article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "Our aim was to study the effect of drainage of cortical veins, including the superficial middle cerebral vein (SMCV), vein of Trolard, and vein of Labbé on neurological outcomes after reperfusion therapy.\n\n\n\nConsecutive ischemic stroke patients who underwent pretreatment computed tomographic perfusion and 24-hour computed tomographic perfusion or magnetic resonance perfusion after intravenous thrombolysis were included. We defined \"absent filling of ipsilateral cortical vein\" (eg, SMCV-) as no contrast filling of the vein across the whole venous phase on 4-dimensional computed tomographic angiography in the ischemic hemisphere.\n\n\n\nOf 228 patients, SMCV-, vein of Trolard- and vein of Labbé- were observed in 50 (21.9%), 27 (11.8%), and 32 (14.0%) patients, respectively. Only SMCV- independently predicted poor outcome (3-month modified Rankin Scale score of >2; odds ratio, 2.710; P=0.040). No difference was found in reperfusion rate after treatment between patients with and without SMCV- (P>0.05). In patients achieving major reperfusion (≥80%), there was no difference in 24-hour infarct volume, or rate of poor outcome between patients with and without SMCV- (P>0.05). However, in those without major reperfusion, patients with SMCV- had larger 24-hour infarct volume (P=0.011), higher rate of poor outcome (P=0.012), and death (P=0.032) compared with those with SMCV filling. SMCV- was significantly associated with brain edema at 24 hours (P=0.037), which, in turn, was associated with poor 3-month outcome (P=0.002).\n\n\n\nLack of SMCV filling contributed to poor outcome after thrombolysis, especially when reperfusion was not achieved. The main deleterious effect of poor venous filling appears related to the development of brain edema.",
"affiliations": "From the Departments of Neurology (S.Z., Y.L., M.L.) and Radiology (X.D.), The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China; Department of Neurology, John Hunter Hospital, The University of Newcastle, NSW, Australia (M.P.); and Department of Physiology and Pharmacology, Loma Linda University, CA (J.H.Z.).;From the Departments of Neurology (S.Z., Y.L., M.L.) and Radiology (X.D.), The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China; Department of Neurology, John Hunter Hospital, The University of Newcastle, NSW, Australia (M.P.); and Department of Physiology and Pharmacology, Loma Linda University, CA (J.H.Z.).;From the Departments of Neurology (S.Z., Y.L., M.L.) and Radiology (X.D.), The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China; Department of Neurology, John Hunter Hospital, The University of Newcastle, NSW, Australia (M.P.); and Department of Physiology and Pharmacology, Loma Linda University, CA (J.H.Z.).;From the Departments of Neurology (S.Z., Y.L., M.L.) and Radiology (X.D.), The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China; Department of Neurology, John Hunter Hospital, The University of Newcastle, NSW, Australia (M.P.); and Department of Physiology and Pharmacology, Loma Linda University, CA (J.H.Z.).;From the Departments of Neurology (S.Z., Y.L., M.L.) and Radiology (X.D.), The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China; Department of Neurology, John Hunter Hospital, The University of Newcastle, NSW, Australia (M.P.); and Department of Physiology and Pharmacology, Loma Linda University, CA (J.H.Z.).;From the Departments of Neurology (S.Z., Y.L., M.L.) and Radiology (X.D.), The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China; Department of Neurology, John Hunter Hospital, The University of Newcastle, NSW, Australia (M.P.); and Department of Physiology and Pharmacology, Loma Linda University, CA (J.H.Z.). loumingxc@vip.sina.com.",
"authors": "Zhang|Sheng|S|;Lai|Yangxiao|Y|;Ding|Xinfa|X|;Parsons|Mark|M|;Zhang|John H|JH|;Lou|Min|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1161/STROKEAHA.116.016174",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0039-2499",
"issue": "48(4)",
"journal": "Stroke",
"keywords": "brain imaging; edema; outcome; reperfusion; vein",
"medline_ta": "Stroke",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia; D002533:Cerebral Angiography; D002550:Cerebral Veins; D002560:Cerebrovascular Circulation; D000072226:Computed Tomography Angiography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D015424:Reperfusion; D020521:Stroke; D015912:Thrombolytic Therapy",
"nlm_unique_id": "0235266",
"other_id": null,
"pages": "907-914",
"pmc": null,
"pmid": "28265013",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article",
"references": "21980202;17060339;1280774;25541326;15770350;23620073;23047270;9788453;20584742;19118245;26860196;27505435;24065722;22039510;19240618;18541276;19509116;19574579;17050515;16970234;25580662;24064495;16463836;23887836;11237965;11559501;26814234;24078013;16387463;23070610;24876260",
"title": "Absent Filling of Ipsilateral Superficial Middle Cerebral Vein Is Associated With Poor Outcome After Reperfusion Therapy.",
"title_normalized": "absent filling of ipsilateral superficial middle cerebral vein is associated with poor outcome after reperfusion therapy"
} | [
{
"companynumb": "CN-ROCHE-1952827",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "OBJECTIVE\nTo gain insight into the main advantages and disadvantages that might result from valproate being unavailable for women who intend to become pregnant.\n\n\nMETHODS\nAnalysis of data from the Australian Pregnancy Register concerning pregnancies exposed to valproate (N = 501) and pregnancies where previous valproate intake had been ceased before pregnancy (N = 101).\n\n\nRESULTS\nThe risk of foetal malformation associated with valproate exposure during pregnancy was dose-related, and there was a tendency for the more major malformations, including those often managed by therapeutic abortion, for example spina bifida, to occur at higher valproate doses. Had there been no exposure to valproate during pregnancy, some 80% of the foetal malformations that occurred might have been avoided. Cessation of previous valproate therapy before pregnancy was associated with an increased hazard of seizure-affected pregnancy. This was particularly the case for women with generalized epilepsies, in whom the incidence of seizure-affected pregnancy was increased by 50% to nearly 100%.\n\n\nCONCLUSIONS\nAvoiding valproate intake during pregnancy is likely to reduce the incidence of foetal malformation, but at a cost of worsened maternal epilepsy control. Individualization of treatment is particularly important in considering withdrawal of valproate in the light of the fact that it is much more widely used in generalized epilepsy, there being fewer alternative drugs than for focal epilepsy and withdrawal is not without risk for both mother and baby. This study may provide a quantitative basis for assessing the balance between benefit and disadvantage for individual women with valproate-treated epilepsy who are considering pregnancy.",
"affiliations": "Department of Medicine and Neurosciences, Royal Melbourne Hospital University of Melbourne, Parkville, Victoria, Australia.;Department of Medicine and Neurosciences, Alfred Hospital and Monash University, Melbourne, Victoria, Australia.;Department of Medicine and Neurosciences, Royal Melbourne Hospital University of Melbourne, Parkville, Victoria, Australia.;Department of Medicine and Neurosciences, Royal Melbourne Hospital University of Melbourne, Parkville, Victoria, Australia.;Royal Brisbane and Women's Hospital and School of Medicine and Biomedical Science, University of Queensland, Brisbane, Queensland, Australia.;Royal Brisbane and Women's Hospital and School of Medicine and Biomedical Science, University of Queensland, Brisbane, Queensland, Australia.",
"authors": "Vajda|Frank J E|FJE|http://orcid.org/0000-0001-5570-7538;O'Brien|Terence J|TJ|;Graham|Janet E|JE|;Hitchcock|Alison A|AA|;Lander|Cecilie M|CM|;Eadie|Mervyn J|MJ|",
"chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ane.13005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-6314",
"issue": "139(1)",
"journal": "Acta neurologica Scandinavica",
"keywords": "epilepsy control; foetal malformations; maternal disadvantages; seizures; spina bifida; valproate",
"medline_ta": "Acta Neurol Scand",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000927:Anticonvulsants; D001315:Australia; D004827:Epilepsy; D005260:Female; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D012042:Registries; D012306:Risk; D012640:Seizures; D014635:Valproic Acid",
"nlm_unique_id": "0370336",
"other_id": null,
"pages": "42-48",
"pmc": null,
"pmid": "30109700",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Valproate-associated foetal malformations-Rates of occurrence, risks in attempted avoidance.",
"title_normalized": "valproate associated foetal malformations rates of occurrence risks in attempted avoidance"
} | [
{
"companynumb": "PHHY2019AU018130",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": null,
"d... |
{
"abstract": "Neoadjuvant chemotherapy has been widely used in patients with locally advanced breast cancer (LABC) to increase the chance of breast conservation. Among the most active adjuvant chemotherapy regimens, doxorubicin and cyclophosphamide are the most common drugs used for breast cancer in adjuvant and advanced settings, and taxanes are added to neoadjuvant regimens to improve the pathological complete response rates. However, chemotherapy is often associated with a variety of acute and long-term side effects, and neutropenia is one of the most common chemotherapy-associated toxicities. Lethal neutropenia is rarely reported in clinics. The present study reports the case of a patient with LABC that received 1 cycle of neoadjuvant chemotherapy [intravenous docetaxel (75 mg/m2), pirarubicin (45 mg/m2) and cyclophosphamide (500 mg/m2) on day 2 in 3-weekly intervals] and succumbed to neutropenia and subsequent multiple organ dysfunction syndrome. The present study suggests that neutropenia may be associated with significant mortality if not managed appropriately. Based on the findings of the present study, individual chemotherapy regimens, dosing schedules, effective methods of the prevention and management of neutropenia, and the management of the discharged patient require additional consideration.",
"affiliations": "Department of Gastrointestinal Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.;Department of Gastrointestinal Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.;Department of Gastrointestinal Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.;Department of Gastrointestinal Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.",
"authors": "Wang|Zhen|Z|;Chen|Jun-Qiang|JQ|;Liu|Jin-Lu|JL|;Qin|Xin-Gan|XG|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2016.4077",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-1074",
"issue": "11(2)",
"journal": "Oncology letters",
"keywords": "breast cancer; case report; neoadjuvant chemotherapy; neutropenia",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "1597-1599",
"pmc": null,
"pmid": "26893787",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": "24027583;21719750;18421049;20528233;24306808;21095116;24904223;18258986;12202663",
"title": "Serious neutropenia following neoadjuvant chemotherapy for locally advanced breast cancer: A case report.",
"title_normalized": "serious neutropenia following neoadjuvant chemotherapy for locally advanced breast cancer a case report"
} | [
{
"companynumb": "CN-SA-2016SA017009",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"dru... |
{
"abstract": "CD19-targeting chimeric antigen receptor T-cell (CART) therapy has emerged as a promising treatment for relapsed/refractory aggressive B-cell lymphoma (r/rABL), culminating in 2 US Food and Drug Administration-approved therapies: tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Following leukapheresis and in preparation for CART infusion, contemporary bridging and lymphodepletion regimens rely mostly on cytotoxic chemotherapy. Here, in a cohort of patients treated with commercial tisa-cel and axi-cel, we show that bridging-RT may offer a supplemental approach.\n\n\n\nThirty-one patients receiving commercial tisa-cel (n = 13) or axi-cel (n = 18) between August 2018 and February 2019 for r/rABL were retrospectively reviewed. Patients were categorized into 2 groups: (1) bridging-RT within 30 days of CART infusion or (2) nonbridging-RT (NBRT), in which patients received either remote RT greater than 30 days before CART infusion or no prior RT.\n\n\n\nFive patients received bridging-RT within 30 days of CART infusion. Median bridging-RT dose was 37.5 Gy and was completed a median of 13 days before infusion. No grade 3 (G3) or higher RT-toxicities occurred. No patients in the bridging-RT group experienced G3 or higher CART-related toxicities (CRS or neurotoxicity), and 23% (n = 6) and 15% (n = 4) experienced G3-5 CRS and G3-5 neurotoxicity in the NBRT group, respectively. Overall treatment response in the bridging-RT and NBRT groups was 80% and 64%, respectively. The axi-cel CART product was associated with CRS (odds ratio [OR] = 26.67, P = .001) and CRS correlated with neurotoxicity (OR = 12.22, P = .028). There was a trend toward an association for CRS with metabolic tumor volume (OR = 1.06/mL, P = .141) and TLG (OR = 1.01/mL x standard uptake value, P = .099).\n\n\n\nBridging-RT before commercial CART does not appear to increase the risk for CART-related toxicities or negatively affect outcomes in r/rABL patients. No G3 or higher RT-toxicities occurred in this series. Pretreatment metabolic tumor burden may be associated with CART-associated CRS; however, larger patient numbers are required to elucidate significant associations. Future work to prospectively assess the value of bridging-RT is warranted.",
"affiliations": "Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: Christopher.wright@pennmedicine.upenn.edu.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Medicine, Hematology/Oncology Division, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Medicine, Hematology/Oncology Division, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Medicine, Hematology/Oncology Division, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Medicine, Hematology/Oncology Division, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Medicine, Hematology/Oncology Division, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Medicine, Hematology/Oncology Division, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Medicine, Hematology/Oncology Division, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Medicine, Hematology/Oncology Division, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.",
"authors": "Wright|Christopher M|CM|;LaRiviere|Michael J|MJ|;Baron|Jonathan A|JA|;Uche|Chibueze|C|;Xiao|Ying|Y|;Arscott|W Tristram|WT|;Anstadt|Emily J|EJ|;Barsky|Andrew R|AR|;Miller|David|D|;LaRose|Meredith I|MI|;Landsburg|Daniel J|DJ|;Svoboda|Jakub|J|;Nasta|Sunita D|SD|;Gerson|James N|JN|;Barta|Stefan K|SK|;Chong|Elise A|EA|;Schuster|Stephen J|SJ|;Paydar|Ima|I|;Maity|Amit|A|;Plastaras|John P|JP|",
"chemical_list": "D000076962:Receptors, Chimeric Antigen",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ijrobp.2020.05.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0360-3016",
"issue": "108(1)",
"journal": "International journal of radiation oncology, biology, physics",
"keywords": null,
"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": "D000328:Adult; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D000076962:Receptors, Chimeric Antigen; D012008:Recurrence; D012189:Retrospective Studies; D017211:Treatment Failure",
"nlm_unique_id": "7603616",
"other_id": null,
"pages": "178-188",
"pmc": null,
"pmid": "32446950",
"pubdate": "2020-09-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Bridging Radiation Therapy Before Commercial Chimeric Antigen Receptor T-Cell Therapy for Relapsed or Refractory Aggressive B-Cell Lymphoma.",
"title_normalized": "bridging radiation therapy before commercial chimeric antigen receptor t cell therapy for relapsed or refractory aggressive b cell lymphoma"
} | [
{
"companynumb": "NVSC2020US259499",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nProtease inhibitors with pegylated interferon (PEG IFN)/ribavirin improve a sustained virological response (SVR) rate to approximately 90% in chronic hepatitis C genotype 1b patients with IL28B rs8099917 genotype TT, but yield only approximately 50% in those with the unfavorable non-TT. Among such treatment-refractory patients, serum vitamin D levels could influence the SVR rate. This randomized controlled trial was conducted to assess the effect of native vitamin D supplementation in simeprevir with PEG IFN/ribavirin for 1b patients with non-TT.\n\n\nMETHODS\nPatients were randomly assigned to receive simeprevir (100 mg/day) for 12 weeks plus PEG IFN/ribavirin for 24 weeks (control group, n = 58), or vitamin D (2000 IU/day) for 16 weeks including a lead-in phase plus PEG IFN/ribavirin for 24 weeks (vitamin D group, n = 57). The primary end-point was sustainably undetectable viremia 24 weeks after the end of treatment (SVR).\n\n\nRESULTS\nSVR rates were 37.9% in the control group and 70.2% in the vitamin D group. In subgroup analysis, SVR rates of prior null responders were 11.8% and 54.5%, respectively. SVR rates for advanced fibrosis were 28.6% and 65.4%. SVR rates for patients with vitamin D3 deficiency at the baseline were 25.0% in the control group and 66.7% in the vitamin D group. Overall, the SVR rate was significantly higher in patients with high serum 25(OH)D3 levels at the beginning of combination therapy than in those with low serum 25(OH)D3 levels.\n\n\nCONCLUSIONS\nNative vitamin D3 supplementation improved SVR rates in simeprevir with PEG IFN/ribavirin for chronic hepatitis C genotype 1b patients with refractory factors.",
"affiliations": "Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai.;Core Research Facilities for Basic Science, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo.;Chiba Tokushukai Hospital, Funabashi.;Machida Municipal Hospital, Tokyo.;Jikei University School of Medicine Katsushika Medical Center.;Tokyo Metropolitan Bokutoh Hospital, Tokyo.;Saiseikai Yokohamashi Tobu Hospital, Yokohama.;Ibaraki Central Hospital, Ibaraki.;Tokyo Medical University, Ibaraki Medical Center, Ibaraki.;Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai.;Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai.;Hakujikai Memorial Hospital, Tokyo.;Nippon Medical School, Tokyo, Japan.;Tokyo Metropolitan Bokutoh Hospital, Tokyo.;Tokyo Medical University, Ibaraki Medical Center, Ibaraki.;Nippon Medical School, Tokyo, Japan.;Jikei University School of Medicine Katsushika Medical Center.",
"authors": "Atsukawa|Masanori|M|;Tsubota|Akihito|A|;Shimada|Noritomo|N|;Yoshizawa|Kai|K|;Abe|Hiroshi|H|;Asano|Toru|T|;Ohkubo|Yusuke|Y|;Araki|Masahiro|M|;Ikegami|Tadashi|T|;Okubo|Tomomi|T|;Kondo|Chisa|C|;Osada|Yuji|Y|;Nakatsuka|Katsuhisa|K|;Chuganji|Yoshimichi|Y|;Matsuzaki|Yasushi|Y|;Iwakiri|Katsuhiko|K|;Aizawa|Yoshio|Y|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1111/hepr.12575",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6346",
"issue": "46(5)",
"journal": "Hepatology research : the official journal of the Japan Society of Hepatology",
"keywords": "native vitamin D; pegylated interferon; ribavirin; simeprevir; sustained virological response",
"medline_ta": "Hepatol Res",
"mesh_terms": null,
"nlm_unique_id": "9711801",
"other_id": null,
"pages": "450-8",
"pmc": null,
"pmid": "26289410",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effect of native vitamin D3 supplementation on refractory chronic hepatitis C patients in simeprevir with pegylated interferon/ribavirin.",
"title_normalized": "effect of native vitamin d3 supplementation on refractory chronic hepatitis c patients in simeprevir with pegylated interferon ribavirin"
} | [
{
"companynumb": "JP-JNJFOC-20160524412",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"... |
{
"abstract": "We present the case of a kidney transplant patient (Cockroft-Gault estimated creatinine clearance 14 ml/min) who was inadvertently eight-fold overdosed with a single dose of 500 mg intravenous ganciclovir. To prevent the immunosuppressed patient from being exposed to severe risks of prolonged ganciclovir overdosing, including potentially fatal bone marrow suppression and severe neurotoxicity, the patient was treated with hemodiafiltration (HDF) to enhance drug elimination. Since the product label reports a 50% decrease of ganciclovir plasma concentrations after intermittent hemodialysis (HD), two HDF sessions were considered necessary to achieve a ≥75% elimination of the drug by precaution, despite targeted intense HDF prescription. Ganciclovir plasma concentration data were obtained during both HDF sessions and were analyzed retrospectively. Pharmacokinetic analysis revealed that prescribed HDF successfully decreased drug plasma concentrations by ≥90%. This ganciclovir reduction ratio matched the urea reduction ratio achieved (≥92%). Model-based assessment of ganciclovir dialysis clearance (estimated to be 445 ml/min), accounting for its two-compartmental kinetics, was higher than urea dialysis clearance (estimated to be 310 ml/min). This suggests potential relevant accumulation of ganciclovir into blood cells, at least in this patient after overdosing. The amount (fraction) of drug removed by 1st HDF was estimated to 269 mg (93% of total amount of 288 mg eliminated during the 1st HDF session; estimated amount in the body prior to 1st HDF: 380 mg). A literature review was performed to summarize and systematically compare available information on ganciclovir elimination during intermittent renal replacement therapy. In conclusion, the high ganciclovir HDF clearance measured in our patient largely exceeded previously reported elimination during HD, meaning that HDF prescription was highly efficient in the present case, and that a second HDF session might not have been necessary. This finding may be considered to guide renal replacement therapy in the scope of drug overdosing. It may also be evaluated for ganciclovir dose adjustment in patients on chronic HD or HDF with high small solute clearance, since a strong correlation between ganciclovir and urea elimination efficiency was observed.",
"affiliations": "Pediatric Pharmacology and Pharmacometrics, University of Basel Children's Hospital, Basel, Switzerland.;Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Basel, Switzerland.;National Poisons Information Centre, Tox Info Suisse, Associated Institute of the University of Zurich, Zurich, Switzerland.;Pediatric Pharmacology and Pharmacometrics, University of Basel Children's Hospital, Basel, Switzerland.;Institute of Clinical Chemistry, University Hospital Zürich, Zurich, Switzerland.;Department of Internal Medicine, Hirslanden Klinik St. Anna, Lucerne, Switzerland.",
"authors": "Gotta|Verena|V|;Leuppi-Taegtmeyer|Anne|A|;Gessler|Mirjam|M|;Pfister|Marc|M|;Müller|Daniel|D|;Jehle|Andreas Werner|AW|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fphar.2020.00882",
