinski M.A. Nikiforov Y.E. RET Rearrangements in Lung Adenocarcinoma and Radiation J. Thorac. Oncol. 2014 9 118 120 10.1097/JTO.0000000000000015 24346100\n16. Tsuta K. Kohno T. Yoshida A. Shimada Y. Asamura H. Furuta K. Kushima R. RET-Rearranged Non-Small-Cell Lung Carcinoma: A Clinicopathological and Molecular Analysis Br. J. Cancer 2014 110 1571 1578 10.1038/bjc.2014.36 24504365\n17. Mukhopadhyay S. Pennell N.A. Ali S.M. Ross J.S. Ma P.C. Velcheti V. RET-Rearranged Lung Adenocarcinomas with Lymphangitic Spread, Psammoma Bodies, and Clinical Responses to Cabozantinib J. Thorac. Oncol. 2014 9 1714 1719 10.1097/JTO.0000000000000323 25436805\n18. Digumarthy S.R. Mendoza D.P. Lin J.J. Rooney M. Do A. Chin E. Yeap B.Y. Shaw A.T. Gainor J.F. Imaging Features and Patterns of Metastasis in Non-Small Cell Lung Cancer with RET Rearrangements Cancers 2020 12 693 10.3390/cancers12030693 32183422\n19. Wang H. Wang Z. Zhang G. Zhang M. Zhang X. Li H. Zheng X. Ma Z. Driver Genes as Predictive Indicators of Brain Metastasis in Patients with Advanced NSCLC: EGFR, ALK, and RET Gene Mutations Cancer Med. 2020 9 487 495 10.1002/cam4.2706 31769228\n20. Offin M. Guo R. Wu S.L. Sabari J. Land J.D. Ni A. Montecalvo J. Halpenny D.F. Buie L.W. Pak T. Immunophenotype and Response to Immunotherapy of RET-Rearranged Lung Cancers JCO Precis. Oncol. 2019 3 PO.18.00386 10.1200/PO.18.00386\n21. Yakes F.M. Chen J. Tan J. Yamaguchi K. Shi Y. Yu P. Qian F. Chu F. Bentzien F. Cancilla B. Cabozantinib (XL184), a Novel MET and VEGFR2 Inhibitor, Simultaneously Suppresses Metastasis, Angiogenesis, and Tumor Growth Mol. Cancer Ther. 2011 10 2298 2308 10.1158/1535-7163.MCT-11-0264 21926191\n22. Ju Y.S. Lee W.-C. Shin J.-Y. Lee S. Bleazard T. Won J.-K. Kim Y.T. Kim J.-I. Kang J.-H. Seo J.-S. A Transforming KIF5B and RET Gene Fusion in Lung Adenocarcinoma Revealed from Whole-Genome and Transcriptome Sequencing Genome Res. 2012 22 436 445 10.1101/gr.133645.111 22194472\n23. Drilon A. Wang L. Hasanovic A. Suehara Y. Lipson D. Stephens P. Ross J. Miller V. Ginsberg M. Zakowski M.F. Response to Cabozantinib in Patients with RET Fusion-Positive Lung Adenocarcinomas Cancer Discov. 2013 3 630 635 10.1158/2159-8290.CD-13-0035 23533264\n24. Drilon A. Rekhtman N. Arcila M. Wang L. Ni A. Albano M. Van Voorthuysen M. Somwar R. Smith R.S. Montecalvo J. A Phase 2 Single Arm Trial of Cabozantinib in Patients with Advanced RET-Rearranged Lung Cancers Lancet Oncol 2016 17 1653 1660 10.1016/S1470-2045(16)30562-9 27825636\n25. Vaishnavi A. Schubert L. Rix U. Marek L.A. Le A.T. Keysar S.B. Glogowska M.J. Smith M.A. Kako S. Sumi N.J. EGFR Mediates Responses to Small Molecule Drugs Targeting Oncogenic Fusion Kinases Cancer Res. 2017 77 3551 3563 10.1158/0008-5472.CAN-17-0109 28428274\n26. Wakelee H.A. Gettinger S. Engelman J. Jänne P.A. West H. Subramaniam D.S. Leach J. Wax M. Yaron Y. Miles D.R. A Phase Ib/II Study of Cabozantinib (XL184) with or without Erlotinib in Patients with Non-Small Cell Lung Cancer Cancer Chemother. Pharmacol. 2017 79 923 932 10.1007/s00280-017-3283-z 28352985\n27. Neal J.W. Dahlberg S.E. Wakelee H.A. Aisner S.C. Bowden M. Huang Y. Carbone D.P. Gerstner G.J. Lerner R.E. Rubin J.L. Erlotinib, Cabozantinib, or Erlotinib plus Cabozantinib as Second- or Third-Line Treatment of Patients with EGFR Wild-Type Advanced Non-Small Cell Lung Cancer (ECOG-ACRIN 1512): A Phase 2 Randomised Controlled Trial Lancet Oncol. 2016 17 1661 1671 10.1016/S1470-2045(16)30561-7 27825638\n28. Carlomagno F. Vitagliano D. Guida T. Ciardiello F. Tortora G. Vecchio G. Ryan A.J. Fontanini G. Fusco A. Santoro M. ZD6474, an Orally Available Inhibitor of KDR Tyrosine Kinase Activity, Efficiently Blocks Oncogenic RET Kinases Cancer Res. 2002 62 7284 7290 12499271\n29. Natale R.B. Thongprasert S. Greco F.A. Thomas M. Tsai C.-M. Sunpaweravong P. Ferry D. Mulatero C. Whorf R. Thompson J. Phase III Trial of Vandetanib Compared with Erlotinib in Patients with Previously Treated Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol. 2011 29 1059 1066 10.1200/JCO.2010.28.5981 21282542\n30. Lee J.S. Hirsh V. Park K. Qin S. Blajman C.R. Perng R.-P. Chen Y.-M. Emerson L. Langmuir P. Manegold C. Vandetanib Versus Placebo in Patients with Advanced Non-Small-Cell Lung Cancer after Prior Therapy with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor: A Randomized, Double-Blind Phase III Trial (ZEPHYR) J. Clin. Oncol. 2012 30 1114 1121 10.1200/JCO.2011.36.1709 22370318\n31. Herbst R.S. Sun Y. Eberhardt W.E. Germonpré P. Saijo N. Zhou C. Wang J. Li L. Kabbinavar F. Ichinose Y. Vandetanib plus Docetaxel versus Docetaxel as Second-Line Treatment for Patients with Advanced Non-Small-Cell Lung Cancer (ZODIAC): A Double-Blind, Randomised, Phase 3 Trial Lancet Oncol. 2010 11 619 626 10.1016/S1470-2045(10)70132-7 20570559\n32. De Boer R.H. Arrieta Ó. Yang C.-H. Gottfried M. Chan V. Raats J. de Marinis F. Abratt R.P. Wolf J. Blackhall F.H. Vandetanib plus Pemetrexed for the Second-Line Treatment of Advanced Non-Small-Cell Lung Cancer: A Randomized, Double-Blind Phase III Trial J. Clin. Oncol. 2011 29 1067 1074 10.1200/JCO.2010.29.5717 21282537\n33. Lee S.-H. Lee J.-K. Ahn M.-J. Kim D.-W. Sun J.-M. Keam B. Kim T.M. Heo D.S. Ahn J.S. Choi Y.-L. Vandetanib in Pretreated Patients with Advanced Non-Small Cell Lung Cancer-Harboring RET Rearrangement: A Phase II Clinical Trial Ann. Oncol. 2017 28 292 297 10.1093/annonc/mdw559 27803005\n34. Yoh K. Seto T. Satouchi M. Nishio M. Yamamoto N. Murakami H. Nogami N. Matsumoto S. Kohno T. Tsuta K. Vandetanib in Patients with Previously Treated RET-Rearranged Advanced Non-Small-Cell Lung Cancer (LURET): An Open-Label, Multicentre Phase 2 Trial Lancet Respir. Med. 2017 5 42 50 10.1016/S2213-2600(16)30322-8 27825616\n35. Hao Z. Wang P. Lenvatinib in Management of Solid Tumors Oncologist 2020 25 e302 e310 10.1634/theoncologist.2019-0407 32043789\n36. Havel L. Lee J.-S. Lee K.H. Bidoli P. Kim J.-H. Ferry D. Kim Y.-C. Losonczy G. Steele N. Woo I.S. E7080 (Lenvatinib) in Addition to Best Supportive Care (BSC) versus BSC Alone in Third-Line or Greater Nonsquamous, Non-Small Cell Lung Cancer (NSCLC) J. Clin. Oncol. 2014 32 8043 10.1200/jco.2014.32.15_suppl.8043\n37. Hida T. Velcheti V. Reckamp K.L. Nokihara H. Sachdev P. Kubota T. Nakada T. Dutcus C.E. Ren M. Tamura T. A Phase 2 Study of Lenvatinib in Patients with RET Fusion-Positive Lung Adenocarcinoma Lung Cancer 2019 138 124 130 10.1016/j.lungcan.2019.09.011 31710864\n38. Taylor M.H. Lee C.-H. Makker V. Rasco D. Dutcus C.E. Wu J. Stepan D.E. Shumaker R.C. Motzer R.J. Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors J. Clin. Oncol. 2020 38 1154 1163 10.1200/JCO.19.01598 31961766\n39. Subbiah V. Velcheti V. Tuch B.B. Ebata K. Busaidy N.L. Cabanillas M.E. Wirth L.J. Stock S. Smith S. Lauriault V. Selective RET Kinase Inhibition for Patients with RET-Altered Cancers Ann. Oncol. 2018 29 1869 1876 10.1093/annonc/mdy137 29912274\n40. Gautschi O. Milia J. Filleron T. Wolf J. Carbone D.P. Owen D. Camidge R. Narayanan V. Doebele R.C. Besse B. Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry J. Clin. Oncol. 2017 35 1403 1410 10.1200/JCO.2016.70.9352 28447912\n41. Drilon A. Oxnard G.R. Tan D.S.W. Loong H.H.F. Johnson M. Gainor J. McCoach C.E. Gautschi O. Besse B. Cho B.C. Efficacy of Selpercatinib in RET Fusion–Positive Non–Small-Cell Lung Cancer N. Engl. J. Med. 2020 10.1056/NEJMoa2005653\n42. Drilon A.E. Subbiah V. Oxnard G.R. Bauer T.M. Velcheti V. Lakhani N.J. Besse B. Park K. Patel J.D. Cabanillas M.E. A Phase 1 Study of LOXO-292, a Potent and Highly Selective RET Inhibitor, in Patients with RET-Altered Cancers J. Clin. Oncol. 2018 36 102 10.1200/JCO.2018.36.15_suppl.102\n43. Drilon A. Lin J.J. Filleron T. Ni A. Milia J. Bergagnini I. Hatzoglou V. Velcheti V. Offin M. Li B. Brief Report: Frequency of Brain Metastases and Multikinase Inhibitor Outcomes in Patients with RET-Rearranged Lung Cancers J. Thorac. Oncol. 2018 13 1595 1601 10.1016/j.jtho.2018.07.004 30017832\n44. Subbiah V. Gainor J.F. Rahal R. Brubaker J.D. Kim J.L. Maynard M. Hu W. Cao Q. Sheets M.P. Wilson D. Precision Targeted Therapy with BLU-667 for RET-Driven Cancers Cancer Discov. 2018 8 836 849 10.1158/2159-8290.CD-18-0338 29657135\n45. Gainor J.F. Lee D.H. Curigliano G. Doebele R.C. Kim D.-W. Baik C.S. Tan D.S.-W. Lopes G. Gadgeel S.M. Cassier P.A. Clinical Activity and Tolerability of BLU-667, a Highly Potent and Selective RET Inhibitor, in Patients (Pts) with Advanced RET-Fusion+ Non-Small Cell Lung Cancer (NSCLC) J. Clin. Oncol. 2019 37 9008 10.1200/JCO.2019.37.15_suppl.9008\n46. Lee D.H. Subbiah V. Gainor J.F. Taylor M.H. Zhu V.W. Doebele R.C. Lopes G. Baik C. Garralda E. Gadgeel S.M. Treatment with Pralsetinib (Formerly BLU-667), a Potent and Selective RET Inhibitor, Provides Rapid Clearance of CtDNA in Patients with RET-Altered Non-Small Cell Lung Cancer (NSCLC) and Medullary Thyroid Cancer (MTC) Ann. Oncol. 2019 30 ix122 10.1093/annonc/mdz431\n47. Gainor J.F. Curigliano G. Kim D.-W. Lee D.H. Besse B. Baik C.S. Doebele R.C. Cassier P.A. Lopes G. Tan D.S.-W. Registrational Dataset from the Phase I/II ARROW Trial of Pralsetinib (BLU-667) in Patients (Pts) with Advanced RET Fusion+ Non-Small Cell Lung Cancer (NSCLC) J. Clin. Oncol. 2020 38 9515 10.1200/JCO.2020.38.15_suppl.9515\n48. Markham A. Pralsetinib: First Approval Drugs 2020 80 1865 1870 10.1007/s40265-020-01427-4 33136236\n49. Solomon B.J. Zhou C.C. Drilon A. Park K. Wolf J. Elamin Y. Davis H.M. Soldatenkova V. Sashegyi A. Lin A.B. Phase III Study of Selpercatinib versus Chemotherapy ± Pembrolizumab in Untreated RET Positive Non-Small-Cell Lung Cancer Futur. Oncol. 2021 17 763 773 10.2217/fon-2020-0935\n50. Hoffmann-La Roche A Phase III, Randomized, Open-Label Study of Pralsetinib Versus Standard of Care for First-Line Treatment of RET Fusion-Positive, Metastatic Non-Small Cell Lung Cancer Available online: https://clinicaltrials.gov/ct2/show/NCT04222972 (accessed on 29 August 2021)\n51. Hoffmann-La Roche A Phase II/III Multicenter Study Evaluating the Efficacy and Safety of Multiple Targeted Therapies as Treatments for Patients With Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) Harboring Actionable Somatic Mutations Detected in Blood (B-FAST: Blood-First Assay Screening Trial) Available online: https://www.clinicaltrials.gov/ct2/show/NCT03178552 (accessed on 29 August 2021)\n52. Fondazione per la Medicina Personalizzata The Rome Trial from Histology to Target: The Road to Personalize Target Therapy and Immunotherapy Available online: https://www.clinicaltrials.gov/ct2/show/NCT04591431 (accessed on 29 August 2021)\n53. Southwest Oncology Group A Phase II Study of LOXO-292 in Patients With RET Fusion-Positive Stage IV or Recurrent Non-Small Cell Lung Cancer (LUNG-MAP Sub-Study) Available online: https://clinicaltrials.gov/ct2/show/NCT04268550 (accessed on 29 August 2021)\n54. Ardizzoni A. 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Ther. 2020 21 863 870 10.1080/15384047.2020.1806643 32835580\n60. Subbiah V. Cascone T. Hess K.R. Subbiah I.M. Nelson S. Morikawa N. Nilsson M.B. Bhatt T. Ali S. William W.N. Multi-Kinase RET Inhibitor Vandetanib Combined with MTOR Inhibitor Everolimus in Patients with RET Rearranged Non-Small Cell Lung Cancer J. Clin. Oncol. 2018 36 9035 10.1200/JCO.2018.36.15_suppl.9035\n61. Solomon B.J. Tan L. Lin J.J. Wong S.Q. Hollizeck S. Ebata K. Tuch B.B. Yoda S. Gainor J.F. Sequist L.V. RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies J. Thorac. Oncol. 2020 15 541 549 10.1016/j.jtho.2020.01.006 31988000\n62. Lin J.J. Liu S.V. McCoach C.E. Zhu V.W. Tan A.C. Yoda S. Peterson J. Do A. Prutisto-Chang K. Dagogo-Jack I. Mechanisms of Resistance to Selective RET Tyrosine Kinase Inhibitors in RET Fusion-Positive Non-Small-Cell Lung Cancer Ann. Oncol. 2020 31 1725 1733 10.1016/j.annonc.2020.09.015 33007380\n63. Rosen E.Y. Johnson M.L. Clifford S.E. Somwar R. Kherani J.F. Son J. Bertram A.A. Davare M.A. Gladstone E. Ivanova E.V. Overcoming MET-Dependent Resistance to Selective RET Inhibition in Patients with RET Fusion–Positive Lung Cancer by Combining Selpercatinib with Crizotinib Clin. Cancer Res. 2021 27 34 42 10.1158/1078-0432.CCR-20-2278 33082208\n64. Drilon A.E. Zhai D. Rogers E. Deng W. Zhang X. Ung J. Lee D. Rodon L. Graber A. Zimmerman Z.F. The Next-Generation RET Inhibitor TPX-0046 Is Active in Drug-Resistant and Naïve RET-Driven Cancer Models J. Clin. Oncol. 2020 38 3616 10.1200/JCO.2020.38.15_suppl.3616\n65. Choudhury N.J. Drilon A. Decade in Review: A New Era for RET-Rearranged Lung Cancers Transl. Lung Cancer Res. 2020 9 2571 2580 10.21037/tlcr-20-346 33489819\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2072-6694",
"issue": "13(17)",
"journal": "Cancers",
"keywords": "NSCLC; RET; cabozantinib; lenvatinib; pralsetinib; selpercatinib; vandetanib",
"medline_ta": "Cancers (Basel)",
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"pmid": "34503226",
"pubdate": "2021-09-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "22194472;28447912;31715421;32183422;28352985;29657135;32043789;33007380;31710864;33402119;31769228;21282542;33489819;23150706;31961766;28881815;23533264;21926191;20570559;30257958;27825638;32665298;12499271;28428274;27794403;33150799;27803005;27825636;32835580;21282537;27683183;31192313;29128428;32462295;24504365;15722196;26187428;22370318;32846060;25436805;23932363;24346100;26762747;31988000;27825616;33136236;30017832;29912274;33082208",
"title": "RET Inhibitors in Non-Small-Cell Lung Cancer.",
"title_normalized": "ret inhibitors in non small cell lung cancer"
} | [
{
"companynumb": "PT-Accord-256636",
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"occurcountry": "PT",
"patient": {
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{
"actiondrug": "1",
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"activesubstancename": "CARBOPLATIN"
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{
"abstract": "A 42-year-old man with a history of childhood asthma presented with a 2-week history of watery diarrhoea and marked peripheral eosinophilia in the setting of recent use of cephalexin. His colonoscopy revealed patchy colitis. Biopsies were consistent with eosinophilic colitis. Two months later he received a course of amoxicillin resulting in recurrence of peripheral eosinophilia. Given the time-frame of β-lactam administration to symptom onset and elimination of all other precipitating causes, he was diagnosed with β-lactam-associated eosinophilic colitis. The patient's symptoms resolved and peripheral eosinophil count decreased with no specific treatment. Eosinophilic colitis is a rare heterogeneous condition, the pathogenesis of which is likely to be an interplay between environmental and genetic factors. It can be secondary to a helminthic infection or a drug reaction and has been associated with ulcerative colitis. If secondary causes of eosinophilic colitis have been excluded, the mainstay of treatment is with corticosteroids.",
"affiliations": "Department of Medicine, The Northern Hospital, Epping, Victoria, Australia.;Department of Healthscope Pathology, The Northern Hospital, Melbourne, Victoria, Australia.;Department of Infectious Diseases, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.",
"authors": "Mogilevski|Tamara|T|;Nickless|David|D|;Hume|Sam|S|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D065093:beta-Lactamase Inhibitors; D000658:Amoxicillin; D002506:Cephalexin",
"country": "England",
"delete": false,
"doi": null,
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"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000658:Amoxicillin; D002506:Cephalexin; D003092:Colitis; D003967:Diarrhea; D018450:Disease Progression; D004802:Eosinophilia; D006801:Humans; D008297:Male; D016896:Treatment Outcome; D065093:beta-Lactamase Inhibitors",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26106168",
"pubdate": "2015-06-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1733744;16911498;14669340;6785145;1558357;9265579;2220886;21914234;8556100;9916676;19052023;15994729;16340639;12378201;17141232",
"title": "β-lactam-associated eosinophilic colitis.",
"title_normalized": "lactam associated eosinophilic colitis"
} | [
{
"companynumb": "AU-ALKEM-001075",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
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{
"abstract": "Double-expressor diffuse large B-cell lymphoma (DLBCL) with 17p deletion is an aggressive and refractory disease. Immune checkpoint blockade and epigenetic drugs have been widely used, but the efficacy of different combined applications varied. We report a case with \"double-expressor\" DLBCL treated with a combined regimen which consisted of programmed cell death protein 1 (PD-1) inhibitor, DNA methyltransferase inhibitor (DNMTi), and histone deacetylase inhibitor (HDACi). A 50-year-old man presented with a 6-month history of hoarseness, and 10 days of progressive shortness of breath was diagnosed of DLBCL, stage IV. The patient failed to respond to the 1st line (R-EPOCH: rituximab, etoposide, vincristine, cyclophosphamide, doxorubicin, and dexamethasone), 2nd line (R-EPOCH + lenalidomide + ibrutinib), and a 3rd line chemotherapy combined with PD-1 inhibitor (sintilimab), decitabine, and GDP (gemcitabine, DDP, and dexamethasone). Surprisingly, patient's condition was improved after treatment with PD-1 inhibitor in combination with DNMTi/HDACi. Restaging PET revealed dramatically radiological response.",
"affiliations": "Department of Hematology, First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510230, China.;Guangzhou Institute of Respiratory Health, Guangzhou Medical University, Guangzhou 510120, China.;Department of Hematology, First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510230, China.;Department of Hematology, First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510230, China.;Department of Hematology, First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510230, China.;Department of Hematology, First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510230, China.",
"authors": "Zheng|Runhui|R|;Chen|Xiaobo|X|;Wang|Chunyan|C|;Qin|Pengfei|P|;Tan|Huo|H|;Luo|Xiaodan|X|https://orcid.org/0000-0002-3225-502X",
"chemical_list": null,
"country": "United States",
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"doi": "10.1155/2020/8879448",
"fulltext": "\n==== Front\nCase Rep Hematol\nCase Rep Hematol\nCRIHEM\nCase Reports in Hematology\n2090-6560 2090-6579 Hindawi \n\n10.1155/2020/8879448\nCase Report\nTriplet Therapy with PD-1 Blockade, Histone Deacetylase Inhibitor, and DNA Methyltransferase Inhibitor Achieves Radiological Response in Refractory Double-Expressor Diffuse Large B-cell Lymphoma with 17p Deletion\nZheng Runhui \n1\n Chen Xiaobo \n2\n Wang Chunyan \n1\n Qin Pengfei \n1\n Tan Huo \n1\n https://orcid.org/0000-0002-3225-502XLuo Xiaodan xdluo@gzhmu.edu.cn\n1\n \n1Department of Hematology, First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510230, China\n\n2Guangzhou Institute of Respiratory Health, Guangzhou Medical University, Guangzhou 510120, China\nAcademic Editor: Sudhir Tauro\n\n\n2020 \n26 8 2020 \n2020 887944829 4 2020 28 7 2020 12 8 2020 Copyright © 2020 Runhui Zheng et al.2020This 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.Double-expressor diffuse large B-cell lymphoma (DLBCL) with 17p deletion is an aggressive and refractory disease. Immune checkpoint blockade and epigenetic drugs have been widely used, but the efficacy of different combined applications varied. We report a case with “double-expressor” DLBCL treated with a combined regimen which consisted of programmed cell death protein 1 (PD-1) inhibitor, DNA methyltransferase inhibitor (DNMTi), and histone deacetylase inhibitor (HDACi). A 50-year-old man presented with a 6-month history of hoarseness, and 10 days of progressive shortness of breath was diagnosed of DLBCL, stage IV. The patient failed to respond to the 1st line (R-EPOCH: rituximab, etoposide, vincristine, cyclophosphamide, doxorubicin, and dexamethasone), 2nd line (R-EPOCH + lenalidomide + ibrutinib), and a 3rd line chemotherapy combined with PD-1 inhibitor (sintilimab), decitabine, and GDP (gemcitabine, DDP, and dexamethasone). Surprisingly, patient's condition was improved after treatment with PD-1 inhibitor in combination with DNMTi/HDACi. Restaging PET revealed dramatically radiological response.\n\nNatural Science Foundation of Guangdong Province2018A030313661\n==== Body\n1. Background\nDiffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) [1, 2]. Approximately 60% of DLBCL patients achieve complete remission (CR) with standard R‐CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy [3]. However, 30–40% are refractory to therapy or later relapse (R/R cases), especially those with 17p deletion and/or TP53 mutation and high-grade B-cell lymphoma with MYC and BCL2 or BCL6 translocation [2, 4, 5]. Programmed cell death protein 1 (PD-1) is a key immune checkpoint receptor that is frequently expressed on tumor-infiltrating T cells in B-cell lymphomas [6]. In recent years, although therapeutic blockade of PD-1/PD-L1 has shown potential clinical activity in several types of NHL, the efficiency in DLBCL was not as satisfactory as in Classical Hodgkin lymphoma (cHL) [2, 4, 7–10]. The diversity of clinical responses to monotherapy with PD-1/PD-L1 inhibitors is in part explained by genetic heterogeneity and the diversity of signal pathways involved in the development of B-NHL [8, 11]. Therefore, a combinational regimen of PD-1/PD-L1 inhibitors with other synergistic drugs is needed. Here, we report a case in which PD-1 inhibitor in combination with DNA methyltransferase inhibitor (DNMTi) and histone deacetylase inhibitor (HDACi) was administered to a patient diagnosed of refractory “double-expressor” DLBCL with 17p deletion.\n\n2. Case Presentation\nA 50-year-old man presented with a 6-month history of hoarseness and 10 days of progressive shortness of breath. Fiberoptic bronchoscopy revealed intratracheal mass in right main bronchi with complete right mainstem bronchus occlusion (Figure 1(a)). Transbronchial biopsy showed a diffuse proliferation of atypical medium- to large-sized lymphoid cells which were positive for CD20, BCL6 (70%), BCL2 (95%), MUM1 (partial), CD79a, PD-L1 (22C3, 25%), PD-L1 (28–8, 25%), TP53, and c-Myc (40%). They are negative for CD3, CD5, and CD10. The Ki67 proliferative fraction is 80%+ (Figure 2). Fluorescence in situ hybridization (FISH) results demonstrated the presence of 17p deletion and BCL-2 rearrangement, while c-Myc translocation was negative. Initial fluorodeoxyglucose positron emission tomography (FDG-PET) revealed left hilum and mediastinal mass (41 × 87 × 76 mm, FDG uptake 20.6) with compression of the pulmonary artery, lower tracheal segment, bilateral main bronchi, and superior vena cava (Figure 1(b)). Vocal cords were involved, and there was a small pericardial effusion. Bone marrow and cerebrospinal fluid are negative for lymphoma. Gene mutation by “Next-generation” sequencing showed STAT6, EZH2, TP53, KMT2D, BCL6, and CREBBP mutation. These findings were consistent with DLBCL, stage IV. The patient was started urgently on dose-adjusted R-EPOCH therapy (rituximab, etoposide, vincristine, cyclophosphamide, doxorubicin, and dexamethasone) since DLBCL patients with poor prognosis treated with R-CHOP usually had shorter remission according to our clinical observations. It is also reported that DA-EPOCH-R produced durable remission in patients with aggressive B-cell lymphomas [12, 13], so we did not risk choosing R-CHOP. A chest computed tomography (CT) scan showed no sign of improvement. In a phase II study from MD Anderson Cancer Center of using rituximab, lenalidomide, and ibrutinib lead in prior to combination with chemotherapy for patients with newly diagnosed DLBCL, the CR rate was 96%. The regimen also has promising activity in R/R Non-Germinal Center B-cell-like DLBCL [14]. Therefore, R2-CHOP-I therapy (rituximab, lenalidomide, ibrutinib, vincristine, cyclophosphamide, doxorubicin, and dexamethasone) was administered as 2nd line. However, the patient developed respiratory distress soon, and a tracheal stent was implanted into the completely occluded bronchus (Figure 1(c)). A repeat PET showed progressive disease. In view of the patient's clinical status with rapidly progressing respiratory distress, a combination regimen with PD-1 inhibitor (Sintilimab, 10 ml: 100 mg), DNMTi (Decitabine, 10 mg), and GDP (gemcitabine, DDP and dexamethasone) was given as 3rd line. Follow-up CT scan showed only a slight improvement (much less than 50%) of bronchus occlusion without the shrinkage of the hilum and mediastinal mass.\n\nFor 4th line, a triple combination of decitabine, sintilimab plus HDACi (Chidamide, 5 mg) were administered (decitabine 10 mg i. v. d1-5, Sintilimab 200 mg, i. v., d1, Chidamide 20 mg p. o. twice a week). Chidamide, which inhibits class I HDACs 1, 2, 3, as well as class II HDAC 10, is the first oral subtype-selective histone deacetylase inhibitor approved in China. It was rapidly absorbed after oral administration and exhibited an elimination half-life in plasma of 17–18 hrs. The recommended dose for lymphomas was 10 mg twice per week for 4 consecutive weeks in a 6-week cycle [15, 16]. Right after the 4th line treatment, a significant clinical improvement was noted. Bilateral bronchus was clear, and restaging PET 2 weeks later revealed over 90% shrinkage of hilum and mediastinal mass (16 × 15 mm, FDG uptake 8.0, PET-CT score 5) and significant improvement of bronchus occlusion (Figures 1(d) and 1(e)). The patient achieved partial remission (PR), and a total of 3 cycles of this combination therapy were given. The patient had only myelosuppression presented with absolute neutrophil count <1.5 × 109/L and platelets <80 × 109/L which lasted for less than a week. The PR duration was about 40 days until a repeat PET-CT showed PD (41 × 33 mm, FDG uptake 18.4, PET-CT score 5). Then, venetoclax was used due to BCL-2 rearrangement, in combination with Chidamide, Sintilimab, and radiotherapy (50 Gy). Decrease in lesion size and FDG uptake were observed (15 × 13 mm, FDG uptake 1.9, PET-CT score 4). However, PET-CT revealed new metastatic foci (10 × 10 mm, FDG uptake 3.4, PET-CT score 5) on the right cardiodiaphragmatic angle 1 month after radiotherapy. Fortunately, the patient had a twin brother as transplant donor and syngeneic stem cell transplantation was performed about 6 months after diagnosis and CR was confirmed by a repeat PET-CT +35 d posttransplant. The patient is alive without lymphoma, and thymosin alpha-1 and recombinant human interleukin-2 are used to induce GVL. Treatment timescales are shown in Table 1, and response assessment was made according to the Lugano classification [17].\n\n3. Discussion\nImmune checkpoint blockade has been considered an important breakthrough in cancer treatment. The field of clinical trials in DLBCL associated with immune checkpoint blockade such as PD-1/PD-L1 inhibitor is being actively studied. Unlike cHL, the clinical response to monotherapy with PD-1/PD-L1 blockade in R/R DLBCL was not confirmed [2, 4, 7–9]. Results in a phase I trial of nivolumab monotherapy were promising with a response rate of 36% in R/R DLBCL. Clinical trials of different PD-1/PD-L1 inhibitors are ongoing, and a subset of patients experienced progressive disease after a short response [18]. Therefore, there is an urgent need to designate an effective PD-1/PD-L1 inhibitor-based combination regimen for R/R DLBCL.\n\nThis “double-expressor” DLBCL with 17p deletion failed the 1st line chemotherapy and presented with increase in overall tumor burden both in lesion size and FDG uptake after 2nd line chemotherapy. It is difficult to identify whether these responses were “tumor flare” or true disease progression since lenalidomide and ibrutinib were used in the 2nd line treatment. “Tumor flare” has been observed in patients treated with immunomodulatory drugs [19], but aggressive lymphoma is different from solid tumor or chronic lymphocytic leukemia possibly presented with self-limited lymphocytosis or increase in the size of lymph nodes. Increased FDG uptake with a concomitant increase in lesion size was consistent with what was found by fiberoptic bronchoscopy in this case. Thus, the Lugano classification was used to assess lymphoma response rather than the lymphoma response to immunomodulatory therapy criteria (LYRIC) [19]. The most important reason to change the regimen was that the rapid progression of mass could result in suffocating and death. The PD-1 inhibitor was chosen since PD-L1 was positive in 25% of tumor cells. Rapid progression of disease did not allow us to choose monotherapy of PD-1 inhibitor because of the low response rates and lack of durability. On one hand, it is reported that PD-L1 expression on tumor cells in DLBCL was shown to be associated with poor prognosis in DLBCL in most clinical data [7, 20]. One the other hand, resistant DLBCL has been identified to simultaneously utilize multiple pathways that could compensate for the one provided by PD1 blockade. The PD-1/PD-L1 signal pathway turns down the activation of the immune response, and PD-1 blockade only modestly improved T cells proliferation and cytokine production but was insufficient to restore the antitumor activity [21]. By targeting multiple pathways, which in addition to PD1, combination regimen may overcome the resistance to anti-PD1 therapy.\n\nMultiple components of DLBCL microenvironment are affected by epigenetic regulators such as HDACis or DNMTi [22]. In this report, STAT6, EZH2, TP53, KMT2D, BCL6, and CREBBP mutations are mostly associated with epigenetic dysregulation. After decitabine was added to the treatment, the patient showed a slight improvement rather than progression for the first time. Moreover, mutation of CREBBP encoding proteins with established roles in histone acetylation often results in impaired p53 activation while also promoting the oncogenic effects of BCL-6 [23]. HDACis as epigenetic modulators could reduce PD-L1 and PD-L2 expression rapidly on tumor cells, upregulate the immune response, and alter the drug resistance [22, 24]. Therefore, a triple combination of DNMTi/HDACi plus PD-1 inhibitor was performed, and the therapy led to a significant radiological response. EZH2 mutation was also found in this case. It is reported that the EZH2 inhibitor demonstrated an enhanced clinical activity in DLBCL, so EZH2 inhibition could be a promising strategy [25].\n\nDespite this triplet therapy provided very good partial metabolic response which lasted for 40 days, the patient had progressive disease inevitably even after radiotherapy was performed. However, over 50% shrinkage of lesion size and decreased FDG uptake were observed after radiotherapy. Though the presence of bulky disease remains a significant predictor of disease recurrence, radiotherapy as bridging strategy for stem cell transplantation played an important role in reducing tumor burden.\n\n4. Conclusions\nThe combination of epigenetic-modulating agents with immune checkpoint blockade provides exciting avenue for future research. This case suggests that PD-1 blockade in combination with DNMTi/HDACi can be encouraging in refractory DLBCL. Further research is warranted to evaluate this novel therapeutic regimen.\n\nAcknowledgments\nThe authors would like to acknowledge Juhong Jiang in the Pathology Department for histological interpretation of lymphoid tissue and providing high-resolution images. This work was supported by grant from the Guangdong Province Natural Science Foundation (2018A030313661).\n\nAbbreviations\nCR:Complete remission\n\ncHL:Classical Hodgkin lymphoma\n\nDLBCL:Diffuse large B-cell lymphoma\n\nDNMTi:DNA methyltransferase inhibitor\n\nFISH:Fluorescence in situ hybridization\n\nGDP:Gemcitabine, DDP, and dexamethasone\n\nHDACi:Histone deacetylase inhibitor\n\nPD-1:Programmed cell death protein 1\n\nPET:Positron emission tomography\n\nPMBCL:Primary mediastinal B-cell lymphoma\n\nNHL:Non-Hodgkin lymphoma\n\nR‐CHOP:Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone\n\nR-EPOCH:Rituximab, etoposide, vincristine, cyclophosphamide, doxorubicin, and dexamethasone\n\nR/R:Relapse or refractory.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nConflicts of Interest\nThe authors declare that they have no competing interests.\n\nAuthors' Contributions\nRunhui Zheng assembled, analyzed, and interpreted the patient data regarding the hematological disease; Xiaodan Luo assembled and analyzed the patient data and wrote the manuscript; Xiaobo Chen performed fiberoptic bronchoscopy and provided related high-resolution images; Chunyan Wang and Pengfei Qin assisted with data analysis and edited the manuscript; Huo Tan assisted with data analysis and edited the manuscript. All authors read and approved the final manuscript. Xiaodan Luo and Runhui Zheng equally contributed to this work.\n\nFigure 1 Fiberoptic bronchoscopy and PET/CT images. (a) Fiberoptic bronchoscopy revealed intratracheal mass in right main bronchi with complete right mainstem bronchus occlusion before treatment. (b) PET/CT image showing left hilum and mediastinal mass (41 × 87 × 76 mm, FDG uptake 20.6) with compression of the pulmonary artery, lower tracheal segment, bilateral main bronchi, and superior vena cava. (c) Right mainstem bronchus was completely occluded, and a tracheal stent was implanted. (d) Bronchus occlusion was significantly improved after treatment with PD-1 inhibitor and DNMTi/HDACi. (e) Restaging PET image showing dramatically shrinkage of hilum and mediastinal mass (16 × 15 mm, FDG uptake 8.0) after a triple combination treatment of DNMTi/HDACi plus PD-1 inhibitor.\n\nFigure 2 Immunohistochemical characteristics of tumor cells. (a) Transbronchial biopsy of the mediastinal mass (H&E staining) showing a diffuse proliferation of atypical medium- to large-sized lymphoid cells. (b) CD20-positive neoplastic cells from mediastinal biopsy aspirate. (c) BCL6-positive neoplastic cells (70%) from mediastinal biopsy aspirate. (d) BCL2-positive neoplastic cells (95%) from mediastinal biopsy aspirate. (e) P53-positive neoplastic cells from mediastinal biopsy aspirate. (f) PD-L1-positive neoplastic cells from mediastinal biopsy aspirate.\n\nTable 1 Treatment timescales.\n\n \tStart time\tTherapy\tNumber of cycles\tTime for repeat CT/PET\tEffect\t\n1st\t2019/7/19\tR-EPOCH: rituximab, etoposide, vincristine, cyclophosphamide, doxorubicin, and dexamethasone\t1\t2019/8/8 (CT)\tStable disease\t\n2nd\t2019/8/15\tR-EPOCH + lenalidomide (25 mg d1-7) + ibrutinib (420 mg once a day)\t1\t2019/9/4 (PET)\tProgressive metabolic disease\t\n3rd\t2019/9/5\tGDP (gemcitabine, DDP, and dexamethasone) + Sintilimab (200 mg d1) + Decitabine (10 mg d1-5)\t1\t2019/9/17 (CT)\tStable disease\t\n4th\t2019/9/29\tSintilimab (200 mg, iv. d1) + Decitabine (10 mg, iv, d1-5) + Chidamide (20 mg, po, twice a week)\t3.\t2019/10/17 (PET)\tPartial metabolic response and >90% shrinkage of mass\t\n2019/10/22\t \t \t\n2019/11/12\t2019/11/26 (PET)\tProgressive metabolic disease\t\n5th\t2019/11/29\tRadiotherapy (50 Gy) + Sintilimab (200 mg d1) + Chidamide (20 mg twice a week) + venetoclax\t1\t2020-2-5 (PET)\tProgressive metabolic disease\t\n2020/2/10\tSyngeneic stem cell transplantation\t2020-3-25 (PET)\tComplete metabolic response\t\nCT, computed tomography; PET, positron emission tomography. Response assessment was made according to the Lugano classification [17]: Stable disease: <50% decrease from baseline in SPD of up to 6 dominant, measurable nodes, and extranodal sites; no criteria for progressive disease are met. Progressive metabolic disease: PET-CT Score 4 or 5 with an increase in intensity of uptake from baseline and/or new foci consistent with lymphoma at interim or end-of-treatment assessment. Partial metabolic response: PET-CT score 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size. Complete metabolic response: score 1, 2, or 3 with or without a residual mass on 5 PET-CT score.\n==== Refs\n1 Sukswai N. Lyapichev K. Khoury J. D. Medeiros L. J. Diffuse large B-cell lymphoma variants: an update Pathology 2019 52 1 53 67 10.1016/j.pathol.2019.08.013 31735345 \n2 Crombie J. L. Armand P. 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"title": "Triplet Therapy with PD-1 Blockade, Histone Deacetylase Inhibitor, and DNA Methyltransferase Inhibitor Achieves Radiological Response in Refractory Double-Expressor Diffuse Large B-cell Lymphoma with 17p Deletion.",
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"authors": "Álvarez|Sergio|S|;Delama|Ignacio|I|;Navajas-Galimany|Lucas|L|;Eymin|Gonzalo|G|;Ceballos|M Elena|ME|;Andino-Navarrete|Romina|R|",
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"abstract": "A 69-year-old man complained of abdominal pain and appetite loss. Advanced gastric cancer with bilateral adrenal metastases( stage Ⅳ)was revealed via an examination. XP(cisplatin and capecitabine)chemotherapy was administered. As a result, the tumor was reduced prominently, and his symptoms disappeared 3 months later. However, the cancer recurred 7 months later. Because of the tumor growth, the stent was detained for a passage obstacle by local increase of the tumor 12 months later. The patient died 14 months later.",
"affiliations": "Dept. of Surgery, Hasuda Hospital.",
"authors": "Hasegawa|Kumi|K|;Asakawa|Ayaka|A|;Kamiya|Ayako|A|;Takatsuno|Yasushi|Y|;Kondo|Ito|I|;Kaneko|Jun|J|;Endo|Takeshi|T|;Maejima|Shizuaki|S|",
"chemical_list": "D000069287:Capecitabine; D002945:Cisplatin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "42(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D002945:Cisplatin; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D012008:Recurrence; D013274:Stomach Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2078-80",
"pmc": null,
"pmid": "26805270",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A Case of Gastric Cancer with Adrenal Metastasis That Responded to Chemotherapy.",
"title_normalized": "a case of gastric cancer with adrenal metastasis that responded to chemotherapy"
} | [
{
"companynumb": "JP-ROCHE-1613781",
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"activesubstancename": "CAPECITABINE"
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{
"abstract": "Phendimetrazine is an anorectic agent which recently has been detected in three medical examiner's cases. In one instance death was attributed to this drug. Methods of detecting and identifying this drug in urine and blood are discussed. In the one instance where death was attributed to this substance, the blood concentration was 300 ng/ml.",
"affiliations": "Office of the Medical Examiner of Wayne County, Detroit, MI 48226.",
"authors": "Hood|I|I|;Monforte|J|J|;Gault|R|R|;Mirchandani|H|H|",
"chemical_list": "D000697:Central Nervous System Stimulants; D009025:Morpholines; D008694:Methamphetamine; C100294:phendimetrazine; D000661:Amphetamine; D010633:Phenmetrazine",
"country": "United States",
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"issue": "26(3-4)",
"journal": "Journal of toxicology. Clinical toxicology",
"keywords": null,
"medline_ta": "J Toxicol Clin Toxicol",
"mesh_terms": "D000328:Adult; D000661:Amphetamine; D000697:Central Nervous System Stimulants; D055598:Chemical Phenomena; D002621:Chemistry; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008694:Methamphetamine; D009025:Morpholines; D010633:Phenmetrazine; D019966:Substance-Related Disorders",
"nlm_unique_id": "8213460",
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"references": null,
"title": "Fatality from illicit phendimetrazine use.",
"title_normalized": "fatality from illicit phendimetrazine use"
} | [
{
"companynumb": "US-BAUSCH-BL-2017-023014",
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"activesubstancename": "PHENDIMETRAZINE TARTRATE"
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{
"abstract": "Anthracyclines have cardiotoxic side effects. Cardioprotective drugs such as angiotensin-converting enzyme inhibitors and beta-blockers are therefore recommended for patients with anthracycline-induced cardiomyopathy. We herein present a 54-year-old woman with recurrent metastatic breast cancer who developed heart failure (HF) with a left ventricular ejection fraction (LVEF) of 22% after undergoing epirubicin chemotherapy. However, her HF symptoms and low LVEF persisted despite 5 months of cardioprotective therapy and additional oral pimobendan. Pimobendan was discontinued because of ventricular arrhythmia and hypotension. After the start of low-dose (0.125 mg daily) digoxin, her LVEF increased to 42%, and her HF symptoms improved with no adverse events.",
"affiliations": "Department of Cardiology, Tokyo Women's Medical University, Japan.;Department of Cardiology, Tokyo Women's Medical University, Japan.;Department of Cardiology, Tokyo Women's Medical University, Japan.;Department of Clinical Pharmacology and Therapeutics, The Jikei University School of Medicine, Japan.",
"authors": "Shiga|Tsuyoshi|T|;Im|Jihaeng|J|;Kikuchi|Noriko|N|;Arakawa|Yasuhiro|Y|",
"chemical_list": "D018943:Anthracyclines; D004077:Digoxin",
"country": "Japan",
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"doi": "10.2169/internalmedicine.6787-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n33746165\n10.2169/internalmedicine.6787-20\nCase Report\nThe Effective Use of Digoxin in a Patient with Metastatic Breast Cancer and Anthracycline-induced Cardiomyopathy\nShiga Tsuyoshi 12\nIm Jihaeng 1\nKikuchi Noriko 1\nArakawa Yasuhiro 2\n1 Department of Cardiology, Tokyo Women's Medical University, Japan\n2 Department of Clinical Pharmacology and Therapeutics, The Jikei University School of Medicine, Japan\nCorrespondence to Dr. Tsuyoshi Shiga, shiga@jikei.ac.jp\n\n22 3 2021\n1 9 2021\n60 17 28192823\n23 11 2020\n1 2 2021\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nAnthracyclines have cardiotoxic side effects. Cardioprotective drugs such as angiotensin-converting enzyme inhibitors and beta-blockers are therefore recommended for patients with anthracycline-induced cardiomyopathy. We herein present a 54-year-old woman with recurrent metastatic breast cancer who developed heart failure (HF) with a left ventricular ejection fraction (LVEF) of 22% after undergoing epirubicin chemotherapy. However, her HF symptoms and low LVEF persisted despite 5 months of cardioprotective therapy and additional oral pimobendan. Pimobendan was discontinued because of ventricular arrhythmia and hypotension. After the start of low-dose (0.125 mg daily) digoxin, her LVEF increased to 42%, and her HF symptoms improved with no adverse events.\n\nanthracycline\ncardiotoxicity\ndigoxin\nheart failure\nleft ventricular ejection fraction\n==== Body\npmcIntroduction\n\nAnthracyclines were one of the first discovered chemotherapeutic agents and they remain in use as a class of chemotherapy drugs for metastatic breast cancer (1). Anthracyclines are an effective anticancer drug but they also have some cardiotoxic side effects. The cardiotoxicity of anthracyclines, especially impaired left ventricular (LV) function and heart failure (HF), is the most common problem that worsens the prognosis or limits the options for further treatment (2,3). Cardioprotective medications such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers and beta-blocker treatment are recommended for patients who develop symptomatic HF or asymptomatic LV dysfunction either during or after chemotherapy (3). However, HF is difficult to treat in patients who show no recovery in LV dysfunction despite undergoing cardioprotective therapy.\n\nDigoxin is an oral inotropic drug that improves the symptoms and decreases hospitalization in patients with HF with no effect on mortality (4). Digoxin has class IIa recommendations for treating HF with reduced ejection fraction (HFrEF) patients in Japan (5). Recently, however, digoxin use in HFrEF patients has decreased because many doubts, especially regarding its safety and very narrow therapeutic window, have been raised (6,7). We herein present a patient with metastatic breast cancer who, following anthracycline administration, developed HF with severe LV dysfunction, which both improved by low-dose digoxin in addition to cardioprotective therapy.\n\nCase Report\n\nA 54-year-old woman with recurrent metastatic breast cancer and HF was referred to our hospital. She underwent left-sided mastectomy 4 years ago in a cancer hospital. Estrogen and progesterone receptors were both positive, and human epidermal growth factor receptor 2 was negative. She received tamoxifen as adjuvant therapy. However, a metastatic workup with a positron-emission tomography/computed tomography (PET/CT) scan revealed left axillary lymph node metastasis and isolated liver metastasis (segments IV and V, 78 mm in diameter) 2 years ago. Therefore, paclitaxel and bevacizumab chemotherapy was started. This treatment was temporarily interrupted at her request, and anastrozole was used alternatively for 3 months. After 24 cycles of paclitaxel and bevacizumab chemotherapy, a follow-up PET/CT scan showed a deceased liver metastasis size (segments IV and V, 46 mm in diameter).\n\nCombination chemotherapy with cyclophosphamide, epirubicin (75 mg/m2) and fluorouracil (CEF) was started one year ago. Before the CEF therapy, her plasma B-type natriuretic peptide (BNP) concentration and serum troponin I level were 7.8 pg/mL (normal range <18.4 pg/mL) and 1.9 pg/mL (normal range <26.2 pg/mL), respectively, and her echocardiography showed a 70% of LV ejection fraction (LVEF) with no structural abnormalities. At the completion of CEF treatment (repeat every 21 days×8 cycles), echocardiography showed a 69% of LVEF. Her cumulative dose of epirubicin was 600 mg/m2.\n\nShe developed dyspnea on exertion and was diagnosed with HF 1 month after completion of therapy; her plasma BNP concentration and serum troponin I were elevated to 843.0 pg/mL and 96.6 pg/mL, respectively, and echocardiography revealed a severely reduced LVEF of 28%. Therefore, she was referred to a cardiologist in another hospital 5 months ago. She was started on 20 mg daily furosemide, 50 mg daily spironolactone, 2.5 mg daily enalapril and 2.5 mg daily of carvedilol. Coronary angiography revealed no significant stenosis. Left ventriculography revealed an enlargement (LV end-diastolic volume index 107 mL/m2) and a low LVEF of 17%. Right ventricular endomyocardial biopsy was also performed. Histopathological examinations revealed atrophy of myocytes, myocytolysis, interstitial edema and fibrosis but no inflammatory cell infiltration, consistent with anthracycline-induced cardiomyopathy. The carvedilol was titrated up to 10 mg daily, and 5 mg daily pimobendane was added. She also received a wearable cardioveter-defibrillator (WCD) because of the occurrence of nonsustained ventricular tachycardia (NSVT) (22 beats, 150 bpm) with low LVEF.\n\nShe remained in New York Heart Association (NYHA) functional class III, and she felt dizzy and respiratory discomfort on exertion. She was referred to the HF clinic in our hospital. Her blood pressure was 74/54 mmHg, and 12-lead electrocardiography (ECG) revealed a sinus rhythm with a heart rate of 94 bpm, poor R wave progression in leads V2-3, a transitional zone between V4 and V5 and a short run of atrial tachycardia (Fig. 1A). Chest radiography revealed cardiomegaly and a cardiothoracic ratio of 54% (Fig. 2A), and her plasma BNP concentration and serum troponin I were 554.9 pg/mL and 11.7 pg/mL, respectively. Echocardiography showed a large LV dimension in diastole (LVDD) of 60 mm, and LVEF (according to the biplane Simpson's method) was 25% (Fig. 3A).\n\nFigure 1. Twelve-lead electrocardiograms obtained before (A) and 5 months after the start of digoxin treatment (B).\n\nFigure 2. Chest radiographs obtained before (A) and 5 months after the start of digoxin treatment (B).\n\nFigure 3. Echocardiography before (A) and 5 months after the start of digoxin treatment (B). IVS: interventricular septum, LV: left ventricle, LVEF: left ventricular ejection fraction, LVDD: left ventricular internal dimension in diastole, LVDS: left ventricular internal dimension in systole, PW: posterior wall\n\nAfter admission, the dose of pimobendane was tapered off for 4 days because of recurrent NSVT and persistent hypotension. Her systolic blood pressure increased to 80-90 mmHg. However, she complained of palpitation and chest discomfort; the mean heart rate was 96 bpm on Holter monitoring, and her plasma BNP concentration was 482.9 pg/mL. Daily digoxin (0.125 mg) was started to improve her symptoms due to HF; her estimated glomerular filtration rate was 68 mL/min/1.74 m2 and her trough serum digoxin concentration was 0.34 ng/mL after 5 days of treatment. No drug-related adverse events were observed, and she was discharged from our hospital. Her WCD, during which time she did not receive any defibrillation shock, was discontinued. Atrial fibrillation was not detected during hospitalization.\n\nOne month after discharge, she was in NYHA functional class II, her plasma BNP concentration was 239.1 pg/mL, and her LVEF had increased to 34% (Fig. 4). Combination therapy with capecitabine and eribulin was also started. She returned to work and maintained her ordinary home life. After 5 months of digoxin therapy, 12-lead ECG showed a reduced heart rate and higher QRS voltage complexes in the limb leads than before the administration of digoxin and a normal transitional zone between V3 and V4 (Fig. 1B). Chest radiography revealed a cardiothoracic ratio of 47% (Fig. 2B), and echocardiography revealed an LVDD of 50 mm and an LVEF of 42% (Fig. 3B). Plasma BNP was 76.9 pg/mL (Fig. 4).\n\nFigure 4. Changes in the left ventricular ejection fraction (LVEF) and plasma B-type natriuretic peptide (BNP) concentration during cardioprotective therapy combined with low-dose digoxin.\n\nOne year after discharge, she continued to receive digoxin therapy and had maintained NYHA functional class II without signs of worsening HF. Her trough serum digoxin concentration was 0.60 ng/mL. Her LVEF was 45% and plasma BNP was 34.1 pg/mL (Fig. 4). Thereafter, she received palliative care and died from metastatic breast cancer 3 months later. Digoxin and enalapril were discontinued 3 weeks before death to avoid digitalis toxicity, but she did not experience worsening HF symptoms.\n\nDiscussion\n\nAnthracycline-induced cardiomyopathy was formerly thought to be irreversible, and the median time to a reduction in LVEF from the end of chemotherapy was reported to be 3.5 months (8). However, the LVEF could recover if cardioprotective therapy including ACE inhibitors and beta-blockers was started within 2 months after the end of chemotherapy (9). In this case, LVEF was normal at the completion of CEF therapy, but a severely reduced LVEF with HF symptoms was observed soon after the diagnosis. Despite 5 months of cardioprotective therapy, including carvedilol, enalapril and spironolactone, her LVEF did not recover.\n\nA recent case report showed that intravenous levosimendan, a calcium sensitizer, increases LVEF in a patient with doxorubicin-induced cardiomyopathy (10). An experimental study demonstrated that the inotropic effects of levosimendan can be mainly explained through its inhibition of phosphodiesterase (PDE) 3 (11). Pimobendan, which is used only in Japan, has positive inotropic and vasodilator effects mainly through PDE 3 inhibition and slight calcium sensitization (12). However, no improvement in LVEF was observed in this patient despite the use of oral pimobendane, but she did demonstrate a higher heart rate in sinus rhythm and recurrent NSVT.\n\nDigoxin has a positive inotropic effect as well as neurohormonal effects, including vagomimetic activity, the ability to improve baroreceptor sensitivity, decrease the norepinephrine serum concentrations and the activation of the renin-angiotensin system, a direct sympathoinhibitory effect and the ability to increase the release of natriuretic peptides with no effect on blood pressure (13). One month after the start of digoxin, despite no changes in her other medications, the patient's LVEF remarkably increased and her plasma BNP concentration decreased, changes that persisted over 1 year. The current guidelines recommend a combination of the maximum tolerated doses of beta-blockers and ACE inhibitors as the optimal medical therapy (14), but it takes a long time to titrate up to the maximum tolerated dose for HF patients with low LVEF. Although a more long-term cardioprotective therapy might have improved HF symptoms and LVEF, this patient did not have much time left and therefore desired other types of chemotherapy. Recently, the If-channel inhibitor ivabradine was recommended for symptomatic HF patients with LVEF ≤35% and a resting heart rate ≥75 bpm in sinus rhythm despite the use of cardioprotective therapy (14). However, there is no evidence regarding the effect of ivabradine on outcomes in patients with anthracycline-induced cardiomyopathy. The fast hemodynamic benefit of digoxin, which has an inotropic effect in addition to a reverse remodeling effect by reducing the heart rate, might have led to the improvement in the HF status in this patient.\n\nThe patient received paclitaxel and bevacizumab before CEF. Paclitaxel and bevacizumab, which are mostly used as concurrent chemotherapy, are also known to induce cardiotoxicity (3,15). Chemotherapy-induced cardiotoxicity is usually observed during treatment or, in some cases, after treatment. In this patient, the LVEF just after the completion of paclitaxel and bevacizumab chemotherapy was normal, but these drugs might have potentially contributed to the development of anthracycline-induced cardiotoxicity.\n\nAlthough the mechanisms of anthracycline-induced cardiomyopathy are not fully understood, the inhibition of topoisomerase 2β in cardiomyocytes by anthracycline increases the production of reactive oxygen species via increased deoxyribonucleic acid (DNA) breaks and mitochondrial dysfunction and results in cellular damage in the form of oxidative stress (16). It is unclear how digoxin affects this mechanism. Ezzat et al. reported that the cardenolide glycoside acovenoside A protected against adriamycin-induced cardiotoxicity in mice by inhibiting oxidative stress and inflammation (17). Wann et al. reported that digoxin exhibited antitumor activities on non-small-cell lung cancer A549 and H1299 cells by inhibiting DNA repair and promoting reactive oxygen species while also inhibiting efforts to slow DNA repair in cardiomyocytes but not in tumor in a nude mouse A549 xenograft model. These results suggested that compared with adriamycin alone, cotreatment with digoxin enhances antitumor efficacy and reduces cardiotoxicity in a cell context-dependent manner (18). It thus remains unclear whether digoxin can inhibit anthracycline-induced cardiomyopathy in humans.\n\nIn this patient, the trough serum digoxin concentration was maintained at less than 1.0 ng/mL to avoid digitalis toxicity (13,19). Low-dose/low-concentration digoxin might exert a positive inotropic effect without excessive calcium overload in cardiomyocyte when combined with beta-blockers. Although her LVEF did not recover to normal levels, her HF symptoms and quality of life improved, and she was able to start chemotherapy with other regimens. Digoxin does not improve survival in HFrEF patients but may improve the quality of life by reducing HF symptoms and hospitalizations. (4, 5, 19) If severely low LVEF and HF symptoms persist in anthracycline-induced cardiomyopathy despite cardioprotective therapy, low-dose digoxin may be a useful tool as an adjunctive therapy. From the viewpoint of palliative care, this approach can also help relieve suffering and improve the quality of life in cancer patients with HF.\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\n\nThe authors thank Dr. Ayano Yoshida and Dr. Kyomi Ashihara for their comments and support.\n==== Refs\n1. Sambi M , Qorri B , Harless W , Szewczuk MR . Therapeutic Options for Metastatic Breast Cancer. In: Breast Cancer Metastasis and Drug Resistance: Challenges and Progress. 2nd ed. AhmadA, Ed. Springer, Cham, 2019: 131-172.\n2. Henriksen PA . Anthracycline cardiotoxicity: an update on mechanisms, monitoring and prevention. Heart 104 : 971-977, 2018.29217634\n3. Zamorano JL , Lancellotti P , Rodriguez Muñoz D , et al . 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 37 : 2768-2801, 2016.27567406\n4. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 336 : 525-533, 1997.9036306\n5. Tsutsui H , Isobe M , Ito H , et al . JCS 2017/JHFS 2017 Guideline on diagnosis and treatment of acute and chronic heart failure - Digest Version. Circ J 83 : 2084-2184, 2019.31511439\n6. Patel N , Ju C , Macon C , et al . Temporal trends of digoxin use in patients hospitalized with heart failure: analysis from the American Heart Association Get With The Guidelines-Heart Failure Registry. JACC Heart Fail 4 : 348-356, 2016.26874392\n7. Whayne TF Jr . Clinical use of digitalis: a state of the art review. Am J Cardiovasc Drugs 18 : 427-440, 2018.30066080\n8. Cardinale D , Colombo A , Bacchiani G , et al . Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 131 : 1981-1988, 2015.25948538\n9. Cardinale D , Colombo A , Lamantia G , et al . Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 55 : 213-220, 2010.20117401\n10. Miaris N , Zezas S , Sgouros J , et al . Effective use of levosimendan in anthracycline-induced cardiomyopathy: a case report. Heart Lung 46 : 382-386, 2017.28733066\n11. Orstavik O , Ata SH , Riise J , et al . Inhibition of phosphodiesterase-3 by levosimendan is sufficient to account for its inotropic effect in failing human heart. Br J Pharmacol 171 : 5169-5181, 2014.24547784\n12. Böhm M , Morano I , Pieske B , et al . Contribution of cAMP-phosphodiesterase inhibition and sensitization of the contractile proteins for calcium to the inotropic effect of pimobendan in the failing human myocardium. Circ Res 68 : 689-701, 1991.1660359\n13. Gheorghiade M , Adams KF Jr , Colucci WS . Digoxin in the management of cardiovascular disorders. Circulation 109 : 2959-2964, 2004.15210613\n14. Ponikowski P , Voors AA , Anker SD , et al . 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 37 : 2129-2200, 2016.27206819\n15. Cameron D , Brown J , Dent R , et al . Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol 14 : 933-942, 2013.23932548\n16. Zhang S , Liu X , Bawa-Khalfe T , et al . Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 18 : 1639-1642, 2012.23104132\n17. Ezzat SM , El Gaafary M , El Sayed AM , et al . The cardenolide glycoside acovenoside A affords protective activity in doxorubicin-induced cardiotoxicity in mice. J Pharmacol Exp Ther 358 : 262-270, 2016.27247000\n18. Wang Y , Ma Q , Zhang S , et al . Digoxin enhances the anticancer effect on non-small cell lung cancer while reducing the cardiotoxicity of adriamycin. Front Pharmacol 11 : 186, 2020.32180730\n19. Aonuma K , Shiga T , Atarashi H , et al . Guidelines for therapeutic drug monitoring of cardiovascular drugs. Clinical use of blood drug concentration monitoring (JCS 2015) - Digest version. Circ J 81 : 581-612, 2017.28302953\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(17)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "anthracycline; cardiotoxicity; digoxin; heart failure; left ventricular ejection fraction",
"medline_ta": "Intern Med",
"mesh_terms": "D018943:Anthracyclines; D001943:Breast Neoplasms; D009202:Cardiomyopathies; D004077:Digoxin; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D013318:Stroke Volume; D016277:Ventricular Function, Left",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2819-2823",
"pmc": null,
"pmid": "33746165",
"pubdate": "2021-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25948538;1660359;27206819;28302953;23104132;15210613;27567406;27247000;32180730;26874392;30066080;23932548;24547784;20117401;9036306;29217634;28733066;31511439",
"title": "The Effective Use of Digoxin in a Patient with Metastatic Breast Cancer and Anthracycline-induced Cardiomyopathy.",
"title_normalized": "the effective use of digoxin in a patient with metastatic breast cancer and anthracycline induced cardiomyopathy"
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"abstract": "This case report focuses on an elderly gentleman with extensive stage small cell lung cancer (SCLC) who experienced episodes of bowel obstruction shortly after commencing first-line chemotherapy with cisplatin and etoposide. The patient had no radiological or pathological evidence of intra-abdominal carcinomatosis or paraneoplastic bowel disease secondary to SCLC. Although neurotoxicity is commonly associated with platinum agents, the effect is predominantly peripheral as opposed to autonomic. The authors conclude that the observations documented in this case were secondary to etoposide; a podophyllotoxin that can bind microtubules and inhibit fast axonal transport. Although paralytic ileus is well recognised with podophyllotoxin poisoning, to our knowledge, this is the first report to associate bowel obstruction with standard doses of etoposide and highlights the need for physicians to be aware of such deleterious effects in patients treated with this cytotoxic agent.",
"affiliations": "Royal Marsden Hospital NHS Foundation Trust, and Barts Cancer Institute, Queen Mary University of London, Fulham Road, London, SW3 6JJ, UK. jim.coward@gmail.com",
"authors": "Coward|Jermaine I G|JI|;Ding|Nicola-Louise|NL|;Feakins|Roger|R|;Kocher|Hermant|H|;Popat|Sanjay|S|;Szlosarek|Piotr W|PW|",
"chemical_list": null,
"country": "United States",
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"issn_linking": "1357-0560",
"issue": "29(4)",
"journal": "Medical oncology (Northwood, London, England)",
"keywords": null,
"medline_ta": "Med Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D006801:Humans; D007415:Intestinal Obstruction; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D055752:Small Cell Lung Carcinoma; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9435512",
"other_id": null,
"pages": "2623-5",
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"pmid": "22203382",
"pubdate": "2012-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "50035;17409868;12237922;8699226;17914079;2618532;10561217;53233;2734645;3856083;7199647;16931906;16133980",
"title": "Chemotherapy-induced bowel obstruction in small cell lung cancer: a case report.",
"title_normalized": "chemotherapy induced bowel obstruction in small cell lung cancer a case report"
} | [
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"companynumb": "GB-PFIZER INC-1620535",
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"abstract": "BACKGROUND\nAutoimmune polyglandular syndrome type 1 (APS 1) is an autosomal recessive disorder characterized by immune injury of multiple organ systems (primarily endocrine) secondary to a mutation in the autoimmune regulator (AIRE) gene. In some cases, patients develop tubulointerstitial nephritis (TIN) and progress to end-stage renal failure (ESRD).\n\n\nMETHODS\nWe describe two patients with APS 1 and TIN. In both cases, TIN was clinically silent and the diagnosis was confirmed by renal biopsy. In one patient, renal function remained stable with immunosuppressive therapy. A second patient progressed to ESRD despite treatment, and received a deceased donor allograft. TIN recurred in the transplanted kidney and was reversed successfully with rituximab. Severe, recurrent esophageal candidiasis also resolved.\n\n\nCONCLUSIONS\nTIN is an important complication of APS 1 that may result in ESRD, and may recur in the transplanted kidney. TIN may be under-recognized, as the presentation is unapparent clinically and urinalysis remains normal. Immunosuppressive therapy may be effective and, therefore, routine monitoring of renal function is warranted in asymptomatic individuals.",
"affiliations": null,
"authors": "Gwertzman|Rachel|R|;Corey|Howard|H|;Roberti|Isabel|I|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "Germany",
"delete": false,
"doi": "10.5414/CN108782",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0430",
"issue": "85(6)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D009395:Nephritis, Interstitial; D016884:Polyendocrinopathies, Autoimmune; D012008:Recurrence; D000069283:Rituximab",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "358-62",
"pmc": null,
"pmid": "27142200",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Autoimmune polyglandular syndrome type I can have significant kidney disease in children including recurrence in renal allograft - a report of two cases.",