"fulltext": "\n==== Front\nFront Pharmacol\nFront Pharmacol\nFront. Pharmacol.\nFrontiers in Pharmacology\n1663-9812 Frontiers Media S.A. \n\n10.3389/fphar.2020.00882\nPharmacology\nCase Report\nIntensive Hemodiafiltration Successfully Removes Ganciclovir Overdose and Largely Exceeds Reported Elimination During Hemodialysis—A Case Report and Review of the Literature\nGotta Verena 1* Leuppi-Taegtmeyer Anne 2 Gessler Mirjam 3 Pfister Marc 1 Müller Daniel 4 Jehle Andreas Werner 56 1Pediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital, Basel, Switzerland\n2Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Basel, Switzerland\n3National Poisons Information Centre, Tox Info Suisse, Associated Institute of the University of Zurich, Zurich, Switzerland\n4Institute of Clinical Chemistry, University Hospital Zürich, Zurich, Switzerland\n5Department of Internal Medicine, Hirslanden Klinik St. Anna, Lucerne, Switzerland\n6Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland\nEdited by: Roberto Paganelli, University of Studies G. d’Annunzio Chieti and Pescara, Italy\n\nReviewed by: Anders Åsberg, University of Oslo, Norway; Bernard J. M. Canaud, Université de Montpellier, France\n\n*Correspondence: Verena Gotta, verena.gotta@ukbb.chThis article was submitted to Translational Pharmacology, a section of the journal Frontiers in Pharmacology\n\n\n12 6 2020 \n2020 \n11 88231 3 2020 28 5 2020 Copyright © 2020 Gotta, Leuppi-Taegtmeyer, Gessler, Pfister, Müller and Jehle2020Gotta, Leuppi-Taegtmeyer, Gessler, Pfister, Müller and JehleThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.We present the case of a kidney transplant patient (Cockroft-Gault estimated creatinine clearance 14 ml/min) who was inadvertently eight-fold overdosed with a single dose of 500 mg intravenous ganciclovir. To prevent the immunosuppressed patient from being exposed to severe risks of prolonged ganciclovir overdosing, including potentially fatal bone marrow suppression and severe neurotoxicity, the patient was treated with hemodiafiltration (HDF) to enhance drug elimination. Since the product label reports a 50% decrease of ganciclovir plasma concentrations after intermittent hemodialysis (HD), two HDF sessions were considered necessary to achieve a ≥75% elimination of the drug by precaution, despite targeted intense HDF prescription. Ganciclovir plasma concentration data were obtained during both HDF sessions and were analyzed retrospectively. Pharmacokinetic analysis revealed that prescribed HDF successfully decreased drug plasma concentrations by ≥90%. This ganciclovir reduction ratio matched the urea reduction ratio achieved (≥92%). Model-based assessment of ganciclovir dialysis clearance (estimated to be 445 ml/min), accounting for its two-compartmental kinetics, was higher than urea dialysis clearance (estimated to be 310 ml/min). This suggests potential relevant accumulation of ganciclovir into blood cells, at least in this patient after overdosing. The amount (fraction) of drug removed by 1st HDF was estimated to 269 mg (93% of total amount of 288 mg eliminated during the 1st HDF session; estimated amount in the body prior to 1st HDF: 380 mg). A literature review was performed to summarize and systematically compare available information on ganciclovir elimination during intermittent renal replacement therapy. In conclusion, the high ganciclovir HDF clearance measured in our patient largely exceeded previously reported elimination during HD, meaning that HDF prescription was highly efficient in the present case, and that a second HDF session might not have been necessary. This finding may be considered to guide renal replacement therapy in the scope of drug overdosing. It may also be evaluated for ganciclovir dose adjustment in patients on chronic HD or HDF with high small solute clearance, since a strong correlation between ganciclovir and urea elimination efficiency was observed.\n\nganciclovirvalganciclovirhemodialysishemodiafiltrationoverdosetoxicityblood-to-plasma concentration ratio\n==== Body\nBackground\nActive cytomegalovirus (CMV) infection and disease is a major and common complication in solid organ transplant recipients and is associated with an increased risk of all types of infections, graft loss, and with decreased survival. Intravenous ganciclovir is an antiviral agent of choice for prevention and treatment of CMV infections in this population (Kotton et al., 2018). It is a nucleoside analogue that requires intracellular activation by phosphorylation via viral and cellular kinases. The active triphosphate derivative acts as an inhibitor of viral DNA polymerases and shows a long intra-cellular half-life (~16.5h) compared to plasma half-life of the unphosphorylated parent drug (2–4 h in patients with normal renal function) (Scott et al., 2004).\n\nGanciclovir is a small molecule (molecular weight 255.2 Da) with low protein binding (2%) and a small volume of distribution (0.54–0.87 l/kg). It is mainly (>90%) cleared renally by glomerular filtration and active tubular secretion (Cymevene Swiss Product Information., ). Hence, dose adjustment in renal impairment is necessary, with the elimination half-life of ganciclovir being prolonged up to >10-fold in patients with renal failure (30 h in patients with endstage renal disease) (Lake et al., 1988). Pharmacological properties suggest efficient elimination by hemodialysis (HD) (diffusive dialysis clearance) and hemodiafiltration (HDF) (by both diffusive and convective clearance) (Gotta et al., 2017; Gotta et al., 2020). The manufacturer states that one HD session decreases ganciclovir plasma concentrations by approximately 50% and suggests considering HD to treat overdosing. Indeed, cases of fatal bone marrow suppression have been reported in patients with renal failure who were accidentally overdosed due to omission of dose adjustment according to renal function (Ar et al., 2009). Under therapeutic doses, neutropenia is a common side effect occurring in approximately one third of patients, however in this setting, it is mostly reversible. Further severe adverse reactions associated with overdose may include neurotoxicity (confusion, hallucinations, seizures, coma), acute renal failure, and hepatitis (Cymevene Swiss Product Information., ).\n\nWe present a case of a kidney transplant patient with an estimated creatinine clearance of 14 ml/min (Cockroft-Gault) who accidentally received an eight-fold overdose with a single dose of 500 mg ganciclovir and who was treated with HDF to enhance drug elimination. According to available literature two HDF sessions were performed to ensure an 75% elimination of the drug. Ganciclovir plasma concentration data obtained during HDF and analyzed retrospectively revealed that the first HDF session successfully decreased drug plasma concentration by 92%, suggesting that a second HDF session might not have been necessary.\n\nWe report our case according to the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network recommended guidelines for case studies on extracorporeal treatments in poisonings (Lavergne et al., 2014).\n\nCase Presentation\nA 70-year old woman, who received a deceased donor renal transplant in 2017, was treated with ganciclovir for CMV disease with ulcerative esophagitis. In this patient weighing 44 kg with an estimated creatinine clearance of 14 ml/min ganciclovir was started at a reduced dose of 65 mg i.v. 22 months after transplantation. At this time the patient was under immunosuppressive therapy with tacrolimus and prednisolone, whereas mycophenolate mofetil was paused due to intermitted neutropenia. Eleven days after start of ganciclovir treatment, the patient received inadvertently an overdose of ganciclovir with a single dose of 500 mg.\n\nTo prevent the immunosuppressed patient from being exposed to severe risks of prolonged ganciclovir overdosing, a first session of intermittent post-dilution HDF with standard blood and dialysate flow (Table 1) and high ultrafiltration (34 L per 4 h session) was started 5 h after recognizing the dosing error. Using a dialysate containing 4 mmol/L potassium and additional administration of potassium phosphate (30 mmol over 4 h) successfully prevented hypokalemia and hypophosphatemia despite highly intense HDF.\n\nTable 1 Patient and hemodiafiltration characteristics.\n\nPatient characteristics\t\nGender\tFemale\t\nAge\t70 years\t\nBody weight\t44 kg\t\nSerum creatinine (pre-dialysis)\t237 µmol/L\t\nEstimated CLcrea (Cockroft-Gault)\t14 ml/min\t\nHematocrit\t27%\t\nSerum albumin\t24.1 g/L\t\nComedication\ttacrolimus, prednisolone, sulfamethoxazole/trimethoprim (prophylaxis), high-dose pantoprazole, chondroitin sulfate/hyaluronic acid, unfractionated heparin (subcutaneous prophylaxis), low-dose acetylsalicylic acid, nebivolol, citalopram, low-dose quetiapine\t\nHemodiafiltration parameters1\t\nFilter type\tFX CorDiax 100, Fresenius\n(2.2 m2, KoAurea: 1545 ml/min (BC Renal Network, 2019))\t\nBlood flow (QB)\t350 ml/min (21 L/h)\t\nDialysate flow (QD)\t525 ml/min (31 L/h)\t\nCalculated ultrafiltration rate\n(postdilution)\t131 ml/min (7.9 L/h, or 34.8 L, 1st session) and\n118 ml/min (7.1 L/h, or 40.1 L, 2nd session)\t\nSession duration\t265 min (4.42 h, 1st session) and\n285 min (4.75 h, 2nd session)\t\nAchieved urea (reference) clearance\t\nUrea (pre- and post dialysis)\t1st session: 21 and 1.6 mmol/L\n2nd session: 2.2 and <0.5 mmol/L\t\nCorresponding urea reduction ratio (URR)\t1st session: 92%\n2nd session: >97%\t\nCorresponding delivered spKt/V\naccording to Daugirdas JT 1993 (Daugirdas, 1993) (reported by dialyzer)\t1st session: 3.2 (reported: 2.41)\n2nd session: >1.6 (reported: 2.74)\t\nPredicted urea clearance from QB, QD and filter KoAurea\t230 ml/min (13.8 L/h)5\n= 79% of in vitro clearance of 292 ml/min (Michaels, 1966) (17.6 L/h) (Michaels, 1966)\t\n1The aggressive therapy was only possible with potassium at 4.1 mmol/l in dialysate and additional administration of 30 mmol potassium phosphate during first hemodiafiltration. During the 2nd session dialysate with 5.1 mmol/l potassium was used. KoA urea, mass-transfer area coefficient of urea; URR, urea reduction ratio calculated as: (Cpre − Cpost)/Cpre × 100%.\n\nA complete summary of patient characteristics, concomitant drug treatments, dialysis prescription, and efficiency in terms of small molecule clearance (measured by urea clearance) is given in Table 1.\n\nWritten informed consent was obtained from the patient for publication of her case.\n\nPharmacokinetic Sampling and Calculated Kinetic Parameters\nPlasma samples for pharmacokinetic analysis were taken before, during and after the two HDF sessions at in total eight time points. Paired pre- and post-filter concentration samples (Cpre-filter and Cpost-filter) were taken at three time points to calculate the extraction ratio (ER) (Table 2A, Figure 1A):\n\n ER=(Cpre-filter−Cpost-filter)/Cpre-filter Table 2 (A) Ganciclovir plasma concentrations measured during 2 dialysis sessions and calculated extraction ratio (ER) and reduction ratio (RR). (B) Predicted RR from model simulations under different alternative scenarios.\n\n(A) Ganciclovir measurements and calculated extraction ratio (ER) and reduction ratio (RR)\t\nSession\tTime (h)\tCpre-filter/Cpost-filter (mg/L)\tCalculated ER\tCalculated RR\t\n1\tStart = 0\t11.59/4.38 (+2 min)\t0.622\t\t\n1\t1\t2.23/Not measured\t–\t\t\n1\t2\t1.67/Not measured\t–\t\t\n1\t4\t1.27/0.74 (+2 min)\t0.417\t\t\n1\tStop = 4.42\t0.94/Not measured\t–\t92%\t\n2\tStart = 11.25\t1.01/0.18 (+5 min)\t0.822\t\t\n2\tStop = 16\t<0.1/Not measured\t–\t>90%\t\n\t\t\tMean: 0.62\nSD: ± 0.20\t\t\n(B) Model simulations: predicted reduction ratio (RR)\t\nScenario\t(a) CLR,off [ml/min]\n→ predicted RR%\t(b) HD duration [h]\n→ predicted RR\t(c) CLD [ml/min]\n→ predicted RR\tTotal predicted RR (scenario a+b+c)\t\n1 = present case\t29 → 93%\t4.4 → 93%\t445 → 93%\t93%\t\n2\t15 → 92%\t4.0 → 92%\t315 (−30%) → 89%\t87%\t\n3\t0 → 92%\t3.5 → 90%\t100 (−80%) → 64%\t51%\t\nThe CLD value in scenario 2 corresponds to a ≈30% reduced clearance expectation in the absence of high ultrafiltration (according to urea kinetic modeling). The CLD value in scenario 3 corresponds approximately to the highest CLD value reported in the literature under chronic hemodialysis. Note that also different distribution parameters may change RR, those were however assumed to be unchanged in model simulations.\n\nER, extraction ratio calculated as: (Cpre-filter – Cpost-filter)/Cpre-filter; RR, ganciclovir reduction ratio calculated as: (Cstart − Cstop)/Cstart × 100%; SD, standard deviation; Cpre-filter, ganciclovir plasma concentration measured from sample drawn before the filter; Cpost-filter, ganciclovir plasma concentration measured from sample drawn after the filter.\n\nFigure 1 (A) Ganciclovir plasma concentration measured (black dots: pre-filter, gray dots: post-filter) and model-predicted individual concentration-time profile since last normal (for renal function adjusted) ganciclovir dose (black line: pre-filter and intra-dialytic plasma concentration, dashed line: post-filter concentration assuming a constant extraction ratio within each hemodiafiltration session). ^: time and dose of i.v. ganciclovir administered. Gray bars indicate time on hemodiafiltration. (B) Urea concentration measured (dots) and model-predicted urea concentration-time profile. Open circles: (pre-filter) concentrations below limit of quantification (LOQ) (0.1 for ganciclovir, 0.5 mmol/L for urea), plotted at LOQ/2. (C) model-predicted amount of ganciclovir in the body (black solid line), and predicted total amount eliminated since start of first HDF session (dashed line), which is the sum of elimination by residual ganciclovir clearance of the patient (yellow shaded area, limited by dotted line) and HDF (red shaded area).\n\nThe ganciclovir reduction ratio (RR) during HDF was calculated in line with the calculated urea reduction ratio (Table 1) from pre-HDF (Cstart, at start of HDF) and post-HDF (Cend, after stopping HDF) ganciclovir pre-filter concentrations:\n\n RR=(Cstart−Cend)/Cstart×100% Calculated ganciclovir HDF clearance (KHDF) was derived from expected diffusive (Kd) and convective clearance (Kc), accounting for the average ER measured:\n\n Kd=QB×Rbp×ER=350ml/min×1×0.62=217ml/min Where QB = prescribed blood flow, Rbp = blood-to-plasma concentration ratio (assumed to equal 1 as average from in silico (Lukacova et al., 2016) and in vitro (Perrottet et al., 2007) estimates), and ER = average extraction ratio of 0.62.\n\n Kc=UF×SR×f=118-131ml/min×1×\n0.38 = 45−50ml/min With UF = ultrafiltration used (131 ml/min for 1st session and 118 ml/min for 2nd session, respectively), SR = solute ratio (or sieving coefficient), assumed to equal 1 for a small molecule like ganciclovir, and f = factor by which Kc is expected to be reduced in the presence of diffusive clearance (=(1-Kd/Qb) in this calculation (Depner, 2012))\n\nTotal calculated KHDF hence calculates to:\n\n KHDF= Kd+Kc=262-267ml/min Note that uncertainties exist concerning Rbp – in literature on ganciclovir dialysis clearance (see below) no distribution into blood cells has partly been assumed (i.e. Rbp = 1-hematocrit, which would result in a lower Kd estimate for our patient of 217 ml/min × (1–0.27) = 158 ml/min, and KHDF of 203–208 ml/min), while pharmacologically distribution into blood cells is necessary for its mechanism of action.\n\nConcentrations were measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) using an accredited and validated method. Imprecision of the method expressed as coefficient of variation was <7.3%, cumulative trueness from the last four rounds of external quality assessment (EQA) was −5.2%. EQA samples were obtained from KKGT (Den Haag, The Netherlands).\n\nModel-Based Estimation of Ganciclovir HDF Clearance and Fraction of Drug Removed by HDF\nDue to uncertainties in KHDF calculation mentioned above, and uncertainties in the volume of distribution to be used for calculating the amount and fraction of drug removed by HDF (Aremoved,HDF and fremoved,HDF, respectively), especially for this drug which is known to have two-comparmental distribution kinetics in plasma, a model-based pharmacokinetic analysis was performed using NONMEM (version 7.4.1, Icon Development Solutions, Ellicott City, MD) to estimate individual ganciclovir renal and HDF clearances (CLR and CLHDF), and to derive Aremoved,HDF and fremoved,HDF. Typical pharmacokinetic parameters of a two-compartmental model were used according to the population pharmacokinetic model published by Caldes et al. developed from a population of solid organ transplant patients with mean body weight of 66 kg (Caldés et al., 2009) (mixed residual error: proportional error: 14.3%, additive error: ± 0.465 mg/L). The last concentration measured below the limit of quantification (LOQ) of 0.1 mg/L was set to LOQ/2.\n\nIn the used model the prior expectation (typical value) of renal clearance (CLR) is a function of estimated creatinine clearance (CLcrea − Cockroft-Gault estimate) (Caldés et al., 2009):\n\n prior CLR(L/h)=7.49L/h×(CLcrea(ml/min)/57ml/min)=7.49×(14/57)L/h=1.83L/h Peripheral distribution parameters (peripheral volume of distribution, V2, and inter-compartmental distribution clearance Q) were additionally allometrically scaled by body weight, since physiologically those kinetic parameters are expected to be lower in a 44 kg patient as compared to a 66 kg patient for a molecule that mainly distributes within total body water:\n\n V2(L)=32.0×weight/66=21.3L Q(L/h)=10.2×(weight/66)0.75=7.52L/h Total clearance (CL) was set equal to the sum of CLR and CLHDF during hemodialysis and to CLR off-dialysis:\n\n CL=CLR+CLHDF=CLtot,on during analysis CL=CLR=CLR,off off-dialysis Based on those parameters, expected inter-patient variability (33% in prior CLR, 48% in central volume of distribution, V1, with prior [typical] value of V1 = 31.9 L (Caldés et al., 2009)), and the measured pre-filter ganciclovir concentration samples, individual parameters of CLR, V1, and CLHDF were estimated using Bayesian feedback to the following maximum a posteriori estimates: CLR = 1.8 (95% CI: 1.29–2.60) L/h [= 30 ml/min], V1 = 14.1 (95% CI: 7.4–26.8) L, and CLHDF = 26.7 L/h (relative standard error <1%) [445 ml/min]. Inter-session variability in CLHDF was evaluated and was—with an estimate of <1%—considered negligible. Based on individual distribution and clearance parameters, the amount of ganciclovir in the body prior to the first HDF session was predicted to be 380 mg, which was reduced by 288 mg (76%) during the first HDF session. 269 mg (93%) were predicted to be eliminated by HDF (=Aremoved,HDF and fremoved,HDF) and 19 mg (7%) by patient’s residual clearance (Figure 1C).\n\nIn a sensitivity analysis, CLHDF was fixed to calculatory KHDF, which yielded individual estimates of CLR= 2.4 L/h [40 ml/min] and V1 = 9.9 L, and a slightly worse model fit (P = 0.02, likelihood ratio test). The amount of ganciclovir in the body prior to the first HDF session was predicted to 320 mg, which was reduced by 220 mg (69%) during the first HDF session. 191 mg (89%) were predicted to be eliminated by HDF (=Aremoved,HDF and fremoved,HDF) and 29 mg (13%) by patient’s residual clearance.\n\nModeling of Post-Filter Ganciclovir Concentrations\nPost-filter concentrations (Cpost-filter) were modeled assuming a constant ER, to estimate the effective kinetic plasma flow through the filter (QEFF) (Atkinson and Umans, 2009):\n\n Cpost-filter=Cpre-filter×(1-ER)=Cpre-filter×(1-CLHDF/QEFF) Assuming diffusive clearance to represent the major mechanism of elimination for a small molecule during HDF (Tattersall and Blankestijn, 2019), QEFF would be limited by the blood flow (QB) through the filter, but can exceed QB for molecules that accumulate in blood cells, i.e. for drugs with a blood-to-plasma concentration ratio (Rbp) >1, since QEFF = QB × Rbp (Atkinson and Umans, 2009). For molecules that do not distribute into blood cells QEFF would in turn equal the plasma water flow, i.e. QEFF = QB × (1 − hematocrit). In HDF, QEFF can further increase by high ultrafiltration.\n\nAllowing for inter-session variability in the ER (suggested in Table 2), QEFF was estimated to be 47.4 L/h (relative standard error <1%) [788 ml/min], corresponding to a mean ER of 0.56, with considerable inter-session variability of 49%. The proportional residual error in predicted Cpost-filter concentrations was estimated to be 25%, an additive error was not quantifiable.\n\nModelling Cpost-filter did not affect the ganciclovir CLHDF estimate.\n\nGanciclovir Model Simulations\nModel simulations using different hypothetical CLR, dialysis duration, and dialysis clearance were performed using Berkeley Madonna (version 8.3.18) to evaluate the impact of those parameters on the reduction ratio (Table 2B), and to better compare our results to literature (see below).\n\nComparative Kinetic Analysis of Urea as Reference Solute\nUrea—just like ganciclovir—follows two-compartmental distribution kinetics (Clark et al., 1999). Urea dialysis clearance (CLHDF,urea) was also estimated kinetically using a model-based analysis. Urea distribution parameters (V1, V2, Q) and residual error were fixed to values predicted from a urea kinetic model accounting for weight-based changes in inter-compartmental clearance (Gotta et al., 2020). Renal urea clearance (CLR,urea) was assumed to be related to creatinine clearance (CLR,crea as follows:\n\n CLR,urea=CLR,crea×0.85/1.15=10.3ml/min considering their correlation with glomerular filtration rate (GRF), which is approximately 15% overpredicted by CLR,crea (undergoing tubular secretion) and 15% underpredicted by CLR,urea (Almond et al., 2008).\n\nThe urea generation rate was initially fixed to 0.104 mmol/min (Clark et al., 1999). In a second step an individual value was estimated using prior values estimated from a small population of patients on chronic HD (prior mean: 0.17 mmol/min, inter-individual variability: 38%) (Pfister et al., 2004). The last concentration measured below the LOQ of 0.5 mmol/L was set to LOQ/2.\n\nTotal urea clearance (CLurea) was set equal to the sum of CLR,urea and CLHDF,urea during hemodialysis and to CLR,urea off-dialysis:\n\n CLurea=CLR,urea+CLHDF,urea\n=CLtot,urea,on during dialysis CLurea=CLR,urea\n=CLR,urea,off off-dialysis This approach yielded an estimate of total CLHDF,urea of 310 ml/min, i.e. larger than the diffusive clearance mechanistically predicted from filter characteristics, blood flow, and dialysate flow (predicted urea clearance: 230 ml/min, Table 1) (Gotta et al., 2020). The individual urea generation rate was estimated to 0.056 mmol/min.\n\nThe complete NONMEM model codes for ganciclovir and urea can be found in the supplemental data. All model predictions are shown in Figure 1.\n\nReview of the Literature\nPublications relating to intermittent renal replacement therapy for comparison of our data were searched on MEDLINE during October 2019 using “renal dialysis” (MeSH) AND (“ganciclovir” OR “valganciclovir”). This search resulted in 32 references, whose abstracts were screened for pharmacokinetic data, which were then extracted from the full publication. In total seven publications reporting pharmacokinetic data in patients on intermittent hemodialysis were identified. Reported and calculated pharmacokinetic parameters of interest are summarized in Table 3.\n\nTable 3 Review of existing literature (chronologically ordered) on ganciclovir elimination during different types of intermittent renal replacement therapy (RRT) and comparison with estimates for the present patient.