"title_normalized": "autoimmune polyglandular syndrome type i can have significant kidney disease in children including recurrence in renal allograft a report of two cases"
} | [
{
"companynumb": "US-ASTELLAS-2016US028249",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": n... |
{
"abstract": "OBJECTIVE\nRefractory status epilepticus (RSE) is a life-threatening emergency, demonstrating, by definition, significant pharmacoresistance. We describe five cases of pediatric RSE treated with mild hypothermia.\n\n\nMETHODS\nRetrospective chart review was performed of records of children who received hypothermia for RSE at two tertiary-care pediatric hospitals between 2009 and 2012.\n\n\nRESULTS\nFive children with RSE received mild hypothermia (32-35°C). Hypothermia reduced seizure burden during and after treatment in all cases. Prior to initiation of hypothermia, four children (80%) received pentobarbital infusions to treat RSE, but relapsed after pentobarbital discontinuation. No child relapsed after treatment with hypothermia. One child died after redirection of care. Remaining four children were discharged.\n\n\nCONCLUSIONS\nThis is the largest pediatric case series reporting treatment of RSE with mild hypothermia. Hypothermia decreased seizure burden during and after pediatric RSE and may prevent RSE relapse.",
"affiliations": "Division of Pediatric and Developmental Neurology, Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA. guilliamsk@neuro.wustl.edu",
"authors": "Guilliams|Kristin|K|;Rosen|Max|M|;Buttram|Sandra|S|;Zempel|John|J|;Pineda|Jose|J|;Miller|Barbara|B|;Shoykhet|Michael|M|",
"chemical_list": "D010424:Pentobarbital",
"country": "United States",
"delete": false,
"doi": "10.1111/epi.12331",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "54(9)",
"journal": "Epilepsia",
"keywords": "Children; Cooling; Pharmacoresistance; Seizures",
"medline_ta": "Epilepsia",
"mesh_terms": "D000293:Adolescent; D002648:Child; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007036:Hypothermia, Induced; D007223:Infant; D008297:Male; D010424:Pentobarbital; D012189:Retrospective Studies; D055502:Secondary Prevention; D012640:Seizures; D013226:Status Epilepticus; D016896:Treatment Outcome",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "1586-94",
"pmc": null,
"pmid": "23906244",
"pubdate": "2013-09",
"publication_types": "D016428:Journal Article",
"references": "12181015;21464374;21357833;23127267;6705545;21873882;21663459;22528274;11903460;18829776;20727481;20100756;22156786;22487868;21163888;18638280;23667778;19797281;20060761;8780085;7560021;21109102;23225633;16221780;20146026;22201842;22291110;10999512;16843675;19817823;10082808;18025795;21951365;702761;20880321;19054397;22388109;11843690;19535947;18093148;4978766;5457637;17784531;11422324;15607599;1395660;15721471;10980736;19535948;22365745;9838100;18415032;11409423",
"title": "Hypothermia for pediatric refractory status epilepticus.",
"title_normalized": "hypothermia for pediatric refractory status epilepticus"
} | [
{
"companynumb": "US-JNJFOC-20130915208",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": null,
"d... |
{
"abstract": "Job's syndrome or hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency. Characterized by recurrent pulmonary and skin infections with elevated IgE serum level, this syndrome has been considered a risk factor for lymphoma. Although the majority of cases were diagnosed in childhood, there are still a few cases that were diagnosed in adulthood. It is necessary to recognize these two conditions since the treatment for lymphoma patients with HIES should be adjusted and needs a thorough care. Here we present a case of diffuse large B cell lymphoma in a patient with symptoms of HIES diagnosed during chemotherapy.",
"affiliations": "Division of Hematology and Medical Oncology, Department of Internal Medicine, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia.;Faculty of Medicine Universitas Indonesia.",
"authors": "Cahyanur|Rahmat|R|;Rahmawati|Sari|S|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": "10.26574/maedica.2020.15.2.269",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1841-9038",
"issue": "15(2)",
"journal": "Maedica",
"keywords": null,
"medline_ta": "Maedica (Bucur)",
"mesh_terms": null,
"nlm_unique_id": "101526930",
"other_id": null,
"pages": "269-271",
"pmc": null,
"pmid": "32952695",
"pubdate": "2020-06",
"publication_types": "D016421:Editorial",
"references": "20226523;2783597;16645241;15621772;17621409;12358995;22085750;9727824;20859667;8977516",
"title": "Diffuse Large B-Cell Lymphoma and Job's Syndrome: A Case Report.",
"title_normalized": "diffuse large b cell lymphoma and job s syndrome a case report"
} | [
{
"companynumb": "ID-ROCHE-2663342",
"fulfillexpeditecriteria": "1",
"occurcountry": "ID",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nThe hearts of amphetamine and cocaine users demonstrate essentially the same microscopic features: hypertrophy, interstitial fibrosis, myocyte hypertrophy and intimal and medial hyperplasia. According to Karch (2016), some investigations suggest that amphetamines have properties that make users less likely to experience myocardial infarction than cocaine users. The exposure to amphetamine is associated with the production of heat shock proteins (HSP) whereas cocaine is not. Not all the HSP are present in normal living conditions of cells but their expression is increased when cells are exposed to stress, like heat, anoxemia, and ischemia. It has been known before that increased HSP production is a myocardial response in adaptation to cardiac ischemia and that the production of HSP might influence myocardial resistance to infarction. Furthermore, production of HSP is an explanation of the known ability of amphetamines to cause hyperthermia. The hypothesis of a cytoprotective function of HSP in amphetamine-associated deaths in comparison to cocaine-associated deaths and controls was investigated.\n\n\nMETHODS\nStudy group: 39 amphetamine-related fatal cases, 27 cocaine-associated deaths.\n\n\nMETHODS\n42 cases with other causes of death. Immunohistochemical staining of HSP 27, HSP 60, and HSP 70 in heart, liver, and kidney.\n\n\nRESULTS\n16 out of 39 (41.0%) amphetamine-related fatal cases showed a positive HSP expression, predominantly HSP 70 in myocardial tissue. In cocaine-associated deaths 15 out of 27 (55.5%) cases were positive, also mainly HSP 70. In the kidney in amphetamine-associated deaths 18 out of 39 (46.1%) cases were positive, in cocaine-associated deaths 21 out of 27 (77.7%) cases. The cocaine group showed significantly increased expression for HSP 27 and 70 in the liver and HSP 70 in the kidney compared to the control as well as amphetamine group. Furthermore, the cocaine group showed significantly increased expression for HSP 27 and 70 in the heart compared to the control but not the amphetamine group.\n\n\nCONCLUSIONS\nThe hypothesis of Karch that in amphetamine-associated deaths a positive HSP expression has in contrast to cocaine-related deaths a cytoprotective function cannot be verified. Furthermore, cocaine and benzoylecgonine seem to independently lead to an increased expression of HSP 27 both in the liver and in the heart.",
"affiliations": "Institute of Forensic Medicine, Institute of Forensic Medicine 12, D-53111 Bonn, Germany. Electronic address: b.madea@uni-bonn.de.;Institute of Forensic Medicine, Institute of Forensic Medicine 12, D-53111 Bonn, Germany.;Institute of Forensic Medicine, Institute of Forensic Medicine 12, D-53111 Bonn, Germany.;Institute of Forensic Medicine, Institute of Forensic Medicine 12, D-53111 Bonn, Germany.;Institute of Forensic Medicine, Institute of Forensic Medicine 12, D-53111 Bonn, Germany.",
"authors": "Madea|Burkhard|B|;Ruppel|Elvira|E|;Prangenberg|Julian|J|;Krämer|Michael|M|;Doberentz|Elke|E|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2021.111088",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "329()",
"journal": "Forensic science international",
"keywords": "Amphetamine- and cocaine-associated deaths; Heat shock proteins; Immunohistochemical expression",
"medline_ta": "Forensic Sci Int",
"mesh_terms": null,
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "111088",
"pmc": null,
"pmid": "34773820",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Expression of heat shock proteins 27, 60, and 70 in amphetamine and cocaine associated deaths.",
"title_normalized": "expression of heat shock proteins 27 60 and 70 in amphetamine and cocaine associated deaths"
} | [
{
"companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2021-07604",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMPHETAMINE SULFATE"
},
... |
{
"abstract": "Ten patients with Stage II (four) and Stage IV (six) breast cancer were enrolled in a trial of conventional-dose induction therapy followed by high-dose therapy with autologous bone marrow support. Cyclophosphamide, methotrexate, and 5-fluorouracil were given to best response or five courses (Stage II). Those patients without progression were eligible for the high-dose portion of the protocol, which consisted of carboplatin 1,500 mg/m2 and mitoxantrone at either 40 mg/m2 (first five patients) or 50 mg/m2. Two patients did not receive the high-dose portion of the treatment due to progression on induction therapy (one) and insurance refusal (one). Of the remaining eight patients who completed the high-dose portion of the protocol, three were Stage II, of whom one died of transplant-related complications, one progressed, and one is alive and free of disease 24 months after therapy. Of the five Stage IV patients, two achieved a partial remission, one of whom died of progressive disease 1 year after therapy and the other died of BMT-related complications; of the other three Stage IV patients, one had stable disease and died at +9 months, one with progression died at +3 months, and one died of BMT-related causes. Overall, three patients died of infectious complications, with two having alpha streptococcal septic shock syndrome.",
"affiliations": "Department of Medicine, Indiana University School of Medicine, Indianapolis.",
"authors": "Broun|E R|ER|;Sledge|G W|GW|;Einhorn|L H|LH|;Tricot|G J|GJ|",
"chemical_list": "D003520:Cyclophosphamide; D016190:Carboplatin; D008942:Mitoxantrone; D005472:Fluorouracil; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "16(1)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D016026:Bone Marrow Transplantation; D001943:Breast Neoplasms; D016190:Carboplatin; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide; D005472:Fluorouracil; D006801:Humans; D008727:Methotrexate; D008875:Middle Aged; D008942:Mitoxantrone; D009367:Neoplasm Staging; D016019:Survival Analysis; D014182:Transplantation, Autologous",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "9-13",
"pmc": null,
"pmid": "8424413",
"pubdate": "1993-02",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "High-dose carboplatin and mitoxantrone with autologous bone marrow support in the treatment of advanced breast cancer.",
"title_normalized": "high dose carboplatin and mitoxantrone with autologous bone marrow support in the treatment of advanced breast cancer"
} | [
{
"companynumb": "US-PFIZER INC-2021101679",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Topiramate (TOPAMAX®) is an anti-epileptic drug for which acute toxicity is infrequently reported. We present the case report of a five-year-old, otherwise healthy boy who presented to the emergency department (ED) for symptoms of acute encephalopathy. He was lethargic, having slurred speech, hallucinating, intermittently agitated, and had multiple episodes of urinating on himself. Computed tomography (CT) of the head, lumbar puncture, electroencephalography, and magnetic resonance imaging (MRI) were all normal. The urine drug screen was also negative. Two days after admission, a saliva toxicology screen was significant for a topiramate level of 3487.8 ng/ml, which he was not taking and which his mother admitted taking for weight loss. The patient was observed for two days, over which time his symptoms completely resolved, and he was back to baseline. The following is the take-away for physicians: Careful history-taking should bedone to identify potential drug exposures in children presenting with acute encephalopathy. Especially, given the emerging off-label use of drugs, like in this case, topiramate, which was used by the mother for weight loss. We postulated a possible idiosyncratic reaction vs true drug toxicity, which correlates with findings in a previous case reportout of Boston Children's Hospital by Taub et al.; and in this case, serum level was about one-third the reported level in this case report. The patient presented with comparable symptoms and time to recovery.",
"affiliations": "Pediatrics, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, USA.;Pediatrics, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, USA.",
"authors": "Baidoun|Mohammad|M|;Elgendy|Mohamed|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.13747",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.13747\nPediatrics\nAcute Topiramate Toxicity in a Five-Year-Old Child\nMuacevic Alexander\nAdler John R\nBaidoun Mohammad 1\nElgendy Mohamed 1\n1 Pediatrics, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, USA\nMohammad Baidoun mohammad.baidoun@med.wmich.edu\n7 3 2021\n3 2021\n13 3 e137476 3 2021\nCopyright © 2021, Baidoun et al.\n2021\nBaidoun et al.\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/53022-acute-topiramate-toxicity-in-a-five-year-old-child\nTopiramate (TOPAMAX®) is an anti-epileptic drug for which acute toxicity is infrequently reported.\n\nWe present the case report of a five-year-old, otherwise healthy boy who presented to the emergency department (ED) for symptoms of acute encephalopathy. He was lethargic, having slurred speech, hallucinating, intermittently agitated, and had multiple episodes of urinating on himself. Computed tomography (CT) of the head, lumbar puncture, electroencephalography, and magnetic resonance imaging (MRI) were all normal. The urine drug screen was also negative. Two days after admission, a saliva toxicology screen was significant for a topiramate level of 3487.8 ng/ml, which he was not taking and which his mother admitted taking for weight loss. The patient was observed for two days, over which time his symptoms completely resolved, and he was back to baseline.\n\nThe following is the take-away for physicians: Careful history-taking should bedone to identify potential drug exposures in children presenting with acute encephalopathy. Especially, given the emerging off-label use of drugs, like in this case, topiramate, which was used by the mother for weight loss. We postulated a possible idiosyncratic reaction vs true drug toxicity, which correlates with findings in a previous case reportout of Boston Children’s Hospital by Taub et al.; and in this case, serum level was about one-third the reported level in this case report. The patient presented with comparable symptoms and time to recovery.\n\ntoxicology\ninpatient pediatrics\ncritical care\ntopiramate\nacute encephalopathy\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nTopiramate is a sulfamate-substituted monosaccharide marketed under the proprietary name TOPAMAX®. The United States Food and Drug Administration (FDA) approved topiramate as initial monotherapy in patients 10 years of age and older with partial-onset or primary generalized tonic-clonic seizures, as adjunctive therapy for adults and pediatric patients ages two to 16 years with partial onset seizures or primary generalized tonic-clonic seizures, and in patients two years of age and older with seizures associated with Lennox-Gastaut syndrome. It is also approved for use in the prophylaxis of migraine headaches.\n\nTopiramate is also used off-label (but is not currently FDA-approved) as a treatment for metabolic disorders, including diabetes mellitus and obesity; eating disorders, such as binge eating disorder and bulimia nervosa [1]; other impulse control disorders, such as pathological gambling; and substance abuse disorders, including alcoholism, nicotine dependence and cocaine abuse [2], cluster headaches [3], essential tremor [4], acute mania [5], and Tourette’s syndrome [6].\n\nThe recommended daily dose for topiramate monotherapy in adults and children 10 years of age and older is 400 mg/day. As adjunctive therapy in adults with partial seizures, the dose is 200-400 mg/day while as adjunctive treatment in adults with primary generalized tonic-clonic seizures, the dose is 400 mg/day. As adjunctive therapy for patients two to 16 years-old with partial seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome, the dose is approximately 5-9 mg/kg/day. Lastly, the dose for prophylaxis of migraine headache is 100 mg/day.\n\nNeurological and psychiatric abnormalities are both reported in patients using topiramate, usually in the context of chronic dosing. We describe a five-year-old boy, not previously treated with topiramate, who developed acute neurological symptoms after what appeared to be a single episode of topiramate ingestion.\n\nCase presentation\n\nAn otherwise healthy, five-year-old boy presented to the emergency department (ED) with altered mental status, agitation, and visual hallucinations. His mother reported that her son was acting strangely after she came back home at night from a short 30-minute trip. He was in his normal state of good health when he returned home from school earlier that day.\n\nThe mother reported that he was combative, agitated, and not responding to her. On presentation to the ED, vital signs were within normal limits for his age: pulse, 69/minute; blood pressure, 112/55 mmHg; respiratory rate, 18/min; temperature, 97.8° Fahrenheit, and oxygen saturation (SpO2) 100% on room air. Examination of the head, eyes, ears, nose, and throat was unremarkable. The neck was supple. The cardiac, lung, abdominal, and skin examinations were all unremarkable. Neurological examination revealed a disoriented male who was intermittently agitated; reflexes and tone were normal.\n\nThe differential diagnosis included sepsis, metabolic disorders, electrolyte derangements, endocrine disorders, hypertension, hepatic failure, renal failure, and drug intoxication. The complete blood count was normal. Serum electrolytes were as follows: sodium, 141 mmol/L; potassium, 3.8 mmol/L; chloride, 108 mmol/L; bicarbonate, 17 mmol/L (normal, 23-32 mmol/L); blood urea nitrogen, 16 mg/dL; creatinine, 0.44 mg/dL; glucose, 110 mg/dL; and calcium, 9.4 mg/dL (Table 1). Urine toxicological testing was negative for amphetamines, barbiturates, cannabinoids, cocaine, methadone, and opiates. Serum acetaminophen and salicylate were undetectable. Computed tomography (CT) of the brain revealed no structural pathology, and subsequent electroencephalography (EEG) was normal. The patient was admitted for observation and lumbar puncture was performed, given the concern for viral encephalitis/meningitis. The patient was transferred to the pediatric intensive care unit (PICU) for worsening altered mental status (AMS), which resolved in a short period of time, and then was transferred to the general inpatient pediatric floor for further care. MRI and EEG were performed, given concern for seizure activity or intracranial brain pathology. MRI revealed a small arachnoid cyst in the left posterior fossa of the left cerebellar hemisphere (Figure 1). Further investigations included ammonia, thyroid-stimulating hormone (TSH), magnesium, erythrocyte sedimentation rate (ESR), procalcitonin, coronavirus disease 2019 (COVID-19) polymerase chain reaction (PCR) and were all negative. Epstein-Barr virus (EBV) serological tests were also negative. A saliva toxicology screen was initially pursued to evaluate for potential drug ingestion. It was drawn on the pediatric floor and returned, two days later, positive for a serum topiramate level of 3487.8 ng/ml. The patient’s symptoms resolved in 48 h. On further history, it was discovered that his mother used topiramate for weight loss. He was then discharged in stable condition.\n\nTable 1 Lab results\n\nBUN: blood urea nitrogen; EBV: Epstein-Barr virus; COVID-19: coronavirus disease 2019; TSH: thyroid-stimulating hormone\n\nNa\t141 mmol/l\tMg\t2.5 mol/l\t\nK\t3.8 mmol/l\tTSH\t1.16 mIU/l\t\nCL\t108 mmol/l\tAmmonia\t39 umol/l\t\nHCo3\t17 mmol/l\tProcalcitonin\t0.05\t\nBUN\t16 mg/dl\tCOVID-19 PCR\tnegative\t\nSerum Cr\t0.44 mg/dl\tEBV na\t6.1\t\nGlucose\t110 mg/dl\tEBV vca\t>8.0\t\nCa\t9.4 mol/l\tEBV ea\t0.2\t\nEBV serologic studies\tSuggest past infection\tEBV vca IGM\t<0.2\t\nUrine drug screen\tNegative for amphetamines, barbiturates, cannabinoids, cocaine, methadone, and opiates\tEBV heterophile AB\t0.2\t\nTopiramate saliva\t3487.8 ng/ml\t \t \t\n\nFigure 1 MRI showed a small arachnoid cyst in the left posterior fossa of the left cerebellar hemisphere\n\nDiscussion\n\nSeveral cognitive/neuropsychiatric adverse events are associated with topiramate use. These include cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration or attention, difficulty with memory and speech or language problems, particularly word-finding difficulties); psychiatric or behavioral disturbances (e.g., depression or mood problems); and somnolence or fatigue. These symptoms may be minimized if the drug is introduced gradually.\n\nOur patient demonstrated several symptoms that may represent acute neurological toxicity of topiramate including somnolence, intermittent agitation, altered mental status, and hallucinations. A five-year-old girl reported by researchers at Boston Children’s Hospital [7] was found to have a serum topiramate level of 10.5 mcg/mL, which is triple the dose ingested by the patient in our case and recovered in about the same time. Notably, saliva measurement of topiramate can serve as an alternative to serum level, as suggested in “Topiramate concentration in saliva: an alternative to serum monitoring” [8].\n\nIn an adult study, oral administration of 100, 200, 400, 800, and 1200 mg of topiramate resulted in peak plasma concentration values of 1.7, 3.7, 7.7, 18.4, and 28.7 mcg/mL, respectively [9]. This patient’s level, as reported, was within the therapeutic range for a patient taking moderate doses of this medication. It is unclear if the patient’s symptoms represented an idiosyncratic reaction, which correlates with findings in the previous case report by Boston Children’s Hospital, as in our case, the saliva level was about one-third the reported level in their case report, both patients presented with comparable symptoms and time to recovery.\n\nConclusions\n\nClinicians should keep exposure to in-home medications in mind when encountering patients with acute encephalopathy. Careful history-taking should be performed to identify any potential exposure in these cases. Given the emerging off-label use of drugs, including topiramate in this situation, all medications need to be taken into consideration when working up acute neurological changes.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Phentermine/topiramate for the treatment of obesity Ann Pharmacother Smith SM Meyer M Trinkley KE 340 349 47 2013 23482732\n2 Binge-eating disorder in adults. A systematic review and meta-analysis Ann Intern Med Brownley KA Berkman ND Peat CM Lohr KN Cullen KE Bann CM Bulik CM 409 420 20 2016\n3 Topiramate pharmacotherapy for alcohol use disorder and other addictions: a narrative review J Addict Med Manhapra A Chakraborty A Arias AJ 7 22 13 2019 30096077\n4 Pharmacotherapy for cluster headache CNS Drugs Brandt RB Doesborg PGG Haan J Ferrari MD Fronczek R 171 184 34 2020 31997136\n5 Topiramate and essential tremor Ann Neurol Galvez-Jimenez N Hargreave M 837 838 47 2000 https://pubmed.ncbi.nlm.nih.gov/10852557/ 10852557\n6 Control of Tourette’s syndrome with topiramate Am J Psychiatry Abuzzahab FS Brown VL 968 158 2001 https://pubmed.ncbi.nlm.nih.gov/11384920/\n7 Acute topiramate toxicity J Toxicol Clin Toxicol Traub SJ Howland MA Hoffman RS Nelson LS 987 990 2003 14705846\n8 Therapeutic drug monitoring of antiepileptic drugs by use of saliva Ther Drug Monit Patsalos PN Berry DJ 4 29 35 2013 23288091\n9 Single-dose pharmacokinetics and effect of food on the bioavailability of topiramate, a novel antiepileptic drug J Clin Pharmacol Doose DR Walker SA Gisclon LG Nayak RK 987 990 10 1996 https://pubmed.ncbi.nlm.nih.gov/8930774/\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(3)",
"journal": "Cureus",
"keywords": "acute encephalopathy; critical care; inpatient pediatrics; topiramate; toxicology",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e13747",
"pmc": null,
"pmid": "33842124",
"pubdate": "2021-03-07",
"publication_types": "D002363:Case Reports",
"references": "23482732;11384920;30096077;10852557;23288091;14705846;27367316;31997136;8930774",
"title": "Acute Topiramate Toxicity in a Five-Year-Old Child.",
"title_normalized": "acute topiramate toxicity in a five year old child"
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"activesubstancename": "TOPIRAMATE"
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{
"abstract": "Gaucher disease (GD) may worsen during pregnancy, leading to the discussion of continuing treatment during pregnancy. We examined fetal outcomes of pregnancies reported in the Gaucher Outcome Survey, an international GD-specific registry established in 2010. A total of 453 pregnancies were reported. Most pregnancies (336/453, 74.2%) were in women who did not receive GD-specific treatment during pregnancy, while enzyme replacement therapy (ERT) was received during 117/453 (25.8%) pregnancies. No pregnancies exposed to substrate reduction therapy were reported. The percentage of normal outcomes (live birth delivered at term with no congenital abnormalities) was similar in untreated and treated pregnancies (92.9% vs. 91.4%). The percentage of spontaneous abortions in untreated pregnancies was 3.6% (95% CI, 1.9%- 6.2%) compared with 6.9% (95% CI, 3.0%-13.1%) in treated pregnancies (p=0.1866). In women who received velaglucerase alfa <1month prior to conception and/or during pregnancy, 34/36 (94.4%) pregnancies had normal outcomes and 2 (5.6%) ended in spontaneous abortion. Normal outcomes were observed in the 20 pregnancies with velaglucerase alfa exposure starting <1month prior to conception and continuing through all trimesters. These observations, in addition to information in the literature, suggest that continuation of ERT during pregnancy may be appropriate for GD patients.",
"affiliations": "Division of Neurogenetics, New York University School of Medicine, New York, NY, United States. Electronic address: heather.lau@nyumc.org.;Referral Centre for Lysosomal Diseases, University Hospital Paris Nord Val de Seine, Clichy, France. Electronic address: nadia.belmatoug@aphp.fr.;Addenbrooke's Hospital, Cambridge, United Kingdom. Electronic address: patrick.deegan@addenbrookes.nhs.uk.;LSD Unit and Center for Clinical Trials, O&O Alpan, LLC Fairfax, VA, United States. Electronic address: ogokeralpan@oandoalpan.com.;Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Genetics Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Electronic address: idadschwartz@gmail.com.;Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States. Electronic address: spshankar@ucdavis.edu.;Shire, Zug, Switzerland.;Shaare Zedek Medical Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel. Electronic address: azimran@gmail.com.",
"authors": "Lau|Heather|H|;Belmatoug|Nadia|N|;Deegan|Patrick|P|;Goker-Alpan|Ozlem|O|;Schwartz|Ida Vanessa D|IVD|;Shankar|Suma P|SP|;Panahloo|Zoya|Z|;Zimran|Ari|A|",
"chemical_list": "D005962:Glucosylceramidase; C550184:Velaglucerase alfa, human",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bcmd.2016.10.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-9796",
"issue": "68()",
"journal": "Blood cells, molecules & diseases",
"keywords": "Enzyme replacement therapy; Gaucher disease; Pregnancy; Velaglucerase alfa",
"medline_ta": "Blood Cells Mol Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D056947:Enzyme Replacement Therapy; D005260:Female; D005776:Gaucher Disease; D005962:Glucosylceramidase; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012042:Registries; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9509932",
"other_id": null,
"pages": "226-231",
"pmc": null,
"pmid": "27839985",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Reported outcomes of 453 pregnancies in patients with Gaucher disease: An analysis from the Gaucher outcome survey.",
"title_normalized": "reported outcomes of 453 pregnancies in patients with gaucher disease an analysis from the gaucher outcome survey"
} | [
{
"companynumb": "US-SA-2017SA269244",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMIGLUCERASE"
},
"drugadditional": "3",
"d... |
{
"abstract": "A 27 year old female with a complex history of congenital heart disease, cardiac surgery, heart failure, and arrhythmias was admitted for a Pseudomonas aeruginosa sternal wound infection and treated with intravenous antibiotics. After discharge and completion of an outpatient course of intravenous antibiotics, suppressive antibiotic therapy with ciprofloxacin was initiated. She presented to clinic with nausea and anorexia within a few days of addition of ciprofloxacin to her current regimen of medications, which included digoxin. The digoxin was discontinued, with all other medications remaining the same, and the symptoms resolved in 48 h. The dose of digoxin was restarted at 50 % of the previous dose with no further complications. The proposed cause of the nausea and anorexia was digoxin toxicity secondary to a drug-drug interaction with ciprofloxacin.\n\n\nCONCLUSIONS\nPatients receiving ciprofloxacin and digoxin should be monitored closely for the risk of digoxin toxicity.",
"affiliations": "Department of Pharmacy, Texas Children's Hospital, 6621 Fannin Street, Suite WB 1120, Houston, TX, 77030, USA, bsmoffet@texaschildrens.org.",
"authors": "Moffett|Brady S|BS|;Valdes|Santiago O|SO|;Kim|Jeffrey J|JJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002316:Cardiotonic Agents; D002939:Ciprofloxacin; D004077:Digoxin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11096-013-9818-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "35(5)",
"journal": "International journal of clinical pharmacy",
"keywords": null,
"medline_ta": "Int J Clin Pharm",
"mesh_terms": "D000328:Adult; D000855:Anorexia; D000900:Anti-Bacterial Agents; D002316:Cardiotonic Agents; D002939:Ciprofloxacin; D004077:Digoxin; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D006333:Heart Failure; D006801:Humans; D009325:Nausea; D010138:Pacemaker, Artificial; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa; D012086:Reoperation; D013530:Surgical Wound Infection; D016896:Treatment Outcome",
"nlm_unique_id": "101554912",
"other_id": null,
"pages": "673-6",
"pmc": null,
"pmid": "23868369",
"pubdate": "2013-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7249508;17389673;15461217;9531908;12362931;10774627;19606089;2497912;15704612",
"title": "Possible digoxin toxicity associated with concomitant ciprofloxacin therapy.",
"title_normalized": "possible digoxin toxicity associated with concomitant ciprofloxacin therapy"
} | [
{
"companynumb": "US-RANBAXY-2013US-74864",
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"occurcountry": "US",
"patient": {
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
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"drugadditional": null,
... |
{
"abstract": "X-linked inhibitor of apoptosis (XIAP) is the most potent human inhibitor of apoptosis, and is also involved in NOD2-dependent NFκB and MAPK signalling cascade activation. The absence or defective function of XIAP leads to the development of a rare and severe primary immunodeficiency known as X-linked lymphoproliferative syndrome type 2 (XLP-2), which is characterized by a triad of clinical manifestations, including a high incidence of haemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and inflammatory bowel disease (IBD), usually with very early onset. Here, we present a novel XIAP mutation identified in a patient with atypical adult-onset IBD complicated by relapsing HLH, splenomegaly and sarcoid-like disease. The c.266delA mutation in the XIAP gene creates a premature stop codon, and causes a severe reduction in XIAP protein expression. The mutation is also associated with impaired spontaneous and staurosporine- and PMA-induced apoptosis accompanied by significantly increased expression of pro-apoptotic genes. We also confirmed the negative impact of this particular XIAP mutation on NOD2-dependent NFκB and MAPK activation, while NOD2-independent activation was found to be unaffected. Moreover, we assume that the mutation has an impact on the overproduction of IL-12 and IFNγ, the shift towards the Th1 immune response and increased numbers of central memory and effector memory CD4+ and CD8+ T cells. All these changes contribute to immune dysregulation and the clinical manifestation of XLP-2.",
"affiliations": "Department of Immunology, 2nd Faculty of Medicine Charles University, University Hospital in Motol, V Uvalu 84, Prague, Czech Republic. zuzana.parackova@fnmotol.cz.;Department of Immunology, 2nd Faculty of Medicine Charles University, University Hospital in Motol, V Uvalu 84, Prague, Czech Republic.;Department of Immunology, 2nd Faculty of Medicine Charles University, University Hospital in Motol, V Uvalu 84, Prague, Czech Republic.;Department of Immunology, 2nd Faculty of Medicine Charles University, University Hospital in Motol, V Uvalu 84, Prague, Czech Republic.;CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.;Molecular Genetics Laboratory, Center of Cardiovascular Surgery and Transplantation, Brno, Czech Republic.;CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.;Department of Immunology, 2nd Faculty of Medicine Charles University, University Hospital in Motol, V Uvalu 84, Prague, Czech Republic.",
"authors": "Parackova|Zuzana|Z|;Milota|Tomas|T|;Vrabcova|Petra|P|;Smetanova|Jitka|J|;Svaton|Michael|M|;Freiberger|Tomas|T|http://orcid.org/0000-0001-6532-7053;Kanderova|Veronika|V|;Sediva|Anna|A|",
"chemical_list": "C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human",
"country": "England",
"delete": false,
"doi": "10.1038/s41419-020-2652-4",
"fulltext": "\n==== Front\nCell Death Dis\nCell Death Dis\nCell Death & Disease\n2041-4889 Nature Publishing Group UK London \n\n2652\n10.1038/s41419-020-2652-4\nArticle\nNovel XIAP mutation causing enhanced spontaneous apoptosis and disturbed NOD2 signalling in a patient with atypical adult-onset Crohn’s disease\nParackova Zuzana zuzana.parackova@fnmotol.cz 1 Milota Tomas 1 Vrabcova Petra 1 Smetanova Jitka 1 Svaton Michael 2 http://orcid.org/0000-0001-6532-7053Freiberger Tomas 34 Kanderova Veronika 2 Sediva Anna 1 1 0000 0004 0611 0905grid.412826.bDepartment of Immunology, 2nd Faculty of Medicine Charles University, University Hospital in Motol, V Uvalu 84, Prague, Czech Republic \n2 0000 0004 0611 0905grid.412826.bCLIP—Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic \n3 Molecular Genetics Laboratory, Center of Cardiovascular Surgery and Transplantation, Brno, Czech Republic \n4 0000 0001 2194 0956grid.10267.32Faculty of Medicine, Masaryk University, Brno, Czech Republic \n8 6 2020 \n8 6 2020 \n6 2020 \n11 6 43023 1 2020 7 5 2020 11 5 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.X-linked inhibitor of apoptosis (XIAP) is the most potent human inhibitor of apoptosis, and is also involved in NOD2-dependent NFκB and MAPK signalling cascade activation. The absence or defective function of XIAP leads to the development of a rare and severe primary immunodeficiency known as X-linked lymphoproliferative syndrome type 2 (XLP-2), which is characterized by a triad of clinical manifestations, including a high incidence of haemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and inflammatory bowel disease (IBD), usually with very early onset. Here, we present a novel XIAP mutation identified in a patient with atypical adult-onset IBD complicated by relapsing HLH, splenomegaly and sarcoid-like disease. The c.266delA mutation in the XIAP gene creates a premature stop codon, and causes a severe reduction in XIAP protein expression. The mutation is also associated with impaired spontaneous and staurosporine- and PMA-induced apoptosis accompanied by significantly increased expression of pro-apoptotic genes. We also confirmed the negative impact of this particular XIAP mutation on NOD2-dependent NFκB and MAPK activation, while NOD2-independent activation was found to be unaffected. Moreover, we assume that the mutation has an impact on the overproduction of IL-12 and IFNγ, the shift towards the Th1 immune response and increased numbers of central memory and effector memory CD4+ and CD8+ T cells. All these changes contribute to immune dysregulation and the clinical manifestation of XLP-2.\n\nSubject terms\nImmune cell deathCrohn's diseasehttps://doi.org/10.13039/501100003243Ministerstvo Zdravotnictví Ceské Republiky (Ministry of Health of the Czech Republic)AZV NV18-05-00162NV19-05-00332Parackova Zuzana https://doi.org/10.13039/100007543Grantová Agentura, Univerzita Karlova (Charles University Grant Agency)GAUK 460218Parackova Zuzana issue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nX-linked inhibitor of apoptosis (XIAP) or baculoviral IAP repeat-containing protein 4 (BIRC4), localized on the X chromosome, is a part of human IAP family. The protein consists of three different domains: (1) three baculoviral IAP repeat (BIR) domains, which are characteristic of all IAPs, (2) UBA domains that allow binding to ubiquitin and (3) a zinc-binding domain C-terminal RING finger domain, which is associated with E3 ubiquitin ligase activity1.\n\nOne of the major roles of XIAP is the prevention of apoptotic cell death, which is achieved by binding and inhibiting the activity of caspases 3, 7 and 92. In addition to its anti-apoptotic functions, XIAP is also involved in other signalling pathways and cellular responses, mostly because of the ubiquitylation activity through its RING domain3,4. XIAP is involved in intracellular pattern-recognition receptor signalling that senses peptidoglycan products, NOD1 and 25, leading to NFκB and mitogen-activated protein kinase (MAPK) cascade activation6–8. In mouse and human models, the absence of XIAP leads to defective secretion of proinflammatory cytokines after stimulation with NOD ligands9,10. Interestingly, NOD2 was the first identified susceptibility gene for Crohn’s disease (CD), a typical condition associated with XIAP deficiency11.\n\nXIAP deficiency is a rare primary immunodeficiency, also known as X-linked lymphoproliferative syndrome type 2 (XLP-2), caused by mutations in the XIAP (BIRC4) gene. The estimated incidence is 1–2 cases per million of live-born children. Nevertheless, the real prevalence seems to be higher as the diagnosis of XIAP deficiency may be overlooked or misclassified. Current assessments suggest that up to 4% of early-onset IBD may represent XIAP-deficient patients12.\n\nDisease onset usually manifests in the first few years of life, and is characterized by a key triad of clinical symptoms consistent with a high incidence of haemophagocytic lymphohistiocytosis (HLH), often triggered by Epstein–Barr (EBV) infections, and characterized by splenomegaly and inflammatory bowel disease (IBD), particularly with features of CD13. HLH is a life-threatening condition characterized by hyperinflammation, in which activated T lymphocytes and macrophages accumulate in organs, and produce and induce massive production of proinflammatory cytokines, particularly IFNγ14, resulting in tissue damage and multiorgan failure that typically affects the liver and bone marrow15. IBD in XIAP-deficient patients usually presents with very early onset16; however, adult onset has also been described17, and is characterized by a complicated course, necessity of extensive surgical procedures and unresponsiveness to standard treatment, including biological treatment. These patients have also significantly increased mortality rate, dying within a few years upon manifestation or diagnosis of IBD18. In comparison with XLP-1, hypogammaglobulinaemia may accompany XIAP deficiency; however, it is less frequent. Moreover, no lymphoma has been reported, which approximately 30% of XLP-1 patients develop. On the other hand, XLP-1 does not present with higher risk of IBD19. Currently, haematopoietic stem cell transplantation is the only causal therapy of XLP-2, although attempts to develop targeted gene therapy seem to be promising20.\n\nHere, we report a novel XLP-2-causing mutation in the XIAP BIR1 domain, leading to a premature stop codon and a loss of protein expression, which results in impaired lymphocyte apoptosis and NOD2-dependent signalling with clinical manifestations that include a complicated course of IBD, unresponsiveness to standard treatment, including biologics (infliximab and vedolizumab) and relapsing HLH.\n\nResults\nCase report\nA 32-year-old patient was born to non-consanguineous Caucasian parents. The patient presented without any health complications or abnormalities during the prenatal, perinatal and postnatal periods, and was diagnosed at 17 years of age with CD based on the clinical presentation and histological verification, which revealed nonspecific granulation tissue composed of multinucleated giant cells and lymphocytic infiltration in the submucosa of the colon. Complex examination, including ultrasonography of the abdomen, also revealed splenomegaly. Standard therapy with chimeric monoclonal anti-TNFα antibody (infliximab) at a standard dose of 5 mg/kg was initiated. However, the course of the CD was complicated by the development of an intra-abdominal abscess compressing the bladder, which required surgical intervention. Then, the biological therapy was switched to fully human monoclonal anti-TNFα (adalimumab), which successfully led to CD remission. Three years later (at the age of 20), the patient was admitted to the hospital for fever, elevation of inflammatory markers (including C-reactive protein), progressive splenomegaly, anaemia, leukocytopenia and decreased platelet count. Further testing revealed hypertriglyceridaemia, elevated transaminases and increased serum concentrations of ferritin. The results from extensive infectious diagnostic work identified the EBV as a possible trigger. The evaluation of bone marrow biopsy samples confirmed the suspicion of HLH. Thus, according to the Histocyte Society standards, the HLH diagnostic criteria were fulfilled, and adequate therapy started with a high-dose corticosteroid regimen (1000 mg of Solu-Medrol per day) for 3 consecutive days and intravenously administered cyclosporine at a dosage of 2 mg/kg/day, which led to normalization of the blood count values and inflammatory marker, liver transaminase, triglyceride and ferritin levels (Supplementary Table 1 and Table 1). Later, the therapy was switched to peroral corticosteroids and cyclosporin as long-term maintenance therapy. Despite this effort, HLH relapse occurred 4 years later (at the age of 24), and no infection or any other trigger was identified. Moreover, the patient developed mediastinal lymphadenopathy, histologically verified as epithelioid granuloma with images indicative of a sarcoid-like disease. Clinical manifestations and therapy are illustrated in Supplementary Fig. 1A. Suspicions about the primary aetiology arose despite the patient’s age, and genetic testing was indicated. WES was performed because of the broad differential diagnosis of HLH and monogenic causes of CD, and the results revealed a novel c.266delA mutation in the XIAP (BIRC4) gene. This finding was subsequently confirmed by Sanger sequencing (Fig. 1a). Further genetic counselling with the patient’s family members revealed that the patient’s mother as a healthy carrier and two healthy siblings were without the mutation (Fig. 1b). When we searched the patient′s pedigree, we also identified the mother’s brother as a potentially affected family member who died of severe infection-induced sepsis accompanied by splenomegaly and lymphadenopathy (major symptoms of HLH); however, biological material was not available for genetic testing to confirm the diagnosis or the cause of death.Table 1 Laboratory values of the patient samples.\n\nImmunology\tPatient’s values\tReferential value\t\nIgG (g/l)\t13.00\t7.65–13.60\t\nIgG1 (g/l)\t7.13\t4.9–11.4\t\nIgG2 (g/l)\t4.13\t1.50–6.40\t\nIgG3 (g/l)\t0.316\t0.2–1.1\t\nIgG4 (g/l)\t0.342\t0.08–1.4\t\nIgA (g/l)\t2.03\t0.91–2.9\t\nIgM (g/l)\t↓ 0.38\t0.47–1.95\t\nIgE (IU/ml)\t↑2.161\t0–150\t\nC3 (g/l)\t0.98\t0.83–2.25\t\nC4 (g/l)\t0.22\t0.14–0.35\t\nTetanus (IU/ml)\t1.01\t0.1\t\nHaemphilus (IU/ml)\t9.00\t6.00\t\nANA\tneg\t–\t\nANCA\tpos (p-ANCA)\t–\t\nRF IgG (IU/ml)\t4.4\t0–22\t\nRF IgA (IU/ml)\t2.3\t0–22\t\nRF IgM (IU/ml)\t2.7\t0–22\t\naTRG (IU/ml)\t2.48\t0–10\t\nASCA IgG (IU/ml)\t↑ 43.713\t0–10\t\nASCA IgA (IU/ml)\t↑ 12.36\t0–10\t\nFig. 1 c.266delA mutation.\na DNA-sequencing chromatogram of the relevant XIAP gene regions in the patient (II/3) and his first-degree relatives. The same mutation was detected in a heterozygous form in his mother (I/1), while other relatives carry wild-type (WT) alleles. Arrows show the mutation position. b Pedigree of the family showing segregation of the XIAP mutation. c Protein structure with highlighted position of the mutation. d Western blot analysis of XIAP presence in the PBMCs of the patient, his mother and the controls.\n\n\n\nNovel c.266delA mutation leads to a premature stop codon and loss of function of the XIAP molecule\nA novel c.266delA frameshift mutation in the XIAP gene of the patient, leading to a premature stop codon after the translation of 41 amino acids (p. Asn89fs*41), was detected by whole-exome sequencing (WES) and confirmed by Sanger sequencing (Fig. 1a). The mother of the patient was confirmed to be a healthy heterozygous carrier (Fig. 1b). The mutation is in the first BIR domain of the protein, as shown in the scheme of the XIAP protein in Fig. 1c. The results from a Western blot analysis showed no XIAP expression in the patient PBMCs and reduced expression of XIAP in the mother’s samples compared with healthy donors (Fig. 1d). We also observed reduced expression of the housekeeping protein β-actin, a finding in agreement with a previously reported role of XIAP in cytoskeleton regulation with reduced β-actin expression21. Expression of HSP90 and tubulin, additional housekeeping proteins, was comparable to controls (Supplementary Fig. 1E).\n\nXIAP LOF mutation results in augmented apoptosis\nAs XIAP is an important molecule in apoptosis regulation, we decided to verify the XIAP LOF by analyzing spontaneous as well as induced apoptosis by staurosporine and PMA. We measured the activation of caspase-3 and -7 with a FAM-FLICA caspase-3,7 assay kit, and noticed elevated numbers of CD3 lymphocytes that were positive for activated caspase-3 and -7 in patient samples. Not only was staurosporine and PMA-induced apoptosis, but also spontaneous apoptosis was markedly enhanced in the patient’s T lymphocytes (Fig. 2a, b). The augmented spontaneous apoptosis was confirmed by Annexin V and DAPI staining, verifying the results of the FLICA experiments (Fig. 2c, d).Fig. 2 Apoptosis.\nPatient PBMCs were treated with staurosporine (1 mmol) and 50 ng/ml PMA for 2, 4 and 6 h, or left untreated for an additional 24 and 48 h. The level of spontaneous and induced apoptosis was detected by a and b FLICA, in which the fluorescein-labelled inhibitor Z-YVAD-fmk is bound to activated caspase-3 and -7 signals as detected by flow cytometry. c, d The level of spontaneous apoptosis detected by flow cytometry of cells stained with Annexin V and DAPI. Annexin + DAPI cells were considered to be undergoing early apoptosis.\n\n\n\nIn addition, we analyzed the expression of pro-apoptotic (BAX and BAK) and anti-apoptotic (Bcl2) genes. The ratio of BAK/Bcl2 and BAX/Bcl2 was highly increased in both induced and spontaneous apoptotic patient cells (Fig. 3a). Interestingly, the genes involved in caspase-independent apoptosis, ENDOG and AIMF1, were reduced in the samples (Fig. 3b). When a caspase inhibitor Z-VAD-FMK was applied, both patient and control samples displayed reduced apoptosis (Supplementary Fig. 2A, B). These observations suggest an enhanced caspase-dependent apoptosis. To test whether there was a compensatory mechanism critical for defective XIAP expression, we analyzed the presence of the BIRC2 (cIAP) gene in patient cells. However, we did not observe enhanced compensatory cIAP expression in patient cells compared with healthy controls (Fig. 3c).Fig. 3 Apoptotic genes’ expression.\na Ratio of pro- and anti-apoptotic genes BAK, BAX and Bcl2 in the patient and control (n = 2) PBMCs after 6 h of stimulation with staurosporine (1 mmol) or PMA (50 ng/ml) as detected by RT-PCR. b Expression of caspase-independent genes involved in apoptosis, AIMF1 and ENDOG, in the patient and control (n = 2) PBMCs after 6 h of stimulation with staurosporine (1 mmol) or PMA (50 ng/ml) as detected by RT-PCR. c Expression of the BIRC2 gene in control (n = 2) PBMCs as detected by RT-PCR. Gene expression was normalized to that of GAPDH.\n\n\n\nXIAP LOF abrogates NOD2 signalling\nMoreover, XIAP is involved in NOD2 signalling; hence, we investigated whether the pathway was affected. Stimulation of NOD2 with muramyl dipeptide (MDP) leads to activation of NFκB and MAPK. We focused on the phosphorylation of the MAP kinases p38 and Erk (Fig. 4a), and observed diminished levels of kinase phosphorylation in response to MDP in patient monocytes detected by flow cytometry. Western blot analysis of MAPK activation confirmed this assessment (Fig. 4b). Furthermore, we examined the NFκB pathway activation after MDP stimulation, expressed as IκB (inhibitor of κB) degradation, and NFκB phosphorylation by flow cytometry and Western blot. Degradation of IκB leads to NFκB activation and its translocation to the nucleus. As anticipated, we detected neither inhibited IκB degradation in the patient’s samples (Fig. 4c, d) nor NFκB phosphorylation in response to MDP stimulation. However, the patient’s cells were able to phosphorylate MAPKs, as well as activate the NFκB pathway in response to PMA or TNFα stimulation (Supplementary Fig. 3A), suggesting that only the NOD2 pathway was affected. Next, we assessed cytokine production (IL-1β, IL-6 and TNFα) after stimulation of patient PBMCs with MDP and lipopolysaccharide (LPS) (Fig. 4e) using the Luminex method. The patient’s cells produced decreased levels of cytokines after MDP stimulation compared with the healthy controls; however, in response to LPS stimulation, the patient’s PBMCs produced comparable levels of cytokines, confirming defective NOD2 signalling in the patient’s cells.Fig. 4 NOD2 signalling.\nPatient and control (n = 5) peripheral blood was stimulated with MDP (10 µg/ml) for 20 min, and phosphorylation of a MAP kinases were detected by phospho-flow cytometry b and by Western blot. NFκB signalling, expressed as IκB degradation and NFκB phosphorylation, was detected by c flow cytometry and d by Western blot after MDP (10 µg/ml) stimulation of patient and control (n = 5) peripheral blood cells. e Production of IL-1β, TNFα, IL-6 and IL-12p70 after MDP (10 µg/ml) or LPS (1 µg/ml) stimulation of patient and control (n = 5) PBMCs was detected by Luminex.\n\n\n\nXIAP deficiency affects T-cell homoeostasis\nTo test whether XIAP deficiency and impaired apoptosis influenced the distribution of the patient’s B- and T-cell subpopulations, we analyzed these subsets. The gating strategies used to distinguish between naive, central memory (CM), effector memory (EM), terminal effector T cells re-expressing CD45RA (TEMRA), recent thymic emigrants (RTEs) and B-cell subsets, are illustrated in Supplementary Fig. 4. The analysis showed a shift towards mature stages of CD4+ and CD8+ T cells in the patient samples (Fig. 5a, b). We found a noteworthy increase in the count of CM and EM, and a reduction in naive forms of the T cells; however, the percentage of RTEs was unaffected. Consequently, we analyzed the patient’s T-lymphocyte ability to produce IFNγ by flow cytometry. The patient’s T cells produced higher levels of IFNγ even in the unstimulated state, which was significantly elevated upon PMA stimulation. The percentage of IFNγ-producing CD4+ T cells (20.1%) was considerably higher than that of the healthy donors (5.3%) (Fig. 5d, e). In addition, analysis of activation marker expression on T cells, HLA-DR as a marker of chronic activation, and CD69 as the earliest activation marker, revealed a shift towards late stages of activation. HLA-DR expression was threefold higher on the CD8+ T cells and twofold higher on CD4+ T cells than it was in the healthy controls (Fig. 5a, b). CD69 expression was unaffected (Supplementary Fig. 3C). T-cell proliferation was negligibly decreased (55.2% patients; controls 74.7% after PMA and ionomycin stimulation) (Supplementary Fig. 3D). Moreover, we also observed higher production of IL-12 in response to LPS in patient PBMCs, supporting a Th1-polarizing environment (Fig. 5f). No significant differences were found in the B-cell department (Fig. 5c).Fig. 5 T cells.\nProportion of a CD4+, b CD8+ T cells and c B-cell subpopulations of the patient and control (n = 3) samples detected by flow cytometry. d, e Percentage of IFNγ-producing T cells upon PMA (20 ng/ml) stimulation for 6 h. e IL-12p70 production upon stimulation with LPS (1 µg/ml), IFNγ (1 µg/ml) or their combination of patient and control (n = 5). PBMCs were detected by Luminex.\n\n\n\nDiscussion\nHere, we report the case of a patient who developed adult-onset IBD refractory to treatment and complicated by several episodes of HLH, and for whom WES revealed a novel previously unpublished c.266delA mutation in the XIAP (BIRC4) gene that led to its loss of function. HLH and IBD are the most common first manifestations of XIAP deficiency, which usually occurs in the first few years of life, and for which the potentially lethal outcome requires HSCT13. Adult-onset HLH and IBD associated with XIAP deficiency, although rare, have also been described17,22. In a large cohort of 54 XIAP-deficient patients, IBD manifestation was the main clinical feature in 17 of them. The remaining patients usually manifested with HLH as a major disease complication. The average age at the time of diagnosis of IBD was 11 years (range 3 months–41 years) compared with patients manifested with HLH (average age 6.5 years and range 0.1–23 years). In our patient, IBD manifested at the age of 17 and HLH at the age of 20. The majority of the first HLH attacks was associated with EBV infection; however, HHV6 and HSV1 were identified as potential triggers as well. IBD-related complications were the main cause of death in three of them at the average age 24 years (range 4–42 years) and after 4 years of disease duration (range 0–7 years). Interestingly, only four patients presented in a form of the adult-onset IBD22,23.\n\nMost of the XIAP mutations identified in XLP-2 patients are nonsense mutations, frameshift mutations or deletions that cause severe aberrations in the encoded protein or loss of its expression. They are distributed along all coding exons10,13,24–26. Neither type nor position of the mutation, as well as residual protein expression, do not correlate with the clinical manifestation and severity of the disease23.\n\nWe report a novel deletion mutation c.266delA, resulting in a premature stop codon (p. Asn89fs*41), loss of protein expression and, as a consequence, a patient suffering from XLP-2 and lower expression in his mother, who is a healthy carrier of the mutation.\n\nXIAP-deficient T cells are characterized by a high susceptibility to apoptosis ex vivo in response to apoptotic stimulus or upon activation17,23,27. Indeed, we observed an enhanced level of apoptosis in response to staurosporine, an inducer of apoptosis, as well as upon activation by PMA. Interestingly, we also observed increased spontaneous apoptosis in patient lymphocytes, which was reduced when a caspase inhibitor was applied. However, the sensitivity to apoptosis of T cells was found to have no influence on circulating blood lymphocyte numbers in patients27. Accordingly, circulating T-cell numbers were in the normal range in the patient, although we observed a shift to their more mature stages. Considering T-lymphocyte function, the expansion and proliferation of virus-specific T lymphocytes might be compromised in XIAP deficiency. XIAP-deficient patients suffer from an increased risk of EBV infections, and in a mouse model28, XIAP and cIAP1 were required for the survival and expansion of virus-specific T cells. In addition, defective NOD2 signalling might also contribute to a higher risk of EBV infection29,30. Apoptosis may be further ameliorated by increased production of IFNγ, which further enhances the expression of pro-apoptotic genes (such as BAX, BAK1 and/or XAF1)31.\n\nThe aforementioned shift in the spectrum of T lymphocytes to their more mature stages seems to be related to the alteration of the apoptosis process. It has been previously reported that T lymphocytes at different stages of development have different sensitivities to apoptosis, possibly resulting from different expression of pro- and anti-apoptotic proteins32,33. These differences may lead to a significant reduction in naive and the subsequent survival of the mature memory forms of T cells, including CM and EM T cells, as observed in the patient.\n\nHLH is the most severe and life-threatening manifestation in patients with XIAP deficiency, but the exact mechanism by which mutated XIAP results in HLH manifestations is not entirely clear. The mechanism differs from other genetic disorders associated with HLH, such as XLP-1, in which the impaired cytotoxic responses by CD8+ lymphocytes and NK cells result in exaggerated amounts of IFNγ and the activation of macrophages, thus explaining the positive effect of the IFNγ blockade on the outcome of HLH15. The patient’s T lymphocytes produced markedly higher levels of IFNγ in comparison with the healthy donors, even though XIAP deficiency was not connected with defects in the cytotoxic responses by CD8+ lymphocytes or NK cells, as is typical in XLP-127. The shift towards the Th1 immune response and increased production of IFNγ was further supported by the overproduction of IL-12, a crucial cytokine for Th1 polarization34. Observations in a mouse model propose, as a possible explanation, that HLH is due to NLRP3 inflammasome dysregulation and increased proinflammatory cytokine production35,36. Although it is still unclear whether XIAP in humans also acts as an NLRP3 inhibitor, impairment to this control might represent a key pathological mechanism. XIAP-deficient mice also develop splenomegaly when treated with an activator of the NLRP3 inflammasome36; therefore, this mechanism may explain two of three typical pathologies associated with XIAP deficiency. Interestingly, mutations in the human NLRC4 inflammasome were identified in patients suffering from recurrent HLH and autoinflammation, supporting a role of the inflammasome in HLH37,38. However, we observed only slightly higher IL-1β and TNFα production in the patient in response to LPS stimulation.\n\nIn line with previous reports, the patient displayed diminished proinflammatory cytokine production after NOD2 ligand stimulation12,39,40, thus connecting the potential role for altered NOD2 signalling with IBD in XIAP patients. NOD2 mutations represent a strong genetic risk factor for CD11, as NOD2-impaired secretion of cytokines and an altered gut microbiome may disturb intestinal homoeostasis. Like HLH, IFNγ is one of the most important cytokines in CD pathophysiology. Indeed, as shown here for the XIAP-deficient patient, altered NOD2-mediated signalling and high IFNγ production by T cells might explain, in an analogy to CD, the gastrointestinal IBD-like presentation as a feature of XIAP deficiency.\n\nTaken together, our data reveal a novel mutation in a patient suffering from recurrent HLH, IBD and splenomegaly, typical conditions associated with XIAP deficiency. The deletion mutation leads to loss of XIAP expression, and it functions as a negative regulator of apoptosis. The absence of XIAP clearly leads to enhanced cell death, which may amplify inflammation. XIAP deficiency negatively influences MDP-induced NOD2 signalling, with implications for IBD. Changes in innate immunity, highlighted together with the role of IFNγ, contribute to XLP-2 pathogenesis and complex clinical presentation. Whereas HSCT in patients with the early onset of the disease represents a method of choice, in adult patients, such as in the index patient in our study, the therapeutic options are more limited. Emapalumab, a monoclonal antibody that targets IFNγ, was approved for the treatment of relapsed/refractory HLH14 with a possible influence on the symptoms of CD, and anti-IL-12/23 (ustekinumab) therapy41 is also available. The overlap in pathogenetic mechanisms gives hope for the use of this strategy to treat XIAP deficiency.\n\nPatient and methods\nInformed written consent was obtained from all subjects involved in the study and all controls in accordance with the Declaration of Helsinki, and according to the procedures established by the Ethical Committee of our institution.\n\nWhole-exome sequencing\nWES was performed on a NextSeq 500 instrument (Illumina, San Diego, CA), and sequencing libraries were prepared using the SureSelectXT Human All Exon V6 + UTR kit (Agilent Technologies, Santa Clara, CA). Sequencing reads were aligned against the human reference genome hg19 by BWA42, and variant calling was performed using SAMtools43 and VarScan 244 and their annotation using SnpEff45.\n\nApoptosis\nPeripheral blood was collected from the patient and healthy volunteers into EDTA-coated tubes. Peripheral blood mononuclear cells (PBMCs) were isolated using Ficoll-Paque (GE Healthcare Biosciences, Uppsala, Sweden). The obtained cells were resuspended in RPMI 1640 medium with a sodium bicarbonate buffer system supplemented with 2% autologous serum, 1% penicillin and streptomycin and 1% GlutaMAX (Thermo Fisher Scientific, Waltham, CA, USA). PBMCs (106/ml) stimulated with staurosporine (1 mmol) (Abcam, Cambridge, UK) for 4 and 6 h, PMA (50 ng/ml) (Sigma-Aldrich, Darmstadt, Germany) for 4 h or left untreated for 4, 6, 24 and 48 h. When indicated, 20 µM Z-VAD-FMK was added in the culture 30 min before apoptosis induction. Then, the cells were washed in Annexin V binding buffer and stained with Annexin V–Dyomics 647 (EXBIO) and DAPI (Thermo Fisher Scientific).\n\nFLICA staining\nActive caspase-3 and -7 were detected using a FLICA caspase-3 and 7 assay kit (Thermo Fisher Scientific). PBMCs were stimulated as described above prior to treatment with the fluorescein-labelled inhibitor Z-YVAD-fmk (10 µM) for 1 h at 37 °C and CD3-A700 (clone MEM-57) (EXBIO, Prague, Czech Republic). The cells were washed three times and analyzed by flow cytometry with a FACS Fortessa flow cytometer (BD Biosciences, San Diego, CA, USA).\n\nPhospho-flow cytometry\nDetection of MAPK and NFκB activation was performed according to a previously published protocol46. Briefly, peripheral blood was stimulated with 10 μg/ml MDP (InvivoGen, San Diego, CA, USA) for 20 min at 37 °C or left unstimulated. Subsequently, the cells were fixed using 4% formaldehyde for 10 min at 25 °C, erythrocytes were lysed using 0.1% Triton X-100 (Sigma-Aldrich) for 15 min at 37 °C and the leukocytes were permeabilized using 80% ice-cold methanol for 30 min.\n\nThe following antibodies were used: CD3—A700 (clone MEM-57), CD14—PEDy594 (EXBIO) and CD19—PC7 (clone J3-119) (Beckman Coulter, USA, Brea, USA), phospho38 (Thr180)—A647 (#4552 S), phosphoErk1/2 (Thr202/Tyr204)—A488 (#4374 S), phosphoSAPJ/JNK (Thr183/185)—PE (#5755 S) (Cell Signaling, Denvers, MA, USA), phosphoNFκB—A647 (#4887) and anti-IκB—A488 (#5743) (both from Cell Signaling).\n\nCytokine production\nCytokines were detected using a multiplex Luminex cytokine-fluorescent bead-based immunoassay (Merck Millipore, Beerlengton, MA, USA) with cell-free supernatants. A total of 2 × 105 PBMCs were stimulated with MDP (10 μg/ml) (InvivoGen), E. coli LPS (1 μg/ml) (Sigma-Aldrich) or left untreated for 24 h.\n\nT- and B-cell analysis\nImmunophenotyping of T and B cells was performed according to a previously published protocol47, and the gating strategy is shown in Supplementary Fig. 2B.