\n\nReference\n(number of patients)\tRRT type\n(duration)\tFilter\tPrescription\tClearance\n(ml/min)\tER/RR\t\n\nLake et al., 1988\n(n = 1)\tHD (4 h)\tCordis Dow 4000 Low UF\tQB = 250 ml/min\nQD: -\tCLD = 68.5 per 1.76 m2\nCLR,off = 10.1 per 1.76 m2\nCLtot,on= 78.6 per 1.76 m2\tER = 0.29\nRR: 50%\t\n\nSommadossi et al., 2019\n(n = 2)\tHD (4 h)\t–\tQB = 300 ml/min\nQD = 800 ml/min\t–\tER: -\nRR = 53 ± 11%\n(up to 70%)\t\n\nSwan et al., 1991\n(n = 1)\tHD (4 h)\tLundia IC 3L Gambro, 0.8 m2\tQB = 250 ml/min\nQD: -\tCLD = 48.3*1\nCLR,off = 35.5\tER = 0.29\nRR = 62%\t\n\nCombarnous et al., 1994\n(n = 1)\tHD (5 h)\thigh permeability dialyzer, 1.1 m2\tQB = 200 ml/min\nQD = 500 ml/min\tCLD: NR\nCLR,off = 2.6\tER: -\nRR = 52%\t\n\nPescovitz et al., 1998\n(n = 6)\tHD (4 h)\t–\t–\t–\tER: -\nRR = 53%\t\n\nCzock et al., 2002\nCzock and Rasche, 2004\n(n = 6)\tHD (4 h)\t–\t–\tCLD = 93.3\nCLR,off = 7.7\nCLtot,on = 106\tER: -\nRR ≈ 67%\n(visually) (Czock et al., 2002)/≈49–58% (Czock and Rasche, 2004),*2\t\nCzock 2004\tHD (4 h)\t–\t–\t–\t\t\nPresent case\n(n = 1)\tHDF\n(4.4–4.7 h)\tFX CorDiax 100, Fresenius\n(2.2 m2, KoAurea: 1545 ml/min)\tQB = 350 ml/min\nQD = 525 ml/min\nUF: 34–40 L/session\tCLD = 445\nCLR,off = 29\nCLtot,on = 474\tER: 0.62 (±0.20)\nRR: ≥90%\t\nRR, reduction ratio, calculated as 1-Cend/Cstart = (Cstart− Cend)/Cstart × 100%; ER, extraction ratio, calculated as (Cpre-filter – Cpost-filter)/Cpre-filter; QB, blood flow (ml/min); QD, dialysate flow (ml/min); UF, ultrafiltration volume; CLD, ganciclovir dialysis clearance reported or calculated; CLR,off, residual renal ganciclovir clearance off-dialysis; CLtot,on, total ganciclovir clearance during dialysis (=CLD + CLR,off). *1Note that distribution exclusively to plasma was assumed in the calculation. *2Assuming this value to approximate the fraction of dose removed from the body, the lower estimate accounts for rebound.\n\nDiscussion\nWe present a case of an inadvertent eight-fold ganciclovir overdose in a 70-year-old kidney transplant patient, successfully treated with two sessions of intermittent HDF. Retrospective analysis of ganciclovir pharmacokinetic data revealed that HDF was much more efficient at removing ganciclovir from the patient’s plasma (reduction ratio: ≥90%) than previously reported for endstage-renal disease patients on chronic HD (50–67%, Table 3).\n\nWhile it must be noted that residual renal ganciclovir clearance in our patient (estimated to be 30 ml/min by Bayesian feedback, i.e. twice her creatinine clearance) may have contributed to the high reduction ratio during a HDF session of 4.4 h, model-based analysis showed that it contributed to only 7% of total clearance during HDF (estimated to be 475 ml/min). A model-based analysis was considered necessary to calculate CLHDF due to the delayed two-compartmental distribution kinetics of the drug (Czock et al., 2002; Caldés et al., 2009) and since assessment of dialysis clearance by the ER only is complicated by limited knowledge about the distribution into blood cells that would be required to make correct assumptions about the effective pharmacokinetic plasma flow through the filter (Atkinson and Umans, 2009). The ganciclovir CLHDF estimate of 445 ml/min was very close to the sum of prescribed blood flow and ultrafiltration rate (350 + 131 ml/min = 481 ml/min) and was higher than urea dialysis clearance estimated (310 ml/min). This suggests an accumulation of ganciclovir in the blood cells in this patient (Rbp > 1). To our knowledge, Rbp has not been measured in vivo for ganciclovir. Based on its pharmacologic action, requiring intracellular phosphorylation leading to a long intra-cellular half-life (discussed in the introduction) and accumulation in peripheral blood mononuclear cells (Billat et al., 2016), it may be hypothesized that an Rbp > 1 would pharmacologically be expected. An erythrocyte/plasma value of 1.11 has indeed been measured in vitro by Perrottet et al. (2007). We acknowledge that an in silico estimate of 0.89 has been proposed (Lukacova et al., 2016)). in contrast to our expectation, which is however usually based on physiochemical properties only (e.g. polarity and lipophilicity) (Peters, 2012) and which may ignore active transmembrane transport mechanisms known for ganciclovir (Lukacova et al., 2016). If ganciclovir would distribute like the small molecule urea (molecular weight: 60 Da) homogenously and passively between plasma and red blood cells (Rbp = 1), CLHDF of ganciclovir could physiologically not exceed the estimated CLHDF,urea value of 310 ml/min. Collection of dialysate and ultrafiltrate to measure the recovered ganciclovir amount and CLHDF directly would have been additionally useful as gold-standard method, but was not practical. Serial measurements of intra-cellular ganciclovir and application of a multi-compartment distribution model (Billat et al., 2016) could have further enhanced our mechanistic understanding of the high CLHDF calculated. Importantly, highly efficient elimination of ganciclovir by HDF as reported here may not be sufficient to prevent hematologic and neurologic toxicity completely as intracellular accumulation still may occur. Our patient did not show any signs of neurotoxicity and she recovered from intermittent leukopenia, which was apparent before overdosing and may have other reasons as cytotoxicity due to CMV infection.\n\nInterestingly however, there was a very strong correlation between the ganciclovir and urea reduction ratio calculated (both ratios calculated to 92% during the first session), which may be an approximation for the amount of drug removed during HDF. This may suggest—independent of red blood cell distribution—that efficiency of urea removal can be used as a surrogate marker for ganciclovir removal. The estimated CLHDF,urea of 310 ml/min exceeded the mechanistically predicted diffusive in vivo urea clearance of 230 ml/min by 35%, suggesting significant contribution of convective clearance by the high ultrafiltration used in this HDF setting. The high blood flow compared to cases reported in the literature probably also contributed to a high diffusive clearance. The difference of 80 ml/min, relating to convective urea clearance, corresponds to 0.61–0.67 of the ultrafiltration rate used. This fraction may be interpreted as net sieving coefficient, which is expected to be reduced in the presence of diffusion (Tattersall and Blankestijn, 2019) compared to its expected value of 1.\n\nIn conclusion, this case illustrates highly efficient elimination of ganciclovir by intermittent HDF in a patient treated for inadvertent overdose potentially associated with intermittent leukopenia. Ganciclovir elimination by targeted intense HDF largely exceeded elimination reported by previous publications for patients on intermittent HD. The high elimination in the present case may be explained by several factors. First, a relevant contribution of convection to CLHDF at the high ultrafiltration rate used could be quantified for the reference molecule urea. Second, the blood flow of 350 ml/min was higher and the HDF session duration of 4.4–4.7 h was longer than in previous references reporting on ganciclovir elimination during HD. Third, while it is difficult to conclude on the importance of filter characteristics, since details were frequently not provided in the literature, the filter used in this case may have been characterized by a larger surface area and higher dialytic efficiency than filters used in the past. In fact, some drug dose recommendations for patients on RRT issued before the year 2000 are likely outdated due to advanced technology (Mueller and Smoyer, 2009). The reduction ratio of reference molecules like urea, which is routinely assessed during HD and HDF, could be evaluated as an indicator of ganciclovir removal in future studies.\n\nData Availability Statement\nAll datasets presented in this study are included in the article/Supplementary Material.\n\nEthics Statement\nWritten informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nConception/data acquisition: MG, AJ. Conception/data analysis: DM, MP, VG, and AL-T. All authors were involved in interpretation of data. VG and AJ drafted the manuscript. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2020.00882/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\nAlmond A. Siddiqui S. Robertson S. Norrie J. Isles C. (2008 ). Comparison of combined urea and creatinine clearance and prediction equations as measures of residual renal function when GFR is low\n. Qjm. \n101 (8 ), 619 –624\n. 10.1093/qjmed/hcn032 \n18540009 \n\nAr M. C. Ozbalak M. Tuzuner N. Bekoz H. Ozer O. Ugurlu K. (2009 ). Severe Bone Marrow Failure Due to Valganciclovir Overdose After Renal Transplantation From Cadaveric Donors: Four Consecutive Cases\n. Transplant. Proc. \n41 (5 ), 1648 –1653\n. 10.1016/j.transproceed.2009.02.093 \n19545700 \n\nAtkinson A. J. Umans J. G. (2009 ). Pharmacokinetic studies in hemodialysis patients\n. Clin. Pharmacol. Ther. \n86 (5 ), 548 –552\n. 10.1038/clpt.2009.147 \n19675540 \n\nBC Renal Network \n2019 \nCommonly used dialyzer specifications and substitution chart for visiting patients\n, accessed 10/2019\nhttp://www.bcrenalagency.ca/.\n\n\nBillat P. A. Woillard J. B. Essig M. Sauvage F. L. Picard N. Alain S. (2016 ). Plasma and intracellular exposure to ganciclovir in adult renal transplant recipients: Is there an association with haematological toxicity\n? J. Antimicrob. Chemother. \n71 (2 ), 484 –489\n. 10.1093/jac/dkv342 \n26538506 \n\nCaldés A. Colom H. Armendariz Y. Garrido M. J. Troconiz I. F. Gil-Vernet S. (2009 ). Population pharmacokinetics of ganciclovir after intravenous ganciclovir and oral valganciclovir administration in solid organ transplant patients infected with cytomegalovirus\n. Antimicrob. Agents Chemother. \n53 (11 ), 4816 –4824\n. 10.1128/AAC.00085-09 \n19738014 \n\nClark W. R. Leypoldt J. K. Henderson L. W. Mueller B. A. Scott M. K. Vonesh E. F. (1999 ). Quantifying the effect of changes in the hemodialysis prescription on effective solute removal with a mathematical model\n. J. Am. Soc. Nephrol. \n10 (3 ), 601 –609\n.\n10073611 \n\nCombarnous E. Fouque D. Bernard N. Boulieu R. Chossegros P. Laville M. (1994 ). Pharmacokinetics of ganciclovir in a patient undergoing chronic haemodialysis\n. Eur. J. Clin. Pharmacol. \n46 , 379 –381\n. 10.1007/BF00194410 \n7957527 \n\nCymevene Swiss Product Information .\n\n\nCzock D. Rasche F. M. (2004 ). New AUC-Based Method to Estimate Drug Fraction Removed by Hemodialysis\n. Kidney Blood Press Res. \n27 (3 ), 172 –176\n. 10.1159/000079806 \n15256813 \n\nCzock D. Scholle C. Rasche F. M. Schaarschmidt D. Keller F. (2002 ). Pharmacoldnctics of valganciclovir and ganciclovir in renal impairment\n. Clin. Pharmacol. Ther. \n72 (2 ), 142 –150\n. 10.1067/mcp.2002.126306 \n12189361 \n\nDaugirdas J. T. (1993 ). Second generation logarithmic estimates of single-pool variable volume Kt/V: an analysis of error\n. J. Am. Soc. Nephrol. \n4 (5 ), 1205 –1213\n.\n8305648 \n\nDepner T. A. (2012 ). “Approach to Hemodialysis Kinetic Modeling\n,” in Principles and Practice of Dialysis. Ed. Henrich W. L. (Philadelphia : Lippincott Williams & Wilkins ), 73 –96\n.\n\n\nGotta V. Dao K. Rodieux F. Buclin T. Livio F. Pfister M. (2017 ). Guidance to develop individual dose recommendations for patients on chronic hemodialysis\n. Expert Rev. Clin. Pharmacol. \n10 (7 ), 737 –752\n. 10.1080/17512433.2017.1323632 \n28447486 \n\nGotta V. Marsenic O. Pfister M. (2020 ). Understanding Urea Kinetic Factors That Enhance Personalized Hemodialysis Prescription in Children\n. ASAIO J. \n66 (1 ), 115 –123\n. 10.1097/mat.0000000000000941 \n30681439 \n\nKotton C. N. Kumar D. Caliendo A. M. Huprikar S. Chou S. Danziger-Isakov L. (2018 ). The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation , Vol. 102 . 10.1097/TP.0000000000002191 \n\n\nLake K. D. Fletcher C. V. Love K. R. Brown D. C. Joyce L. D. Pritzker M. R. (1988 ). Ganciclovir pharmacokinetics during renal impairment\n. Antimicrob. Agents Chemother. \n32 (12 ), 1899 –1900\n. 10.1128/AAC.32.12.1899 \n2854457 \n\nLavergne V. Ouellet G. Bouchard J. Galvao T. Kielstein J. T. Roberts D. M. (2014 ). Guidelines for reporting case studies on extracorporeal treatments in poisonings: Methodology\n. Semin. Dial. \n27 (4 ), 407 –414\n. 10.1111/sdi.12251 \n24890576 \n\nLukacova V. Goelzer P. Reddy M. Greig G. Reigner B. (2016 ). Parrott N. A Physiologically Based Pharmacokinetic Model for Ganciclovir and Its Prodrug Valganciclovir in Adults and Children\n. AAPS J. \n18 (6 ), 1453 –1463\n. 10.1208/s12248-016-9956-4 \n27450227 \n\nMichaels A. S. (1966 ). Operating parameters and performance criteria for hemodialyzers and other membrane-separation devices\n. Trans. Am. Soc. Artif. Intern Organs. \n12 , 387 –392\n.\n5960730 \n\nMueller B. A. Smoyer W. E. (2009 ). Challenges in developing evidence-based drug dosing guidelines for adults and children receiving renal replacement therapy\n. Clin. Pharmacol. Ther. \n86 (5 ), 479 –482\n. 10.1038/clpt.2009.150 \n19844225 \n\nPerrottet N. Beguin A. Meylan P. Pascual M. Manuel O. Buclin T. (2007 ). Determination of aciclovir and ganciclovir in human plasma by liquid chromatography-spectrofluorimetric detection and stability studies in blood samples\n. J. Chromatogr B Anal. Technol. BioMed. Life Sci. \n852 (1-2 ), 420 –429\n. 10.1016/j.jchromb.2007.01.045 \n\n\nPescovitz M. D. Pruett T. L. Gonwa T. Brook B. McGory R. Wicker K. (1998 ). Oral ganciclovir dosing in transplant recipients and dialysis patients based on renal function\n. Transplantation. \n66 (8 ), 1104 –1107\n. 10.1097/00007890-199810270-00023 \n9808499 \n\nPeters S. A. (2012 ). Physiologically-Based Pharmacokinetic (PBPK) Modeling and Simulations: Principles, Methods, and Applications in the Pharmaceutical Industry . 1st ed. (Hoboken, New Jersey : Wiley ).\n\n\nPfister M. Uehlinger D. E. Hung A. M. Schaedeli F. Sheiner L. B. (2004 ). A new Bayesian method to forecast and fine tune individual hemodialysis dose\n. Hemodial Int. \n8 (3 ), 244 –256\n. 10.1111/j.1492-7535.2004.01102.x \n19379424 \n\nScott J. C. Partovi N. Ensom M. H. H. (2004 ). Ganciclovir in Solid Organ Transplant Recipients\n. Ther. Drug Monit. \n26 (1 ), 68 –77\n. 10.1097/00007691-200402000-00014 \n14749553 \n\nSommadossi A. J. Bevan R. Ling F. Lee T. Mastre B. Chaplin M. D. (2019 ). “Clinical Pharmacokinetics of Ganciclovir in Patients with Normal and Impaired Renal Function Source : Reviews of Infectious Diseases\n,” in Cytomegalovirus Infection and Treatment with Ganciclovir , vol. 10 , S507 –S5S5\n, Supplement 3 .\n\n\nSwan S. Munar M. Wigger M. Bennett W. (1991 ). Pharmacokinetics of ganciclovir in a patient undergoing hemodialysis\n. Am. J. Kidney Dis. \n17 (1 ), 69 –72\n. 10.1016/S0272-6386(12)80253-8 \n1846060 \n\nTattersall A. J. Blankestijn P. J. (2019 ). “Technical aspects of hemodiafiltration\n,” in UpToDate. Eds. Palevsky P. M. Motwani S. (Waltham, MA : Wolters Kluwer ), 1 –15\n.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1663-9812",
"issue": "11()",
"journal": "Frontiers in pharmacology",
"keywords": "blood-to-plasma concentration ratio; ganciclovir; hemodiafiltration; hemodialysis; overdose; toxicity; valganciclovir",
"medline_ta": "Front Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "101548923",
"other_id": null,
"pages": "882",
"pmc": null,
"pmid": "32595505",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "12189361;7957527;24890576;19844225;10073611;27450227;1846060;2854457;18540009;26538506;29596116;19675540;14749553;19379424;2847287;28447486;19738014;19545700;17303480;8305648;15256813;30681439;9808499;5960730",
"title": "Intensive Hemodiafiltration Successfully Removes Ganciclovir Overdose and Largely Exceeds Reported Elimination During Hemodialysis-A Case Report and Review of the Literature.",
"title_normalized": "intensive hemodiafiltration successfully removes ganciclovir overdose and largely exceeds reported elimination during hemodialysis a case report and review of the literature"
} | [
{
"companynumb": "CH-CHEPLA-C20202018",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"... |
{
"abstract": "Results suggest that the combination of bevacizumab plus temozolomide is active in terms of response rate, survival, performance, quality of life, and cognition in elderly patients with glioblastoma multiforme with poor performance status.Whether this combination is superior to temozolomide alone remains to be demonstrated by a randomized study.\n\n\n\nThe optimal treatment of glioblastoma multiforme (GBM) in patients aged ≥70 years with a Karnofsky performance status (KPS) <70 is not established. This clinical trial evaluated the efficacy and safety of upfront temozolomide (TMZ) and bevacizumab (Bev) in patients aged ≥70 years and a KPS <70.\n\n\n\nPatients aged ≥70 years with a KPS <70 and biopsy-proven GBM were eligible for this multicenter, prospective, nonrandomized, phase II trial of older patients with impaired performance status. Treatment consisted of TMZ administered at 130-150 mg/m2 per day for 5 days every 4 weeks plus Bev administered at 10 mg/kg every 2 weeks.\n\n\n\nThe trial included 66 patients (median age of 76 years; median KPS of 60). The median overall survival (OS) was 23.9 weeks (95% confidence interval [CI], 19-27.6), and the median progression-free survival (PFS) was 15.3 weeks (95% CI, 12.9-19.3). Twenty-two (33%) patients became transiently capable of self-care (i.e., KPS >70). Cognition and quality of life significantly improved over time during treatment. Grade ≥3 hematological adverse events occurred in 13 (20%) patients, high blood pressure in 16 (24%), venous thromboembolism in 3 (4.5%), cerebral hemorrhage in 2 (3%), and intestinal perforation in 2 (3%).\n\n\n\nThis study suggests that TMZ + Bev treatment is active in elderly patients with GBM with low KPS and has an acceptable tolerance level.",
"affiliations": "Service de Neurologie 2 Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France germanreyes77@hotmail.com.;Department of Neuro-Oncology, Hospices Civils de Lyon, Hôpital Neurologique, Lyon, France.;Aix-Marseille Université AP-HMCHU Timone Service de Neuro-Oncologie, Marseille, France.;Aix-Marseille Université AP-HMCHU Timone Service de Neuro-Oncologie, Marseille, France.;CHU Nancy, Nancy, France.;CHU Nancy, Nancy, France.;Hôpital Saint André CHU, Bordeaux, France.;Centre Antoine Lacassagne, Nice, France.;CHU Caen, Caen, France.;Institut Regional de Cancer Montpellier, Montpellier, France.;Centre Léon Bérard, Lyon, France.;CHU Rangueil, Toulouse, France.;Centre Oscar Lambret, Lille, France.;CHU Nimes, Nimes, France.;Centre Henri Becquerel CLCC, Rouen, France.;Georges François Leclerc Cancer Center, Dijon, France.;APHP CHU Pitié-Salpêtrière, Paris, France.;APHP CHU Pitié-Salpêtrière, Paris, France.;Department of Neuro-Oncology, Hospices Civils de Lyon, Hôpital Neurologique, Lyon, France.;Service de Neurologie 2 Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.",
"authors": "Reyes-Botero|Germán|G|;Cartalat-Carel|Stéphanie|S|;Chinot|Olivier L|OL|;Barrie|Maryline|M|;Taillandier|Luc|L|;Beauchesne|Patrick|P|;Catry-Thomas|Isabelle|I|;Barrière|Jérôme|J|;Guillamo|Jean-Sebastien|JS|;Fabbro|Michel|M|;Frappaz|Didier|D|;Benouaich-Amiel|Alexandra|A|;Le Rhun|Emilie|E|;Campello|Chantal|C|;Tennevet|Isabelle|I|;Ghiringhelli|François|F|;Tanguy|Marie-Laure|ML|;Mokhtari|Karima|K|;Honnorat|Jérôme|J|;Delattre|Jean-Yves|JY|",
"chemical_list": "D000068258:Bevacizumab; D000077204:Temozolomide",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2017-0689",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "23(5)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000068258:Bevacizumab; D005260:Female; D005909:Glioblastoma; D006801:Humans; D008297:Male; D000077204:Temozolomide",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "524-e44",
"pmc": null,
"pmid": "29472310",
"pubdate": "2018-05",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "24552317;21709196;22877848;23095881;24552318;17429084;9070498;19720927;25035291;25204470;26392096;24723487;22578793;22517216;23634286;15758009",
"title": "Temozolomide Plus Bevacizumab in Elderly Patients with Newly Diagnosed Glioblastoma and Poor Performance Status: An ANOCEF Phase II Trial (ATAG).",
"title_normalized": "temozolomide plus bevacizumab in elderly patients with newly diagnosed glioblastoma and poor performance status an anocef phase ii trial atag"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1038171",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAttention deficit hyperactivity disorder (ADHD) is the most common psychiatric childhood disorder. The most commonly used drugs in the treatment of ADHD are methylphenidate (MPH) and atomoxetine (ATX); the former of the two is prescribed in USA more than it is in Western Europe. Some of the most important safety concerns about ADHD drug treatment are sudden cardiac death and suicidal behavior. In this study, we present a series of cases of Italian children who had presented suicidal ideation during ADHD pharmacological therapy with ATX.\n\n\nMETHODS\nData were obtained from the ADHD Italian Register. The data assessed the use of MPH and ATX, which had been prescribed to patients who were aged < 18 years and diagnosed with ADHD. All patients enrolled in the ADHD Italian Register treated with ATX or MPH who experienced suicidal thoughts or thoughts of self-harming were considered and assessed.\n\n\nRESULTS\nWe describe the clinical cases of seven Italian children (enrolled in the ADHD Italian Register) treated with ATX and affected by suicidal ideation, self-harming or other similar symptoms. Our results highlighted that all seven patients developed suicidal ideation or intentional self-harming during pharmaceutical treatment with ATX and, particularly, after the dose increase of the drug.\n\n\nCONCLUSIONS\nThere is a need to improve our knowledge about the efficacy and safety of ATX, MPH and other drugs used in the treatment of ADHD both in children and adults during the post-marketing experience.",
"affiliations": "Second University of Naples, Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Faculty of Medicine and Surgery , Via De Crecchio, 7, 80138 Naples , Italy +39 0815667669 ; +39 0815667652 ; annalisa.capuano@unina2.it.",
"authors": "Capuano|Annalisa|A|;Scavone|Cristina|C|;Rafaniello|Concetta|C|;Arcieri|Romano|R|;Rossi|Francesco|F|;Panei|Pietro|P|",
"chemical_list": "D018759:Adrenergic Uptake Inhibitors; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1517/14740338.2014.941804",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-0338",
"issue": "13 Suppl 1()",
"journal": "Expert opinion on drug safety",
"keywords": "adverse drug reaction; atomoxetine; attention deficit hyperactivity disorder; suicidal ideation",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D011437:Propylamines; D012042:Registries; D016728:Self-Injurious Behavior; D059020:Suicidal Ideation",
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "S69-78",
"pmc": null,
"pmid": "25171160",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Atomoxetine in the treatment of attention deficit hyperactivity disorder and suicidal ideation.",
"title_normalized": "atomoxetine in the treatment of attention deficit hyperactivity disorder and suicidal ideation"
} | [
{
"companynumb": "PHHY2014IT130582",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
"dru... |
{
"abstract": "Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent infections and a dysregulated inflammatory response. Infection-triggered hemophagocytic lymphohistiocytosis (HLH), which manifests itself as pathologic hyperactive inflammation, has been observed in subjects with CGD. However, there have been no reports of HLH as the initial presentation with subsequent diagnosis of CGD. Furthermore, the primary therapeutic strategy for HLH focuses on immunosuppressive therapies, which limits immune-mediated tissue damage. With immunodeficiency, this therapeutic strategy may worsen the outcome. This article discusses an 8-week-old Hispanic male who presented with fever of unknown origin. The initial diagnostic evaluation demonstrated pathologic hyperactive inflammation, meeting the HLH-2004 diagnostic criteria without an identified infectious etiology. Immunosuppressive therapy was initiated, with subsequent disseminated candida septic shock and sepsis-induced multisystem organ failure. Additional evaluations ultimately established the diagnosis of CGD. We transitioned to an immune-enhancing strategy with granulocyte and immunoglobulin infusions, and intensified antifungal therapies. These interventions ultimately led to the clearance of the fungal infection and the resolution of the hyperactive inflammatory state. This case represents the first reported case of HLH as the presenting finding leading to the subsequent diagnosis of CGD. It serves as a reminder that both immunodeficiency and inflammatory disorders may share features of pathologic hyperactive inflammation and highlights the conundrum that clinicians face when treating HLH in the setting of an unresolved infection. In this case report, we demonstrate that immune-enhancing therapies may aid in the control and the clearance of the infection, thus paradoxically decreasing the pathologic hyperactive inflammatory response.",