\n\nFor IFNγ-producing cell detection, we applied an already-published protocol46.\n\nT-cell proliferation\nThe proliferation of CD3+ T lymphocytes was determined according to a previously published protocol48.\n\nRT-PCR\nPBMCs were stimulated as stated in the ‘Apoptosis’ section. RNA isolation, reverse transcription and RT-PCR were performed according to a previously published protocol49. TaqMan primer/probe sets (Thermo Fisher Scientific) were used. The sample data were matched to a standard curve generated by amplifying serially diluted products using the same PCR, and normalized to GAPDH (TIB Molbiol, Berlin, Germany) to obtain the relative expression value. Real-time assays were run on an FX96 cycler (Bio-Rad). The primer/probe sets are available from the authors upon request.\n\nWestern blotting\nDetection of proteins was performed according to a previously published protocol46. The membranes were incubated with the following primary antibodies: anti-XIAP (clone D2Z8W), anti-β-actin (clone D6A8), anti-GAPDH (clone D16H11), IκB anti (clone L35A5), anti-NFκB (clone D14E12) (all from Cell Signaling), anti-tubulin (clone TU-07), anti-HSP-90 (clone MBH90AB) (both from Exbio), anti-Erk1/2 (ab17942), anti-p-Erk1/2 (ab76299), anti-p-p38 (ab4822), anti-p38 (ab170099), anti-p-JNK1/2/3 (ab124956), anti-JNK1/2/3 (ab208035) and anti-p-NFκB (ab76302) (all from Abcam) overnight, followed by incubation with peroxidase-conjugated anti-rabbit or anti-mouse secondary antibodies for 2 h. The membranes were developed using SuperSignal West Femto (Thermo Fisher Scientific).\n\nSupplementary information\n\nSupplementary Figure Legends\n\n \nSupplementary Figure 1\n\n \nSupplementary Figure 2\n\n \nSupplementary Figure 3\n\n \nSupplementary Figure 4\n\n \nSupplementary Table\n\n \nSupplementary Material\n\n \n\n\nEdited by H.-U. Simon\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary Information accompanies this paper at (10.1038/s41419-020-2652-4).\n\nAcknowledgements\nThe study was supported by the Czech Ministry of Health AZV NV18-05-00162, GAUK 460218 issued by Charles University in Prague, Czech Republic and by the NV19-05-00332 project of the Czech Ministry of Health. The infrastructure was supported by CZ.2.16/3.1.00/24505. We thank the patient and the healthy volunteers for the blood samples used in this study. We confirm that this paper has not been published elsewhere and is not under consideration by another journal.\n\nAuthor contributions\nZ.P. designed the study and experiments, performed the experiments, analyzed the data, interpreted the results and wrote the paper. T.M. designed the experiments, interpreted the results, and provided patient information. P.V. performed the RT-PCR. J.S. acquired the data regarding apoptosis and T-cell proliferation. M.S. provided the NGS results. T.F. provided the Sanger sequencing data. V.K. performed the T- and B-cell analysis. A.S. reviewed and edited the paper.\n\nConflict of interest\nThe authors declare that they have no conflict of interest.\n==== Refs\nReferences\n1. Wilkinson JC Cepero E Boise LH Duckett CS Upstream regulatory role for XIAP in receptor-mediated apoptosis Mol. Cell. Biol. 2004 24 7003 7014 15282301 \n2. Deveraux QL Takahashi R Salvesen GS Reed JC X-linked IAP is a direct inhibitor of cell-death proteases Nature 1997 388 300 304 9230442 \n3. Kenneth NS Duckett CS IAP proteins: regulators of cell migration and development Curr. Opin. Cell Biol. 2012 24 871 875 23219152 \n4. Galbán S Duckett CS XIAP as a ubiquitin ligase in cellular signaling Cell Death Differ. 2010 17 54 60 19590513 \n5. Bertrand MJM Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2 Immunity 2009 30 789 801 19464198 \n6. Wang C TAK1 is a ubiquitin-dependent kinase of MKK and IKK Nature 2001 412 346 351 11460167 \n7. Hasegawa M A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-κB activation EMBO J. 2008 27 373 383 18079694 \n8. Krieg A XIAP mediates NOD signaling via interaction with RIP2 Proc. Natl Acad. Sci. USA 2009 106 14524 14529 19667203 \n9. 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Quaranta M Consequences of identifying XIAP deficiency in an adult patient with inflammatory bowel disease Gastroenterology 2018 155 231 234 29894681 \n23. Schmid JP Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency) Blood 2011 117 1522 1529 21119115 \n24. Yang X Clinical and genetic characteristics of XIAP deficiency in Japan J. Clin. Immunol. 2012 32 411 420 22228567 \n25. Marsh RA XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease Blood 2010 116 1079 1082 20489057 \n26. Filipovich AH Zhang K Snow AL Marsh RA X-linked lymphoproliferative syndromes: brothers or distant cousins? Blood 2010 116 3398 3408 20660790 \n27. Rigaud S XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome Nature 2006 444 110 114 17080092 \n28. 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Ammann S A new functional assay for the diagnosis of X-linked inhibitor of apoptosis (XIAP) deficiency Clin. Exp. Immunol. 2014 176 394 400 24611904 \n41. Engel T Effectiveness and safety of Ustekinumab for Crohn′s disease; systematic review and pooled analysis of real-world evidence Dig. Liver Dis. 2019 51 1232 1240 31202609 \n42. Li H Durbin R Fast and accurate short read alignment with Burrows-Wheeler transform Bioinformatics 2009 25 1754 1760 19451168 \n43. Li H The Sequence Alignment/Map format and SAMtools Bioinformatics 2009 25 2078 2079 19505943 \n44. Koboldt DC VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing Genome Res. 2012 22 568 576 22300766 \n45. Cingolani P Using Drosophila melanogaster as a model for genotoxic chemical mutational studies with a new program, SnpSift Front. Genet. 2012 3 35 22435069 \n46. Parackova, Z. et al. Mutual alteration of NOD2-associated Blau syndrome and IFNγR1 deficiency. J. Clin. Immunol. 10.1007/s10875-019-00720-6 (2019).\n47. Kanderova, V. et al. Lymphoproliferation, immunodeficiency and early-onset inflammatory bowel disease associated with a novel mutation in Caspase 8. Haematologica10.3324/haematol.2018.201673 (2018).\n48. Lašťovička J Rataj M Bartůňková J Assessment of lymphocyte proliferation for diagnostic purpose: comparison of CFSE staining, Ki-67 expression and 3H-thymidine incorporation Hum. Immunol. 2016 77 1215 1222 27562802 \n49. Zentsova, I. et al. Monocytes contribute to DNA sensing through the TBK1 signaling pathway in type 1 diabetes patients. J. Autoimmun. 10.1016/j.jaut.2019.06.005 (2019).\n\n",
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"mesh_terms": "D000328:Adult; D017209:Apoptosis; D003424:Crohn Disease; D006801:Humans; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D015398:Signal Transduction; D051636:X-Linked Inhibitor of Apoptosis Protein",
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"title": "Novel XIAP mutation causing enhanced spontaneous apoptosis and disturbed NOD2 signalling in a patient with atypical adult-onset Crohn's disease.",
"title_normalized": "novel xiap mutation causing enhanced spontaneous apoptosis and disturbed nod2 signalling in a patient with atypical adult onset crohn s disease"
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"abstract": "BACKGROUND\nThe hormonal management of patients with androgen insensitivity can be challenging.\n\n\nMETHODS\nAn illustrative case is presented of a newborn with ambiguous genitalia who was raised female. She was diagnosed as 46,XY Disorder of Sexual Development with partial androgen insensitivity. To induce puberty, conjugated equine estrogens were administered beginning at age 12. At age 13, she instead began taking combined oral contraceptives for maternal concerns about height and continued taking them for social reasons. Invasive ductal carcinoma was diagnosed at age 27, and the patient was treated with chemotherapy, radiation therapy, bilateral mastectomies, and endocrine therapy.\n\n\nCONCLUSIONS\nThe current literature is reviewed, and hormonal management and other risks for breast cancer are discussed.",
"affiliations": "Division of Pediatric and Adolescent Gynecology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO.;Division of Pediatric and Adolescent Gynecology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO. Electronic address: merritd@wustl.edu.",
"authors": "Hoefgen|Holly R|HR|;Merritt|Diane F|DF|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
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"issn_linking": "1083-3188",
"issue": "28(4)",
"journal": "Journal of pediatric and adolescent gynecology",
"keywords": "46,XY disorders of sexual development; Androgen insensitivity syndrome; Breast Neoplasms",
"medline_ta": "J Pediatr Adolesc Gynecol",
"mesh_terms": "D013734:Androgen-Insensitivity Syndrome; D001943:Breast Neoplasms; D044584:Carcinoma, Ductal; D005260:Female; D005500:Follow-Up Studies; D020249:Hormone Replacement Therapy; D006801:Humans; D007231:Infant, Newborn; D008297:Male",
"nlm_unique_id": "9610774",
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"pages": "e95-7",
"pmc": null,
"pmid": "26024935",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Invasive Ductal Carcinoma in a 46,XY Partial Androgen Insensitivity Syndrome Patient on Hormone Therapy.",
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"abstract": "Chronic subdural hematomas are a common neurosurgical presentation. They are difficult to treat, and current interventions - namely surgical evacuation - are not without complications or recurrences. Embolization of the middle meningeal artery is a promising new treatment option for this pathology. We have noted an interesting phenomenon in our patients following endovascular embolization, which is that the subdural hematoma is stained with contrast following the procedure. This ties into the basic physiology of chronic subdurals, which parasitize the middle meningeal artery during the process of membrane formation and neovascularization, which has previously been reported.",
"affiliations": "Department of Neurosurgery, Albany Medical Center, Albany, USA.;Department of Neurosurgery, Albany Medical Center, Albany, USA.;Department of Neurosurgery, Albany Medical Center, Albany, USA.;Department of Neurosurgery, Albany Medical Center, Albany, USA.;Department of Neurosurgery, Albany Medical Center, Albany, USA.",
"authors": "Entezami|Pouya|P|https://orcid.org/0000-0003-0208-049X;Boulos|Alan|A|;Paul|Alexandra|A|;Nourollahzadeh|Emad|E|;Dalfino|John|J|",
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"keywords": "Chronic subdural hematoma; capillary; embolization; endovascular; middle meningeal artery; neovascularization",
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"mesh_terms": "D000058:Accidental Falls; D000368:Aged; D000369:Aged, 80 and over; D003287:Contrast Media; D004621:Embolization, Therapeutic; D005260:Female; D020200:Hematoma, Subdural, Chronic; D006801:Humans; D007089:Image Enhancement; D008297:Male; D008576:Meningeal Arteries; D009389:Neovascularization, Pathologic; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
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"title": "Contrast enhancement of chronic subdural hematomas after embolization of the middle meningeal artery.",
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"abstract": "Gastrointestinal mucormycosis is a rare infection in solid organ transplant recipients. Our patient, a 79-year-old male, presented with severe dysphagia and odynophagia about 2 weeks after receiving a renal transplant. An upper gastrointestinal (UGI) endoscopy revealed esophagitis and gastric ulceration, the cultures from which grew Rhizopus species. A usual treatment strategy should include Amphotericin B as monotherapy or in combination with Posaconazole or Isavuconazole for such infections. Our patient was treated with Isavuconazole monotherapy, in an effort to minimize renal toxicity from Amphotericin B to the new allograft. Unique to our case was a successful clinical response and resolution of UGI lesions with Isavuconazole monotherapy. Due to the vagueness of presenting symptoms, such infections can be easily missed in an immunocompromised patient which can have tragic outcomes. Prompt diagnosis and modulation of immunosuppression are essential to decrease mortality and morbidity. Isavuconazole is a novel agent and can be used as a monotherapy for such infections, especially in renal transplant recipients.",
"affiliations": "Department of Nephrology, Hypertension and Transplant Medicine, Augusta University Health, Augusta, GA, USA.;Division of Transplant Surgery, Department of Surgery, Augusta University Health, Augusta, GA, USA.;Division of Transplant Surgery, Department of Surgery, Augusta University Health, Augusta, GA, USA.;Department of Pharmacy, Augusta University Health, Augusta, GA, USA.;Department of Pathology, Augusta University Health, Augusta, GA, USA.;Department of Nephrology, Hypertension and Transplant Medicine, Augusta University Health, Augusta, GA, USA.;Division of Transplant Surgery, Department of Surgery, Augusta University Health, Augusta, GA, USA.;Department of Nephrology, Hypertension and Transplant Medicine, Augusta University Health, Augusta, GA, USA.",
"authors": "Gani|Imran|I|0000-0002-4813-5022;Doroodchi|Atbin|A|;Falkenstrom|Kristina|K|;Berry|Holly|H|;Lee|Won|W|0000-0002-0722-669X;Mulloy|Laura|L|;Saeed|Muhammad|M|0000-0002-0627-1253;Kapoor|Rajan|R|0000-0002-8633-7717",
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"fulltext": "\n==== Front\nCase Rep TransplantCase Rep TransplantCRITCase Reports in Transplantation2090-69432090-6951Hindawi 10.1155/2019/9839780Case ReportGastric Mucormycosis in a Renal Transplant Patient Treated with Isavuconazole Monotherapy http://orcid.org/0000-0002-4813-5022Gani Imran IGANI@augusta.edu\n1\nDoroodchi Atbin \n2\nFalkenstrom Kristina \n2\nBerry Holly \n3\nhttp://orcid.org/0000-0002-0722-669XLee Won \n4\nMulloy Laura \n1\nhttp://orcid.org/0000-0002-0627-1253Saeed Muhammad \n2\nhttp://orcid.org/0000-0002-8633-7717Kapoor Rajan \n1\n\n1Department of Nephrology, Hypertension and Transplant Medicine, Augusta University Health, Augusta, GA, USA\n2Division of Transplant Surgery, Department of Surgery, Augusta University Health, Augusta, GA, USA\n3Department of Pharmacy, Augusta University Health, Augusta, GA, USA\n4Department of Pathology, Augusta University Health, Augusta, GA, USAAcademic Editor: Graeme Forrest\n\n2019 17 3 2019 2019 98397808 11 2018 20 2 2019 Copyright © 2019 Imran Gani et al.2019This 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.Gastrointestinal mucormycosis is a rare infection in solid organ transplant recipients. Our patient, a 79-year-old male, presented with severe dysphagia and odynophagia about 2 weeks after receiving a renal transplant. An upper gastrointestinal (UGI) endoscopy revealed esophagitis and gastric ulceration, the cultures from which grew Rhizopus species. A usual treatment strategy should include Amphotericin B as monotherapy or in combination with Posaconazole or Isavuconazole for such infections. Our patient was treated with Isavuconazole monotherapy, in an effort to minimize renal toxicity from Amphotericin B to the new allograft. Unique to our case was a successful clinical response and resolution of UGI lesions with Isavuconazole monotherapy. Due to the vagueness of presenting symptoms, such infections can be easily missed in an immunocompromised patient which can have tragic outcomes. Prompt diagnosis and modulation of immunosuppression are essential to decrease mortality and morbidity. Isavuconazole is a novel agent and can be used as a monotherapy for such infections, especially in renal transplant recipients.\n==== Body\n1. Introduction\nMucormycosis has emerged as a debilitating infection in renal transplant patients with a high incidence of allograft loss if the infection is disseminated. It carries high morbidity and mortality rates despite treatment. Rhizopus species has been reported to be the most common cause of mucormycosis infection in immunocompromised patients. Isavuconazole so far has not been used as monotherapy for the first line treatment for gastric mucormycosis in a renal transplant patient due to lack of clinical data.\n\nWe present a rare case scenario of a 79-year-old African-American male who developed severe gastrointestinal mucormycosis from Rhizopus species infection 2 weeks after receiving a renal transplant and was successfully treated with Isavuconazole monotherapy.\n\n2. Case Report\nOur patient, a 79-year-old African-American male with a past medical history of end-stage renal disease secondary to hypertension, DM Type 2, coronary artery disease received an uneventful deceased donor kidney transplantation. His induction immunosuppression consisted of antithymocyte immunoglobulin and steroids and his maintenance regimen consisted of Mycophenolate Mofetil, Tacrolimus, and Prednisone. He received Trimethoprim-Sulfamethoxazole, Valgancyclovir, and Nystatin for opportunistic infection prophylaxis. His immediate posttransplant course was complicated by transient delayed graft function and Clostridium difficile diarrhea which resolved after treatment by postoperative day 10.\n\nOn postoperative day 16, he started experiencing dysphagia and odynophagia and was unable to take solid food. An esophagogastroduodenoscopy (EGD) was performed revealing Los Angeles Grade D esophagitis, 20 cm in length (Figure 1), along with a large semicircumferential gastric ulcer with heaped up margins covered by greenish exudate (Figure 2). Histologic examination of the biopsy specimen revealed fungal elements in the background of necrotic and acute inflammatory exudate with unremarkable gastric foveolar epithelium (Figures 3 and 4). CMV and HSV stains were negative and the biopsy was negative for H. pylori and malignancy as well. Fungal culture grew Rhizopus species. The patient was started on Isavuconazole (372 mg every eight hours for 6 doses followed by 372 mg daily) and the dose of Mycophenolate Mofetil and Tacrolimus was reduced. He started experiencing resolution of symptoms in 48 hours and was able to tolerate oral feeds well. A repeat EGD on postoperative day 20 showed partial resolution of the mass (Figure 5). The patient was put on lifelong Isavuconazole (372 mg p.o daily) given the patient's immunosuppressed status and he has remained asymptomatic at 6 months after transplant, which was his last clinic follow-up visit.\n\n3. Discussion\nGastrointestinal (GI) infections are common in recipients of solid organ transplant patients due to underlying immunosuppression. Common causes include Clostridium difficile, Cytomegalovirus, Herpes Simplex Virus, Helicobacter pylori, and enteric bacteria (Campylobacter, Escherichia coli, Salmonella). Other infectious agents implicated include parasites (Giardia intestinalis, Strongyloidiasis) and viruses (Norovirus and Rotavirus) [1, 2]. The most common cause of gastrointestinal fungal infection in transplant patients is Candida [3]. Mucormycosis is caused by fungi in the order Mucorales of class Zygomycetes. Rhizopus, Mucor, Rhizomucor, Absidia, and Cunninghamella genera species are usually the causative agents in human infections [4]. In the genus Rhizopus, most frequent infectious species is Rhizopus Arrhizus. \"Mucormycosis\" and “Zygomycosis” have been used interchangeably in medical literature as the majority of human disease is caused by fungi of order Mucorales [5–7].\n\nMucormycosis can be a life-threatening opportunistic fungal infection. The incidence of mucormycosis among solid organ transplant recipients is 0.4-16 % depending upon the organ being transplanted, and it is 0.2% – 1.2% in renal transplant recipients [8, 9]. In one study, Zygomycetes were the predominant causative agents of nonaspergillus opportunistic fungal infections in solid organ transplant recipients [10]. Usual presentation is within 3–6 months of transplant but may occur many years after the transplant [11]. As in our case, early posttransplant mucormycosis has also been reported [12–14]. Risk factors for mucormycosis infection include immunosuppression, hematological malignancies, diabetes mellitus, steroid use, neutropenia, trauma and burns [15]. Other risk factors are metabolic acidosis, disruption of gastrointestinal mucosal barrier by peptic acid disease, iron overload and deferoxamine treatment [16, 17]. Mucormycosis commonly presents as a sinus-rhino-cerebral disease in solid organ transplant patients [4]. Exposure usually occurs through inhalation, ingestion or inoculation of spores. Other presentations include pulmonary, cutaneous, gastrointestinal, graft organ and disseminated disease. Gastrointestinal mucormycosis is a rare presentation of the disease and is usually due to ingestion of spores. In GI mucormycosis stomach is the most common site of involvement followed by the colon and small bowel. Liver, spleen, and pancreas may rarely be involved as well. Symptoms can be nonspecific and patients can present with abdominal pain, anorexia, abdominal distension, nausea, vomiting and swallowing difficulty. Gastrointestinal bleeding and/or catastrophic gastric or bowel perforation may also be the presenting symptoms. Mucor hyphae have a tendency to grow rapidly and lead to disseminated infection [4]. By invading blood vessels, the fungus can cause thrombosis, tissue necrosis with high morbidity and mortality. Diagnosis is often delayed due to nonspecific presentation and rarity of the disease, therefore a high index of suspicion is required. Beta D glucan testing is not reliable for diagnosing mucormycosis. Diagnosis is usually made after histopathological examination and culture of endoscopy specimens. Rhizopus species are the most common cause of culture-confirmed mucormycosis and histologically, broad, thin-walled, aseptate or sparsely septate hyphae are seen. EGD in gastric mucormycosis shows a discolored mucosa with a shaggy appearance or ulcers with necrotic centers.\n\nMucormycosis involving the stomach in a renal transplant patient has been reported before [18–22]. Alfano et al. described a case of a 42-year-old female who had a posttransplant upper GI bleed due to gastric ulcers which grew Rhizopus. The patient had a successful outcome with immunosuppression reduction, Amphotericin B and Posaconazole combination. Winkler et al. presented a similar case of a 37-year-old female who developed upper GI bleed on postoperative day 25 due to Rhizopus infection related gastric ulcer that was successfully managed with Amphotericin B. Tinmouth et al. describe a fatal case of gastrointestinal mucormycosis involving the stomach and colon that did not respond to treatment with Amphotericin B, surgical debridement and cessation of all immunosuppression. Radha et al. also describe a fatal case of gastric mucormycosis that did not respond to reduction of immunosuppression and surgical debridement. Kim et al. report a patient with perforating gastric mucormycosis who was successfully managed with emergent total gastrectomy, Amphotericin B and Posaconazole. In contrast, our case was an elderly male who developed esophageal lesions along with gastric ulcer, slightly earlier than as reported in these cases and was successfully treated with Isavuconazole monotherapy and immunosuppressant reduction. Early treatment with antifungal agents and reduction of immunosuppression in solid organ transplant patients is the standard of care. The total duration of antifungal therapy is unclear as there are no definitive guidelines. Treatment duration should be individualized on a case by case basis according to the clinical response.\n\nDespite antifungal therapy, surgical debridement/debulking and reduction of immunosuppressive therapy, mortality can be high due to the aggressive nature of this fungus. The most commonly used antifungal agent for mucormycosis treatment is Amphotericin B [23, 24]. Liposomal Amphotericin B is preferred due to comparative less nephrotoxicity. Posaconazole is also used but its absorption can be erratic and unpredictable and can be associated with severe gastrointestinal side effects such as nausea, vomiting, and diarrhea. Fluconazole, Itraconazole, Voriconazole are not effective. Due to the known nephrotoxic potential of Amphotericin B and drug interaction profiles of other azole compounds with calcineurin inhibitors, Isavuconazole was chosen for antifungal therapy in our case. Isavuconazole is a novel second-generation triazole with a broad spectrum of antifungal activity, approved by the FDA for the treatment of adults with invasive Aspergillosis and mucormycosis. It is available in both intravenous and oral formulations. Since its approval in 2015 [25], Isavuconazole has displayed similar efficacy and a favorable pharmacokinetic profile that has led to less therapeutic drug monitoring, an improved safety profile and less drug-drug interactions [26]. Its once-daily dose oral formulation was favorable in our patient given his extensive medication profile and duration of treatment. Surgical options were not considered in our case as our patient showed a good and prompt response to medical therapy alone.\n\nTo the best of our knowledge, this is the first reported case of a patient with gastric mucormycosis after renal transplant successfully treated with Isavuconazole monotherapy. There has been one previous case report published where there was a successful result using Isavuconazole in addition to Amphotericin B and surgical debridement in disseminated pulmonary infection in a renal transplant patient [27]. We acknowledge that we present evidence from a single patient but we highlight the efficacy of Isavuconazole monotherapy in the treatment of mucormycosis in an immunocompromised patient. We also want to highlight the safety profile, low nephrotoxicity and favorable drug interaction profile with calcineurin inhibitors in solid organ transplant patients. Updated guidelines on mucormycosis treatment are needed to reflect the current evidence and to further elucidate the efficacy of Isavuconazole in the treatment of mucormycosis.\n\n4. Conclusion\nWe report a rare case of gastric mucormycosis successfully treated with Isavuconazole monotherapy in a renal transplant patient. Mucormycosis, though rare, can affect gastrointestinal tract in immunocompromised solid organ transplant patients. Symptoms are nonspecific; therefore a high index of suspicion is required to make the diagnosis by endoscopy. Timely introduction of antifungal therapy and the reduction of immunosuppression is the standard of care.\n\nConsent\nAn informed consent was obtained from the patient.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n\nFigure 1 Endoscopic imaging showing severe esophagitis.\n\nFigure 2 Endoscopic imaging of gastric lesion before the initiation of treatment.\n\nFigure 3 Fungal elements in a background of necrotic and acute inflammatory exudate and unremarkable gastric foveolar epithelia. No evidence of malignancy (x2000).\n\nFigure 4 Fungal hyphae highlighted by Grocott-Gomori's Methenamine Silver (GMS) stain in a background of necrotic and acute inflammatory exudate and unremarkable gastric foveolar epithelia. No evidence of malignancy (x1000).\n\nFigure 5 Endoscopic images of the gastric lesion after treatment with Isavuconazole.\n==== Refs\n1 Helderman J. H. Goral S. Gastrointestinal complications of transplant immunosuppression Journals of the American Society of Nephrology 2002 13 1 277 287 \n2 Ponticelli C. Passerini P. Gastrointestinal complications in renal transplant recipients Transplant International 2005 18 6 643 650 2-s2.0-23244451207 10.1111/j.1432-2277.2005.00134.x 15910287 \n3 Silveira F. P. Husain S. Fungal infections in solid organ transplantation Medical Mycology 2007 45 4 305 320 2-s2.0-34249701218 10.1080/13693780701200372 17510855 \n4 Roden M. M. Zaoutis T. E. Buchanan W. L. Epidemiology and outcome of zygomycosis: a review of 929 reported cases Clinical Infectious Diseases 2005 41 5 634 653 10.1086/432579 2-s2.0-23844464106 16080086 \n5 Staff Springfield News-Leader Aggressive Fungus Strikes Joplin Tornado Victims PI 2011 Seattle, Wash, USA Hearst Communications Inc \n6 Spellberg B. Edwards J. Jr. Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management Clinical Microbiology Reviews 2005 18 3 556 569 10.1128/cmr.18.3.556-569.2005 2-s2.0-22244466058 16020690 \n7 Prabhu R. M. Patel R. Mucormycosis and entomophthoramycosis: a review of the clinical manifestations, diagnosis and treatment Clinical Microbiology and Infection 2004 10 1 31 47 10.1111/j.1470-9465.2004.00843.x 2-s2.0-1642287033 14748801 \n8 Pappas P. G. Alexander B. D. Andes D. R. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET) Clinical Infectious Diseases 2010 50 8 1101 1111 20218876 \n9 Park B. J. Pappas P. G. Wannemuehler K. A. Invasive non-aspergillus mold infections in transplant recipients, United States, 2001–2006 Emerging Infectious Diseases journal 2001 17 10 1855 1864 10.3201/eid1710.110087 \n10 Stelzmueller I. Lass-Floerl C. Geltner C. Zygomycosis and other rare filamentous fungal infections in solid organ transplant recipients Transplant International 2008 21 6 534 546 10.1111/j.1432-2277.2008.00657.x 18363572 \n11 Sun H.-Y. Aguado J. M. Bonatti H. Pulmonary zygomycosis in solid organ transplant recipients in the current era American Journal of Transplantation 2009 9 9 2166 2171 10.1111/j.1600-6143.2009.02754.x 2-s2.0-69149089696 19681829 \n12 Kaplan A. H. Poza-Juncal E. Shapiro R. Stapleton J. T. Cure of mucormycosis in a renal transplant patient receiving ciclosporin with maintenance of immunosuppression American Journal of Nephrology 1988 8 2 139 142 10.1159/000167573 3293443 \n13 Vera A. Hubscher S. G. McMaster P. Buckels J. A. C. Invasive gastrointestinal zygomycosis in a liver transplant recipient: case report Transplantation 2002 73 1 145 147 10.1097/00007890-200201150-00027 2-s2.0-0037080743 11792995 \n14 Knoop C. Antoine M. Vachiéry J. L. Gastric perforation due to mucormycosis after heart-lung and heart transplantation Transplantation 1998 66 7 932 935 2-s2.0-0032532769 10.1097/00007890-199810150-00021 9798707 \n15 Ibrahim A. S. Spellberg B. Walsh T. J. Kontoyiannis D. P. Pathogenesis of mucormycosis Clinical Infectious Diseases 2012 54 supplement 1 S16 S22 10.1093/cid/cir865 2-s2.0-84855889114 22247441 \n16 Artis W. M. Fountain J. A. Delcher H. K. Jones H. E. A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability Diabetes 1982 31 12 1109 1114 10.2337/diacare.31.12.1109 2-s2.0-0020381256 6816646 \n17 Boelaert J. R. De Locht M. Van Cutsem J. Mucormycosis during deferoxamine therapy is a siderophore-mediated infection: In vitro and in vivo animal studies The Journal of Clinical Investigation 1993 91 5 1979 1986 2-s2.0-0027160171 10.1172/JCI116419 8486769 \n18 Alfano G. Fontana F. Francesca D. Gastric mucormycosis in a liver and kidney transplant recipient: case report and concise review of literature Transplantation Proceedings 2018 50 3 905 909 10.1016/j.transproceed.2017.11.036 29573830 \n19 Winkler S. Susani S. Willinger B. Gastric mucormycosis due to Rhizopus oryzae in a renal transplant recipient Journal of Clinical Microbiology 1996 34 10 p. 2585 \n20 Tinmouth J. Baker J. Gardiner G. Gastrointestinal mucormycosis in a renal transplant patient Canadian Journal of Gastroenterology & Hepatology 2001 15 3 237384 10.1155/2001/237384 2-s2.0-0034986995 \n21 Radha S. Tameem T. Fernandez D. Satyanarayana G. Gastric Zygomycosis (Mucormycosis) The Internet Journal of Pathology 2007 5 2 10.5580/1032 \n22 Kim H. N. Han S. A. Park H. Y. Successful treatment of invasive gastric mucormycosis in a kidney transplant recipient The Journal of the Korean Society for Transplantation 2018 32 4 104 107 10.4285/jkstn.2018.32.4.104 \n23 Park W. Jang M. Hwang E. Allograft mucormycosis due to Rhizopus microsporus in a kidney transplant recipient Transplantation Proceedings 2014 46 2 623 625 2-s2.0-84896470506 10.1016/j.transproceed.2013.12.017 24656029 \n24 Kontoyiannis D. P. Lewis R. E. Invasive zygomycosis: update on pathogenesis, clinical manifestations, and management Infectious Disease Clinics of North America 2006 20 3 581 607 10.1016/j.idc.2006.06.003 2-s2.0-33748519574 16984870 \n25 Isavuconazonium sulfate (Cresemba)-a new antifungal The Medical Letter on Drugs and Therapeutics 2016 58 1490 37 38 26963156 \n26 Jenks J. D. Salzer H. J. F. Prattes J. Krause R. Buchheidt D. Hoenigl M. Spotlight on isavuconazole in the treatment of invasive aspergillosis and mucormycosis: Design, development, and place in therapy Drug Design, Development and Therapy 2018 12 1033 1044 2-s2.0-85046680458 10.2147/DDDT.S145545 \n27 Martin M. S. Smith A. A. Lobo M. Paramesh A. S. Successful treatment of recurrent pulmonary mucormycosis in a renal transplant patient: a case report and literature review Case Reports in Transplantation 2017 2017 5 1925070 10.1155/2017/1925070\n\n",
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"abstract": "Patients with severe diabetic acidosis may present varying electrocardiography (ECG) abnormalities including ST-segment elevation. The authors described a case of 70-year-old type 2 diabetic woman hospitalized due to ST elevation myocardial infarction and serious metabolic disorders. According to the clinical presentation, the ECG abnormalities and the significant rise in myocardial necrosis biomarkers the patient was diagnosed with myocardial infarction and received a typical pharmacological treatment. In the autopsy, no signs of myocardial infarction and no significant stenoses in the coronary arteries were found, while the features of acute upper gastrointestinal bleeding were observed. This case report demonstrates that together with the clinical presentation of metabolic disorders, ST elevation must always be interpreted very cautiously and each case require an individual proceeding.",
"affiliations": "Cardiology and Internal Medicine Department, Miedzyleski Specialistic Hospital, Warsaw, Poland.;3rd Department of Internal Medicine and Cardiology, 2nd Medical Faculty, Medical University of Warsaw, Warsaw, Poland.;3rd Department of Internal Medicine and Cardiology, 2nd Medical Faculty, Medical University of Warsaw, Warsaw, Poland.",
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"title": "ST-segment elevation myocardial infarction with non-obstructive coronary arteries in a patient with severe diabetic acidosis.",
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"abstract": "OBJECTIVE\nTo study the effect of intravitreal (IVT) ranibizumab on the retinal arteriolar diameter in patients with neovascular age-related macular degeneration (AMD).\n\n\nMETHODS\nTen eyes of 10 patients with previously untreated neovascular AMD were included. All eyes had three monthly IVT injections of ranibizumab and then were retreated as needed, based on visual acuity and optical coherence tomography (OCT) criteria. The diameter of the retinal arterioles was measured in vivo with a retinal vessel analyser (RVA) before the first IVT injection, 7 and 30 days after the first, the second and the third injection, and at month 12 of follow-up.\n\n\nRESULTS\nA significant vasoconstriction of the retinal arterioles was observed following each one of the first three IVT injections of ranibizumab. Thirty days following the first, second and third injection, there was a mean decrease of 8.4 ± 3.2%, 11.9 ± 4.5% and 18.5 ± 7.2%, respectively, of the retinal arteriolar diameter compared with baseline (p < 0.01). At month 12, the vasoconstriction was still present with a mean decrease of 19.1 ± 8.3% of the retinal arteriolar diameter compared with baseline (p < 0.01). Median number of ranibizumab injections was 4 (range 3-10). There was no correlation between the number of injections and percentage diameter decrease at month 12 (r = -0.54, p > 0.1). There was no significant change in mean arterial pressure (MAP) during the period of follow-up (p > 0.05).\n\n\nCONCLUSIONS\nThese results suggest that IVT ranibizumab induces sustained retinal arteriolar vasoconstriction in eyes with neovascular AMD.",
"affiliations": "Vitreo-retinal Unit, Department of Ophthalmology, Faculty of Medicine, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.",
"authors": "Mendrinos|Efstratios|E|;Mangioris|Georgios|G|;Papadopoulou|Domniki N|DN|;Donati|Guy|G|;Pournaras|Constantin J|CJ|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab",
"country": "England",
"delete": false,
"doi": "10.1111/aos.12008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1755-375X",
"issue": "91(3)",
"journal": "Acta ophthalmologica",
"keywords": null,
"medline_ta": "Acta Ophthalmol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D062186:Arterial Pressure; D001160:Arterioles; D001794:Blood Pressure; D003251:Constriction, Pathologic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007429:Intraocular Pressure; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D000069579:Ranibizumab; D012161:Retinal Artery; D019233:Retreatment; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity; D057135:Wet Macular Degeneration",
"nlm_unique_id": "101468102",
"other_id": null,
"pages": "e184-90",
"pmc": null,
"pmid": "23590391",
"pubdate": "2013-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term results of the effect of intravitreal ranibizumab on the retinal arteriolar diameter in patients with neovascular age-related macular degeneration.",
"title_normalized": "long term results of the effect of intravitreal ranibizumab on the retinal arteriolar diameter in patients with neovascular age related macular degeneration"
} | [
{
"companynumb": "CH-ROCHE-2208295",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BENOXINATE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Fungal endophthalmitis is a rare condition often associated with poor prognosis. We present a case of postoperative acute fungal endophthalmitis caused by the yeast-like fungus Stephanoascus ciferrii (Candida ciferrii). The fungus was resistant to fluconazole, voriconazole, and amphotericin B but susceptible to caspofungin. Because the degree of vitreal penetration of caspofungin after its intravenous administration is unclear, we performed multiple intravitreal injections, first with 50 µg/0.1 ml and then with 250 µg/0.1 ml caspofungin. Despite the recurrence of symptoms, intravitreal injection of caspofungin finally abolished the inflammation and achieved ambulatory vision that persisted until 1 year of follow-up. To our knowledge, this is the first report of S. ciferrii endophthalmitis and its successful treatment with intravitreal caspofungin.",
"affiliations": "Department of Ophthalmology, University of Medicine and Pharmacy \"Gr.T.Popa,\", Iasi, Romania.;Department of Ophthalmology, University of Medicine and Pharmacy \"Gr.T.Popa,\", Iasi, Romania.;Department of Ophthalmology, University of Medicine and Pharmacy \"Gr.T.Popa,\", Iasi, Romania.",
"authors": "Danielescu|Ciprian|C|;Cantemir|Alina|A|;Chiselita|Dorin|D|",
"chemical_list": "D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077336:Caspofungin",
"country": "Brazil",
"delete": false,
"doi": "10.5935/0004-2749.20170048",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-2749",
"issue": "80(3)",
"journal": "Arquivos brasileiros de oftalmologia",
"keywords": null,
"medline_ta": "Arq Bras Oftalmol",
"mesh_terms": "D000935:Antifungal Agents; D000077336:Caspofungin; D054714:Echinocandins; D009877:Endophthalmitis; D015821:Eye Infections, Fungal; D005260:Female; D006801:Humans; D058449:Intravitreal Injections; D055666:Lipopeptides; D008875:Middle Aged; D018918:Phacoemulsification; D015203:Reproducibility of Results; D004718:Saccharomycetales; D016896:Treatment Outcome; D014792:Visual Acuity; D014821:Vitrectomy",
"nlm_unique_id": "0400645",
"other_id": null,
"pages": "196-198",
"pmc": null,
"pmid": "28832730",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of fungal endophthalmitis using intravitreal caspofungin.",
"title_normalized": "successful treatment of fungal endophthalmitis using intravitreal caspofungin"
} | [
{
"companynumb": "RO-ALVOGEN-2017-ALVOGEN-093368",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "The renal function is a key-issue in HIV/HCV co-infected patients, nevertheless, it has not established so far whether HCV treatment with new direct acting agents could impact on estimated glomerular filtration rate (eGFR) variations. In the present work, we examined the real-life data on renal function that have been prospectively collected in the SIMIT compassionate-use program of ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r + DSV) in 144 HIV/HCV genotype 1 co-infected patients. The population was 74% male, 30.5% in CDC stage C, with median age of 52 years (48.0-56.5) and median liver stiffness of 7.8 kPa (6.7-9.2). Median baseline eGFR was 102.0 (90.8-108.1), changing to 99.8 (83.5-104.8) at the end of treatment (EoT), and 100.0 (87.3-105.6) 12 weeks after the EoT (FU12), p<0.0001. No patient had grade 3-4 increase of creatinine. At EoT 60/144 (41.7%) patients had ≥ 5% reduction in their eGFR, confirmed at FU12 in 39/60 (65.0%) cases. Longer duration of HCV infection (cut-off 12.9 years), lower HCV-RNA viral load (cut-off 1,970,160 IU/ml) and lower platelet count (cut-off 167,000 x106/L) were significantly associated with eGFR decline at logistic analysis (adjOR 2.9, 95%CI 1.0-8.8, p = 0.05; adjOR 3.5, 95%CI 1.2-10.4, p = 0.02; adjOR 2.8, 95%CI 1.1-6.8, p = 0.03, respectively). After repeating the analysis throughout a mixed model, a higher eGFR decline was highlighted in patients concomitantly treated with tenofovir (p = 0.0001), ribavirin (p = 0.0001), or integrase inhibitors (p <0.0001), with longer duration of HIV (p = 0.0002) and HCV infection (p = 0.035), lower baseline HCV RNA (p <0.0001), previous HCV treatment (p<0.0001), and older age (p<0.0001). In conclusion, our study confirms a good renal safety profile of OBV/PTV/r + DSV treatment in HIV/HCV patients, and the median decline of 2 ml/min in eGFR, albeit statistically significant, is of doubtful clinical significance. The role of aging, concomitant therapies and duration of HIV/HCV infection needs to be further investigated.",
"affiliations": "University of Genova (DISSAL), Infectious Diseases Clinic, Policlinico Hospital San Martino, Genova, Italy.;Infectious Diseases Clinic, Policlinico Hospital San Martino, Genova, Italy.;Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy.;University of Genova (DISSAL), Infectious Diseases Clinic, Policlinico Hospital San Martino, Genova, Italy.;Clinical Department, National Institute for Infectious Diseases, INMI L. Spallanzani, Rome, Italy.;Department of Biomedical and Clinical Science, University of Milan, Milan, Italy.;Department of Biomedical and Clinical Science, University of Milan, Milan, Italy.;1st Division of Infectious Diseases, ASST Fatebenefratelli-Sacco, Milan, Italy.;1st Division of Infectious Diseases, ASST Fatebenefratelli-Sacco, Milan, Italy.;Institute of Infectious Disease, University of Bari, Bari, Italy.;Division of Infectious and Tropical Diseases, IRCCS Policlinico San Matteo, Pavia, Italy.;Infectious Diseases Clinic, University Hospital, Modena, Italy.;Department of Internal and Specialty Medicine University Infectious Diseases Unit, AOU Senese, Siena, Italy.;Department of Infectious and Tropical Diseases, University Hospital, Padova, Italy.;Department of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.;Department of Clinical Medicine, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.;Clinic of Infectious and Tropical Diseases, Department of Health Sciences, University of Milan, Milan, Italy.;Infectious Diseases Unit, Sapienza University of Rome, Latina, Italy, and Department of Public Health and Infectious Diseases, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.;Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.;Division of Infectious Diseases, AO Papa Giovanni XXIII, Bergamo, Italy.;Division of Infectious Diseases, AO Niguarda Ca' Granda Hospital, Milan, Italy.;Division of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;Division of Infectious Diseases, Department of Internal Medicine, San Gerardo Hospital, University of Milan-Bicocca, Milan, Italy.;First Division of Infectious Diseases, S. Giovanni di Dio e Ruggi d'Aragona Hospital, Salerno, Italy.;Division of Infectious Diseases, Department of Clinical and Experimental Medicine, ARNAS Garibaldi Hospital, University of Catania, Catania, Italy.;Infectious Diseases Unit, Department of Biomedical Sciences and Public Health, Marche Polytechnic University c/o Ospedali Riuniti, Ancona, Italy.;Infectious Disease Unit, Pescara General Hospital, Pescara, Italy.;Department of Public Health and Infectious Diseases, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.;III U.O.C. P.O. Cotugno, AORN Ospedali dei Colli, Naples, Italy.;Clinical Infectious Diseases, Department. of Systems Medicine, Tor Vergata University, Rome, Italy.;Clinical Infectious Diseases, Sant'Andrea Hospital-Sapienza University of Rome, Rome, Italy.;Unit of Infectious Diseases, University Hospital of Ferrara, Ferrara, Italy.;Clinical Infectious Diseases, Department. of Systems Medicine, Tor Vergata University, Rome, Italy.",
"authors": "Taramasso|Lucia|L|;Di Biagio|Antonio|A|0000-0003-1436-5089;Bovis|Francesca|F|;Nicolini|Laura Ambra|LA|;Antinori|Andrea|A|;Milazzo|Laura|L|;Sollima|Salvatore|S|;Gubertini|Guido|G|;Niero|Fosca|F|;Saracino|Annalisa|A|;Bruno|Raffaele|R|;Borghi|Vanni|V|;Montagnani|Francesca|F|;Cattelan|Annamaria|A|;Hasson|Hamid|H|;Taliani|Gloria|G|;D'Arminio Monforte|Antonella|A|;Mastroianni|Claudio|C|;Di Perri|Giovanni|G|;Bigoni|Sara|S|;Puoti|Massimo|M|;Spinetti|Angiola|A|;Gori|Andrea|A|;Boffa|Nicola|N|;Cacopardo|Bruno|B|;Giacometti|Andrea|A|;Parruti|Giustino|G|;Vullo|Vincenzo|V|;Chirianni|Antonio|A|;Teti|Elisabetta|E|;Pasquazzi|Caterina|C|;Segala|Daniela|D|;Andreoni|Massimo|M|",
"chemical_list": "D000998:Antiviral Agents; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; D012254:Ribavirin; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D019438:Ritonavir; C585405:paritaprevir",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0192627",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0192627PONE-D-17-31618Research ArticleMedicine and Health SciencesNephrologyChronic Kidney DiseaseMedicine and health sciencesInfectious diseasesViral diseasesHIV infectionsBiology and Life SciencesAnatomyRenal SystemMedicine and Health SciencesAnatomyRenal SystemBiology and Life SciencesBiochemistryBiomarkersCreatinineBiology and Life SciencesPhysiologyRenal PhysiologyGlomerular Filtration RateMedicine and Health SciencesPhysiologyRenal PhysiologyGlomerular Filtration RateBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesVascular MedicineBlood PressureHypertensionBiology and life sciencesOrganismsVirusesRNA virusesFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensFlavivirusesHepacivirusHepatitis C virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesOrganismsVirusesViral pathogensFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensHepatitis virusesHepatitis C virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensHepatitis virusesHepatitis C virusBiology and life sciencesOrganismsVirusesViral pathogensHepatitis virusesHepatitis C virusTrend of estimated glomerular filtration rate during ombistasvir/paritaprevir/ritonavir plus dasabuvir ± ribavirin in HIV/HCV co-infected patients eGFR trend during therapy with ombistasvir/paritaprevir/ritonavir plus dasabuvirTaramasso Lucia ConceptualizationData curationMethodologyWriting – original draft1http://orcid.org/0000-0003-1436-5089Di Biagio Antonio Conceptualization2*Bovis Francesca Formal analysis3Nicolini Laura Ambra InvestigationWriting – original draft1Antinori Andrea InvestigationWriting – review & editing4Milazzo Laura InvestigationWriting – review & editing5Sollima Salvatore Data curationInvestigationWriting – review & editing5Gubertini Guido Investigation6Niero Fosca Investigation6Saracino Annalisa InvestigationWriting – review & editing7Bruno Raffaele InvestigationWriting – review & editing8Borghi Vanni InvestigationWriting – review & editing9Montagnani Francesca Investigation10Cattelan Annamaria InvestigationWriting – review & editing11Hasson Hamid InvestigationWriting – review & editing12Taliani Gloria InvestigationWriting – review & editing13D’Arminio Monforte Antonella InvestigationWriting – review & editing14Mastroianni Claudio InvestigationWriting – review & editing15Di Perri Giovanni InvestigationWriting – review & editing16Bigoni Sara InvestigationWriting – original draft17Puoti Massimo InvestigationWriting – review & editing18Spinetti Angiola InvestigationWriting – review & editing19Gori Andrea InvestigationWriting – review & editing20Boffa Nicola InvestigationWriting – review & editing21Cacopardo Bruno InvestigationWriting – review & editing22Giacometti Andrea InvestigationWriting – review & editing23Parruti Giustino InvestigationWriting – review & editing24Vullo Vincenzo InvestigationWriting – review & editing25Chirianni Antonio InvestigationWriting – review & editing26Teti Elisabetta InvestigationWriting – review & editing27Pasquazzi Caterina InvestigationWriting – original draft28Segala Daniela ConceptualizationInvestigationWriting – review & editing29Andreoni Massimo ConceptualizationMethodologyProject administrationSupervisionWriting – review & editing271 \nUniversity of Genova (DISSAL), Infectious Diseases Clinic, Policlinico Hospital San Martino, Genova, Italy2 \nInfectious Diseases Clinic, Policlinico Hospital San Martino, Genova, Italy3 \nBiostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy4 \nClinical Department, National Institute for Infectious Diseases, INMI L. Spallanzani, Rome, Italy5 \nDepartment of Biomedical and Clinical Science, University of Milan, Milan, Italy6 \n1st Division of Infectious Diseases, ASST Fatebenefratelli-Sacco, Milan, Italy7 \nInstitute of Infectious Disease, University of Bari, Bari, Italy8 \nDivision of Infectious and Tropical Diseases, IRCCS Policlinico San Matteo, Pavia, Italy9 \nInfectious Diseases Clinic, University Hospital, Modena, Italy10 \nDepartment of Internal and Specialty Medicine University Infectious Diseases Unit, AOU Senese, Siena, Italy11 \nDepartment of Infectious and Tropical Diseases, University Hospital, Padova, Italy12 \nDepartment of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy13 \nDepartment of Clinical Medicine, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy14 \nClinic of Infectious and Tropical Diseases, Department of Health Sciences, University of Milan, Milan, Italy15 \nInfectious Diseases Unit, Sapienza University of Rome, Latina, Italy, and Department of Public Health and Infectious Diseases, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy16 \nUnit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy17 \nDivision of Infectious Diseases, AO Papa Giovanni XXIII, Bergamo, Italy18 \nDivision of Infectious Diseases, AO Niguarda Ca' Granda Hospital, Milan, Italy19 \nDivision of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy20 \nDivision of Infectious Diseases, Department of Internal Medicine, San Gerardo Hospital, University of Milan-Bicocca, Milan, Italy21 \nFirst Division of Infectious Diseases, S. Giovanni di Dio e Ruggi d'Aragona Hospital, Salerno, Italy22 \nDivision of Infectious Diseases, Department of Clinical and Experimental Medicine, ARNAS Garibaldi Hospital, University of Catania, Catania, Italy23 \nInfectious Diseases Unit, Department of Biomedical Sciences and Public Health, Marche Polytechnic University c/o Ospedali Riuniti, Ancona, Italy24 \nInfectious Disease Unit, Pescara General Hospital, Pescara, Italy25 \nDepartment of Public Health and Infectious Diseases, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy26 \nIII U.O.C. P.O. Cotugno, AORN Ospedali dei Colli, Naples, Italy27 \nClinical Infectious Diseases, Department. of Systems Medicine, Tor Vergata University, Rome, Italy28 \nClinical Infectious Diseases, Sant'Andrea Hospital—Sapienza University of Rome, Rome, Italy29 \nUnit of Infectious Diseases, University Hospital of Ferrara, Ferrara, ItalyLiu Chen-Hua EditorNational Taiwan University Hospital, TAIWANCompeting Interests: AbbVie provided study drugs at no charge which were distributed through a competitive enrollment program. This does not alter our adherence to PLOS ONE policies on sharing data and materials.\n\n* E-mail: antonio.dibiagio@hsanmartino.it20 2 2018 2018 13 2 e01926274 9 2017 26 1 2018 © 2018 Taramasso et al2018Taramasso et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The renal function is a key-issue in HIV/HCV co-infected patients, nevertheless, it has not established so far whether HCV treatment with new direct acting agents could impact on estimated glomerular filtration rate (eGFR) variations. In the present work, we examined the real-life data on renal function that have been prospectively collected in the SIMIT compassionate-use program of ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r + DSV) in 144 HIV/HCV genotype 1 co-infected patients. The population was 74% male, 30.5% in CDC stage C, with median age of 52 years (48.0–56.5) and median liver stiffness of 7.8 kPa (6.7–9.2). Median baseline eGFR was 102.0 (90.8–108.1), changing to 99.8 (83.5–104.8) at the end of treatment (EoT), and 100.0 (87.3–105.6) 12 weeks after the EoT (FU12), p<0.0001. No patient had grade 3–4 increase of creatinine. At EoT 60/144 (41.7%) patients had ≥ 5% reduction in their eGFR, confirmed at FU12 in 39/60 (65.0%) cases. Longer duration of HCV infection (cut-off 12.9 years), lower HCV-RNA viral load (cut-off 1,970,160 IU/ml) and lower platelet count (cut-off 167,000 x106/L) were significantly associated with eGFR decline at logistic analysis (adjOR 2.9, 95%CI 1.0–8.8, p = 0.05; adjOR 3.5, 95%CI 1.2–10.4, p = 0.02; adjOR 2.8, 95%CI 1.1–6.8, p = 0.03, respectively). After repeating the analysis throughout a mixed model, a higher eGFR decline was highlighted in patients concomitantly treated with tenofovir (p = 0.0001), ribavirin (p = 0.0001), or integrase inhibitors (p <0.0001), with longer duration of HIV (p = 0.0002) and HCV infection (p = 0.035), lower baseline HCV RNA (p <0.0001), previous HCV treatment (p<0.0001), and older age (p<0.0001). In conclusion, our study confirms a good renal safety profile of OBV/PTV/r + DSV treatment in HIV/HCV patients, and the median decline of 2 ml/min in eGFR, albeit statistically significant, is of doubtful clinical significance. The role of aging, concomitant therapies and duration of HIV/HCV infection needs to be further investigated.\n\nAbbVie (ITA)AbbVie provided study drugs at no charge which were distributed through a competitive enrollment program. No additional financial support was provided for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nNew direct-acting antiviral (DAA) agents have radically changed the therapeutic scenario of chronic HCV infection in both mono-infected and HIV co-infected patients [1, 2]. The 3-DAA regimen of ombitasvir, paritaprevir plus ritonavir, and dasabuvir (OBV/PTV/r + DSV) has showed high efficacy in clinical trials in HIV/HCV co-infected patients [3, 4] and recent data on compassionate-use program for OBV/PTV/r + DSV, coordinated by the Italian Society of Infectious and Tropical Diseases (SIMIT), have confirmed high efficacy in real-life setting in HCV genotype 1 infected patients [5]. Moreover, good tolerability without major adverse events attributable to the study drugs has been reported in the same context [5], but an analysis focalized on the trend of the renal function has not been performed yet. In patients co-infected with HIV/HCV the renal safety is an issue of primary interest, as HCV and HIV both constitute risk factors for renal disease. HIV infection may be linked to HIV-associated nephropathy (HIVAN) or favour renal thrombotic microangiopathy, focal segmental glomerulosclerosis and immunecomplexes deposition in the glomerulus [6]. Moreover, some of the drugs used in combined antiretroviral therapy (cART) have possible renal side effects or long-term toxicity [7]. On the same time, HCV infection is linked to a series of immune-mediated glomerulopathies as well as to possible cryoglobulinemia-linked renal vasculitis [8] and hepatorenal syndromes in more advanced stages of liver disease [9]. Nevertheless, little is known on the trend of estimated glomerular filtration rate (eGFR) in patients who clear HCV infection during and after treatment with new DAAs, especially in real life settings [10, 11]. A worsening of renal function after DAA treatment has been reported in patients with cirrhosis, and in those treated with OBV/PTV/r + DSV [10]. Nevertheless, it has not established so far whether HCV clearance is related or not with an improvement in GFR, or if, on the contrary, the combination of antiretroviral drugs and DAAs can even cause a reduction of GFR, throughout a direct mechanism or indirectly, for drug-drug interactions (DDI).\n\nWith the aim of analysing the creatinine and eGFR trends in a specific population of HIV/HCV genotype 1 co-infected individuals treated with the same DAA regimen, we examined the data on renal function of the population treated in the SIMIT compassionate-use program of OBV/PTV/r + DSV [5].\n\nMaterials and methods\nThe SIMIT compassionate-use program provided access to treatment for patients co-infected with HIV and HCV genotype 1 or 4, with or without compensated cirrhosis.\n\nThe program enrolled 213 patients at 26 sites. Patients were treated for 12 or 24 weeks based on the absence or presence of cirrhosis. Ribavirin (RBV) was administered twice daily according to body weight and label recommendations [12]. Patients receiving a ritonavir-boosted ART regimen discontinued the ritonavir component of their ART regimen as recommended by the local OBV/PTV/r + DSV label [13, 14].\n\nIn this sub-study, the inclusion criteria were: a) Patient is at least 18 years of age, infected with HIV and with HCV genotype 1 (subgenotype 1a, 1b, other) or 4; b) Patient has compensated cirrhosis (Child Pugh score A) OR liver fibrosis ≤F3 (by Metavir or equivalent assessment including those by an alternative technology such as FibroScan®) and a condition which contraindicates an IFN based treatment, or clinically significant extra-hepatic manifestation(s) of HCV infection, or rapidly progressive fibrosis OR Patient has a liver transplant and HCV Genotype 1 infection and is at least 12 months post liver transplantation, has had a recent (within 6 months) assessment of liver fibrosis as ≤F2, does not have a diagnosis of fibrosing cholestatic hepatitis; c) Patients has creatinine levels available at baseline (BL), at the end of treatment (EoT) and 12 weeks after the end of treatment (FU12). Duration of HIV and HCV infection was estimated assuming that infection was contracted at June 15th of the year in which the first positive serologic test was reported. Laboratory data were prospectively collected at BL, EoT, FU12 and 24 weeks after the end of treatment (FU24). GFR was calculated according to the CKD-EPI equation [15], while the stage of kidney disease was classified according to KDIGO (Kidney Disease: Improving Global Outcomes) definition [16]. Creatinine increase was classified according to tables for grading the severity of adult and pediatric adverse events of the division of AIDS (DAIDS) [17]. Fibrosis scores were assigned on the basis of the liver stiffness measured by Fibroscan®, F1 (<7.1 kPa), F2 (7.1–9.6 kPa), F3 (> 9.6–12.5 kPa), F4 (>12.5 kPa) [5]. The complete dataset used to perform the statistical analysis is available in S1 Table. Quantitative data were presented as medians (1st and 3rd quartile) and categorical data as absolute numbers and percentages. Some variables (i.e. age, HIV and HCV duration, BL HCV-RNA) were dichotomized according to the best threshold obtained from the receiver operating characteristic (ROC) curve analysis [18]. Dichotomization of explanatory variables has the advantage of providing clinically meaningful odds ratios (ORs) with 95% confidence intervals (95% CIs). A logistic regression model was used to assess the impact of baseline characteristics of patients (age, gender, BMI, CDC stage, grade of liver fibrosis, BL HCV-RNA, years of HIV and HCV infection, BL CD4+ T-lymphocytes and nadir, CKD stage), lifestyle habits (smoke, alcohol use), comorbidities (diabetes, hypertension, symptomatic cryoglobulinemia) concomitant treatments in course of OBV/PTV/r + DSV (tenofovir [TDF] and ribavirin [RBV] use), and previous treatment for HCV, on the reduction of at least 5% in eGFR at both EoT and FU12. The same variables were also studied in a logistic regression model in the post-hoc analyses, to investigate if they could influence a ≥5% improvement of eGFR in a subgroup of patients. Factors significant at univariate analysis were added in a multivariate model after stepwise procedure. A two-way repeated measures mixed model ANOVA analysis with Tuckey post-test was run to establish if there was a relationship between eGFR at follow-up and age, hypertension, stage of fibrosis, TDF, integrase strand transfer inhibitors (INSTI), protease inhibitors (PI) and RBV use, previous HCV treatment, years of HCV and HIV infection, CD4+T-lymphocyte nadir and BL HCV-RNA.\n\nThe compassionate use of the combination of OBV/PTV/r + DSV was approved on individual base for each patient (AbbVie® named-Patient Program). The full list of Ethical Committees that approved the program is available in S1 File. All patients in the study provided written informed consent. The study was conducted in accordance with the International Conference on Harmonization guidelines, applicable regulations, and the principles of the Declaration of Helsinki.\n\nResults\nAmong patients included in the SIMIT compassionate-use program, 144 HIV/HCV co-infected people satisfied inclusion criteria. The population was 74% male (107/144 patients), with median age of 52 years (48.0–56.5), and median CD4+T-cell count of 658 cells /μl (480–929).The median CD4+T cell nadir was 190 cells /μl (74–314). All but three (2.1%) patients had HIV-RNA load <50 copies/ml. According to Centers for Disease Control and Prevention (CDC) definition, 66 (45.8%) patients were stage A, 44 (30.5%) stage B and 29 (30.5%) stage C. All patients had documented HCV genotype 1 infection (1a in 94, 1b in 44, 1a/b in five and 1 not further characterized in one). Median liver stiffness was 7.8 kPa (6.7–9.2) at baseline. Regarding the route of HIV/HCV transmission, the majority of patients (n = 107, 74.3%) reported previous intravenous drug use, 26 (18.1%) unprotected sexual intercourse (5.6% homo/bi-sexual and 12.5% eterosexual), five (3.4%) transfusions of blood components, while in the remaining seven (4.9%) it was unknown. Three patients had more than one risk factor: two patients with previous intravenous drug use and one with previous transfusions of blood components, that also reported unprotected sexual intercourse. Demographic and clinic characteristics of the study population are summarized in Table 1.\n\n10.1371/journal.pone.0192627.t001Table 1 General characteristics of the study population at baseline (BL).\nData are expressed as medians (1st - 3rd quartiles) or absolute frequencies (percentage).\n\nVariable\tN\tMedian (q1-q3)\t\nAge\t144\t52 (48.0–56.05)\t\nYears of HCV\t119\t17.9 (10.9–20.9)\t\nYears of HIV\t142\t23.9 (16.9–27.9)\t\nBL CD4\t143\t658 (480–929)\t\nCD4 nadir\t133\t190 (74–314)\t\nBL HCV-RNA (IU/ml)\t144\t1,137,573 (517,764.5–3,041,840)\t\nBL HIV-RNA (copies/ml)\t144\t0.0 (0.0–0.0)\t\nBL AST (IU/L)\t142\t48.5 (34–77.5)\t\nBL ALT (IU/L)\t143\t64 (41–99.5)\t\nBL PLT (x106/L)\t143\t179,000 (145,000–266,500)\t\nVariable\tN\tn (%)\t\nFemale\t144\t37 (25.69)\t\nCaucasian\t144\t144 (100.00)\t\nExperienced to HCV treatment\t142\t65 (45.77)\t\nBMI\t134\t\t\n<20\t\t16 (11.94)\t\n20–25\t\t75 (55.97)\t\n>25\t\t43 (32.09)\t\nCDC stage\t139\t\t\nA\t\t66 (47.48)\t\nB\t\t44 (31.65)\t\nC\t\t29 (20.86)\t\nCKD stage\t144\t\t\n1\t\t111 (77.08)\t\n2\t\t30 (20.83)\t\n3\t\t3 (2.08)\t\nHCV Genotype\t144\t\t\n1a\t\t94 (65.28)\t\n1b\t\t44 (30.55)\t\n1 a/b\t\t5 (3.47)\t\n1 (unknown)\t\t1 (0.69)\t\nRISK FACTOR\t144\t\t\nIVDU\t\t106 (73.6)\t\nHomosexual/ bisexual\t\t8 (5.56)\t\nHeterosexual\t\t18 (12.5)\t\nHemotransfusion\t\t5 (3.47)\t\nOther/unknown\t\t7 (4.86)\t\nHABITS AND COMORBIDITIES\t\t\t\nSmoking\t132\t76 (57.58)\t\nAlcool use\t140\t48 (34.29)\t\nDiabetes\t144\t14 (9.72)\t\nHypertension\t144\t34 (23.61)\t\nSymptomatic Cryoglobulinemia\t144\t11 (7.64)\t\nCONCOMITANT THERAPIES\t144\t\t\ncART\t\t143 (99.31)\t\nRBV\t\t115 (79.86)\t\nTDF\t\t111 (77.08)\t\nINSTI\t\t110 (76.39)\t\nPI\t\t38 (26.39)\t\nN = number of patients for which data was available; n = absolute number of patients with each variable; % = percentage of patients with the specific variable, calculated as n/N; q1 = first quartile; q3 = third quartile; AST = aspartate aminotransferase; ALT = alanine aminotransferase; PLT = platelets; IVDU = intravenous drug use; BMI = body mass index; CKD chronic kidney disease; cART = combined antiretroviral therapy; RBV = ribavirin; TDF = tenofovir; INSTI = integrase inhibitors; PI = protease inhibitors.