"affiliations": "Section of Pediatric Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.;Section of Pediatric Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.;Section of Pediatric Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.;Section of Pediatric Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas ylai@bcm.edu.",
"authors": "Valentine|Gregory|G|;Thomas|Tessy A|TA|;Nguyen|Trung|T|;Lai|Yi-Chen|YC|",
"chemical_list": "D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D047071:beta-Glucans; C010770:polysaccharide-K; D007371:Interferon-gamma; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2014-2175",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "134(6)",
"journal": "Pediatrics",
"keywords": "chronic granulomatous disease; fungemia; hemophagocytic lymphohistiocytosis; immunocompromised host; immunomodulation",
"medline_ta": "Pediatrics",
"mesh_terms": "D003131:Combined Modality Therapy; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D018450:Disease Progression; D005335:Fever of Unknown Origin; D016469:Fungemia; D006098:Granulocytes; D006105:Granulomatous Disease, Chronic; D006801:Humans; D007116:Immunization, Passive; D007166:Immunosuppressive Agents; D007223:Infant; D007371:Interferon-gamma; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D009894:Opportunistic Infections; D011509:Proteoglycans; D047071:beta-Glucans",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "e1727-30",
"pmc": null,
"pmid": "25422023",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Chronic granulomatous disease presenting as hemophagocytic lymphohistiocytosis: a case report.",
"title_normalized": "chronic granulomatous disease presenting as hemophagocytic lymphohistiocytosis a case report"
} | [
{
"companynumb": "US-MYLANLABS-2014M1015870",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Daratumumab is a humanized anti-CD38 IgG1 monoclonal antibody which could be used for multiple myeloma (MM). MM with plasma-cell leukemia (PCL) transformation is highly aggressive and is resistant to conventional therapy. Novel therapeutics are needed for PCL, and daratumumab may play role. We report a case of relapsed/refractory multiple myeloma (RRMM)-transformed PCL successfully treated with daratumumab. The case was a 42-year-old man who was diagnosed with MM 2 years ago and relapsed after six cycles of bortezomib-based chemotherapy. The patient rapidly developed hyperleukocytosis and disseminated intravascular coagulation, and was diagnosed with PCL. Daratumumab-based therapy was tried and the case miraculously obtained complete remission (CR) after four doses of a weekly infusion of daratumumab. Finally the patient received autologous hematopoietic stem-cell transplantation (auto-HSCT) and maintained CR. Moreover, we monitored the immune cell dynamics by flow cytometry (FCM) during daratumumab-based treatment. The immune cell subset analysis revealed significant down-regulation of CD38+ natural killer (NK) cells, regulatory T cells (Tregs) and regulatory B cells (Bregs). Meanwhile cytotoxic T-lymphocyte expansion was observed. In conclusion, daratumumab could rapidly decrease tumor burden, improve the condition of the PCL patient, and serve as a bridging salvage chemotherapy for further chimeric antigen recptor T cell therapy (Car-T) or HSCT, which could potentially improve patient survival. The immune cell dynamic findings in this case suggest that the immunomodulatory mechanism may contribute to the antimyeloma effect of daratumumab.",
"affiliations": "Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu, China.;Department of Laboratory Medicine, West China Hospital, Sichuan University Chengdu, China.;Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu, China.;Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu, China.;Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, Guoxue Alley 37, Chengdu 610041, China.",
"authors": "Yang|Chen-Lu|CL|;Jiang|Neng-Gang|NG|;Zhang|Li|L|;Shen|Kai|K|;Wu|Yu|Y|https://orcid.org/0000-0001-8708-9711",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2040620721989578",
"fulltext": "\n==== Front\nTher Adv Hematol\nTher Adv Hematol\nTAH\nsptah\nTherapeutic Advances in Hematology\n2040-6207\n2040-6215\nSAGE Publications Sage UK: London, England\n\n10.1177/2040620721989578\n10.1177_2040620721989578\nAdvances in Multiple Myeloma (MM)\nCase Report\nRelapsed/refractory multiple myeloma-transformed plasma-cell leukemia successfully treated with daratumumab followed by autologous stem cell transplantation\nYang Chen-lu *Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu, China\n\nJiang Neng-gang *Department of Laboratory Medicine, West China Hospital, Sichuan University Chengdu, China\n\nZhang Li Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu, China\n\nShen Kai Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu, China\n\nhttps://orcid.org/0000-0001-8708-9711\nWu Yu Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, Guoxue Alley 37, Chengdu 610041, China\n\nwu_yu@scu.edu.cn\n* These authors contributed equally to this study\n\n28 1 2021\n2021\n12 20406207219895785 8 2020\n4 1 2021\n© The Author(s), 2021\n2021\nSAGE Publications\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nDaratumumab is a humanized anti-CD38 IgG1 monoclonal antibody which could be used for multiple myeloma (MM). MM with plasma-cell leukemia (PCL) transformation is highly aggressive and is resistant to conventional therapy. Novel therapeutics are needed for PCL, and daratumumab may play role. We report a case of relapsed/refractory multiple myeloma (RRMM)-transformed PCL successfully treated with daratumumab. The case was a 42-year-old man who was diagnosed with MM 2 years ago and relapsed after six cycles of bortezomib-based chemotherapy. The patient rapidly developed hyperleukocytosis and disseminated intravascular coagulation, and was diagnosed with PCL. Daratumumab-based therapy was tried and the case miraculously obtained complete remission (CR) after four doses of a weekly infusion of daratumumab. Finally the patient received autologous hematopoietic stem-cell transplantation (auto-HSCT) and maintained CR. Moreover, we monitored the immune cell dynamics by flow cytometry (FCM) during daratumumab-based treatment. The immune cell subset analysis revealed significant down-regulation of CD38+ natural killer (NK) cells, regulatory T cells (Tregs) and regulatory B cells (Bregs). Meanwhile cytotoxic T-lymphocyte expansion was observed. In conclusion, daratumumab could rapidly decrease tumor burden, improve the condition of the PCL patient, and serve as a bridging salvage chemotherapy for further chimeric antigen recptor T cell therapy (Car-T) or HSCT, which could potentially improve patient survival. The immune cell dynamic findings in this case suggest that the immunomodulatory mechanism may contribute to the antimyeloma effect of daratumumab.\n\nplasma-cell leukemia\ndaratumumab\nimmunomodulatory effect\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nMultiple myeloma (MM) with plasma-cell leukemia (PCL) transformation is highly aggressive, has a poor prognosis, and is difficult to treat. We report a case of relapsed/refractory multiple myeloma (RRMM)-transformed PCL successfully treated with daratumumab. Complete remission (CR) was obtained, and the patient received autologous hematopoietic stem cell transplantation (auto-HSCT).\n\nCase presentation\n\nA 42-year-old man was diagnosed with MM following a right humeral fracture. Postoperative pathology revealed extramedullary myeloma involvement, whereas the complete blood count, serum calcium, albumin and globulin levels and renal function test results were normal. Urine and serum immunofixation electrophoresis revealed a concentrated band in the κ light chain lane, with no monoclonal heavy chain. His κ free light chain (FLC) concentration was 1030 mg/l (normal 6.7–22.4 mg/l), and λ FLC concentration was 5.59 mg/l (normal 8.3–27.0 mg/l). The thrombin time was 52.4 s (normal 14–22 s). The β2 microglobulin level was 4.56 mg/l (normal 0.70–1.3 mg/l). Bone marrow (BM) smear revealed 75.5% plasma cells, and flow cytometry (FCM) showed 23.9% abnormal plasma cells with restrictive κ light chain expression. Chromosomal karyotyping revealed 50,XY,t(8;14) (q24;q32), +9, +11, −14, +der(14)t(8;14), +18, +mar[3]/46, XY[17]. Accordingly, the patient was diagnosed with κ light chain MM (Durie Salmon stage IIA, Internatinoal Staging System stage II) having a complex karyotype.\n\nThis high-risk patient was initially treated with a BCD regimen (bortezomib 2.4 mg days 1, 8, 15 and 22; cyclophosphamide 450 mg days 1, 8, 15 and 22; and dexamethasone 20 mg days 1–2, 8–9, 15–16 and 22–23). Even though his cycle intervals were prolonged due to amenability issue and infection events, partial response was achieved after four BCD cycles, which improved to very good partial response after six cycles. Before peripheral stem cell harvesting, the κ FLC concentration recovered, indicating MM progression. The patient was switched to the BRD regimen (bortezomib, dexamethasone and lenalidomide), which stabilized the disease. However, soon after, he developed petechiae and ecchymosis and was admitted to the emergency department. His hemoglobin level was 72 g/l, platelet count 31 × 109/l and white blood cell (WBC) count 122.68 × 109/l with 78.0% unclassifiable nucleated cells, the morphology of which resembled plasma cells. The thrombin time was >120 s, and κ FLC increased to 1630 mg/l. The alanine aminotransferase level was high at 534 µ/l (normal <50 µ/l) and the lactate dehydrogenase level was 1788 µ/l (normal <182 µ/l). Peripheral blood (PB) FCM confirmed the presence of numerous clonal plasma cells. It appeared that MM had progressed to PCL. He was in a critical condition with disseminated intravascular coagulation (DIC) and hepatic dysfunction as a result of high tumor burden and liver infiltration.\n\nConsidering the nature of PCL and its resistance to conventional therapy, we initiated daratumumab in combination with lenalidomide and dexamethasone (DRd). The first dose of daratumumab (16 mg/kg) was divided to 3 days in week 1 to alleviate tumor lysis syndrome. Lenalidomide (10 mg daily) was administered orally. Remarkably, PB plasma cells were reduced to only 0.2% with negative CD38 expression on FCM analysis after the first week of infusion. In week 2, 1000 mg daratumumab was infused in a single day, and his tumor burden continued reducing, with κ FLC concentration decreasing to 52.4 mg/l, β2 microglobulin level of 3.6 mg/l and no detectable clonal plasma cells in the PB using FCM. However, after week 2 of treatment, the patient developed neutropenia with intermittent fever and WBC count decreasing to 0.31 × 109/l. Lenalidomide was discontinued, and daratumumab infusion was postponed. Following antibiotic therapy and granulocyte colony-stimulating factor (G-CSF) support for 1 week, the third and fourth daratumumab (1000 mg) infusions were re-initiated. After the 4-week regimen, BM smears revealed no plasma cells. Minimal residual disease (MRD) was negative on BM FCM, and the serum FLC ratio returned to normal (Figure 1). Considering the continued CR, absence of MRD and the aggressive nature of his disease, we proposed allogenic HSCT. However, no human leukocyte antigen (HLA)-matching donor was available after checking his siblings and the Chinese Bone Marrow Donor Program. Therefore, stem cells were collected after the first course of DRd therapy using the hematopoietic stem cell mobilizing agents G-CSF and plerixafor. Auto-HSCT was performed after another two cycles of DRd. He received auto-HSCT on 2 April 2020, with melphalan 200 mg/m2 used as preconditioning. The transplant was successful, and at 3 months after transplantation, the patient remained in CR. Lenalidomide was used as the maintenance therapy after transplantation.\n\nFigure 1. Free light chain concentration of the patient in different treatment stages.\n\nWe used FCM to monitor immune cell dynamics weekly during DRd therapy after the first dose of daratumumab. Besides the rapid clearance of plasma cells, both natural killer (NK) cells, B cells and CD38+ regulatory T cells (Tregs) were significantly downregulated, and the proportion of T cells quickly increased, with a higher proportion of CD8+ than CD4+ T cells (Figure 2). NK cell subgroup analysis revealed that CD38high NK cells showed a more significant decrease compared with CD38low NK cells. CD38high NK cells decreased from 13.7% to 1.2%; CD38low NK cells showed no significant decrease (2.7% before treatment, 0.8% after).\n\nFigure 2. Immune cell dynamics using flow cytometry before and after daratumumab-based therapy.\n\nRapid downregulation of NK cells, B cells, Bregs, and Tregs can be noted after 4 weeks of daratumumab-based therapy. Meanwhile, the proportion of T cells is increased, with a higher increase of CD8+ compared with CD4+ T cells.\n\nBregs, regulatory B cells; Tregs, regulatory T cells; NK, natural killer.\n\nDiscussion\n\nThis high-risk patient with MM showed rapid disease progression to PCL during proteasome inhibitor and immunomodulator-based treatment and was salvaged by daratumumab-based novel therapy. Daratumumab is a humanized anti-CD38 IgG1 monoclonal antibody (mAb), the safety and efficacy of which for MM treatment is well documented. Daratumumab may be effective in approximately 20% of patients with RRMM. However, documentation on the use of daratumumab in primary PCL is scarce.1,2 To the best of our knowledge, our case is the first report of daratumumab treatment of RRMM-transformed PCL resulting in CR and followed by auto-HSCT.\n\nDaratumumab was well tolerated in this patient whose condition was critical when the disease progressed to PCL with DIC. Abnormal coagulation function improved after only 1 week of daratumumab treatment. Deep remission was achieved only after the first DRd cycle, as shown by the normalized FLC ratio and undetectable clonal plasma cells in the BM. No tumor lysis syndrome was observed, indicating that daratumumab has a rapid action and appears suitable for patients with heavy tumor burden. The risk of BM suppression should be considered, particularly when lenalidomide is added.\n\nThe immune cell subset analysis in our study revealed significant CD38+ NK cell, Treg, and Breg downregulation along with augmented CTL activity, which is consistent with the outcome of GEN501 and SIRIUS studies.3 In our previous study, we found that regulatory B cells (Bregs) in MM can abrogate NK cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) against MM cells. Therefore, decreasing Bregs may enhance the ADCC activity and cytotoxicity against MM triggered by anti-SLAMF7, anti-CD38 and mAbs against other MM-specific antigens.4 Although a recent study using immune profiling has shown that daratumumab may further reduce CD38+ NK cells as well as cause CD38 downregulation in target cells, a subgroup analysis of NK cells in the same study revealed that CD38high NK cells showed a more significant decrease compared with CD38low NK cells.5 Another study further indicated that the remaining CD38low PB NK cells could survive the daratumumab fratricide and retain their anti-MM potential.6 CD38 is expressed at higher levels on Tregs than on conventional T cells (Tcons) in patients with MM. Therefore, anti-CD38 mAb results in the preferential depletion of Tregs, relieving Tcons from Treg suppression, which elicits CD8+ T cell and NK cell-induced MM cell killing. Moreover, these immune effects induced by anti-CD38 mAbs were reportedly further enhanced by immunomodulatory drugs (IMiDs), which favor the combination use of anti-CD38 mAb with IMiDs in patients with RRMM.3 Moreover, it has been proposed that anti-CD38 targeting induces the activation and degranulation of NK cell and leads to an increased expression of CD80/CD86 T cell costimulatory molecules on monocytes, which induces monocyte polarization and activation and stimulates T cell expansion via CD28 binding.7\n\nIn some phase I and II clinical trials on MM, NK cell decline following daratumumab exposure did not show significant impact on the efficacy and toxicity outcomes. However, immune cell dynamics other than NK cell fratricide could be employed as a potential efficacy predictor for anti-CD38 mAb therapy, among which Tregs, Bregs and CTLs may be promising candidates. Nonetheless, these immune markers should be validated in clinical cohorts.\n\nIn conclusion, this case suggests that daratumumab can be used in RRMM-transformed PCL by rapidly decreasing tumor burden and stabilizing patient condition. Daratumumab may serve as an ideal bridging salvage chemotherapy for further treatment, such as chimeric antigen recptor T cell therapy (Car-T) or HSCT.\n\nAuthor contributions: Yu Wu initiated this work and is responsible for the final approval of the version to be published. Chen-lu Yang and Kai Shen are responsible for clinical data collection, analysis, and interpretation and manuscript drafting. Neng-gang Jiang and Li Zhang have contributed substantially to the FCM analysis.\n\nConflict of interest: The author(s) declare that there is no conflict of interest.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Innovation Supporting Program of Sichuan Province, China (2018RZ0137) and the Innovation Development Program of Chengdu (2019-YF05-01242-SN).\n\nInformed consent and ethics: Written informed consent was obtained from the patient, and the study was approved by the West China Hospital of Sichuan University Biomedical Research Ethics Committee (#2019-114).\n\nORCID iD: Yu Wu https://orcid.org/0000-0001-8708-9711\n==== Refs\nReferences\n\n1. Nalghranyan S Singh AP Schinke C . The combination of venetoclax, daratumumab and dexamethasone for the treatment of refractory primary plasma cell leukemia. Am J Hematol 2020; 95 : E34–E35.31709578\n2. Horisawa Y Kondo T Hishizawa M , et al . A case of allogeneic hematopoietic stem cell transplantation for primary plasma cell leukemia after treatment with daratumumab. Ann Hematol 2020; 99 : 2699–2701.32318778\n3. Zambello R Barilà G Manni S , et al . NK cells and CD38: implication for (immuno)therapy in plasma cell dyscrasias. Cells 2020; 9 : 768.\n4. Zhang L Tai YT Ho M , et al . Regulatory B cell–myeloma cell interaction confers immunosuppression and promotes their survival in the bone marrow milieu. Blood Cancer J 2017; 7 : e547.\n5. Casneuf T Adams HC III van de Donk NWCJ , et al . Deep immune profiling of patients treated with lenalidomide and dexamethasone with or without daratumumab. Leukemia. Epub ahead of print 26 5 2020. DOI: 10.1038/s41375-020-0855-4\n6. Sarkar S Chauhan SKS Daly J , et al . The CD38low natural killer cell line KHYG1 transiently expressing CD16F158V in combination with daratumumab targets multiple myeloma cells with minimal effector NK cell fratricide. Cancer Immunol Immunother 2020; 69 : 421–434.31919623\n7. Viola D Dona A Caserta E , et al . Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting. Leukemia. Epub ahead of print 16 4 2020. DOI: 10.1038/s41375-020-0810-4\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2040-6207",
"issue": "12()",
"journal": "Therapeutic advances in hematology",
"keywords": "daratumumab; immunomodulatory effect; plasma-cell leukemia",
"medline_ta": "Ther Adv Hematol",
"mesh_terms": null,
"nlm_unique_id": "101549589",
"other_id": null,
"pages": "2040620721989578",
"pmc": null,
"pmid": "33796234",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32457357;31709578;32296125;31919623;28338671;32318778;32245149",
"title": "Relapsed/refractory multiple myeloma-transformed plasma-cell leukemia successfully treated with daratumumab followed by autologous stem cell transplantation.",
"title_normalized": "relapsed refractory multiple myeloma transformed plasma cell leukemia successfully treated with daratumumab followed by autologous stem cell transplantation"
} | [
{
"companynumb": "CN-TAKEDA-2021TUS012657",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPotent and potentially harmful new psychoactive substances (NPS) are continuously introduced on the recreational drugs market. This report from the Swedish STRIDA project describes analytically confirmed cases of intoxication involving the fentanyl analogs acetylfentanyl, 4-methoxybutyrfentanyl, and furanylfentanyl.\n\n\nMETHODS\nPatients with suspected NPS exposure presenting in emergency departments and intensive care units in Sweden and requiring hospital care are invited to the STRIDA project. Toxicological analysis of serum and urine samples was performed by multi-component liquid chromatographic-mass spectrometric methods. Data on clinical features were retrieved from telephone consultations with the Swedish Poisons Information Centre and from medical records.\n\n\nRESULTS\nBetween April and November 2015, 14 analytically confirmed intoxications involving acetylfentanyl (nine cases), 4-methoxybutyrfentanyl (3), furanylfentanyl (1), and 4-methoxybutyrfentanyl together with furanylfentanyl (1) were identified. The patients were aged 20-40 (mean 28.5) years and 86% were men. Twelve patients (86%) were admitted to intensive care, where two required intubation and mechanical ventilation. Typical clinical features were decreased consciousness, respiratory depression, and miosis. In eight cases, the antidote naloxone was administered to counter the effects. The serum acetylfentanyl concentration (N = 7) was 0.6-51.6 (mean 18.3 and median 14.8) ng/mL, and in urine (N = 8) 0.1-686 (mean 155 and median 66.6) ng/mmol creatinine. The serum 4-methoxybutyrfentanyl concentration (N = 2) was 1.3 and 3.1 ng/mL, and 5.1-51.3 ng/mmol creatinine in urine (N = 3). For furanylfentanyl, the serum concentrations were 4.4 and 148 ng/mL and in urine 9.2 and 85 ng/mmol creatinine, respectively. In 13 cases (93%), other NPS and/or classical drugs were also detected. Drug products brought to hospital by patients contained acetylfentanyl (nasal spray and pink tablet), 4-methoxybutyrfentanyl (green tablet), furanylfentanyl/traces of 4-methoxybutyrfentanyl (nasal spray), and 4-fluorobutyrfentanyl (purple tablet).\n\n\nCONCLUSIONS\nPotentially life-threatening opioid toxicity was seen in acute intoxications involving acetylfentanyl, 4-methoxybutyrfentanyl, and furanylfentanyl. Intensive care treatment for one month was necessary in one acetylfentanyl case and one acetylfentanyl patient died from cerebral hemorrhage.",
"affiliations": "a Department of Laboratory Medicine , Karolinska Institutet , Stockholm , Sweden ;;c Swedish Poisons Information Centre , Stockholm , Sweden.;a Department of Laboratory Medicine , Karolinska Institutet , Stockholm , Sweden ;",
"authors": "Helander|Anders|A|;Bäckberg|Matilda|M|;Beck|Olof|O|",
"chemical_list": "D000701:Analgesics, Opioid; D011619:Psychotropic Drugs; C000594854:N-(1-phenethylpiperidin-4-yl)-N-phenylacetamide; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2016.1139715",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "54(4)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "4-fluorobutyrfentanyl; 4-methoxybutyrfentanyl; Acetylfentanyl; Internet drug; butyrfentanyl; fentanyl analog; furanylfentanyl; mass spectrometry method; new psychoactive substances; opioid analgesic drug",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D005260:Female; D005283:Fentanyl; D006801:Humans; D008297:Male; D011619:Psychotropic Drugs; D012017:Referral and Consultation",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "324-32",