\n\nThe eGFR was available for all 144 patients at BL, at the EoT and at FU12, according to inclusion criteria, while 73/144 (50.7%) patients also had an available follow-up at FU24. Median BL eGFR was 102.0 (90.8–108.1), changing to 99.8 (83.5–104.8) at the EoT, and 100.0 (87.3–105.6) at FU12 (p<0.0001). No patient had grade 3–4 increase of creatinine. The maximum increase of creatinine levels during treatment was 0.35 mg/dl. At the EoT 60/144 (41.7%) patients had ≥ 5% reduction in their GFR, confirmed at FU12 in 39/60 (65.0%) cases. FU24 was available for 30/60 (50%). Of them, 15/30 (50%) had confirmed eGFR decline ≥ 5% also at FU24.\n\nFor 39 patients with confirmed eGFR decline both at the EoT and FU12, the possible association among renal function impairment and other comorbidities (hypertension, diabetes), TDF, PI, INSTI or RBV use, as well as baseline characteristics of the patients (age, sex, duration of HIV and HCV infection, HIV stage, baseline HCV-RNA and platelet count, CD4+ T-cell nadir and BL CD4+T-cell count, liver stiffness and previous HCV treatment) was investigated (Table 2).\n\n10.1371/journal.pone.0192627.t002Table 2 Univariate and multivariate predictors of event (eGFR decline > 5%) in the study population (144 patients).\n\tOR (95% CI)\nunivariate\tp-value\tadjOR (95%CI) multivariate\tp-value\t\nAge >45 years*\t3.0 (0.8–10.7)\t0.09\t\t\t\nGender (Male)\t1.2 (0.5–2.9)\t0.66\t\t\t\nSmoke\t0.7 (0.3–1.6)\t0.46\t\t\t\nAlcohol\t1.2 (0.6–2.7)\t0.59\t\t\t\nDiabetes\t1.6 (0.5–5.0)\t0.45\t\t\t\nHypertension\t1.4 (0.6–3.2)\t0.43\t\t\t\nSymptomatic cryoglobulinemia\t1.0 (0.2–4.0)\t0.99\t\t\t\nCDC stage B vs. A\t1.4 (0.6–3.1)\t0.44\t\t\t\nCDC stage C vs. A\t0.7 (0.2–2.0)\t0.50\t\t\t\nGrade of liver fibrosis F2 vs. F1\t0.5 (0.1–2.2)\t0.33\t\t\t\nGrade of liver fibrosis F3 vs. F1\t0.8 (0.2–4.4)\t0.83\t\t\t\nRBV use\t1.6 (0.6–3.7)\t0.32\t\t\t\nTDF use\t1 (0.4–2.4)\t0.98\t\t\t\nPI use\t0.4 (0.2–1.1)\t0.07\t\t\t\nINSTI use\t2.6 (0.9–7.3)\t0.07\t\t\t\nPrevious HCV treatment\t0.6 (0.3–1.2)\t0.12\t\t\t\nBMI (<20) vs. (20–25)\t0.7 (0.2–2.4)\t0.58\t\t\t\nBMI 2 (>25) vs. (20–25)\t0.5 (0.2–1.2)\t0.12\t\t\t\nYears of HCV > 12.9*\t3.1 (1.1–8.8)\t0.03\t2.9 (1.0–8.8)\t0.05\t\nYears of HIV > 16.9*\t2.3 (0.9–5.9)\t0.10\t\t\t\nCKD stage 2 vs. 1\t0.8 (0.3–2.0)\t0.61\t\t\t\nCKD stage 3 vs. 1\t1.3 (0.1–14.7)\t0.84\t\t\t\nBaseline CD4 < = 350*\t0.2 (0.3–1.8)\t0.16\t\t\t\nCD4 Nadir < 100 cells/μl\t1.3 (0.6–2.9)\t0.48\t\t\t\nBL HCV RNA < = 1,970,160*\t3.4 (1.3–8.8)\t0.01\t3.5 (1.2–10.4)\t0.02\t\nPLT < = 167,000*\t4.1 (1.9–8.8)\t0.0004\t2.8 (1.1–6.8)\t0.03\t\nTDF: tenofovir; RBV: ribavirin; PI: protease inhibitors; INSTI: integrase strand transfer inhibitors; PLT: platelets; OR: odds ratio; adjOR: adjusted odds ratio; CI: confidence interval.\n\n*Dichotomized as per ROC\n\nIn a multivariate model including duration of HCV infection (cut-off 12.9 years, dichotomized as per ROC), BL HCV-RNA viral load (cut-off level 1,970,160 IU/ml, dichotomized as per ROC), and BL platelet count (cut-off level 167,000 platelets x106/L, dichotomized as per ROC), longer HCV infection and lower HCV-RNA levels were significantly associated with eGFR decline > 5% (adjOR 2.9, 95%CI 1.0–8.8, p = 0.05, and adjOR 3.5, 95%CI 1.2–10.4, p = 0.02, respectively), as well as lower platelet count (adjOR 2.8, 95%CI 1.1–6.8, p = 0.03).\n\nThe results obtained without the dichotomizations as per ROC of continue variables (age, BL HCV-RNA, platelet count, transaminases and years of HCV and HIV infection) were also studied and are presented in S2 Table.\n\nTo account for possible differences into restricted subgroups of patients, differences among eGFR values were also estimated at all available time-points, including FU24, for all 144 patients throughout a mixed model (Table 3).\n\n10.1371/journal.pone.0192627.t003Table 3 Number of patients tested throughout mixed models and correlation with eGFR decline at different time-points.\nVariable\t \tn\tcorrelation with GFR decline (adjusted p)\t\nfrom BL toEoT\n\tfrom BL toFU12\n\tfrom BL to FU24\n\t\nTDF\tY\t111\t0.0001\t0.119\t0.078\t\nN\t33\t0.408\t0.686\t0.970\t\nRBV\tY\t115\t0.0005\t0.151\t0.067\t\nN\t29\t0.117\t0.536\t0.998\t\nPI\tY\t38\t0.994\t0.994\t1.000\t\nN\t106\t<0.0001\t0.024\t0.016\t\nINSTI\tY\t110\t<0.0001\t0.031\t0.046\t\nN\t34\t0.918\t0.991\t0.999\t\nAge >45 years*\tY\t120\t0.0001\t0.032\t0.1096\t\nN\t24\t0.4645\t0.9969\t0.9854\t\nHypertension\tY\t34\t0.9961\t0.9126\t0.9564\t\nN\t110\t<0.0001\t0.0595\t0.0984\t\nMetavir stage of fibrosis\tF1\t117\t0.0028\t0.0407\t0.4627\t\nF2\t17\t0.6405\t1.0000\t0.9996\t\nF3\t8\t0.2521\t0.9996\t0.1427\t\nExperienced to HCV treatment\tY\t65\t<0.0001\t0.2631\t0.0739\t\nN\t77\t0.2198\t0.343\t0.8492\t\nHCV since >12.9 years*\tY\t80\t0.0035\t0.094\t0.1861\t\nN\t39\t0.3615\t1.0000\t0.9961\t\nHIV since >16.9 years*\tY\t106\t0.0002\t0.0034\t0.0319\t\nN\t36\t0,3547\t1.0000\t0.9998\t\nNadir CD4>100 cells/μL\tY\t90\t0.0035\t0.2951\t0.5598\t\nN\t43\t0.0082\t0.0813\t0.2733\t\nBL HCV-RNA< = 1,970,160* IU/ml\tY\t98\t<0.0001\t0.001\t0.0879\t\nN\t46\t0.9723\t1.0000\t0.9739\t\nGFR: glomerular filtration rate; n: number of patients; Y: yes; N: no; BL: baseline; EoT: end of treatment; FU12: 12 weeks after the end of treatment; FU24: 24 weeks after the end of treatment; TDF: tenofovir; RBV: ribavirin.\n\n*Dichotomized as per ROC. Metavir stage of fibrosis is given according to stiffness evaluation by Fibroscan®\n\nIn particular, patients on concomitant treatment with TDF or RBV were at risk for significant eGFR decline compared to people who were not (p = 0.0001 and p = 0.0001, respectively) in the time between BL and EoT, but the difference was not confirmed when comparing BL to FU12 and FU24, nor between values of these time-points compared in pairs. A significant eGFR decline between BL and EoT was also found in patients with at least one of the following characteristics: age > 45 years (p<0.0001), previous HCV treatment (p<0.0001), longer duration of HIV and HCV infections (p = 0.0002 for more than 16.9 years of HIV infection and p = 0.035 for more than 12.9 years of HCV infection), lower baseline HCV-RNA (p <0.0001 for HCVRNA values ≤ 1,970,160 IU/ml), treatment with an INSTI (<0.0001) and not on a PI-containing cART (<0.0001). A longer duration of HIV infection (p = 0.0034), an older age (p = 0.0324), a lower baseline HCV RNA (p = 0.001), INSTI use (p = 0.031) and not being on PI-based cART (p = 0.024) were associated with a significant decrease in eGFR levels in the time between BL and FU12. A longer duration of HIV infection and INSTI use also maintained correlation with a decrease of the eGFR at FU24 (Table 3). The trend of eGFR according to baseline CKD stage is shown in Fig 1. In order to clarify if there was a sub-group of patients who improved their eGFR, a post-hoc analysis was also performed. Overall, 14 patients had confirmed eGFR improvement of ≥ 5% at both EoT and FU12. The logistic analysis revealed that the improvement was more probable in CKD stage 2 and 3 when compared to CKD stage 1 (Odds Ratio, OR, 9.7, 95%CI 2.7–35.2, p = 0.0005 and OR 53.5, 95%CI 4.0–720.1, p = 0.003, respectively), while no significant correlation was found with other factors.\n\n10.1371/journal.pone.0192627.g001Fig 1 Trend of estimated glomerular filtration rate (eGFR) in the global population, according to GITMO renal stage at baseline (BL).\nn = number of patients in each chronic kidney disease (CKD) stage. EoT: End of treatment; FU12: follow-up 12 weeks after the EoT; FU24: follow-up 24 weeks after the EoT.\n\nDiscussion\nThis study analyses the eGFR trend in a large and homogeneous cohort of patients with HIV/HCV genotype 1 co-infection and mild fibrosis prospectively treated with OBV/PTV/r + DSV.\n\nThe main findings is that no patient experienced grade 3–4 increase of creatinine levels throughout HCV treatment and FU, and the finding of a median decline of 2 ml/min in eGFR, albeit statistically significant, was of doubtful clinical significance.\n\nPrevious trials evidenced the good safety profile and efficacy (higher than 90%) of OBV/PTV/r + DSV among patients with stage IV or V CKD [19]. A very few cases (2/179 patients) of creatinine clearance decrease to <50 ml/min (in a single determination) have been reported in PEARL II study, (3/419 patients, all in treatment with ribavirine) in PEARL III and (3/305 patients, 1 who was in treatment with RBV, and 2 who were not) in PEARL IV [20–22]. Mehta et al. [23] have recently analysed the eGFR trend in HCV mono-infected patients treated with OBV/PTV/r + DSV in phase 3 trials SAPPHIRE I/ II, TOPAZ I /II, and RUBY I /II. In this comprehensive analysis, they found a change in eGFR of + 0.39 ml/min in patients enrolled in SAPPHIRE I/II trials (n = 776 patients), with significant improvement in the subgroup of patients with CKD stage 2 and 3. On the other hand, in TOPAZ I/II (n = 2206 patients) and in RUBY I/II trials (n = 78 patients), the overall eGFR decreased, with a significant negative trend (p<0.001) in patients in CKD stage 1 enrolled in TOPAZ I/II trials. Similarly, in our study, we found HIV/HCV co-infected patients had a significant decrease of the eGFR, driven by the high prevalence of CKD stage 1, while, in patients in CKD stages 2 and 3, the eGFR improved. In other trials and registration studies of other DAAs, on-treatment assessments included the evaluations of renal function, but specific analyses on the trend of creatinine clearance have not been performed [22–34]. Some studies had arisen more specifically the issue of renal safety using different criteria for CKD classification and progression as, at present, the evaluation of renal function in course of DAA therapy has not been standardized so far. As a consequence, some studies have reported the numbers of abnormal creatinine rises of any grade [35], while others only those of grade 3–4 [36–38], using different scaling systems. Additionally, the number of patients with an increase in creatinine levels of 0.4 mg/dl or more during treatment has also been used [36,37], or the change in mean creatinine clearance through week 12 [37, 39]. In the general population, the age-related decline in eGFR is generally believed to be less than 1 ml/min each year, i.e. about 1% of eGFR, assuming a filtration rate of 100 ml/min [40], while, in HIV infected patients, a rapid eGFR decline is usually defined by a reduction in eGFR ≥5 ml/min/year in patients with baseline eGFR > 90 ml/min [41]. This corresponds to about 5% decline in patients with normal eGFR (CKD stage 1), while, in patients with baseline eGFR<90 ml/min, a 5% decline permits to take into account also lower absolute changes in eGFR.\n\nWe chose to use a decline of eGFR of ≥5% within 12 weeks, i.e. 5-fold higher than what expected in one year period, as a marker of abnormal renal function decline.\n\nOf note, we did not found any creatinine rise of grade >2 or of ≥0.4 ml/min and the reported median decline of 2 ml/min in eGFR, even if statistically significant, has doubtful clinical significance. In fact, current guidelines recommend to refer to a nephrologist in case of eGFR decline by > 25% or to a level < 60 ml/min [42]. Moreover, we cannot exclude that this slight decline could be followed by a late improvement, as previously found in liver transplant recipients with mild chronic kidney disease that achieved SVR after interferon-based regimens [43].\n\nAnother remarkable finding of our study is that a ≥5% eGFR decline was related to a longer history of HCV infection and to lower baseline HCV-RNA and platelet count. The correlation with duration of HCV infection could be expected, as, even if the linkage between HCV and CKD is controversial, many evidences underline a possible correlation. In the veteran cohort, HCV infection was found not to have a relation with progressive CKD [44], but, in other large cohorts, both HCV viremic and HCV aviremic individuals were found at increased risk for moderate and advanced CKD compared with HIV-infected subjects who were HCV seronegative [45] and HCV co-infection was found as an independent risk factor for CKD in HIV [46]. On the contrary, the higher probability of eGFR decline in patients with lower BL HCV-RNA was unexpected, and is in contrast with the evidence of higher Odds Ratios for CKD that have been found in patients with higher HCV-RNA [46, 47]. A previous paper on 1,676 HIV/HCV co-infected patients treated for HCV, revealed an incidence of CKD of 5.32 per 1000 person/years of follow-up, without significant differences between patients who achieved sustained virologic response (SVR) and those who not, suggesting a possible minor role for the current viremia on the development of renal injury [48]. On the other hand, higher risks of CKD have been found in patients with detectable HCV RNA than in those who cleared the infection [49] and a higher HCV-RNA has been demonstrated an independent predictor of CKD [50]. We think that these evidences, all together, underline a major role of the global burden of the HCV disease, that is correlated to high HCV-RNA and to years of HCV infection. In the same direction also goes the association between eGFR decrease and lower platelet count, that might suggest a higher probability of renal injury in more advanced stages of HCV disease. Indeed, HCV-RNA is fluctuating and the punctual value at the time of study entry might not represent the real burden of HCV disease in the study population. Another unexpected finding of our study was that the classical risk factors for kidney disease, such as increasing age, male gender, history of smoking, diabetes, and hypertension, had no correlation with impairment of renal function, although it is possible that the effect of such factors could not be appreciable in a relatively young population with low prevalence of diabetes and hypertension.\n\nWe also tested eGFR trend within the groups for each measure period, through a mixed model for multiple comparisons that permitted to consider also the interaction between the variables and the time. The results confirmed a role of the longer duration of HCV infection and lower BL HCV-RNA, but also revealed other potential risk factors linked to significant eGFR decline, i.e. TDF, INSTI or RBV use, age > 45 years, previous HCV treatment (mainly IFN-based), and longer duration of HIV infection. Indeed, TDF and IFN are drugs with recognized potential nephrotoxicity, which has also been hypothesized for RBV [51–53] while the effect of INSTI on possible creatinine increase, driven by both dolutegravir and, to a lesser extent, raltegravir [54–55], might have had a role in patients who switched to INSTI to avoid drug interactions during DAA treatment. Moreover, HIV infection and ageing have potential influence on renal function [56]. However, although these results may be of great interest, they must be interpreted with caution, because a significant trend toward reduction was seen in the general population in correlation with time (and in particular between BL and EoT), and it is possible that it is confirmed in any group big enough to allow a reliable analysis. For the same reason, the lack of significance in eGFR decline in patients treated with PI and in those with a history of hypertension do not allow to interpret these factors as protective, but should be rather interpreted as a non-significance, probably due to small number of patients.\n\nThis study has several limitations. The lack of a control group constitutes a major limit of this study, as we could not compare the eGFR trend of the study population with that of HIV/HCV co-infected people not undergoing HCV treatment, nor with that of patients treated with other DAA regimens, including those that are now the preferred first-line agents for HCV treatment [57–58]. Moreover, we had no available urinalysis for the study population, and it limits the accuracy of a precise diagnosis of renal injury. Also, we did not have complete data about potentially nephrotoxic concomitant therapies, other than the cART, that could also have played a role, and FU24 was not available for a large part of the study population, so that the possibility of a recovery 24 weeks after the EoT was not adequately investigated. Lastly, we dichotomized the continues variables included in the regression model, as binary covariates offer a simple risk classification into high versus low and, in the regression setting, the interpretation of the impact of a binary covariate on outcome is easier than that for a change of 1 unit in a continuous covariate [59]. However, this approach could have influenced the significance of some results, as it can sometimes lead to biased estimates in regression settings. When categorizing continuous covariates, there is always the possibility of loss of information, possible loss of power to detect actual significance, and possibility of false positive results as well, and using two groups conceals any non-linearity in the relation between the variable and outcome [60].\n\nDespite these limitations, we found that the eGFR decline was significant during HCV treatment, but the same was not found prolonging observation to FU12 in the majority of groups examined through the mixed models. This could lead us to speculate that a temporary nephrotoxicity is possible in course of therapy, but, at least in part, reversible. Low baseline HCV-RNA seems not to be protective in our series, while duration of HCV infection and low platelet count are risk factors for >5% eGFR decline, independently from chronological age. On the contrary, patients with poor renal function at the beginning of treatment had higher probability of renal improvement, even if numbers are too low to draw conclusions.\n\nIn summary, our study confirms a good renal safety profile of OBV/PTV/r + DSV treatment in a large homogeneous cohort of HIV/HCV patients. The role of aging, concomitant therapy with TDF, INSTI or RBV, previous HCV treatment and duration of HIV infection need to be further investigated, and studies on larger populations and with longer follow-up are desirable to better clarify the dynamics of renal function in the contest of DAA treatment.\n\nSupporting information\nS1 Table Complete dataset used to perform the statistical analysis.\n(XLSX)\n\nClick here for additional data file.\n\n S2 Table Analysis performed on continue variables without dichotomization.\n(DOCX)\n\nClick here for additional data file.\n\n S1 File Ethical Committees that approved the compassionate use of ombitasvir/paritaprevir/ritonavir + dasabuvir, on individual base for each patient (AbbVie® named-Patient Program).\n(DOCX)\n\nClick here for additional data file.\n\n This study was coordinated by the Italian Society of Infectious and Tropical Diseases (SIMIT). SIMIT Scientific Director: Professor Massimo Andreoni, simit@promoleader.com.\n\nAbbVie® provided study drugs at no charge which were distributed through a competitive enrollment program. No additional financial support was provided for this study. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n==== Refs\nReferences\n1 Milazzo L , Lai A , Calvi E , Ronzi P , Micheli V , Binda F , et al\nDirect-acting antivirals in hepatitis C virus (HCV)-infected and HCV/HIV-coinfected patients: real-life safety and efficacy . HIV Med . 2017 ;18 :284 –291 . doi: 10.1111/hiv.12429 \n27477612 \n2 Hawkins C , Grant J , Ammerman LR , Palella F , Mclaughlin M , Green R , et al\nHigh rates of hepatitis C virus (HCV) cure using direct-acting antivirals in HIV/HCV-coinfected patients: a real-world perspective . 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"fulltext_license": "CC BY",
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"mesh_terms": "D015081:2-Naphthylamine; D000998:Antiviral Agents; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D005919:Glomerular Filtration Rate; D015658:HIV Infections; D006526:Hepatitis C; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D008297:Male; D008875:Middle Aged; D011392:Proline; D012254:Ribavirin; D019438:Ritonavir; D013449:Sulfonamides; D014498:Uracil",
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"title": "Trend of estimated glomerular filtration rate during ombistasvir/paritaprevir/ritonavir plus dasabuvir ± ribavirin in HIV/HCV co-infected patients.",
"title_normalized": "trend of estimated glomerular filtration rate during ombistasvir paritaprevir ritonavir plus dasabuvir ribavirin in hiv hcv co infected patients"
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"abstract": "Sulfasalazine is a compound of 5-aminosalicylic acid (5-ASA) and sulfapyridine joined by an azo bond. It is a widely used drug in the treatment of chronic inflammatory bowel disease. Fatal toxicity of sulfasalazine arises from its effects on the bone marrow and the resulting blood dyscrasias. Pulmonary toxicity from sulfasalazine is a rather rare finding. Here, we present the case of a patient who developed acute eosinophilic pneumonia with sulfasalazine use.",
"affiliations": "Department of Respiratory Medicine, St. Vincent's University Hospital, Dublin, Ireland.;Department of Histopathology, St. Vincent's University Hospital, Dublin, Ireland.;Department of Respiratory Medicine, St. Vincent's University Hospital, Dublin, Ireland.",
"authors": "Nadarajan|P|P|;Fabre|A|A|;Kelly|E|E|",
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"doi": "10.1016/j.rmcr.2016.03.006",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(16)30021-110.1016/j.rmcr.2016.03.006Case ReportSulfasalazine: A rare cause of acute eosinophilic pneumonia Nadarajan P. sonadarp2@yahoo.iea∗Fabre A. bKelly E. aa Department of Respiratory Medicine, St. Vincent's University Hospital, Dublin, Irelandb Department of Histopathology, St. Vincent's University Hospital, Dublin, Ireland∗ Corresponding author. Department of Respiratory Medicine, Education & Research Centre, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland.Department of Respiratory MedicineEducation & Research CentreSt. Vincent's University HospitalElm ParkDublin 4Ireland sonadarp2@yahoo.ie22 3 2016 2016 22 3 2016 18 35 36 18 1 2016 11 3 2016 20 3 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Sulfasalazine is a compound of 5-aminosalicylic acid (5-ASA) and sulfapyridine joined by an azo bond. It is a widely used drug in the treatment of chronic inflammatory bowel disease. Fatal toxicity of sulfasalazine arises from its effects on the bone marrow and the resulting blood dyscrasias. Pulmonary toxicity from sulfasalazine is a rather rare finding. Here, we present the case of a patient who developed acute eosinophilic pneumonia with sulfasalazine use.\n\nKeywords\nEosinophilic pneumoniaInterstitial lung diseaseDrug induced lung diseaseAbbreviations\nASA, Aminosalicylic AcidBAL, Bronchoalveolar LavageCRP, C-reactive proteinMGG, May-Grunwald-GiemsaTNF-α, Tumour necrosis factor alpha\n==== Body\n1 Introduction\nSulfasalazine is a compound of 5-aminosalicylic acid (5-ASA) and sulfapyridine joined by an azo bond. It is a widely used drug in the treatment of chronic inflammatory bowel disease. Fatal toxicity of sulfasalazine arises from its effects on the bone marrow and the resulting blood dyscrasias [1]. Pulmonary toxicity from sulfasalazine is a rather rare finding. Acute eosinophilic pneumonia is characterized by the rapid accumulation of eosinophils in the lung in response to allergens, inflammation or infection. Symptom onset is usually rapid and can include dyspnoea, fever, cough and chest pain. Cigarette smoke, drugs and occupational factors have been shown to trigger acute eosinophilic pneumonia. Here, we report a patient who developed acute eosinophilic pneumonia with sulfasalazine use. This resolved completely with sulfasalazine withdrawal and treatment with oral corticosteroids.\n\n2 Case report\nA 44-year old woman with a background of ulcerative colitis presented to the Emergency Department with a 5-week history of fever, cough, dyspnoea and weight loss. She had been on Sulfasalazine for a 12-week period and Adalimumab, a tumour necrosis factor-alpha (TNF-α) antagonist. Both medications were held on admission. She was pyrexial (38.2 °C), tachypnoeic (respiratory rate of 20/min) with normal oxygen saturations on room air (98%). Physical examination revealed scattered crepitation over both lungs on auscultation. Blood tests showed a peripheral eosinophilia (0.6 × 109/L) and a raised C-reactive protein (CRP). An autoimmune screen was negative. Chest radiograph (Fig. 1) showed new, bilateral multilobar pulmonary infiltrates. Sputum culture was negative for pathogenic bacteria and acid-fast bacilli. A tuberculin-skin test was negative. She proceeded to have to fibreoptic bronchoscopy that was unremarkable. Bronchoalveolar lavage (BAL) (Fig. 2) was negative for infective aetiologies including viral, tuberculous and fungal infections. However, the differential cell count from the BAL showed 41% eosinophils. A diagnosis of Sulfasalazine-induced eosinophilic pneumonia was made based on our findings and a review of her medications. Oral corticosteroids were started and she improved significantly with gradual improvement in her respiratory symptoms. After consultation with the gastroenterologist, Adalimumab was restarted but the Sulfasalazine was discontinued. She was reviewed in the respiratory clinic 2 weeks later. Her chest radiograph (Fig. 3) had dramatically improved with near complete resolution of the bilateral pulmonary infiltrates.\n\n3 Discussion\nThe sulfapyridine moiety in sulfasalazine, which acts as a carrier to transport 5-ASA to the colon, is believed to be responsible for most of the hypersensitivity reactions that occur. Pulmonary hypersensitivity reactions such as eosinophilic pneumonia, fibrosing alveolitis and bronchiolitis obliterans remain rare with use of sulfasalazine and are usually self-limiting. However there have been case reports with fatal outcomes, particularly in cases where the drug was not withdrawn [2], [3]. We believe that sulfasalazine is the offending drug in our patient despite the time lag between commencing sulfasalazine and the onset of symptoms, as her symptoms appeared after sulfasalazine was administered, improved once sulfasalazine was discontinued and there are no other alternative causes that could have caused the reaction.\n\nEosinophilic pneumonia should be considered in patients who are on sulfasalazine treatment who present with pulmonary symptoms and abnormal chest radiography, accompanied by peripheral eosinophilia. The symptom triad of dyspnoea, cough and fever will occur in about 50% of cases [1]. BAL findings can support the diagnosis but the absence of eosinophils in the lavage fluid does not out rule eosinophilic pneumonia. The pulmonary symptoms mentioned above will resolve completely in a few weeks after withdrawal of the drug in the majority of cases. Although the evidence for corticosteroids in sulfasalazine induced lung toxicity is weak, a trial of systemic steroid therapy can be considered if the patient is very ill despite sulfasalazine withdrawal. There have been suggestions that a re-challenge or a provocation test is essential to establish a temporal relation, however given the significant morbidity of eosinophilic pneumonia and the availability of alternative 5-ASA agents such as mesalazine and olsalazine [4] for treatment of ulcerative colitis, we deemed this inadvisable in the case of this patient.\n\nConflict of interest\nThe authors have no conflicts of interest, direct or indirect, to declare.\n\nAuthor contribution\n1. Parthiban Nadarajan: Manuscript preparation, literature search, images.\n\n2. Emer Kelly: Manuscript preparation, review of manuscript, literature search.\n\n3. Aurelie Fabre: Data analysis, review of manuscript, images.\n\nFunding\nThe authors wish to declare that we have not received any form of funding for our work.\n\nFig. 1 Chest radiograph on admission.\n\nFig. 2 Bronchoalveolar lavage cytology showing eosinophils (MGG stain).\n\nFig. 3 Chest radiograph 2 weeks after treatment with oral corticosteroids.\n==== Refs\nReferences\n1 Parry S.D. Barbatzas C. Peel E.T. Barton J.R. Sulphasalazine and lung toxicity Eur. Respir. J. 19 2002 756 764 11999006 \n2 Davies D. MacFarlane A. Fibrosing alveolitis and treatment with sulphasalazine Gut 15 1974 185 188 4152289 \n3 Baillie J. Sulfasalazine and pulmonary infiltrates Am. J. Gastroenterol. 79 1984 77 6140846 \n4 Scherpenisse J. van der Valk P.D. van den Bosch J.M. van Hees P.A. Nadorp J.H. J. Clin. Gastroenterol. 10 2 1988 218 220 2901442\n\n",
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"keywords": "ASA, Aminosalicylic Acid; BAL, Bronchoalveolar Lavage; CRP, C-reactive protein; Drug induced lung disease; Eosinophilic pneumonia; Interstitial lung disease; MGG, May-Grunwald-Giemsa; TNF-α, Tumour necrosis factor alpha",
"medline_ta": "Respir Med Case Rep",
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"title": "Sulfasalazine: A rare cause of acute eosinophilic pneumonia.",
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"abstract": "Severe pulmonary arterial hypertension (PAH) rarely develops in children with an atrial septal defect (ASD), even those with a large defect. We herein report the case of a 27-year-old man with a moderate-sized secundum ASD and right ventricular failure due to severe PAH, which developed in his early teens. He was diagnosed as having a genetic mutation of the bone morphogenetic protein receptor-2 (BMPR2) gene and was successfully treated with bilateral lung transplantation with ASD path closure. In patients with congenital heart disease, a genetic analysis may provide information about the lifetime risk of developing PAH.",
"affiliations": "Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan.;Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan.;Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan.;Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan.;Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan.;Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan.;Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan.;Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan.;Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan.;Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan.;Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan.;Department of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Japan.;Department of Pathology, Tohoku University School of Medicine, Japan.;Division of Pulmonary Circulation, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Japan.;Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Japan.;Department of Pediatrics, Iwate Medical University, Japan.;Department of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Japan.;Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Japan.;Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan.",