"pmc": null,
"pmid": "26850293",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intoxications involving the fentanyl analogs acetylfentanyl, 4-methoxybutyrfentanyl and furanylfentanyl: results from the Swedish STRIDA project.",
"title_normalized": "intoxications involving the fentanyl analogs acetylfentanyl 4 methoxybutyrfentanyl and furanylfentanyl results from the swedish strida project"
} | [
{
"companynumb": "SE-MYLANLABS-2016M1028349",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": "3",
... |
{
"abstract": "We aimed to investigate whether response-guided therapy (RGT) with peginterferon-alpha plus ribavirin by using hepatitis C virus (HCV) genotype, pretreatment HCV RNA levels, and rapid virological response (RVR, undetectable HCV RNA at treatment week 4) could be applied for active HCV/hepatitis B virus (HBV) dually infected patients, without compromised the treatment efficacy.A total of 203 patients, seropositive of HCV antibody, HCV RNA and HBV surface antigen (HBsAg), and seronegative for HBV e antigen for >6 months, were randomized to receive peginterferon-alpha/ribavirin by either genotype-guided therapy (GGT, n = 102: HCV genotype 1 [HCV-1], 48 weeks; HCV-2/3, 24 weeks) or RGT (n = 101: HCV-1, 48 or 24 weeks if patients with baseline VL <400,000 IU/mL and RVR; HCV-2/3, 24 or 16 weeks if patients with RVR). The primary endpoint was HCV-sustained virological response (SVR).The HCV SVR rate was comparable between the GGT (77.5%, 79/102) and RGT groups (70.3%, 71/101, P = 0.267), either among HCV-1/HBV (69.4% [43/62] vs 63.5% [40/63], P = 0.571) or among HCV-2/3/HBV (90.0% [36/40] vs 81.6% [31/38], P = 0.342) dually infected patients based on intention-to-treat analysis. In HCV-1/HBV dually infected patients, RVR (odds ratio [OR]: 6.05; 95% confidence intervals [CI]: 2.148-17.025, P = 0.001) and lower pretreatment blood glucose levels (OR: 0.97; CI: 0.944-0.989, P = 0.003) were independent predictors of HCV SVR. Although RVR (OR: 10.68; CI: 1.948-58.514, P = 0.006) was the only significant factor associated with HCV SVR in HCV-2/3/HBV dually infected patients. HBsAg loss at 1 year posttreatment was observed in 17 of 185 (9.2%) patients. The rates of discontinuation and adverse events were similar between the 2 groups.RGT with peginterferon-alpha/RBV may be considered for HBeAg-negative HBV/HCV dually infected patients.",
"affiliations": "From the Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital (M-LYeh, M-YH, C-FH, P-CL, Y-HL, Z-YL, S-CC, J-FH, C-YD, W-LC, M-LYu), Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University (M-LYeh, C-FH, M-HH, Z-YL, S-CC, J-FH, C-YD, W-LC; M-LYu), Institute of Biomedical Sciences, National Sun Yat-Sen University (M-LYu), Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital (C-IH, N-JH), Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University (C-FH), Department of Preventive Medicine, Kaohsiung Medical University Hospital (M-HH), Graduate Institute of Medicine, College of Medicine (M-LYeh, C-YD), Center for Infectious Disease and Cancer Research; and Center for Lipid Science and Aging Research, Kaohsiung Medical University, Kaohsiung, Taiwan (C-YD, W-LC, M-LYu).",
"authors": "Yeh|Ming-Lun|ML|;Hsieh|Ming-Yen|MY|;Huang|Ching-I|CI|;Huang|Chung-Feng|CF|;Hsieh|Meng-Hsuan|MH|;Liang|Po-Cheng|PC|;Lin|Yi-Hung|YH|;Hou|Nai-Jen|NJ|;Lin|Zu-Yau|ZY|;Chen|Shinn-Cherng|SC|;Huang|Jee-Fu|JF|;Dai|Chia-Yen|CY|;Chuang|Wan-Long|WL|;Yu|Ming-Lung|ML|",
"chemical_list": "D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000001837",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 10.1097/MD.0000000000001837018374500Research ArticleClinical Trial/Experimental StudyPersonalized Therapy of Chronic Hepatitis C and B Dually Infected Patients With Pegylated Interferon Plus Ribavirin A Randomized StudyYeh Ming-Lun MDHsieh Ming-Yen MDHuang Ching-I. MDHuang Chung-Feng MDHsieh Meng-Hsuan MDLiang Po-Cheng MDLin Yi-Hung MDHou Nai-Jen MDLin Zu-Yau MDChen Shinn-Cherng MD, PhDHuang Jee-Fu MD, PhDDai Chia-Yen MD, PhDChuang Wan-Long MD, PhDYu Ming-Lung MD, PhDAmedee. Angela From the Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital (M-LYeh, M-YH, C-FH, P-CL, Y-HL, Z-YL, S-CC, J-FH, C-YD, W-LC, M-LYu), Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University (M-LYeh, C-FH, M-HH, Z-YL, S-CC, J-FH, C-YD, W-LC; M-LYu), Institute of Biomedical Sciences, National Sun Yat-Sen University (M-LYu), Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital (C-IH, N-JH), Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University (C-FH), Department of Preventive Medicine, Kaohsiung Medical University Hospital (M-HH), Graduate Institute of Medicine, College of Medicine (M-LYeh, C-YD), Center for Infectious Disease and Cancer Research; and Center for Lipid Science and Aging Research, Kaohsiung Medical University, Kaohsiung, Taiwan (C-YD, W-LC, M-LYu).Correspondence: Ming-Lung Yu, Wan-Long Chuang, Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan (e-mail: fish6069@gmail.com).10 2015 23 10 2015 94 42 e183722 6 2015 19 9 2015 23 9 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article distributed under the Creative Commons Attribution-NonCommercial License, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be used commercially. http://creativecommons.org/licenses/by-nc/4.0Abstract\nWe aimed to investigate whether response-guided therapy (RGT) with peginterferon-alpha plus ribavirin by using hepatitis C virus (HCV) genotype, pretreatment HCV RNA levels, and rapid virological response (RVR, undetectable HCV RNA at treatment week 4) could be applied for active HCV/hepatitis B virus (HBV) dually infected patients, without compromised the treatment efficacy.\n\nA total of 203 patients, seropositive of HCV antibody, HCV RNA and HBV surface antigen (HBsAg), and seronegative for HBV e antigen for >6 months, were randomized to receive peginterferon-alpha/ribavirin by either genotype-guided therapy (GGT, n = 102: HCV genotype 1 [HCV-1], 48 weeks; HCV-2/3, 24 weeks) or RGT (n = 101: HCV-1, 48 or 24 weeks if patients with baseline VL <400,000 IU/mL and RVR; HCV-2/3, 24 or 16 weeks if patients with RVR). The primary endpoint was HCV-sustained virological response (SVR).\n\nThe HCV SVR rate was comparable between the GGT (77.5%, 79/102) and RGT groups (70.3%, 71/101, P = 0.267), either among HCV-1/HBV (69.4% [43/62] vs 63.5% [40/63], P = 0.571) or among HCV-2/3/HBV (90.0% [36/40] vs 81.6% [31/38], P = 0.342) dually infected patients based on intention-to-treat analysis. In HCV-1/HBV dually infected patients, RVR (odds ratio [OR]: 6.05; 95% confidence intervals [CI]: 2.148–17.025, P = 0.001) and lower pretreatment blood glucose levels (OR: 0.97; CI: 0.944–0.989, P = 0.003) were independent predictors of HCV SVR. Although RVR (OR: 10.68; CI: 1.948–58.514, P = 0.006) was the only significant factor associated with HCV SVR in HCV-2/3/HBV dually infected patients. HBsAg loss at 1 year posttreatment was observed in 17 of 185 (9.2%) patients. The rates of discontinuation and adverse events were similar between the 2 groups.\n\nRGT with peginterferon-alpha/RBV may be considered for HBeAg-negative HBV/HCV dually infected patients.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nHepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the leading causes of liver cirrhosis and hepatocellular carcinoma.1,2 In HBV and HCV high endemic areas, such as the Asia-Pacific region, dual infection with HBV and HCV is not uncommon. Approximately 10% of patients are dually infected with both viruses in Taiwan.3 Dually infected patients have been at a much higher risk for the aggravation and progression of liver disease than those with monoinfection.4,5\n\nCurrent guidelines for the management of HBV/HCV dual infections suggest that which virus is dominant for patients with concurrent HBV/HCV dual infections should be determined and to accordingly treat patients as monoinfections.6 PEGylated interferon (Peg-IFN) and ribavirin (RBV) combination therapy is the currently standard of care for HBV/HCV dually infected patients with active hepatitis C: 48 weeks of Peg-IFN/RBV for HCV genotype 1 (HCV-1)/HBV dually infected patients and 24 weeks of Peg-IFN/RBV for HCV-2/HBV dually infected patients.7 With the strategy of genotype-guided therapy (GGT), the sustained virological response (SVR) rate of HCV was comparable between HCV/HBV dually infected patients and HCV-monoinfected patients (around 75% for HCV-1 and 85% for HCV-2, respectively).8 Additionally, IFN plus RBV therapy also effectively suppressed HBV replication. Long-term follow-up studies in HBV/HCV dually infected patients also revealed a high cumulative hepatitis B surface antigen (HBsAg) seroclearance rate after IFN/RBV therapy.9,10\n\nResponse-guided therapy (RGT) based on on-treatment virological responses has achieved comparable efficacy for HCV monoinfected patients when compared to those with standard duration of Peg-IFN/RBV. A similar SVR rate between 24 and 48 weeks Peg-IFN/RBV therapy was observed in HCV-1 monoinfected patients with low baseline viral loads (LVLs) and a rapid virological response (RVR).11–14 Similarly, 16 weeks of Peg-IFN plus weight-based RBV is recommended for HCV-2/3 patients with an RVR.14–18 However, whether the concept of RGT with Peg-FIN/RBV can be applied in patients with HBV/HCV dual infections with active hepatitis C has not been studied.\n\nThis randomized-controlled study aimed to investigate the efficacy of a tailored regimen of Peg-IFN/RBV based on RGT in the treatment of patients with HBV and active HCV dual infections.\n\nMATERIALS AND METHODS\nStudy Population\nThis is an open label, randomized-controlled, comparative trial, conducted in a medical center in the Southern Taiwan. Eligible subjects were previously untreated patients or had previously failed interferon monotherapy with chronic HBV/HCV dual infections, aged 18 to 65 years, who were seropositive for HBsAg, HCV antibodies (Anti-HCV) and HCV RNA for >6 months; were seronegative for hepatitis B e antigen (HBeAg); and serum alanine aminotransferase levels between 1 and 10-fold of the upper limit of normal (ULN). Other eligibility criteria included neutrophil count >1500 mm3, platelet count >9 × 104 mm3, hemoglobin level >12 g/dL for men and >11 g/dL for women, no pregnancy or lactation, and the use of a reliable method of contraception.\n\nThe exclusion criteria included human immunodeficiency virus infection, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, Wilson disease, α1-antitrypsin deficiency, overt hepatic failure, psychiatric condition, previous liver transplantation, with evidence of hepatocellular carcinoma, decompensated liver disease (Child–Pugh score ≥7); pregnant or breast-feeding women; serum creatinine ≥2 mg/dL; evidence of alcoholism or drug abuse; any other known disease that was not suitable for Peg-IFN therapy.\n\nStudy Design\nThe study design is illustrated in Figure 1. Eligible subjects were randomized into 2 groups at treatment initiation. Subjects who were randomized into the GGT group received Peg-IFN and weight-based dose RBV (1000–1200 mg/day) for 48 weeks in subjects dually infected with HCV-1/HBV or Peg-IFN and fixed low dose RBV (800 mg/day) for 24 weeks in subjects dually infected with HCV-2/3/HBV; the patients were then followed for 6 months. For subjects who were randomized into the RGT group, all patients were treated with Peg-IFN and weight-based RBV. For HCV-1/HBV dually infected patients, treatment duration was 24 weeks for patients with a low LVL (LVL, <400,000 IU/mL, defined based on our previous study11) and RVR (HCV RNA undetectable at treatment week 4); the others were treated with 48-week regimen. For HCV-2/3/HBV dually infected patients, the treatment duration was 16 weeks for patients with RVR; the others were treated with 24 weeks. The randomization was performed by computer software.\n\nFIGURE 1 Study design of the open label, randomized-controlled, comparative trial. G-1 = genotype 1, G-2/3 = genotype 2/3, GGT = genotype guided therapy, HVL = high viral load, pretreatment HCV RNA >400,000 IU/mL, LD RBV = low dose ribavirin, 800 mg/day, LVL = low viral load, pretreatment HCV RNA ≤400,000 IU/mL, RGT = response guided therapy, RVR = rapid virological response, HCV RNA <50 IU/mL at treatment week 4, SD RBV = standard dose ribavirin, 1000-1200 mg/day.\n\nLaboratory Testing\nHBsAg, HBeAg, and anti-HBe were tested using commercially available enzyme-linked immunosorbent assay kits (Abbott Laboratories, North Chicago, IL). Anti-HCV was determined by a third-generation enzyme immunoassay (Abbott Laboratories, North Chicago, IL). HCV RNA was measured using a qualitative polymerase chain reaction assay (CobasAmplicor Hepatitis C Virus Test, version 2.0; Roche Diagnostics, Branchburg, NJ; detection limit: 50 IU/mL). Serum levels of HCV RNA were quantified by the branched DNA assay (Versant HCV RNA3.0, Bayer, Tarrytown, NJ; quantification limit: 615 IU/mL) if qualitative HCV RNA seropositivity. HCV genotypes were determined using the method described by Okamoto et al.19 Serum HBV DNA levels were determined using the CobasAmpliPrep/CobasTaqMan HBV assay (CAP/CTM version 2.0, Roche Diagnostics, Indianapolis, IN; dynamic range 20 IU/mL–1.7 × 108IU/mL).\n\nTreatment Responses\nThe primary endpoint was HCV SVR, defined as HCV RNA negativity 24 weeks after the end-of-treatment. On-treatment HCV virological responses included RVR (defined as HCV RNA negativity at treatment week 4), early virological response (EVR, defined as HCV RNA negativity at treatment week 12), and end-of-treatment virological response (EOTVR, defined as HCV RNA negativity at treatment cessation).\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki and the principles of Good Clinical Practice and was approved by the local ethics committees. Written informed consent was obtained from all patients.\n\nStatistics\nThe primary efficacy was analyzed using the intent-to-treat (ITT) analysis. Patients who received at least 1 dose of the study medication would be included into the ITT analysis. Per-protocol (PP) analysis was also performed in population who had received 80-80-80 adherence and with HCV RNA available 24 weeks after EOT. Safety analysis included any patient who had received at least 1 dose of study medication. According to the publications from Taiwan11,12,18 and an estimated 3:2 ratio of enrolled patients with genotype 1 and genotype 2/3, we assumed a difference of SVR rate of 13% between GGT and RGT groups. Using the assumption, a sample size of 95patients per group will provide a statistical power of at least 80% to detect a between group difference at the significant level of 0.05. A withdrawal rate of 5% will be allowed and the sample size will be finally set at 100 patients per group.\n\nContinuous variables were expressed as the mean ± standard deviation or the median (25th, 75th percentile). The Student's t-test and Mann–Whitney U test were used to compare continuous variables and the Chi-square and Fisher exact tests were used to compare categorical variables. Binary logistic regression analysis was used to identify the independent factors associated with SVR. All tests were 2-sided and P < 0.05 was considered statistically significant. All analyses were performed using the SPSS ver17.0 statistical package (SPSS, Inc., Chicago, IL).\n\nRESULTS\nDemographics and Comparison of Baseline Characteristics\nA total of 203 patients were enrolled into the study, 102 in GGT group and 101 in RGT group. Of GGT group, 62 patients were HCV-1 and 40 were HCV-2/3. Of RGT group, 63 patients were HCV-1 and 38 were HCV-2/3 (Fig. 2). Table 1 showed the demographics of all the patients and the comparison of baseline characteristics between GGT and RGT groups. The baseline characteristics were comparable between the 2 groups.\n\nFIGURE 2 Patient flowchart. F/U = follow-up, GGT = genotype guided therapy, GT = genotype, HBsAg = hepatitis B surface antigen, HCC = hepatocellular carcinoma, HCV = hepatitis C virus, RGT = response guided therapy, SAE = serious adverse event,.\n\nTABLE 1 Demographics and Comparison of Baseline Characteristics Between Genotype-Guided and Response-Guided Group\n\nHCV Response\nThe HCV treatment response was shown in Table 2. In the ITT analysis, for patients of HCV-1/HBV, 59.7%, 83.9%, 88.7%, and 69.4% of patients in the GGT group compared with 44.4%, 92.1%, 93.7%, and 63.5% of the patients in the RGT group achieved RVR, EVR, EOTVR, and SVR (P = 0.108, 0.180, 0.363, and 0.571), respectively. For patients of HCV-2/3/HBV, 95.0%, 97.5%, 97.5%, and 90.0% of patients in the GGT group compared with 84.2%, 97.4%, 94.7%, and 81.6% of patients in the RGT group achieved RVR, EVR, EOTVR, and SVR (P = 0.149, 1.000, 0.610, and 0.342), respectively. Taken together, 77.5% of patients in the GGT group compared with 70.3% of patients in the RGT group achieved HCV SVR in the ITT analysis (P = 0.267), respectively.\n\nTABLE 2 Comparison of HCV Response Between Genotype-Guided and Response-Guided Groups\n\nA total of 12 patients, who did not receive 80-80-80 adherence or without HCV RNA available 24 weeks after EOT, were not included into PP analysis. In the PP analysis, for patients of HCV-1/HBV, 62.7%, 88.1%, 93.2%, and 72.9% of patients in the GGT group compared with 44.6%, 96.4%, 98.2%, and 71.4% of patients in the RGT group achieved RVR, EVR, EOTVR, and SVR (P = 0.063, 0.164, 0.365, and 1.000), respectively. For patients of HCV-2/3/HBV, 94.9%, 100%, 100%, and 92.3% of patients in the GGT group compared with 86.5%, 97.3%, 94.6%, and 83.8% of patients in the RGT group achieved RVR, EVR, EOTVR, and SVR (P = 0.256, 0.487, 0.234, and 0.303), respectively. Taken together, 80.6% of patients in the GGT group compared with76.3% of patients in the RGT group achieved HCV SVR in the PP analysis (P = 0.487), respectively.\n\nFactors Associated With HCV SVR\nThe factors associated with SVR were further analyzed. In univariate analysis, pretreatment low serum glucose levels (P = 0.006), low HCV RNA levels (P = 0.002), and RVR (P < 0.001) were factors associated with HCV SVR in HCV-1/HBV dually infected patients. The multivariate analysis showed that only pretreatment low serum glucose levels (OR: 0.97, 95%CI: 0.944–0.989, P = 0.003) and RVR (OR: 6.05, 95%CI: 2.148 – 17.025, P = 0.001) were independently associated factors (Table 3). For HCV-2/3/HBV dually infected patients, the univariate analysis identified RVR (P = 0.012) as the only factor associated with HCV SVR. Further multivariate analysis demonstrated that RVR (OR: 10.68, 95%CI: 1.948–58.514, P = 0.006) was the only independent factors associated with HCV SVR (Table 3). We further analyzed factors associated with HCV SVR in GGT and RGT groups, independently (Table 4). For HCV/HBV dually infected patients in GGT group, the multivariate analysis showed that RVR (OR: 18.92, 95%CI: 4.689–76.354, P < 0.001) was the only factor associated with HCV SVR. By contrast, for those in RGT group, multivariate analysis demonstrated that pretreatment HCV RNA level (OR: 0.49, 95%CI: 0.256–0.934, P = 0.030) was the only factor independently associated with HCV SVR.\n\nTABLE 3 Univariate and Multiple Logistic Regression Analyses of Factors Associated With HCV SVR in HCV-1, and HCV-2/3/HBV Dually Infected Patients\n\nTABLE 4 Univariate and Multiple Logistic Regression Analyses of Factors Associated With HCV SVR of HCV/HBV Dually Infected Patients in GGT and RGT Groups\n\nHBV Response\nA total of 139 patients with baseline HBV DNA available demonstrated that HBV DNA was detectable among 45 (32.4%) patients (mean, 3.9 log10 IU/mL, range 1.8–7.9 log10 IU/mL), with no difference between the 2 groups (Table 5). At the end-of-treatment, the HBV DNA was detectable among 13 (18.6%) patients in GGT group (mean, 3.3 log10 IU/mL, range 2.1–6.0 log10 IU/mL) and 15 (21.7%) patients in RGT group (mean, 3.4 log10 IU/mL, range 1.8–7.9 log10 IU/mL, P = 0.772). At 24 weeks posttreatment, the HBV DNA was detectable among 28 (40.0%) patients in GGT group (mean, 3.7 log10 IU/mL, range 2.2–7.1 log10 IU/mL) and 16 (23.2%) patients in RGT group (mean, 3.5 log10 IU/mL, range 2.1–7.9 log10 IU/mL, P = 0.678). Among 94 patients with undetectable HBV DNA at baseline, reappearance of HBV DNA was found in 7 (7.4%) of the 94 patients at the end-of-treatment and in 18 (19.1%) at 24 weeks posttreatment. Significantly higher rate of HBV DNA reappearance at 24 weeks posttreatment was observed in the GGT group than in the RGT group (32.6% vs 6.2%, P = 0.001). Six (33.3%) of the 18 patients with HBV DNA reappearance at 24 weeks posttreatment had reappeared HBV DNA level greater than 2000 IU/mL and all of them were in the GGT group. Among 45 patients with baseline detectable HBV DNA, 24 (53.3%) and 20 (44.4%) had HBV DNA undetectable in 24 at the end-of-treatment and in 24 weeks posttreatment, respectively. The rate of HBV DNA undetectable 24 weeks posttreatment did not differ between GGT (45.8%) and RGT (38.1%) groups. Among 45 patients with baseline detectable HBV DNA, none had increased HBV DNA level greater than 1 log10 IU/mL at the end-of-treatment and 2 had increased HBV DNA level greater than 1 log10 IU/mL 24 weeks posttreatment.\n\nTABLE 5 HBV Virological Response After PEGylated Interferon and Ribavirin Therapy\n\nHBsAg loss was observed in 17 (9.2%) of the 185 patients who had HBsAg data available 1 year posttreatment, including 9 (9.5%) of the 95 patients in GGT group and 8 (8.9%) of the 90 patients in RGT group (P = 1.000).\n\nSafety Profile\nThe type of adverse events (AEs) in dual-infected patients were similar to those seen in HCV-monoinfected patients. There was no difference of incidence of AEs, serious adverse events (SAE), and dose modification between GGT and RGT groups (Table 6). A total of 13 patients, 5 in GGT and 8 in RGT groups happened SAE during study period. Seven of the 13 patients with SAE, 4 in GGT and 3 in RGT groups, discontinued Peg-IFN/RBV therapy.\n\nTABLE 6 Rates of Serious Adverse Events, Grade 3 or 4 Adverse Events, Dose Modification, and Adverse Events\n\nNotably, there were 3 patients experienced severe acute hepatitis flare (alanine aminotransferase level >10-folds ULN and total bilirubin level >2-folds ULN) correlated to HBV DNA surge within 48 weeks posttreatment. One patient suffered from liver decompensation related to HBV cirrhosis. All of the 4 patients received NUC therapy immediately and were well controlled thereafter. Another patient had severe liver decompensation which was not related to HBV (HBV DNA level less than 60 IU/mL) at 4th week of Peg-IFN/RBV therapy and died within 1 month.\n\nDISCUSSION\nThe current study demonstrated that the concept of RGT for HCV-monoinfected patients might also be applied in HBeAg-negative HBV/HCV dually infected patients with an HCV SVR rate of 63.5% in HCV-1/HBV and 81.6% in HCV-2/3/HBV dually infected patients.\n\nIn HCV monoinfected patients, a fixed duration therapy with Peg-IFN/RBV achieved approximately 50% SVR in HCV-1 and 83% SVR in HCV-2/3 patients in Western countries.16,17,20–24 For Asian patients with HCV monoinfection, better SVR rates of approximately 77% in HCV-1 and over 90% in HCV-2/3 patients have been observed.18,25 Different patterns of on-treatment virological responses have been reported.26 A shortened duration of 24-week Peg-IFN/RBV therapy could achieve a comparable SVR rate with standard 48-week therapy for HCV-1 patients with pretreatment LVL and RVR.11–14 Similarly, 16 weeks of Peg-IFN combined with standard dose of RBV had a noninferior SVR rate compared with 24-week therapy for HCV-2/3 patients with RVR in meta-analysis.14 Therefore, Peg-IFN/RBV RGT for HCV monoinfection was recommended in European and Asian-Pacific guidelines in the era before directly acting antiviral agents (DAAs) were available.6,27\n\nFor HBV/HCV dually infected patients with active hepatitis C, the treatment duration and efficacy of Peg-IFN/RBV therapy has recently confirmed.8,27,28 A Taiwanese multicenter clinical trial demonstrated that 48 and 24 weeks of Peg-IFN/RBV therapy achieved similar HCV SVR rate between HCV/HBV dually infected and HCV-monoinfected patients, for HCV-1 or HCV-2/3 infections, respectively.8 The following study also revealed a durable HCV SVR in 97% of patients during long-term follow-up.10 Similar results were also reported from Europe and Korea.29,30 However, these results were based on an HCV GGT with fixed duration of Peg-IFN/RBV, 48 weeks in HCV-1 and 24 weeks in HCV-2/3 patients. Whether a tailored abbreviated treatment regimen using the concept of RGT for patients with RVR could be applied for HBV/HCV dually infected patients has never been studied.\n\nThe current study first demonstrated that a tailored duration of Peg-IFN/RBV therapy according to pretreatment viral load (VL) and RVR had comparable HCV SVR rates compared with fixed duration of GGT in HBV/HCV dually infected patients with either HCV-1 or HCV-2/3 infections. These findings indicated that the strategies of RGT for HCV monoinfection could also be translated to HBV/HCV dual infections.\n\nWe also observed that pretreatment low glucose levels and RVR were factors associated with SVR in dually infected patients with HCV-1/HBV dually infections, and RVR was the only factor associated with SVR in patients with HCV-2/3 infections. These findings echoed the impact of insulin resistance on the treatment response to Peg-IFN/RBV for HCV-1-monoinfected patients31 and the leading role of RVR in determining the SVR to Peg-IFN/RBV therapy for HCV-monoinfected patients.32\n\nInteractions between HBV and HCV are important issues in dually infected patients. HBsAg loss and DNA suppression following Peg-IFN/RBV have been observed. By contrast, reappearance of HBV DNA might occur in patients with pretreatment undetectable HBV DNA.8 In the current study, the rate of HBsAg loss was similar between GGT and RGT groups, both were comparable with previous reports.10,33 The rate (19.1%) of posttreatment HBV reappearance in patients with baseline undetectable HBV DNA and the rate (44.4%) of HBV virologic response in patients with baseline detectable HBV DNA were also consistent with previous studies. Interestingly, we found that among patients with baseline undetectable HBV DNA, GGT group had a significantly higher rate of posttreatment HBV DNA reappearance than the RGT group did. The findings implicated that close observation of certain HBV/HCV dually infected patients after Peg-IFN/RBV therapy is warranted. Fortunately, only 4 patients experienced significant HBV-related clinical reactivation. All the patients were controlled after immediately treated with HBV nucleot(s)ide analogs.\n\nConsistent with previous studies, Peg-IFN/RBV combination therapy was well tolerated with high adherence and low discontinuation rate in the current study. The incidence and severity of AEs and laboratory abnormalities were similar to those reported previously in HCV-monoinfected patients.34 There was also no significant difference of AEs and laboratory abnormalities between patients of GGT and RGT groups.\n\nThe substantial lower SVR rate was observed in HCV-2/3/HBV dually infected patients treated with RGT in the current study. As for HCV-2/3-monoinfected patients, an abbreviated treatment duration of Peg-IFN/RBV is not recommended for those with unfavorable predictors, such as obesity, cirrhosis, and high baseline VL, even they achieving an RVR. Nevertheless, our findings indicated that 24 and 16 weeks of Peg-IFN/RBV may be considered for low VL HCV-1/HBV and HCV-2/HBV dually infected patients, respectively, if they achieve an HCV RVR.\n\nRecently, introduction of newly developed DAAs with or without IFN and/or RBV have a great achievement in treatment efficacy and safety for anti-HCV therapy with SVR rates of higher than 90% for HCV-1 or 2 patients.35–37 However, there is no DAAs data available for HCV/HBV dually infected patients. Whether the high efficacy and good safety of newly introduced DAA-based therapy for HCV monoinfection could be translated to HCV/HBV dually infected patients still needs further studies. Moreover, lack of Peg-IFN effect on HBV, the safety of DAA IFN-free regimens for HCV/HBV dually infected patients, remains to be explored carefully, in terms of HBV reactivation after HCV eradication. Peg-IFN/RBV would be the mainstay for the treatment of HBV/HCV dually infected patients before new therapeutic agents with better efficacy and safety available.38 Our data support a cost-effective strategy with Peg-IFN/RBV for the treatment of HBeAg-negative HCV/HBV dually infected patients and the chance to treat both infections at once, which may not be achieved by the new DAAs. Furthermore, in the era of new DAAs, our findings may also provide evidence to obviate unnecessary protease inhibitor39 or to conduct RGT based on HCV genotype and pretreatment/on-treatment viral kinetics when applying DAA plus Peg-IFN/RBV combination therapy for HBeAg-negative chronic dual HCV/HBV infections.40\n\nIn conclusion, RGT with Peg-IFN plus RBV according to HCV genotype, baseline HCV VL and RVR had comparable efficacy as GGT for HBeAg-negative HBV/HCV dually infected patients. Strategy of RGT with abbreviated regimens may be considered for the clinical settings.\n\nACKNOWLEDGEMENTS\nThe authors thank grants from Kaohsiung Medical University Hospital (grant number KMUH100-0R05 and KMUH101-1R05) and grants from Kaohsiung Medical University “Aim for the Top Universities Grant, grant No. KMU-TP103E06, KMU-TP103D12, KMU-TP103D13, and KMU-TP103D14.” The authors also thank secretary, serum processing helps from Taiwan Liver Research Foundation (TLRF). They did not influence how the study was conducted or the approval of the manuscript. The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.\n\nAbbreviations: AE = adverse event, Anti-HCV = HCV antibodies, DAA = directly acting antiviral agent, EOTVR = end-of-treatment virological response, EVR = early virological response, GGT = genotype-guided therapy, HBeAg = hepatitis B e antigen, HBsAg = HBV surface antigen, HBV = hepatitis B virus, HCV = hepatitis C virus, HCV-1 = HCV genotype 1, ITT = intent-to-treat, LVL = low baseline viral load, Peg-IFN = PEGylated interferon-alpha, PP = per-protocol, RBV = ribavirin, RGT = response-guided therapy, RVR = rapid virological response, SAE = serious adverse events, SVR = sustained virological response, ULN = upper limit of normal, VL = viral load.\n\nThe study was approved by ethics committee of Kaohsiung Medical University Hospital (KMUH-IRB-980019).\n\nThe coauthor M-LYu and W-LC are the members of advisory board of Merck Sharp & Dohme (MSD), Roche, Bristol-Myers Squibb (BMS), Gilead Science and Abbvie. This does not alter the authors’ adherence to the journal “Medicine” policies on sharing data and materials.\n\nThis work was supported partially by grants from Kaohsiung Medical University Hospital (grant number KMUH100-0R05 and KMUH101-1R05) and grants from Kaohsiung Medical University “Aim for the Top Universities Grant, grant No. KMU-TP103E06, KMU-TP103D12, KMU-TP103D13, and KMU-TP103D14.”\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Liaw YF Chen YC Sheen IS \nImpact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection . Gastroenterology \n2004 ; 126 :1024 –1029 .15057742 \n2. Chuang WL Chang WY Lu SN \nThe role of hepatitis B and C viruses in hepatocellular carcinoma in a hepatitis B endemic area. A case-control study . Cancer \n1992 ; 69 :2052 –2054 .1311978 \n3. Yang JF Lin CI Huang JF \nViral hepatitis infections in southern Taiwan: a multicenter community-based study . Kaohsiung J Med Sci \n2010 ; 26 :461 –469 .20837342 \n4. Liaw YF \nRole of hepatitis C virus in dual and triple hepatitis virus infection . Hepatology \n1995 ; 22 :1101 –1108 .7557857 \n5. Dai CY Yu ML Chuang WL \nInfluence of hepatitis C virus on the profiles of patients with chronic hepatitis B virus infection . J Gastroenterol Hepatol \n2001 ; 16 :636 –640 .11422616 \n6. Wong GL Chan HL Tse YK \nOn-treatment alpha-fetoprotein is a specific tumor marker for hepatocellular carcinoma in patients with chronic hepatitis B receiving entecavir . Hepatology \n2014 ; 59 :986 –995 .24123097 \n7. Manns M Zeuzem S Sood A \nReduced dose and duration of peginterferon alfa-2b and weight-based ribavirin in patients with genotype 2 and 3 chronic hepatitis C . J Hepatol \n2011 ; 55 :554 –563 .21237227 \n8. Liu CJ Chuang WL Lee CM \nPeginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with hepatitis B and C viruses . Gastroenterology \n2009 ; 136 :496.e3 –504.e3 .19084016 \n9. Yeh ML Hung CH Huang JF \nLong-term effect of interferon plus ribavirin on hepatitis B surface antigen seroclearance in patients dually infected with hepatitis B and C viruses . PLoS One \n2011 ; 6 :e20752 .21695152 \n10. Yu ML Lee CM Chen CL \nSustained hepatitis C virus clearance and increased hepatitis B surface antigen seroclearance in patients with dual chronic hepatitis C and B during posttreatment follow-up . Hepatology \n2013 ; 57 :2135 –2142 .23322699 \n11. Yu ML Dai CY Huang JF \nRapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial . Hepatology \n2008 ; 47 :1884 –1893 .18508296 \n12. Liu CH Liu CJ Lin CL \nPegylated interferon-alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus genotype 1 infection: a multicenter, randomized controlled trial . Clin Infect Dis \n2008 ; 47 :1260 –1269 .18834319 \n13. Zeuzem S Buti M Ferenci P \nEfficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia . J Hepatol \n2006 ; 44 :97 –103 .16290907 \n14. Di Martino V Richou C Cervoni JP \nResponse-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: meta-analyses of randomized, controlled trials and implications for the future . Hepatology \n2011 ; 54 :789 –800 .21674553 \n15. Dalgard O Bjoro K Hellum KB \nTreatment with pegylated interferon and ribavarin in HCV infection with genotype 2 or 3 for 14 weeks: a pilot study . Hepatology \n2004 ; 40 :1260 –1265 .15558712 \n16. von Wagner M Huber M Berg T \nPeginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C . Gastroenterology \n2005 ; 129 :522 –527 .16083709 \n17. Mangia A Santoro R Minerva N \nPeginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3 . N Engl J Med \n2005 ; 352 :2609 –2617 .15972867 \n18. Yu ML Dai CY Huang JF \nA randomised study of peginterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic hepatitis C . Gut \n2007 ; 56 :553 –559 .16956917 \n19. Okamoto H Tokita H Sakamoto M \nCharacterization of the genomic sequence of type V (or 3a) hepatitis C virus isolates and PCR primers for specific detection . J Gen Virol \n1993 ; 74 :2385 –2390 .7504073 \n20. Manns MP McHutchison JG Gordon SC \nPeginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial . Lancet \n2001 ; 358 :958 –965 .11583749 \n21. Fried MW Shiffman ML Reddy KR \nPeginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection . N Engl J Med \n2002 ; 347 :975 –982 .12324553 \n22. Hadziyannis SJ Sette H JrMorgan TR \nPeginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose . Ann Intern Med \n2004 ; 140 :346 –355 .14996676 \n23. Ferenci P Formann E Laferl H \nRandomized, double-blind, placebo-controlled study of peginterferon alfa-2a (40KD) plus ribavirin with or without amantadine in treatment-naive patients with chronic hepatitis C genotype 1 infection . J Hepatol \n2006 ; 44 :275 –282 .16338019 \n24. Zeuzem S Pawlotsky JM Lukasiewicz E \nInternational, multicenter, randomized, controlled study comparing dynamically individualized versus standard treatment in patients with chronic hepatitis C . J Hepatol \n2005 ; 43 :250 –257 .16082736 \n25. Yu ML Dai CY Lin ZY \nA randomized trial of 24- vs. 48-week courses of PEG interferon alpha-2b plus ribavirin for genotype-1b-infected chronic hepatitis C patients: a pilot study in Taiwan . Liver Int \n2006 ; 26 :73 –81 .16420512 \n26. Yu ML Chuang WL \nTreatment of chronic hepatitis C in Asia: when East meets West . J Gastroenterol Hepatol \n2009 ; 24 :336 –345 .19335784 \n27. Omata M Kanda T Yu ML \nAPASL consensus statements and management algorithms for hepatitis C virus infection . Hepatol Int \n2012 ; 6 :409 –435 .26201405 \n28. Chuang WL Dai CY Chang WY \nViral interaction and responses in chronic hepatitis C and B coinfected patients with interferon-alpha plus ribavirin combination therapy . Antivir Ther \n2005 ; 10 :125 –133 .15751770 \n29. Kim YJ Lee JW Kim YS \nClinical features and treatment efficacy of peginterferon alfa plus ribavirin in chronic hepatitis C patients coinfected with hepatitis B virus . Korean J Hepatol \n2011 ; 17 :199 –205 .22102386 \n30. Potthoff A Wedemeyer H Boecher WO \nThe HEP-NET B/C co-infection trial: A prospective multicenter study to investigate the efficacy of pegylated interferon-alpha2b and ribavirin in patients with HBV/HCV co-infection . J Hepatol \n2008 ; 49 :688 –694 .18490077 \n31. Dai CY Huang JF Hsieh MY \nInsulin resistance predicts response to peginterferon-alpha/ribavirin combination therapy in chronic hepatitis C patients . J Hepatol \n2009 ; 50 :712 –718 .19231011 \n32. Fried MW Hadziyannis SJ Shiffman ML \nRapid virological response is the most important predictor of sustained virological response across genotypes in patients with chronic hepatitis C virus infection . J Hepatol \n2011 ; 55 :69 –75 .21145856 \n33. Yu ML Lee CM Chuang WL \nHBsAg profiles in patients receiving peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with hepatitis B and C viruses . J Infect Dis \n2010 ; 202 :86 –92 .20482252 \n34. Huang CF Yang JF Dai CY \nEfficacy and safety of pegylated interferon combined with ribavirin for the treatment of older patients with chronic hepatitis C . J Infect Dis \n2010 ; 201 :751 –759 .20102281 \n35. European Association for Study of Liver . EASL Clinical Practice Guidelines: management of hepatitis C virus infection . J Hepatol \n2014 ; 60 :392 –420 .24331294 \n36. Aghemo A De Francesco R \nNew horizons in hepatitis C antiviral therapy with direct-acting antivirals . Hepatology \n2013 ; 58 :428 –438 .23467911 \n37. Sarkar S Lim JK \nAdvances in interferon-free hepatitis C therapy: 2014 and beyond . Hepatology \n2014 ; 59 :1641 –1644 .24590916 \n38. Yu ML Chuang WL \nNew treatments for HCV: perspective from Asia . Clin Liver Dis \n2015 ; 5 :17 –21 .\n39. Pearlman BL Ehleben C \nHepatitis C genotype 1 virus with low viral load and rapid virologic response to peginterferon/ribavirin obviates a protease inhibitor . Hepatology \n2014 ; 59 :71 –77 .23873583 \n40. Bichoupan K Martel-Laferriere V Sachs D \nCosts of telaprevir-based triple therapy for hepatitis C: $189,000 per sustained virological response . Hepatology \n2014 ; 60 :1187 –1195 .25065814\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0025-7974",
"issue": "94(42)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D019694:Hepatitis B, Chronic; D019698:Hepatitis C, Chronic; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D057285:Precision Medicine; D011994:Recombinant Proteins; D012254:Ribavirin",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e1837",
"pmc": null,
"pmid": "26496327",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Personalized Therapy of Chronic Hepatitis C and B Dually Infected Patients With Pegylated Interferon Plus Ribavirin: A Randomized Study.",
"title_normalized": "personalized therapy of chronic hepatitis c and b dually infected patients with pegylated interferon plus ribavirin a randomized study"
} | [
{
"companynumb": "TW-ROCHE-1675710",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Mastocytosis describes a heterogeneous group of disorders arising from a clonal proliferation of mast cells. Given the lack of curative treatments for the cutaneous form, there is a significant need for superior therapies. Omalizumab is a recombinant DNA-derived humanized IgG monoclonal antibody that selectively binds to human immunoglobulin E (IgE). It represents a potential treatment for the management of cutaneous mastocytosis, which currently has no standard treatment.\n\n\n\nTwo patients were treated with subcutaneous omalizumab 300 mg every 4 weeks.\n\n\n\nPatient 1 experienced 50% reduction in cutaneous infiltration and moderate improvement in pruritus. Patient 2 underwent 90% complete clearance of cutaneous lesions and reported full resolution of pruritus. The median duration of treatment was 24 weeks and time to response was 8 weeks. No significant changes in tryptase levels were observed. Both patients experienced injection site reactions.\n\n\n\nWe provide evidence from two cases supporting the efficacy of IgE-mediated therapy in the treatment of cutaneous mastocytosis. Even at a higher-than-standard dose (300 mg vs. 150 mg), the drug was well-tolerated. As we await the results of pivotal clinical trials, omalizumab appears to be a promising treatment option in patients with cutaneous mastocytosis unresponsive to traditional therapies.",
"affiliations": "Dermatology Department, Center for Clinical Studies, Houston, Texas.;Department of Internal Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Dermatology, University of Texas Health Science Center at Houston, Houston, Texas.;School of Medicine, Baylor College of Medicine, Houston, Texas.;Dermatology Department, Center for Clinical Studies, Houston, Texas.;Dermatology Department, Center for Clinical Studies, Houston, Texas.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Dermatology Department, Center for Clinical Studies, Houston, Texas.",
"authors": "Hinojosa|Tiffany|T|0000-0001-5809-698X;Lewis|Daniel J|DJ|;Vangipuram|Ramya|R|;Safeer|Laraib|L|;Mui|Uyen Ngoc|UN|;Haley|Christopher|C|;Konoplev|Sergej|S|;Tyring|Stephen K|SK|",
"chemical_list": "D018926:Anti-Allergic Agents; D000069444:Omalizumab; D007073:Immunoglobulin E",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.12848",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "32(3)",
"journal": "Dermatologic therapy",
"keywords": "IgE; maculopapular cutaneous mastocytosis; mastocytosis; omalizumab",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000328:Adult; D018926:Anti-Allergic Agents; D005260:Female; D006801:Humans; D007073:Immunoglobulin E; D007279:Injections, Subcutaneous; D034701:Mastocytosis, Cutaneous; D008875:Middle Aged; D000069444:Omalizumab; D011537:Pruritus; D016896:Treatment Outcome",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e12848",
"pmc": null,
"pmid": "30697883",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The efficacy of omalizumab in Cutaneous Mastocytosis: A case series.",
"title_normalized": "the efficacy of omalizumab in cutaneous mastocytosis a case series"
} | [
{
"companynumb": "US-009507513-1907USA003026",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MONTELUKAST SODIUM"
},
"drugadditional": nul... |
{
"abstract": "No systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma.\n\n\n\nWe report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review.\n\n\n\nIn the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event.\n\n\n\nAmong patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498 .).",
"affiliations": "From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).;From the Departments of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston (M.R.M.), and South Texas Accelerated Research Therapeutics (START), San Antonio (K.P.P.) - both in Texas; the Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (D.R., A.A.T.), the Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, VIC (A.G.), the Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA (A.M.L.), and Royal Brisbane and Women's Hospital and University of Queensland, Brisbane (B.G.M.H.) - all in Australia; the Department of Dermatology, Brigham and Women's Hospital (C.D.S.), the Department of Dermatology, Harvard Medical School (C.D.S.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (G.R.) - all in Boston; Schleswig-Holstein University Hospital, Kiel (A.H.), and University Hospital Essen, Essen and German Cancer Consortium, Essen (D.S.) - both in Germany; University of Colorado Denver, School of Medicine, Aurora (K.D.L.); the Departments of Head and Neck-Endocrine Oncology (C.H.C.) and Cutaneous Oncology (N.I.K.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; the Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis (L.H.-A.); the Department of Dermatology, Stanford University School of Medicine, Redwood City (A.L.S.C.), and the Division of Dermatology, City of Hope, Duarte (B.M.) - both in California; the Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (L.A.D.), and Regeneron Pharmaceuticals, Tarrytown (F.S., M.M., K.M., G.D.Y., I.L., M.G.F.) - both in New York; Regeneron Pharmaceuticals, Basking Ridge, NJ (B.G., S.L., J.L., J.B., E.S.); University of Arizona Cancer Center, Tucson (H.M.B.), and Banner MD Anderson Cancer (J.H.) and the Department of Medical Oncology, Banner MD Anderson Cancer Center (J.N.), Gilbert - all in Arizona; Medical Oncology Department, Vall D'Hebron University Hospital (I.B.), and Institut Català D'Oncologia, Oncobell Program (IDIBELL), L'Hospitalet de Llobregat (M.G.-M.), Barcelona, and START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid (V.M.) - all in Spain; Sarah Cannon Research Institute, Nashville (M.L.J.); and the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta (T.K.O.).",
"authors": "Migden|Michael R|MR|;Rischin|Danny|D|;Schmults|Chrysalyne D|CD|;Guminski|Alexander|A|;Hauschild|Axel|A|;Lewis|Karl D|KD|;Chung|Christine H|CH|;Hernandez-Aya|Leonel|L|;Lim|Annette M|AM|;Chang|Anne Lynn S|ALS|;Rabinowits|Guilherme|G|;Thai|Alesha A|AA|;Dunn|Lara A|LA|;Hughes|Brett G M|BGM|;Khushalani|Nikhil I|NI|;Modi|Badri|B|;Schadendorf|Dirk|D|;Gao|Bo|B|;Seebach|Frank|F|;Li|Siyu|S|;Li|Jingjin|J|;Mathias|Melissa|M|;Booth|Jocelyn|J|;Mohan|Kosalai|K|;Stankevich|Elizabeth|E|;Babiker|Hani M|HM|;Brana|Irene|I|;Gil-Martin|Marta|M|;Homsi|Jade|J|;Johnson|Melissa L|ML|;Moreno|Victor|V|;Niu|Jiaxin|J|;Owonikoko|Taofeek K|TK|;Papadopoulos|Kyriakos P|KP|;Yancopoulos|George D|GD|;Lowy|Israel|I|;Fury|Matthew G|MG|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C000627974:cemiplimab",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1805131",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "379(4)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D061026:Programmed Cell Death 1 Receptor; D012878:Skin Neoplasms",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "341-351",
"pmc": null,
"pmid": "29863979",
"pubdate": "2018-07-26",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma.",
"title_normalized": "pd 1 blockade with cemiplimab in advanced cutaneous squamous cell carcinoma"
} | [
{
"companynumb": "US-REGENERON PHARMACEUTICALS, INC.-2018-47638",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEMIPLIMAB"
},
"drugaddit... |
{
"abstract": "A 14-year-old young adult took an overdose of 1.2 g of fluoxetine, a selective serotonin reuptake inhibitor (SSRI) that he had been prescribed for depression. He had a generalised tonic/clonic seizure at 6 hours postingestion.After the seizure, he developed signs consistent with serotonin syndrome: fine tremor, agitation, sweating and hyperreflexia. This was followed by severe muscle pain and rhabdomyolysis with peak creatine kinase (CK) of 33 941 at 74 hours. He was managed with intravenous fluids and analgesia and discharged after 4 days, having avoided renal injury. The use of SSRI's such as fluoxetine in teenagers has increased in recent years. While it is generally considered benign in overdose, this report illustrates the severe consequences of overdose at high quantities and discusses appropriate management in these cases. We note that in this case, there was a delayed onset of rhabdomyolysis with peak CK at 74 hours postingestion.",