"authors": "Tatebe|Shunsuke|S|;Sugimura|Koichiro|K|;Aoki|Tatsuo|T|;Yamamoto|Saori|S|;Yaoita|Nobuhiro|N|;Suzuki|Hideaki|H|;Sato|Haruka|H|;Kozu|Katsuya|K|;Konno|Ryo|R|;Satoh|Kimio|K|;Fukuda|Koji|K|;Adachi|Osamu|O|;Saito|Ryoko|R|;Nakanishi|Norifumi|N|;Morisaki|Hiroko|H|;Oyama|Kotaro|K|;Saiki|Yoshikatsu|Y|;Okada|Yoshinori|Y|;Shimokawa|Hiroaki|H|",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2902145010.2169/internalmedicine.8686-16Case ReportThe Efficacy of a Genetic Analysis of the BMPR2 Gene in a Patient with Severe Pulmonary Arterial Hypertension and an Atrial Septal Defect Treated with Bilateral Lung Transplantation Tatebe Shunsuke 1Sugimura Koichiro 1Aoki Tatsuo 1Yamamoto Saori 1Yaoita Nobuhiro 1Suzuki Hideaki 1Sato Haruka 1Kozu Katsuya 1Konno Ryo 1Satoh Kimio 1Fukuda Koji 1Adachi Osamu 2Saito Ryoko 3Nakanishi Norifumi 4Morisaki Hiroko 56Oyama Kotaro 7Saiki Yoshikatsu 2Okada Yoshinori 8Shimokawa Hiroaki 1\n1 Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan\n2 Department of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Japan\n3 Department of Pathology, Tohoku University School of Medicine, Japan\n4 Division of Pulmonary Circulation, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Japan\n5 Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Japan\n6 Department of Medical Genetics, Sakakibara Heart Institute, Japan\n7 Department of Pediatrics, Iwate Medical University, Japan\n8 Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, JapanCorrespondence to Dr. Shunsuke Tatabe, shuntatebe@cardio.med.tohoku.ac.jp\n\n11 10 2017 1 12 2017 56 23 3193 3197 9 12 2016 12 4 2017 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Severe pulmonary arterial hypertension (PAH) rarely develops in children with an atrial septal defect (ASD), even those with a large defect. We herein report the case of a 27-year-old man with a moderate-sized secundum ASD and right ventricular failure due to severe PAH, which developed in his early teens. He was diagnosed as having a genetic mutation of the bone morphogenetic protein receptor-2 (BMPR2) gene and was successfully treated with bilateral lung transplantation with ASD path closure. In patients with congenital heart disease, a genetic analysis may provide information about the lifetime risk of developing PAH. \n\nBMPR2 mutationpulmonary arterial hypertensionatrial septal defectEisenmenger syndromelung transplantationcongenital heart disease\n==== Body\nIntroduction\nSevere pulmonary arterial hypertension (PAH) rarely occurs in children with atrial septal defect (ASD), even in patients with a large defect (1). This is because -in contrast to ventricular septal defect (VSD)-ASD only imposes a volume overload on the pulmonary circulation. Thus, pulmonary vascular disease (PVD) may not develop until the third or fourth decade of life. This observation raises the possibility that young ASD patients with severe PAH and patients with idiopathic PAH have common risk factors for developing PAH. A mutation in the bone morphogenetic protein receptor-2 (BMPR2) gene has been identified not only familial and idiopathic PAH but also in PAH associated with congenital heart disease (CHD) (2), indicating a common pathogenesis underlying the development of PAH in both groups.\n\nWe herein report the case of a 27-year-old man with a moderate-sized secundum ASD and right heart failure (RHF) due to severe PAH, in whom a genetic analysis allowed us to understand the clinical course, including the childhood onset of PAH.\n\nCase Report\nA 27-year-old man with severe PAH and ASD was referred to Tohoku University Hospital to evaluate further treatment options in August 2012. Moderate cyanosis was initially noted at 13 years of age when he caught a cold. Right heart catheterization (RHC) at the referring hospital revealed severe PAH with irreversible PVD (Table) and a moderate-sized secundum ASD of 15 mm in size, with a bidirectional shunt. Because there was no indication for surgical ASD closure, treatment with beraprost sodium was started. However, his shortness of breath on exertion and general fatigue had gradually worsened over the past 5 years, despite the administration of bosentan and sildenafil. Syncope was also noted 2 years prior to his admission to our hospital. There was no family history of PAH or CHD.\n\nTable. Time-course of Hemodynamic Data.\n\n\t13 years old\t27 years old\t30 years old\t\nBaseline\tO2 (10L/min)\tBaseline\tNO (40ppm)\t(3 months after LTx) Baseline\t\nPAP, mmHg\t102/49 (69)\t102/43 (66)\t60/35 (48)\t62/37 (48)\t22/8 (13)\t\nmRAP, mmHg\t6\t6\t7\t4\t0\t\nmPCWP, mmHg\t6\t7\t6\t5\t9\t\nAoP, mmHg\t104/78 (87)\t102/71 (84)\t95/78 (80)\t105/73 (80)\t143/80 (100)\t\nQp, L/min\t3.75\t3.11\t2.06\t2.13\t4.64\t\nQs, L/min\t3.38\t2.72\t2.46\t2.62\t4.64\t\nQp/Qs\t1.05\t1.15\t0.84\t0.81\t1.0\t\nRp, Wood Units\t16.8\t18.6\t20.4\t20.2\t0.9\t\nRs, Wood Units\t23.9\t28.7\t29.7\t29.0\t21.6\t\nRp/Rs\t0.74\t0.65\t0.69\t0.70\t0.04\t\nAoP: aortic pressure, LTx: lung transplantation, mPCWP: mean pulmonary capillary wedge pressure, mRAP: mean right atrial pressure, PAP: pulmonary artery pressure, Qp: pulmonary blood flow, Qs: systemic blood flow, Qp/Qs: pulmonary to systemic flow ratio, Rp: pulmonary vascular resistance, Rs: systemic valcular resistance, Rp/Rs: pulmonary to systemic resistance ratio\n\nOn physical examination, his blood pressure was 106/64 mmHg, and his pulse rate 90 bpm. Moderate cyanosis, an percutaneous oxygen saturation (SpO2) of 80% in room air and clubbed fingers were observed. The precordial impulses were visible and palpable. Auscultation revealed an accentuated pulmonic component of S2, a grade 2/6 ejection systolic murmur along the lower left sternal border, and a right-sided S3 in the tricuspid region. Blood examination demonstrated secondary polycythemia with a hemoglobin level of 20.1 g/dL, a hematocrit value of 60%, and elevated brain-type natriuretic peptide (BNP) level of 499 pg/mL. Chest X-ray showed marked enlargement of the cardiac silhouette and dilatation of the hilar pulmonary arterial shadow (Fig. 1A). Furthermore, a 12-lead electrocardiogram (ECG) demonstrated a normal sinus rhythm, right axis deviation, first-degree atrioventricular block, and complete right bundle block with a QRS duration of 200 ms (Fig. 1B). Transthoracic echocardiography showed severely impaired systolic function of the right ventricle (RV) with a tricuspid annular plane systolic excursion of 11 mm and an RV fractional area change of 14%. The RV was markedly enlarged (Fig. 1C). Tricuspid regurgitation was moderate with an estimated RV pressure of 75 mmHg. A secundum ASD of 16 mm in diameter with bidirectional flow was also identified (Fig. 1C). The left ventricular ejection fraction (LVEF), as measured by cardiac magnetic resonance imaging decreased to 35% because of interventricular septal bowing and compression of the left ventricle (LV) (Fig. 1D). Chest CT showed no evidence of thromboembolism, tumors or lung disorders such as chronic obstructive or interstitial lung disease. Spirometry showed a vital capacity of 3.9 L (83% of the predicted) and an forced expiratory volume (FEV) 1/forced vital capacity (FVC) ratio of 74%. Although both the lung diffusion capacity of carbon monoxide (DLCO)(89.6% of the predicted value) and the diffusing capacity divided by the alveolar volume (DLCO/VA)(89.6% of the predicted value) were within the normal limits, the patient's exercise capacity was decreased; the 6-minute-walk distance was 378 m, with a marked drop in SpO2 from 81% to 68% and a peak oxygen consumption of 11.3 mL/kg/min on bicycle ergometer. RHC revealed a pulmonary capillary wedge pressure of 6 mmHg, mean pulmonary arterial pressure of 48 mmHg, mean RA pressure of 7 mmHg (Table). The pulmonary to systemic flow ratio was 0.84. The pulmonary and systemic vascular resistance was 20.4 and 29.7 Wood Units, respectively. No pulmonary vasoreactivity to inhaled nitric oxide (40 ppm for 10 minutes) was noted.\n\nFigure 1. The examinations preformed on admission. (A) Marked enlargement of the heart silhouette on a chest X-ray. (B) Twelve-lead ECG showing first-degree atrioventricular block, right axis deviation, and complete right bundle branch block with a QRS duration of 200 ms. (C) The apical 4-chamber view of the transthoracic echocardiogram with color flow Doppler demonstrating severe enlargement of the right ventricle and the secundum atrial septal defect of 16 mm with a right to left flow (arrow). (D) A short-axis image obtained by cardiac MRI showing the massive enlargement of the right ventricle, leading to interventricular septal bowing toward the left ventricle (arrow).\n\nGiven the poor prognosis of PAH with medically refractory RHF, the patient was referred for lung transplantation and was registered in the Japan Organ Transplantation Network in December 2012. A genetic analysis revealed a heterozygous missense mutation in exon 12 of the BMPR2 gene (NM_001204.6: c.2474A>G), leading to the substitution of tryptophan to cysteine at amino acid position 825 (p.Tyr825Cys). Parental material was not available.\n\nThree years later, the patient underwent bilateral lung transplantation and concomitant cardiac surgery. A secundum ASD of 16 mm was surgically confirmed and was closed with an autologous pericardial patch. A histological examination revealed increased muscularization of the intra-acinar arterioles, medial hypertrophy and intimal thickening of the small pulmonary arteries, and multiple channels at branch points of the large preacinar pulmonary arteries (Fig. 2A-C), the latter of which was thought to have developed as a result of plexiform lesions. The postoperative course was complicated by symptomatic ventricular tachycardia (VT), possibly due to preexisting myocardial damage. The patient's VT was successfully controlled by the combination of bisoprolol, mexiletine and sotalol. A subcutaneous implantable cardioverter-defibrillator (sICD) was implanted to allow the use of immunosuppressive drugs for preventing allograft rejection. At 6 months after the lung transplantation, the patient was discharged with a marked improvement in his cardiopulmonary symptoms. RHC before discharge confirmed the complete resolution of PAH with a normal cardiac output (Table). However, biventricular dysfunction partially remained with an LVEF of 52% and a right ventricular ejection fraction (RVEF) of 42% on cardiac MRI.\n\nFigure 2. The histopathological findings of the lung tissue (Elastica-Masson Goldner staining). (A) Muscularization of the intra-acinar arterioles (arrows). (B) Muscular hypertrophy with intimal fibrotic proliferation in small pulmonary arteries (arrows). (C) The development of collateral channels (asterisks) around the occluded parent pulmonary artery (arrows), indicating the formation of plexiform lesions.\n\nDiscussion\nPVD can occur in various types of CHD, leading to severe PAH and a fatal outcome (3). The causes of PVD associated with CHD are multifactorial and include chronic volume and pressure overload of the pulmonary artery due to left-to-right shunt, hypoxic vasoconstriction, and elevated pulmonary venous pressure (3). Although the time of the onset of advanced PVD varies in each patient according to their anatomy and physiology, an isolated ASD does not usually cause severe PAH in younger patients because the pulmonary vasculature is only exposed to excess pulmonary blood flow (4). In contrast, the vast majority of patients with unrestrictive VSD will develop severe PVD if they are not treated within the first years of life because the pulmonary vasculature is exposed to both an increased pulmonary flow and increased systemic arterial pressure (4). The present case was interesting because the patient had severe PAH with irreversible PVD at his initial presentation at 13 years of age. Although the ASD was relatively large, there was no evidence to suggest a large left-to-right shunt, such as growth failure or exercise intolerance prior to the initial admission to the referral hospital. Thus, a risk factor other than the increased pulmonary blood flow might have been involved in the early development of severe PAH in our patient.\n\nGenetic factors play a major role in the development of PAH (2). Both familial and idiopathic PAH are linked to mutations in the BMPR2 gene, a member of the transforming growth factor-beta (TGF-β) receptor superfamily. BMPR2 mutations are identified in approximately 70% of patients with familial PAH and 25% of patients with idiopathic PAH (2). The possible molecular mechanisms triggering PAH in such patients include abnormal proliferation of vascular smooth muscle cells and increased endothelial apoptosis in the pulmonary artery (5). Interestingly, BMPR2 mutations are also associated with patients with CHD and PAH. Roberts et al. reported that 6 out of 106 CHD patients with PAH had BMPR2 missense mutations (6). In all 6 cases, PAH was diagnosed before the patients reached their teens. However all of the patients had at least one post-tricuspid shunt, such as VSD, atrio-ventricular septal defect, or patent ductus arteriosus, and the two of them had additional genetic syndrome. Thus, it is difficult to simply compare our patient to these cases. More recently, Liu et al. reported that the rate of BMPR2 mutations in CHD patients with PVD was significantly higher in comparison to those without PVD (7.5% vs. 1.2%, p=0.004) (7). In contrast, Therrien et al. found no BMPR2 mutations in Eisenmenger syndrome patients with ASD or ASD controls (1), indicating that a BMPR2 mutation is an important factor for triggering PAH in patients with CHD, whereas hemodynamic stress alone can produce irreversible PVD in patients with a large defect that causes Eisenmenger syndrome.\n\nThe BMPR2 gene is located on chromosome 2q33-q34 and has 13 exons (8). We identified a novel heterozygous missense mutation, c.2474A>G, in exon 12 of the BMPR2 gene. Exon 12 encodes an intracellular tail domain with an unknown function (8). To determine whether this mutation had been previously reported, we checked ExAC (http://exac.broadinstitute.org/), ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) databases, and the Human Gene Mutation Database (HGMD, http://www.hgmd.org). However, it was not found in these databases and was considered to be novel. An in silico analysis, using SIFT (http://sift.jcvi.org) predicted that the c.2474A>G in BMPR2 was damaging, while an analysis using Mutation Taster (http://www.mutationtaster.org/), predicted that it was disease causing, and an analysis using PolyPhen2 (http://genetics.bwh.harvard.edu/pph2/) predicted that it was probably damaging. This suggests that the mutation found in the present case occurred in a highly conserved site across species and that it may have affected the BMPR2 function. The mode of inheritance was unclear because there were no available material from relatives and because the patient had no family history of PAH or CHD.\n\nThe early onset of irreversible PVD in the present case may be explained by the “two-hit” theory. Evans et al. reported that PAH patients with BMPR2 mutations presented at a younger age with more severe disease and had a poor prognosis in comparison to patients without BMPR2 mutations (9). Interactions between abnormal cell signals [via BMPR2 mutation (5)] and hemodynamic overload (via ASD) can promote the rapid progression of pulmonary vascular lesions, resulting in severe PAH in patients in their teens. Thus, it seems useful for CHD patients with PAH to undergo a genetic analysis for idiopathic or familial PAH to evaluate the pathophysiology of developing PAH and in order to select an appropriate treatment. The determination of BMPR2 mutations appears to help in identifying CHD patients with PAH who have a high- risk of developing severe PVD at a much earlier stage in comparison to patients in whom it is expected based on the hemodynamic overload of the pulmonary circulation and the need for early corrective surgery. It may also be helpful to assess the risk of persistent or recurrent PH after the correction of the defect.\n\nTGF-β/BMP signaling is essential for heart development and the maintenance of the cardiac function; abnormalities in this signaling can cause congenital heart defects, such as atrioventricular defect and truncus arteriosus (10, 11). Talati et al. reported that both impaired fatty acid oxidation and the increased expression of the lipid transporter molecule CD36 are the mechanisms underlying the accumulation of lipids in the BMPR2 mutant RV (12). Van der Bruggen et al. showed that PAH patients with BMPR2 mutations had more severe RV dysfunction in comparison to those without the mutation, despite a similar RV afterload (13). Thus, the BMPR2 mutation in our case may have affected both the progression of PVD and the abnormal atrial septal formation and/or the early development of RHF, which required lung transplantation.\n\nConclusion\nIn conclusion, we reported the case of a young man with a BMPR2 gene mutation who presented with severe PAH in his early teens. A genetic analysis of CHD patients with PAH may help to evaluate the pathophysiological mechanisms underlying the development of PAH and facilitate the selection of an appropriate treatment.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nWe would like to thank Miki Akiba, our transplant coordinator, for her outstanding dedication and commitment to the patient.\n==== Refs\n1. \nTherrien J , Rambihar S , Newman B , et al \nEisenmenger syndrome and atrial septal defect: nature or nurture? \nCan J Cardiol \n22 : 1133 -1136 , 2006 .17102831 \n2. \nSoubrier F , Chung WK , Machado R , et al \nGenetics and genomics of pulmonary arterial hypertension . J Am Coll Cardiol \n62 : D13 -D21 , 2013 .24355637 \n3. \nDiller GP , Gatzoulis MA \nPulmonary vascular disease in adults with congenital heart disease . Circulation \n115 : 1039 -1050 , 2007 .17325254 \n4. \nD'Alto M , Mahadevan VS \nPulmonary arterial hypertension associated with congenital heart disease . Eur Respir Rev \n21 : 328 -337 , 2012 .23204121 \n5. \nRabinovitch M \nMolecular pathogenesis of pulmonary arterial hypertension . J Clin Invest \n122 : 4306 -4313 , 2012 .23202738 \n6. \nRoberts KE , McElroy JJ , Wong WP , et al \nBMPR2 mutations in pulmonary arterial hypertension with congenital heart disease . Eur Respir J \n24 : 371 -374 , 2004 .15358693 \n7. \nLiu D , Liu QQ , Guan LH , et al \nBMPR2 mutation is a potential predisposing genetic risk factor for congenital heart disease associated pulmonary vascular disease . Int J Cardiol \n211 : 132 -136 , 2016 .27002414 \n8. \nMorse JH \nBone morphogenetic protein receptor 2 mutations in pulmonary hypertension . Chest \n121 : 50S -53S , 2002 .11893684 \n9. \nEvans JD , Girerd B , Montani D , et al \nBMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis . Lancet Respir Med \n4 : 129 -137 , 2016 .26795434 \n10. \nSchneider MD , Gaussin V , Lyons KM \nTempting fate: BMP signals for cardiac morphogenesis . Cytokine Growth Factor Rev \n14 : 1 -4 , 2003 .12485614 \n11. \nKoitabashi N , Danner T , Zaiman AL , et al \nPivotal role of cardiomyocyte TGF-beta signaling in the murine pathological response to sustained pressure overload . J Clin Invest \n121 : 2301 -2312 , 2011 .21537080 \n12. \nTalati MH , Brittain EL , Fessel JP , et al \nMechanisms of lipid accumulation in the bone morphogenetic protein receptor type 2 mutant right ventricle . Am J Respir Crit Care Med \n194 : 719 -728 , 2016 .27077479 \n13. \nVan der Bruggen CE , Happe CM , Dorfmuller P , et al \nBone morphogenetic protein receptor type 2 mutation in pulmonary arterial hypertension: A view on the right ventricle . Circulation \n133 : 1747 -1760 , 2016 .26984938\n\n",
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"keywords": "BMPR2 mutation; Eisenmenger syndrome; atrial septal defect; congenital heart disease; lung transplantation; pulmonary arterial hypertension",
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D052006:Bone Morphogenetic Protein Receptors, Type II; D065627:Familial Primary Pulmonary Hypertension; D005820:Genetic Testing; D006330:Heart Defects, Congenital; D006344:Heart Septal Defects, Atrial; D006801:Humans; D006976:Hypertension, Pulmonary; D016040:Lung Transplantation; D008297:Male; D012720:Severity of Illness Index; D016896:Treatment Outcome",
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"title": "The Efficacy of a Genetic Analysis of the BMPR2 Gene in a Patient with Severe Pulmonary Arterial Hypertension and an Atrial Septal Defect Treated with Bilateral Lung Transplantation.",
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"abstract": "A female patient (47 years) who suffered from a severe episode of a recurrent depression with psychotic symptoms (F33.3) firstly underwent several unsuccessful treatments. She was then submitted to a combined treatment with 2×300 mg/day extended-release venlafaxine (VEN) and lithium (0.7 mmol/l). She responded within 7 weeks and, after 9 weeks, she showed full remission. Moreover, she tolerated this medication well. Steady-state plasma concentrations of VEN and its metabolites and their enantiomers were measured. The concentrations of VEN and its metabolite O-demethyl-VEN (ODV) were 1024 and 234 ng/ml, respectively. The unusually high concentration of the parent compound in comparison to the metabolite is mainly explained by an impaired metabolism of R-VEN in this patient, who by genotyping was shown to have a genetic deficiency of CYP2D6. In conclusion, in patients suffering from non-response to an antidepressant treatment, an individualised treatment strategy should be developed, and stereoselective therapeutic drug monitoring and genotyping may be recommended.",
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"issue": "8(3)",
"journal": "International journal of psychiatry in clinical practice",
"keywords": "CYP2D6; depression; enantiomers; non-response, lithium; pharmacogenetics; plasma concentrations; venlafaxine",
"medline_ta": "Int J Psychiatry Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "9709509",
"other_id": null,
"pages": "191-5",
"pmc": null,
"pmid": "24941211",
"pubdate": "2004",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "High-dose venlafaxine treatment in a depressed patient with a genetic CYP2D6 deficiency.",
"title_normalized": "high dose venlafaxine treatment in a depressed patient with a genetic cyp2d6 deficiency"
} | [
{
"companynumb": "PL-BAUSCH-BL-2019-019456",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LITHIUM"
},
"drugadditional": "3",
"... |
{
"abstract": "Oral isotretinoin is a synthetic analog of vitamin - A, reserved for cases with severe resistant acne. We hereby report a case of drug-induced vasculitis (DV) from isotretinoin exposure leading to life-threatening pulmonary-renal syndrome requiring immunosuppression and plasmapheresis. A previously healthy 21-year-old female receiving oral isotretinoin presented with a 10-day history of worsening myalgias, arthralgias, and abdominal pain. Soon after admission she progressed to severe pulmonary-renal syndrome requiring intubation and renal replacement therapy. Urinalysis revealed >50 dysmorphic RBC with casts and renal ultrasound was unremarkable. Serological testing was only positive for antineutrophil cytoplasmic antibodies (ANCA) at 1:80 with Anti- proteinase 3 (PR3) at 830 AU/mL and Anti-histone Ab at 2.9. As clinical presentation and serology are highly suggestive of ANCA associated DV, plasmapheresis, and rituximab were also initiated along with the continuation of steroids. She clinically improved but remained dialysis dependent and received a live donor renal transplant. The temporal relationship of symptom onset and drug initiation with no other possible identifiable etiologies-DV in our case was attributed to isotretinoin exposure. Though considered safe, oral Isotretinoin in rare instances can cause the life-threatening pulmonary-renal syndrome. Given its widespread use, it is prudent that prescribers should educate patients regarding the possible symptoms of vasculitis and to seek immediate medical attention when warranted. Physicians should also be vigilant of this complication and should act swiftly to avoid uneventful outcomes.",
"affiliations": "University of Kentucky College of Medicine, Division of Pulmonary Critical Care and Sleep Medicine, Lexington, KY, USA.;University of Kentucky College of Medicine, Division of Pulmonary Critical Care and Sleep Medicine, Lexington, KY, USA.",
"authors": "Annangi|Srinadh|S|;Pasha|Sara|S|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/atm-20-4212",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2305-5839",
"issue": "9(7)",
"journal": "Annals of translational medicine",
"keywords": "Vasculitis; antineutrophil cytoplasmic antibodies (ANCA); drug-induced vasculitis; isotretinoin; pulmonary-renal syndrome",
"medline_ta": "Ann Transl Med",
"mesh_terms": null,
"nlm_unique_id": "101617978",
"other_id": null,
"pages": "584",
"pmc": null,
"pmid": "33987282",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports",
"references": "2572922;1967805;1655091;9703117;24276086;19424772;9181282;6297657;28542914;23045170;20647199;11816242;11907498;1739240;18281855;1519607;21980179;29519741;10693882",
"title": "Isotretinoin induced small vessel vasculitis: a life-threatening pulmonary-renal syndrome-a case report.",
"title_normalized": "isotretinoin induced small vessel vasculitis a life threatening pulmonary renal syndrome a case report"
} | [
{
"companynumb": "US-MYLANLABS-2020M1005688",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISOTRETINOIN"
},
"drugadditional": "3",
... |
{
"abstract": "Isolated cardiac lymphomas are very rare, especially in immunocompetent patients. As a consequence, little is known about the best therapeutic management and about patients' outcomes in these cases. Diffuse large B-cell lymphoma is the most frequent subtype; anthracycline-based chemotherapy has been the most successful treatment. We describe the case of a primary cardiac lymphoma in an immunocompetent 71-year-old man. As of December 2015, the patient had been in clinical remission for 2 years. The most relevant literature on primary cardiac lymphoma is reported and discussed.",
"affiliations": null,
"authors": "Montanaro|Claudia|C|;Loiacono|Ferdinando|F|;Fragasso|Gabriele|G|;De Cobelli|Francesco|F|;Foppoli|Marco|M|;Margonato|Alberto|A|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.14503/THIJ-14-4269",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0730-2347",
"issue": "42(6)",
"journal": "Texas Heart Institute journal",
"keywords": "Biopsy, endomyocardial; cyclophosphamide; etoposide; heart neoplasms/therapy; immunocompetence; lymphoma, large B-cell, diffuse/diagnosis/drug therapy; lymphoma, non-Hodgkin/drug therapy; prednisone; rituximab; vincristine",
"medline_ta": "Tex Heart Inst J",
"mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D006338:Heart Neoplasms; D006801:Humans; D007121:Immunocompetence; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D011241:Prednisone; D012074:Remission Induction; D000069283:Rituximab; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "8214622",
"other_id": null,
"pages": "561-4",
"pmc": null,
"pmid": "26664312",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9797085;19536397;9458144;8980266;10543485;14722737;2237901;22571682;21934230;8540447;23748548;2438777;20354959;18402831;11519090;19747857;10389448;17670730;15160956;22385558;22078057;12447675;20661340;9338475;14515922;24422789;12152391;3800610;16846425",
"title": "Primary Cardiac Lymphoma in an Immunocompetent 71-Year-Old Man.",
"title_normalized": "primary cardiac lymphoma in an immunocompetent 71 year old man"
} | [
{
"companynumb": "IT-PFIZER INC-2016469607",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Adverse drug reaction (ADR) reporting rates and high-quality data within case summary reports are crucial to detect emerging safety concerns and implement regulatory action. In this study we aimed to improve the data quality and reporting rates of ADR reports in Malta through a series of national activities.\nBetween April 2018 and July 2019, we carried out the following activities: i) a review of wholesale dealers ADR reporting forms; ii) a series of educational workshops targeting physicians and pharmacists; iii) a quality system audit of the Authority's ADR management process.\nTwelve wholesaler dealer forms were reviewed, and 155 improvements were identified. Incident reporting forms modified to capture ADRs had the most opportunities for improvement. Five workshops were organized and in total 62 physicians and 22 pharmacists attended. Although feedback from participants was positive, in our case, an increase in reporting was not observed following the workshops. The quality system audit resulted in the introduction of the 'four-eye principle' to the Authority's ADR management process.\nThe implementation of such activities is expected to contribute to the overall pharmacovigilance systems in Malta and our experience could benefit other entities involved in spontaneous ADR reporting.",
"affiliations": "Medicines Authority, Sir Temi Żammit Buildings, Malta Life Sciences Park, San Ġwann, Malta.;Medicines Authority, Sir Temi Żammit Buildings, Malta Life Sciences Park, San Ġwann, Malta.;Medicines Authority, Sir Temi Żammit Buildings, Malta Life Sciences Park, San Ġwann, Malta.;Medicines Authority, Sir Temi Żammit Buildings, Malta Life Sciences Park, San Ġwann, Malta.;Medicines Authority, Sir Temi Żammit Buildings, Malta Life Sciences Park, San Ġwann, Malta.",
"authors": "Zuccarelli|Marta|M|;Micallef|Benjamin|B|;Butler|Dianne|D|;Serracino-Inglott|Anthony|A|;Borg|John-Joseph|JJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/14740338.2022.1993820",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-0338",
"issue": null,
"journal": "Expert opinion on drug safety",
"keywords": "Adverse drug reactions; adverse drug reactions reporting; causality assessment; drug safety; individual case safety report reporting; pharmacovigilance",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": null,
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "1-16",
"pmc": null,
"pmid": "34649475",
"pubdate": "2021-10-22",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Improving the data quality of spontaneous ADR reports: a practical example from Malta.",
"title_normalized": "improving the data quality of spontaneous adr reports a practical example from malta"
} | [
{
"companynumb": "MT-LUPIN PHARMACEUTICALS INC.-2022-05273",
"fulfillexpeditecriteria": "2",
"occurcountry": "MT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NORETHINDRONE"
},
"drugadditio... |
{
"abstract": "Glucocorticoid use during pregnancy is known to increase the risk of preterm birth and preterm premature rupture of membranes (pPROM). Here, we investigated the mechanism of how glucocorticoids weaken the fetal membranes. The amnion mesenchymal layer was significantly thinner in pregnant women treated with prednisolone and in corticosterone-injected mice than in control groups. Matrix metalloproteinase (MMP)-9 mRNA and its activity, COX2 mRNA levels, and prostaglandin E2 synthesis were increased, whereas type 1 collagen (COL1A1) mRNA levels were decreased in the fetal membranes of corticosterone-injected mice. Unexpectedly, the proliferation and migration of macrophages were observed around the corticosterone-injected amnion, and IL-1β was released from these macrophages. In human amnion mesenchymal cells, cortisol did not change MMP mRNA expression, whereas IL-1β treatment robustly increased MMP and COX2 mRNA expression. COL1A1 mRNA level was decreased by both cortisol and IL-1β. These data suggest that the recruitment of amniotic macrophages by glucocorticoids plays a pivotal role in weakening of the fetal membranes, leading to the pathogenesis of pPROM.",
"affiliations": "Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.",
"authors": "Kiyokawa|Hikaru|H|;Mogami|Haruta|H|;Ueda|Yusuke|Y|;Kawamura|Yosuke|Y|;Sato|Mai|M|;Chigusa|Yoshitsugu|Y|;Mandai|Masaki|M|;Kondoh|Eiji|E|",
"chemical_list": "D005938:Glucocorticoids; D011239:Prednisolone; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; D003345:Corticosterone",
"country": "United States",
"delete": false,
"doi": "10.1210/en.2018-01039",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-7227",
"issue": "160(4)",
"journal": "Endocrinology",
"keywords": null,
"medline_ta": "Endocrinology",
"mesh_terms": "D000328:Adult; D000650:Amnion; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D003345:Corticosterone; D051546:Cyclooxygenase 2; D005321:Extraembryonic Membranes; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008264:Macrophages; D020780:Matrix Metalloproteinase 9; D051379:Mice; D011239:Prednisolone; D055815:Young Adult",
"nlm_unique_id": "0375040",
"other_id": null,
"pages": "925-937",
"pmc": null,
"pmid": "30776301",
"pubdate": "2019-04-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Maternal Glucocorticoids Make the Fetal Membrane Thinner: Involvement of Amniotic Macrophages.",
"title_normalized": "maternal glucocorticoids make the fetal membrane thinner involvement of amniotic macrophages"
} | [
{
"companynumb": "JP-VISTAPHARM, INC.-VER202005-001063",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional":... |
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