"affiliations": "Paediatrics, Great Western Hospitals NHS Foundation Trust, Swindon, UK.;Paediatrics, Great Western Hospitals NHS Foundation Trust, Swindon, UK.;Paediatrics, Great Western Hospitals NHS Foundation Trust, Swindon, UK.",
"authors": "Lee-Kelland|Richard|R|;Zehra|Sabeeka|S|;Mappa|Pradeesh|P|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D005473:Fluoxetine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225529",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "child and adolescent psychiatry (paediatrics); unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000293:Adolescent; D003866:Depressive Disorder; D003937:Diagnosis, Differential; D062787:Drug Overdose; D005473:Fluoxetine; D006801:Humans; D008297:Male; D012206:Rhabdomyolysis; D012640:Seizures; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors; D013406:Suicide, Attempted",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30301727",
"pubdate": "2018-10-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9596448;24946698;16169281;1586402;7618791;15362595;19015631;3871767;15784664;25581857;24998011",
"title": "Fluoxetine overdose in a teenager resulting in serotonin syndrome, seizure and delayed onset rhabdomyolysis.",
"title_normalized": "fluoxetine overdose in a teenager resulting in serotonin syndrome seizure and delayed onset rhabdomyolysis"
} | [
{
"companynumb": "GB-LANNETT COMPANY, INC.-GB-2018LAN001386",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
... |
{
"abstract": "The purpose of this study was to evaluate the efficacy and safety of direct oral anticoagulants vs. warfarin for portal vein thrombosis treatment.\n\n\n\nThis was a single-center, retrospective study. Adult patients initiated on a direct oral anticoagulant or warfarin for treatment of a new portal vein thrombosis were included. The primary failure outcome was the absolute difference in recurrent thromboembolic events 90 days following initiation of a direct oral anticoagulant vs. warfarin. The primary safety outcome was the absolute difference in bleeding events 90 days following initiation of a direct oral anticoagulant vs. warfarin. Descriptive statistics, Fisher's exact, and Student's t-tests were utilized as appropriate.\n\n\n\nThirty-three patients were included. Thirteen (39.4%) patients received direct oral anticoagulants, and 20 (60.6%) received warfarin. None of the patients receiving direct oral anticoagulants experienced a primary failure event compared to four receiving warfarin (P < 0.001). None of the patients receiving direct oral anticoagulants experienced a primary safety event vs. one receiving warfarin (P < 0.001).\n\n\n\nDirect oral anticoagulants appear to be effective and safe in the treatment of portal vein thrombosis and in preventing recurrent thromboembolic events. Future studies with larger sample sizes are warranted to confirm direct oral anticoagulants' efficacy in portal vein thrombosis.",
"affiliations": "St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis, St. Louis, Missouri.;West Virginia University School of Pharmacy.;West Virginia University Medicine, Morgantown, West Virginia, USA.",
"authors": "Ilcewicz|Haley N|HN|;Martello|Jay L|JL|;Piechowski|Kara|K|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000001958",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "33(6)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants; D006801:Humans; D011169:Portal Vein; D012189:Retrospective Studies; D020246:Venous Thrombosis; D014859:Warfarin",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "911-916",
"pmc": null,
"pmid": "33079786",
"pubdate": "2021-06-01",
"publication_types": "D016428:Journal Article",
"references": "18316627;26867832;30060258;29886103;28342265;26516032;31293916;25941431;30992777;25566699;17892532;32078681;26725062;28675619;27880998;29916054;28009449;27778440;22712870;25313630;19399912;29973997;26764429;28479379;32039373",
"title": "Evaluation of the efficacy and safety of direct oral anticoagulants in the treatment of portal vein thrombosis.",
"title_normalized": "evaluation of the efficacy and safety of direct oral anticoagulants in the treatment of portal vein thrombosis"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-093971",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"dr... |
{
"abstract": "Chronic inflammatory bowel disease (IBD) includes Crohn's disease and ulcerative colitis. Both are characterized by inflammation of part of the digestive tract lining. Azathioprine (AZA) is a well-known immunosuppressant that has been known for many years for its ability to provide long-term disease remission in IBDs, but has important side effects, most of which are related to a single nucleotide polymorphism in the gene for thiopurine methyltransferase (TPMT), which ensures the degradation and efficacy of AZA. Since a direct correlation between TPMT gene polymorphisms and the haematological toxicity of the AZA treatment has been widely demonstrated, TPMT genotyping has been made necessary prior to any introduction of AZA. The monitoring of thiopurine metabolites presents one of the factors that limit wide adaptation of these thiopurines in clinical practice. Thus, identifying patients with asymmetric metabolism could help clinicians provide an ideal treatment recommendation to improve response and reduce adverse effects. Here, we review the role of AZA in the treatment of IBD and discuss the usefulness of TPMT genotyping to guide clinical decision-making. In addition, we report the identification of a new molecular alteration, never described, TPMT mutation affecting the TPMT activity and responsible for deleterious side effects in a clinical case of a 20-year-old woman patient.",
"affiliations": "Laboratoire de Biologie des Tumeurs Solides, Département de Pathologie et Oncobiologie, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France.;Laboratoire de Biologie des Tumeurs Solides, Département de Pathologie et Oncobiologie, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France.",
"authors": "Harmand|Pierre-Olivier|PO|;Solassol|Jérôme|J|0000-0002-0293-6158",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D008780:Methyltransferases; C000628225:TPMT protein, human; D001379:Azathioprine",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/genes11101212",
"fulltext": "\n==== Front\nGenes (Basel)\nGenes (Basel)\ngenes\nGenes\n2073-4425 MDPI \n\n33081236\n10.3390/genes11101212\ngenes-11-01212\nReview\nThiopurine Drugs in the Treatment of Ulcerative Colitis: Identification of a Novel Deleterious Mutation in TPMT\nHarmand Pierre-Olivier 1 https://orcid.org/0000-0002-0293-6158Solassol Jérôme 12* 1 Laboratoire de Biologie des Tumeurs Solides, Département de Pathologie et Oncobiologie, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France; po-harmand@chu-montpellier.fr\n2 Institut de Recherche en Cancérologie de Montpellier, INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier, 34298 Montpellier, France\n* Correspondence: j-solassol@chu-montpellier.fr; Tel.: + 33-4673-358-71\n16 10 2020 \n10 2020 \n11 10 121201 9 2020 14 10 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/).Chronic inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis. Both are characterized by inflammation of part of the digestive tract lining. Azathioprine (AZA) is a well-known immunosuppressant that has been known for many years for its ability to provide long-term disease remission in IBDs, but has important side effects, most of which are related to a single nucleotide polymorphism in the gene for thiopurine methyltransferase (TPMT), which ensures the degradation and efficacy of AZA. Since a direct correlation between TPMT gene polymorphisms and the haematological toxicity of the AZA treatment has been widely demonstrated, TPMT genotyping has been made necessary prior to any introduction of AZA. The monitoring of thiopurine metabolites presents one of the factors that limit wide adaptation of these thiopurines in clinical practice. Thus, identifying patients with asymmetric metabolism could help clinicians provide an ideal treatment recommendation to improve response and reduce adverse effects. Here, we review the role of AZA in the treatment of IBD and discuss the usefulness of TPMT genotyping to guide clinical decision-making. In addition, we report the identification of a new molecular alteration, never described, TPMT mutation affecting the TPMT activity and responsible for deleterious side effects in a clinical case of a 20-year-old woman patient.\n\nTPMTulcerative colitisazathioprinemutationtargeted therapies\n==== Body\n1. Introduction\nInflammatory bowel disease (IBD) is a term expressed to define a set of intestinal disorders involved in the whole (or part) of the digestive tract, comprising two main pathologies: Ulcerative colitis (UC) and Crohn’s disease (CD). IBD affects 0.3% of the population of Europe and North America, and tends to increase in populations of countries with increasing industrialization (Africa, South America, Asia, Middle East) [1,2]. Although UC and CD share important clinical signs, their symptoms differ greatly in their location and treatment to address them. Indeed, UC is located only in the inner wall of the large colon, while CD is involved in the entire digestive tract (from the esophagus to the rectum), but also in other organs such as the skin, liver, or eyes. The immune system of people with IBD does not respond well to environmental triggers, activating T-cells and triggering chronic inflammation of the gastrointestinal tract [3].\n\nAminosalicylated derivatives such as mesalazine or sulfasalazine are drugs prescribed in first line to induce and maintain remission in UC; to which if necessary, glucocorticoids can be added. Cyclosporine is used in more critical UC, if intravenous steroids do not produce the desired induction of remission. Azathioprine (AZA) and 6-mercaptopurine (6-MP), two analogues of thiopurine, have been the mainstay of IBD treatment as steroid sparing agents thanks to their modulation of the immune system [4,5]. They are used to maintain the remission acquired during the use of corticosteroids, but especially in combination with biological therapy. More recently, chimeric monoclonal antibodies anti-TNF-α (TNF-α) (infliximab and adalimumab) have been proposed for the induction of remission and the maintenance therapy of therapy-refractory UC [6].\n\nThe combination of immunosuppressants and biotherapies that have been shown to be effective has been reported to have better results, either by potentiating immunosuppression or by decreasing the immunogenicity inherent in biotherapy [7]. Thus, given the high risk of relapse in CD, the high dependence on corticosteroids, and the high response rate to the use of immunosuppressants when introduced early, azathioprine is the most appropriate drug to maintain the remission achieved through the use of systemic corticosteroids. However, there is considerable inter-patient variability which explains the clinically observed differences in the efficacy and toxicity of azathioprine and 6-mercaptopurine. Among the factors that may influence the response to pharmacotherapy, and the risk of developing significant and disabling adverse events (AEs) are environmental factors such as smoking but also, more importantly, genetic factors [8,9]. Thus, it is estimated that polymorphisms of certain genes can explain up to 95% of the observed variability in drug effects. Primary candidate genes of interest include those encoding drug receptors, metabolizing enzymes, and transporters. Therefore, since a direct correlation between TPMT gene polymorphisms and hematological toxicity of thiopurine treatment has been largely demonstrated, TPMT genotyping has been rendered necessary prior to any AZA introduction.\n\nIn this review, we summarize the main pharmacological features of AZA and 6-MP, describe the genetic variants in TPMT that influence their toxicity, and report the identification of a new molecular alteration responsible for deleterious side effects in a clinical case.\n\n2. Azathioprine and 6-Mercaptopurine\n6-MP or the prodrug AZA are purine analogues that stop the synthesis of adenine and guanine. This interruption causes a poor base incorporation and prevents the proper development of DNA repair mechanisms [10,11,12]. At low doses, AZA has a considerable effect on T-lymphocytes; it acts as an anti-inflammatory; whereas in high doses, it has an immunosuppressive and above all cytotoxic effect [3]. The molecules of the thiopurine family are conventionally used to treat malignant tumors, rheumatic diseases, and dermatological conditions; but they are also employed in the prevention of post-transplant organ rejection and in the treatment of inflammatory gastrointestinal disorders such as IBD.\n\nInitially, in patients with CD, AZA was administered at a low dose (1.0–2.5 mg/kg/day) and was shown to be effective in reducing the risk of disease recurrence for a period ranging from 6 months to 2 years [13]. However, very quickly, the conventional AZA administration strategy was defined by a method of constant dose increase to avoid undesirable events, such as myelosuppression or hepatotoxicity [14]. \n\nThiopurines are normally administered to sustain long-term remission because of their slow onset, requiring at least 12 to 17 weeks of regular treatment to produce discernible results. In order to more rapidly induce remission during the initial stages of IBD treatment, thiopurines can be combined with a short-term treatment: Typically, a steroid or anti-TNF agent. It is not wholly understood how the combination of immunosuppressants and anti-TNF agents operates, but any beneficial synergy could be due to the improved pharmacokinetic profiles produced by the interaction of the drugs combined with the presence of multiple therapeutic targets. The combination of anti-TNF therapies with thiopurines can induce better therapeutic efficacy [15,16]. The implication of AZA monotherapy in IBD for the maintenance of remission is still a matter of debate for clinicians. However, the European organization of IBD has published a consensus statement in which clinicians agree to the use of thiopurines as monotherapy or in addition to infliximab against corticosteroid-dependent IBDs, stating the significant efficacy of thiopurines compared with aminosalicylates to slow the rise of UC [17,18].\n\n2.1. Mechanism of Action \nAZA plays an important role in the treatment of autoimmune diseases. It is a prodrug converted to 6-MP in vivo where it is then metabolized into the active metabolite 6-thioguanine triphosphate (6-TGTP) by a cascade of enzymes (hypoxanthine guanine phosphoribosyl transferase (HGPRT), inosine monophosphate dehydrogenase (IMPDH), guanosine monophosphate synthetase (GMPS), and nucleotide diphosphate kinase (DNPK)) or in inactive metabolites as 6-methylmercaptopurine (6-MeMP), 6-methylmercaptopurine ribonucleotide (6-MeMPR), 6-methyl thioinosine monophosphate MeTIMP), or as 6-methylthioguanosine monophosphate (6-MeTGMP) by the enzyme TPMT [19,20]. Thus, the 6-thioguanosine nucleotides (6-TGN = 6-TGTP) determines the cytotoxicity or efficacy of AZA. As shown in Figure 1, there are three metabolic pathways of AZA: Once in the form of 6-MP, the latter can be converted into thiouric acid (6-TU) through the AOX1 and XDH enzymes of the family Xanthine oxidases (XO). 6-MP can also be converted to 6-TIMP (6-thioinosine monophosphate) by the enzyme HGPRT, which will then be converted to active metabolites such as 6-TGTP and 6-deoxyTGTP by IMPDH1, GMPS, NDPK, and ribonucloside reductase (RNR) (for 6-deoxyTGTP). Then, 6-TGTP and 6-deoxyTGTP obtained, respectively induce cytotoxicity on RNA and DNA by poor incorporation of nucleotides. Finally, thiopurine-S-methyltranferase (TPMT) will induce the methylation of each metabolite of AZA (6-MP to 6-MeMP, 6-TIMP to 6-MeTIMP, and 6-TGMP to 6-MeTGMP) in order to make them inactive, and thus prevent the cytotoxic function of the AZA metabolic pathway [21]. In order to determine the amount of 6-MP catalyzed into 6-TGN, the TPMT enzyme directly competes with HGPRT and XO [22,23].\n\nThe metabolic pathway for AZA is developing, but is not yet well defined. Genes such as MOCOS, NUD15, and FTO are thought to be involved in the metabolism of AZA [24,25,26,27]. The MOCOS gene (molybdenum cofactor sulfurase) is thought to have an action on the enzymes AOX1 and XDH [25,28], while the NUD15 gene (nucleoside diphosphate linked moiety X type 15) dephosphoryl 6-TGTP into 6-TGMP [27,29]. As for the FTO gene (fat mass and obesity associated), it could be a potential pharmacogenetic biomarker for treatment with thiopurine [24]. In order to better define the roles of these genes, studies are currently underway.\n\nAt normal levels of TPMT activity, 6-TGTP and 6-deoxyTGTP inhibit intracellular signaling pathways and induce lymphocytic apoptosis. A change in these activity levels necessarily creates an imbalance: In fact, an abnormal increase in the TPMT enzyme activity induces a decrease in 6-TGN and therefore a decrease in the effectiveness of the drug. Conversely, the decrease in the TPMT activity, or even a total absence of TPMT activity (as observed when TPMT exhibits polymorphisms) this time leads to a significant increase in the presence of 6-TGN, which will be incorporated into DNA and trigger cytotoxicity [30,31].\n\n2.2. Pharmacology \nCurrently, AZA is administered intravenously (current dose of 1 to 1.5 mg/kg) or orally (daily dose of 0.5 mg/kg), either as a tablet or an oral delayed release (DR) capsule. In 1996, Van Os et al. [32] carried out a comparative study on the different types of administration of AZA (50 mg): Intravenous, oral tablet, oral DR capsule, and hydrophilic or hydrophobic rectal foam. Rectal foam has been found to be ideal because its application to the colon avoids first-pass metabolism by the liver. In contrast, it is a low-intensity process because its absorption through the colon mucosa is reduced compared to that in the gastric [32]. In erythrocytes, the half-life of AZA would be 25 to 80 min (or 3 to 5 h if the metabolites are included) [33], while that of 6-TGN would be 5 days, inducing a period long enough of 3 to 6 months necessary to reach a state of equilibrium [34]. This may explain why an extended treatment period is necessary before a clinical response occurs.\n\nIn clinical practice, AZA is systematically administered initially at a low dose (25 to 50 mg/day); then the dose is increased by 25 to 50 mg/day every 1 to 2 weeks, up to 2.0 to 2.5 mg/kg, with regular monitoring in order to detect the appearance of AEs, in particular haematological or hepatic [35,36]. Thus, the first phase therapeutic strategy based on the remission induction treatment is followed by the second phase to maintain remission. However, this progressive titration method is still insufficient to anticipate the onset of severe myelosuppression. The dose of 6-mercaptopurine in mg/kg is equivalent to a factor of 2.08 times the pharmaceutical dose of AZA [37].\n\n2.3. Thiopurine Side Effects\nMany side effects induced by AZA have been reported including nausea, myelosuppression, erythrocyte aplasia, and in very rare cases lead to death [38]. All of these effects have been categorized into two groups of reactions: One with dose-independent reactions and the other dose-dependent. The reactions induced by AZA given initially in the first few weeks tend to be hypersensitive reactions of the allergic type. Dose-independent reactions cause symptoms such as fever, joint pain, rash, pancreatitis, or gastrointestinal disturbances [39]. While dose-dependent reactions appear at post-treatment stages due to accumulated metabolites and are often characterized by symptoms such as rare bacterial infections, nausea, leukopenia, hepatitis, cholestatic jaundice, and myelosuppression. If the side effects associated with the dose-dependent disappear as soon as the dose of AZA is lowered, the dose-independent reactions continue until the treatment is stopped.\n\nMany studies disagree on the significant association between the thiopurine treatment for patients with IBD and the increased risk of malignant tumors [40,41,42]. According to Lewis et al., thiopurine remains a major molecule in the treatment against IBD, despite a risk factor for lymphoma multiplied by 4. The increased risk would have to be greater than 9.8-fold for the benefit of AZA therapy to be replaced by the benefit of alternative therapies [34,43]. Usually, patients treated with AZA will also receive combination therapy with a corticosteroid, the dose of which will be gradually reduced until it is stopped once the remission status of the condition is reached. Indeed, the study by De Jong et al. shows that patients receiving this combined therapy, with a higher dose of corticosteroid, have a lower number of adverse events and especially less serious [44]. In addition, it has been determined that 20–30% of patients treated with AZA monotherapy alone discontinue treatment due to an adverse drug reaction [8,23].\n\nIn order to determine an individual’s risk of major toxicity, the level of TPMT activity is measured. This process makes it possible to adjust the dose or even avoid the administration of the drug, and thus prevents the risk for the patient of developing myelosuppression, neutropenia, leukopenia, or thrombocytopenia. Thus, determination of the concentrations of 6-TGN and 6-MP in red blood cells after at least four weeks of therapy has been proposed and a level of 235–450 pmol/8 × 108 erythrocytes of 6-TGN has been recommended [27,45]. It is estimated that 20% of treated patients exhibit hypermethylation of AZA, inducing an increase in 6-MMp with low levels of 6-TGN. The metabolism of AZA is skewed, resulting in treatment failure [46]. These elevated levels of 6-MMP tend to increase hepatotoxicity, causing the 6-MMP/6-TGN ratio to increase; which results in a low therapeutic efficacy [47]. Thus, the identification of patients with asymmetric metabolism would be a major asset for improving the therapeutic response and above all reducing adverse events [29,48].\n\n2.4. Pharmagenetics\nGenetic variations of genes encoding enzymes involved in thiopurine metabolism give rise to varying degrees of therapeutic response and toxicity. Indeed, these allelic variants are known as single-nucleotide polymorphisms (SNPs), which are characterized by a substitution of one base for another in the human DNA sequence. A SNP is a genetic mutation whose specific allele switch is observed in more than 1% of the population [49]. We can see in Figure 1, that TPMT, HGPRT, and xanthine oxidase are the enzymes involved in the metabolism of AZA. The formation of SNPs on these enzymes result in variable active metabolites that influence the metabolism of AZA. The TPMT gene is the most studied [50].\n\nThe genetic polymorphisms of TPMT have been well-documented as causing myelosuppression when patients are treated with azathioprine. This is due to the inability of the TPMT enzyme to metabolize 6-MP, resulting in the conversion of 6-TGN and, when incorporated into DNA, exerts cytotoxicity which triggers the arrest of the cell cycle and apoptosis [51]. Therefore, since TPMT polymorphisms have been associated with many severe thiopurine-induced adverse drug reactions, prior to starting thiopurine therapy, genotyping of common TPMT alleles is now recommended in the clinical practice. To precisely define those at risk and optimize therapy, the identification of new variants is essential. \n\n3. TPMT\nThe TPMT gene located on chromosome 6 (6p22.3) is 34 kb long and consists of 10 exons, eight of which encode the protein thiopurine methyltransferase (28 kDa) [11]. Thiopurine S-methyltransferase is a cytosolic enzyme which catalyzes the S-methylation of aromatic or heterocyclic sulfhydryl compounds, especially exogenous substances such as 6-MP. The TPMT gene exhibits an autosomal codominant genetic polymorphism, which can lead to an absence or a low level of TPMT activity in heterozygous or homozygous individuals [22]. \n\nThe presence of TPMT polymorphisms should be considered and especially not overlooked in the treatment with thiopurine-based drugs, as they may affect the tolerance and efficacy of the drugs. In fact, the activity of TPMT in humans is extremely variable from one individual to another and divides the population into three categories: A majority group of subjects for whom the TPMT activity is high (or normal), a group of individuals for whom the activity is said to be intermediate, and a small group of subjects for whom the TPMT activity is undetectable [51,52]. \n\nThe TPMT activity phenotype is inherited in the autosomal co-dominant mode; thus, the deficient individuals are homozygous or heterozygous for one or two non-functional alleles of the TPMT gene, while the intermediate individuals are heterozygous, that is to say carriers of a functional allele and a non-functional allele of the gene. Patients with intermediate TPMT activity have a high probability of reporting adverse events if treated with standard doses of thiopurines. Conversely, these same patients may not have major side effects when the dose is properly adjusted [53]. \n\nThe hereditary nature of TPMT activity deficit has been shown in family studies. In fact, in the Caucasian population of Europe and North America, approximately 89% of subjects have a high (or normal) enzyme activity, 11% of them have an intermediate activity, while less than 1% have a total deficit of activity [54]. \n\nAnalysis of the TPMT gene sequence, performed in populations of various ethnic origins, has confirmed the genetic origin of the TPMT activity polymorphism and elucidated its molecular mechanisms [55], and identified more than forty allelic variants of the TPMT gene [56].\n\nThe wild type TPMT * 1/TPMT * 1 genotype is consistent with the normal TPMT enzymatic activity. Standard doses of thiopurine drugs are less likely to be toxic in individuals with this genotype. It is retained that the heterozygotes with 1 wild-type allele and 1 variant (such as the TPMT * 1/* 2, TPMT * 1/TPMT * 1/* 3A, TPMT * 1/* 3B, TPMT * 1/* 3C, TPMT genotypes * 1/* 8 and TPMT * 1/* 16) have an intermediate TPMT activity, have an increased risk of haematological toxicity, and may require a lower dosage (Figure 2). The star alleles described are referenced in the TPMT nomenclature committee database (https://liu.se/en/research/tpmt-nomenclature-committee) which lists the TPMT variants. The Pharmacogenic Variation Consortium (PharmVar) continues to update new alleles to provide the clinical and research communities of a repository and standardized nomenclature of pharmacogene variation.\n\nPatients who lack the wild-type allele are predicted to have low or no detectable enzyme activity and are at high risk for life-threatening haematologic toxicity if given full doses of thiopurine medication. Alternative therapy or reduced dosage should be considered for these patients.\n\nIt should be noted that the TPMT * 3B, TPMT * 3C, TPMT * 8, and TPMT * 16 alleles each carry a variant which is specific to it. However, some alleles carry two variants such as the TPMT * 3A allele, which contains the polymorphisms found in the TPMT * 3B and TPMT * 3C alleles.\n\nTPMT * 2, * 3A, and * 3C represent more than 90% of inactive alleles [57]. Among the most common is the TPMT * 2 allele, which compared to the wild-type sequence of the gene (TPMT * 1), carries a missense mutation in exon 5 (c.238G > C, p.Ala80Pro). This sequence variation alters the tertiary structure of the protein, which alters the stability of the enzyme, and leads to its rapid degradation by proteolysis [58]. The TPMT * 3A allele harbors two missense variants in Cis found in the TPMT * 3B (c.460G > A, p.Ala154Thr) and TPMT * 3C (c.719A > G, p.Tyr240Cys) alleles, located at exons 7 and 10, respectively. These two-point mutations, present in most Caucasians with a phenotype with undetectable TPMT activity, lead to a decrease in the quantity of protein [59]. This reduction would be the result of a post-translational mechanism linked to an activation of the proteolytic pathways, the consequence of which is the increase in the rate of degradation of the enzyme by the proteasome [58,60]. Finally, the third non-functional allelic variant, the TPMT * 3B allele, contains only the c.460G > A, p.Ala154Thr mutation in exon 7 [59].\n\nThese three mutations, c.238G > C,p.Ala80Pro, c.460G > A,p.Ala154Thr, and c.719A > G,p.Tyr240Cys, are at the origin of the non-functional alleles of TPMT most frequently encountered regardless of the ethnic origin of individuals, with increasing frequency c.238G > C, c.460G > A, c.719A > G [61] (see Table 1). \n\n4. Case Report\nA 20-year-old woman was diagnosed with UC based on standard clinical, endoscopic, and histological criteria. The patient began to take 4 g of mesalazine per day but heart palpitations rapidly (tachychardia) occurred and the treatment was stopped. Subsequently, this young woman was treated with prednisolone and 6-mercaptopurine, but therapy was also stopped due to leukopenia. TPMT genotyping was performed by sequence analysis of all coding exons and flanking intron regions of the TPMT gene and the result was available after the patient received azathioprine. Known “hot spot” mutations (Table 2) on exons 5, 7, and 10 of the TPMT gene were carried out by Sanger sequencing. \n\nThe genotyping of TPMT * 2, * 3A, and * 3C mutations were not detected. However, a novel class 5 deleterious mutation, c.483_484del, p.Asp162Serfs * 26 (submitted to the TPMT nomenclature committee), was found in exon 7 (Figure 3). This deletion involves a shift in the reading frame of the sequence and induces a STOP codon located at position 188 of the amino acids (Tyrosine → Stop) in the middle of exon 8. This molecular alteration generates a truncated TPMT protein without exons 9 and 10. In addition, the TPMT * 16 “hot spot” appears (G488A), inducing a mutation in one of the alleles. \n\nBriefly, the PCR reaction was carried out in a reaction mixture of 50 μL containing nuclease free water, 10 × buffer, 25 mM MgCl2, 5 mM of each deoxyribonucleotide triphosphate, 10 µM of each primer (sense primer 5′-CTCCACACCCAGGTCCACACATT-3 ’and reverse primer 5′-GTATAGTATACTAAAAAATTAAGACAGCTAAAC-3′), 5 U/µL of HotStar Taq DNA polymerase (Qiagen, Hilden, GERMANY), and 100 ng of genomic DNA. Cycling conditions were an initial denaturation of 95 °C for 10 min, followed by 14 cycles of amplification at 95 °C for 40 s, 55 °C for 40 s, 72 °C for 50 s, followed by 21 cycles of amplification at 95 °C for 40 s, 60 °C for 40 s, 72 °C for 50 s, and a final extension step of 72 °C for 5 min. Ten microliters of PCR product was visualized on an ethidium bromide-stained 2% agarose gel. The remaining 10 µL of PCR product was purified using a filter plate Multiscreen® (Merck, Millipore Ltd., Burlington, MA, USA) and sequenced in both directions using the ABI BigDye Terminator version 1.1 chemistry on an ABI 3130X l DNA Analyzer (Applied Biosystems, Foster City, CA, USA). \n\nThereafter, the patient underwent a first line of anti–TNF-α biotherapies with adalimumab (160 mg, 80 mg, and 40 mg every 2 weeks), but after a transient improvement, the symptomatology recurred. She received vedolizumab and then therapeutic exhaustion occurred despite optimization with 300 mg monthly. Then, golimumab (100 mg) was administered monthly with a partial improvement. Finally, she received ustekinumab with initial improvement but a recurrence 3 months later in the form of severe acute colic with a 6 kg weight loss stopped this therapy. As the disease had not been brought under control, treatment with azathioprine was recently reintroduced, but at a reduced dose because of a mutation in the TPMT gene. Finally, despite a combination therapy with optimized infleximab and AZA, the patient experienced disease progression and she initiated a new therapy with tofacitinib.\n\n5. Conclusions\nAlthough the role of azathioprine monotherapy in IBD for the maintenance of remission is still a point of discussion among clinicians, AZA remains an affordable and viable option for the public sector. However, genetic screening for the presence of SNP on the TPMT gene of patients with IBD is necessary to ensure therapeutic efficacy [62]. The mutations in the TPMT gene cause a TPMT deficiency, which is a reduction in the activity of the TPMT enzyme. Without enough of this enzyme, the body cannot “turn off” thiopurine drugs by metabolizing them into inactive compounds, damaging the bone marrow through haematopoietic toxicity. More than 20% of patients with inflammatory bowel disease stop the treatment due to serious side effects of the thiopurines [8,23]. Therefore, there are strong reasons to recommend that all patients be screened for TPMT deficiency before starting a course of these drugs. Measuring the enzyme activity remains a standard but this test is unfortunately unavailable in many centers. If necessary, low doses of azathioprine can be administered, which can be increased if the drug is tolerated. However, it should be noted that profound myelosuppression in TPMT-deficient patients is not always avoidable and the majority of cases of myelosuppression associated with thiopurines appear in individuals who fall into the normal range of TPMT activity. \n\nGenotyping can provide a useful adjunct in these situations. Here, we have reported a new clinically important TPMT * 16 mutation in a young patient who received the thiopurine treatment. This molecular alteration has never been described to our knowledge and is not referenced in genetic databases such as ClinVar, Alamut, or Ensembl. This reinforces the clinical significance of TPMT * 16 in the azathioprine treatment and also the utility of careful therapeutic monitoring of thiopurine metabolites in the presence of TPMT variants. With the reduction in the cost of DNA sequencing and an increase in sequence-based genotyping for non-synonymous SNPs using next-generation sequencing (NGS), an increasing number of new TPMT alleles are likely to be identified in the future.\n\nIt is important not to overlook the possibility of new genes involved in the thiopurine pathway. Indeed, a significant association has been identified between the enzymatic activity of TPMT and the MOCOS gene (molybdenum cofactor sulfurase). The latter is thought to have an action on the enzymes xanthine dehydrogenase (XDH) and aldeyde oxidase 1 (AOX1) involved in the degradation of thiopurines [63]. Moreover, the work of Coelho et al. [25] made it possible to detect a nominal association between tolerance to thiopurines and the GMPS gene (guanosine monophosphate synthetase). The involvement of this gene in the phosphorylation of 6-TIMP (6-thioinosine monophosphate) to 6-TGN (thioguanine nucleotides) allows thiopurines to exert their cytotoxic effects. Therefore, mutations in these MOCOS and GMPS genes would induce thiopurine toxicity. As the study by Coehlo et al. [25] points out, although NGS does not clearly provide an advantage as a biochemical test in predicting toxicity, it is a solid tool in the identification of pathogenic variants in patients not detected by the standard genotyping. The identification and then the study in NGS of a panel of genes involved in the metabolic pathway of thiopurine must be extended, in order to assess their toxicity and guide clinicians in the treatment strategy.\n\nThus, genotyping may become increasingly important in clinical practice because it provides clear benefits to the patient and allows the adaptation of pre-therapeutic doses for patients carrying the mutation.\n\nAcknowledgments\nNo acknowledgments.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor Contributions\nConceptualization, J.S.; methodology, J.S.; writing—original draft preparation, P.-O.H.; writing—review and editing, J.S. and P.-O.H. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Involvement of TPMT on the thiopurine metabolic pathway. AZA (azathioprine); AOX1 (aldehyde oxidase type 1); FTO (fat mass and obesity associated); GST (gluthation s-transferase); GMPS (guanosine monophosphate synthetase); HGPRT (hypoxanthine guanine phosphoribosyl transferase); IMPDH1 (inosine 5-monophosphate deshydrogenase type 1); IPTA (inosine triphosphate pyrophosphatase); MOCOS (molybdenum cofactor sulfurase); NDPK (nucleotide diphosphate kinase); NUD15 (nucleoside diphosphate linked moiety X type 15); RNR (ribonucleotide reductase); TPMT (thiopurine s-methyltransferase); XDH (synonym-Xanthine oxidase); 6-MP (6-mercaptopurine); 6-MeMP (6-methyl-mercaptopurine); 6-MeMPR (6-methyl-mercaptopurine ribonucleotide); 6-MeTGMP (6-methyl-thioguanine monophosphate); 6-MeTIMP (6-methyl-thioinosine monophosphate); 6-deoxyTGMP (6-deoxy-thioguanine monophosphate); 6-deoxyTGDP (6-deoxy-thioguanine diphosphate); 6-deoxyTGTP (6-deoxy-thioguanine triphosphate); 6-TGMP (6- thioguanine monophosphate); 6-TGDP (6-thioguanine diphosphate); 6-TGTP (6-thioguanine triphosphate); 6-TIMP (6-thioinosine monophosphate); 6-TITP (6-thionosine triphosphate); 6-TXMP (6-thioxanthine monophsphate); 6-TU (thiouric acid); 6-TX (6-thioxanthine).\n\nFigure 2 Allelic variants of the human TPMT locus. The TPMT gene is located on 6p22.3 (NM_000367.2, OMIM 187680) and comprises 10 exons and nine introns. Boxes depict exons in the human TPMT gene and spaces between boxes are introns. White boxes show untranslated exonic regions and black boxes represent exons in the open reading frame (ORF). Grey boxes correspond to different exons with molecular alterations inducing changes in amino acids. The positions of the most frequent SNPs are indicated by vertical arrows. The red box shows exon 7 with the c.483_484del, p.Asp162Serfs * 26 mutation inducing a TPMT * 16 mutation (c.488G > A,p.Arg163His).\n\nFigure 3 Electropherogram obtained with the SeqScape v2.5v software ( APPLIED Biosystem, Foster City, CA, USA) representing part of the sequence of TPMT exon 7. The black arrow shows a silencing mutation. The red arrow shows a novel c.483_484del, p.Asp162Serfs * 26 mutation that generates a premature stop codon in exon 8.\n\ngenes-11-01212-t001_Table 1Table 1 Nomenclature of the most frequent non-functional alleles of the TPMT gene.\n\nCommon Allele Name\tExon\tCoding DNA\tProtein\t\nTPMT * 2\t5\tc.238G > C\tp.Ala80Pro\t\nTPMT * 3A\t7\tc.460G > A\tp.Ala154Thr\t\nTPMT * 3A\t10\tc.719A > G\tp.Tyr240Cys\t\nTPMT * 3B\t7\tc.460G > A\tp.Ala154Thr\t\nTPMT * 3C\t10\tc.719A > G\tp.Tyr240Cys\t\nTPMT * 8\t10\tc.644G > A\tp.Arg215His\t\ngenes-11-01212-t002_Table 2Table 2 Genotyping of the TPMT gene-list of targeted molecular alterations.\n\nEXON 5 :\tEXON 7 :\tEXON 10 :\t\nVariant\tNucleotide\tProtein\tVariant\tNucleotide\tProtein\tVariant\tNucleotide\tProtein\t\nTPMT * 2\tc.238G > C\tp.Ala80Pro\tTPMT * 10\tc.430G > C\tp.Gly144Gln\tTPMT * 8\tc.644G > A\tp.Arg215His\t\nTPMT * 3D\tc.292G > T\tp.Glu98*\tTPMT * 3A\tc.460G > A\tp.Ala154Arg\tTPMT * 7\tc.681T > G\tp.His227Gln\t\nTPMT * 9\tc.356A > C\tp.Lys119Thr\tTPMT * 3B\tc.460G > A\tp.Ala154Arg\tTPMT * 20\tc.712A > G\tp.Lys238Glu\t\nTPMT * 19\tc.365A > C\tp.Lys122Thr\tTPMT * 22\tc.474T > C\tp.Ile158Ile\tTPMT * 3A\tc.719A > G\tp.Tyr240Cys\t\nTPMT * 34\tc.319T > G\tp.Tyr107Asp\tTPMT * 16\tc.488G > A\tp.Arg163His\tTPMT * 3C\tc.719A > G\tp.tyr240Cys\t\nTPMT * 28\tc.349G > C\tp.Gly117Arg\tTPMT * 22\tc.488G > C\tp.Arg158Pro\tTPMT * 41\tc.719A > C\tp.Tyr240Ser\t\nTPMT * 32\tc.340G > A\tp.Glu114Lys\tTPMT * 33\tc.487C > T\tp.Arg158Cys\tTPMT * 25\tc.634T > C\tp.Cys212Ser\t\n\n\t\n\t\n\t\n\t\n\t\n\tTPMT * 37\tc.648T > A\tp.Cys216*\t\n\n\t\n\t\n\t\n\t\n\t\n\tTPMT * 40\tc.677G > A\tp.Arg226Gln\n==== Refs\nReferences\n1. Kaplan G.G. The global burden of IBD: From 2015 to 2025 Nat. Rev. Gastroenterol. Hepatol. 2015 12 720 727 10.1038/nrgastro.2015.150 26323879 \n2. Ng S.C. Shi H.Y. Hamidi N. Underwood F.E. Tang W. Benchimol E.I. Panaccione R. Ghosh S. Wu J.C.Y. Chan F.K.L. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies Lancet 2018 390 2769 2778 10.1016/S0140-6736(17)32448-0 29050646 \n3. Baumgart D.C. Carding S.R. Inflammatory bowel disease: Cause and immunobiology Lancet 2007 369 1627 1640 10.1016/S0140-6736(07)60750-8 17499605 \n4. Damiao A. de Azevedo M.F.C. Carlos A.S. Wada M.Y. Silva T.V.M. Feitosa F.C. Conventional therapy for moderate to severe inflammatory bowel disease: A systematic literature review World J. Gastroenterol. 2019 25 1142 1157 10.3748/wjg.v25.i9.1142 30863001 \n5. Lamb C.A. Kennedy N.A. Raine T. Hendy P.A. Smith P.J. Limdi J.K. Hayee B. Lomer M.C.E. Parkes G.C. Selinger C. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults Gut 2019 68 s1 s106 10.1136/gutjnl-2019-318484 31562236 \n6. Conrad M.A. Kelsen J.R. The Treatment of Pediatric Inflammatory Bowel Disease with Biologic Therapies Curr. Gastroenterol. Rep. 2020 22 36 10.1007/s11894-020-00773-3 32542562 \n7. Soh J.S. Yun W.J. Kim K.J. Won C.H. Park S.H. Yang D.H. Ye B.D. Byeon J.S. Myung S.J. Yang S.K. Concomitant use of azathioprine/6-mercaptopurine decreases the risk of anti-TNF-induced skin lesions Inflamm. Bowel Dis. 2015 21 832 839 10.1097/MIB.0000000000000342 25789922 \n8. Coenen M.J. de Jong D.J. van Marrewijk C.J. Derijks L.J. Vermeulen S.H. Wong D.R. Klungel O.H. Verbeek A.L. Hooymans P.M. Peters W.H. Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease Gastroenterology 2015 149 907 917.e907 10.1053/j.gastro.2015.06.002 26072396 \n9. Schwab M. Schaffeler E. Marx C. Fischer C. Lang T. Behrens C. Gregor M. Eichelbaum M. Zanger U.M. Kaskas B.A. Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease: Impact of thiopurine S-methyltransferase polymorphism Pharmacogenetics 2002 12 429 436 10.1097/00008571-200208000-00003 12172211 \n10. Dean L. Pratt V.M. McLeod H.L. Rubinstein W.S. Scott S.A. Dean L.C. Kattman B.L. Malheiro A.J. Eds Azathioprine Therapy and TPMT and NUDT15 Genotype Medical Genetics Summaries National Center for Biotechnology Information (US) Bethesda, MD, USA 2012 \n11. Fong W.Y. Ho C.C. Poon W.T. Comparison of Direct Sequencing, Real-Time PCR-High Resolution Melt (PCR-HRM) and PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) Analysis for Genotyping of Common Thiopurine Intolerant Variant Alleles NUDT15 c.415C>T and TPMT c.719A>G (TPMT * 3C) Diagnostics 2017 7 27 10.3390/diagnostics7020027 \n12. Pasternak B. Svanstrom H. Schmiegelow K. Jess T. Hviid A. Use of azathioprine and the risk of cancer in inflammatory bowel disease Am. J. Epidemiol. 2013 177 1296 1305 10.1093/aje/kws375 23514635 \n13. Prefontaine E. Sutherland L.R. Macdonald J.K. Cepoiu M. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease Cochrane Database Syst. Rev. 2009 CD000067 10.1002/14651858.CD000067.pub2 19160175 \n14. Amin J. Huang B. Yoon J. Shih D.Q. Update 2014: Advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD Inflamm. Bowel Dis. 2015 21 445 452 10.1097/MIB.0000000000000197 25248004 \n15. Colombel J.F. Sandborn W.J. Reinisch W. Mantzaris G.J. Kornbluth A. Rachmilewitz D. Lichtiger S. D’Haens G. Diamond R.H. Broussard D.L. Infliximab, azathioprine, or combination therapy for Crohn’s disease N. Engl. J. Med. 2010 362 1383 1395 10.1056/NEJMoa0904492 20393175 \n16. Panaccione R. Ghosh S. Middleton S. Marquez J.R. Scott B.B. Flint L. van Hoogstraten H.J. Chen A.C. Zheng H. Danese S. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis Gastroenterology 2014 146 392 400.e3 10.1053/j.gastro.2013.10.052 24512909 \n17. Gomollon F. Dignass A. Annese V. Tilg H. Van Assche G. Lindsay J.O. Peyrin-Biroulet L. Cullen G.J. Daperno M. Kucharzik T. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical Management J. Crohns Colitis 2017 11 3 25 10.1093/ecco-jcc/jjw168 27660341 \n18. Harbord M. Eliakim R. Bettenworth D. Karmiris K. Katsanos K. Kopylov U. Kucharzik T. Molnar T. Raine T. Sebastian S. Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 2: Current Management J. Crohns Colitis 2017 11 769 784 10.1093/ecco-jcc/jjx009 28513805 \n19. Swann P.F. Waters T.R. Moulton D.C. Xu Y.Z. Zheng Q. Edwards M. Mace R. Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine Science 1996 273 1109 1111 10.1126/science.273.5278.1109 8688098 \n20. Lennard L. Rees C.A. Lilleyman J.S. Maddocks J.L. Childhood leukaemia: A relationship between intracellular 6-mercaptopurine metabolites and neutropenia Br. J. Clin. Pharmacol. 1983 16 359 363 10.1111/j.1365-2125.1983.tb02178.x 6578834 \n21. Van Scoik K.G. Johnson C.A. Porter W.R. The pharmacology and metabolism of the thiopurine drugs 6-mercaptopurine and azathioprine Drug. Metab. Rev. 1985 16 157 174 10.3109/03602538508991433 3905317 \n22. Hon Y.Y. Fessing M.Y. Pui C.H. Relling M.V. Krynetski E.Y. Evans W.E. Polymorphism of the thiopurine S-methyltransferase gene in African-Americans Hum. Mol. Genet. 1999 8 371 376 10.1093/hmg/8.2.371 9931346 \n23. Abaji R. Krajinovic M. Thiopurine S-methyltransferase polymorphisms in acute lymphoblastic leukemia, inflammatory bowel disease and autoimmune disorders: Influence on treatment response Pharmgenomics Pers. Med. 2017 10 143 156 10.2147/PGPM.S108123 28507448 \n24. Chen S. Tan W.Z. Sutiman N. Lim C. Lee S.S. Leong W.F. Tjai M. Wang C. Kong C.S.C. Chuah S.W. An intronic FTO variant rs16952570 confers protection against thiopurine-induced myelotoxicities in multiethnic Asian IBD patients Pharm. J. 2020 20 505 515 10.1038/s41397-019-0126-9 \n25. Coelho T. Andreoletti G. Ashton J.J. Batra A. Afzal N.A. Gao Y. Williams A.P. Beattie R.M. Ennis S. Genes implicated in thiopurine-induced toxicity: Comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort Sci. Rep. 2016 6 34658 10.1038/srep34658 27703193 \n26. Gonzalez-Lama Y. Gisbert J.P. Monitoring thiopurine metabolites in inflammatory bowel disease Frontline Gastroenterol. 2016 7 301 307 10.1136/flgastro-2015-100681 28839871 \n27. Lim S.Z. Chua E.W. Revisiting the Role of Thiopurines in Inflammatory Bowel Disease Through Pharmacogenomics and Use of Novel Methods for Therapeutic Drug Monitoring Front. Pharmacol. 2018 9 1107 10.3389/fphar.2018.01107 30349479 \n28. Choi R. Sohn I. Kim M.J. Woo H.I. Lee J.W. Ma Y. Yi E.S. Koo H.H. Lee S.Y. Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia Br. J. Clin. Pharmacol. 2019 85 1585 1597 10.1111/bcp.13943 30927276 \n29. Chang J.Y. Cheon J.H. Thiopurine Therapy in Patients With Inflammatory Bowel Disease: A Focus on Metabolism and Pharmacogenetics Dig. Dis. Sci. 2019 64 2395 2403 10.1007/s10620-019-05720-5 31290039 \n30. Dubinsky M.C. Azathioprine, 6-mercaptopurine in inflammatory bowel disease: Pharmacology, efficacy, and safety Clin. Gastroenterol. Hepatol. 2004 2 731 743 10.1016/S1542-3565(04)00344-1 15354273 \n31. Lennard L. Van Loon J.A. Weinshilboum R.M. Pharmacogenetics of acute azathioprine toxicity: Relationship to thiopurine methyltransferase genetic polymorphism Clin. Pharm. Ther. 1989 46 149 154 10.1038/clpt.1989.119 \n32. Van Os E.C. Zins B.J. Sandborn W.J. Mays D.C. Tremaine W.J. Mahoney D.W. Zinsmeister A.R. Lipsky J.J. Azathioprine pharmacokinetics after intravenous, oral, delayed release oral and rectal foam administration Gut 1996 39 63 68 10.1136/gut.39.1.63 8881811 \n33. Chrzanowska M. Hermann T. Gapinska M. Kinetics of azathioprine metabolism in fresh human blood Pol. J. Pharm. Pharm. 1985 37 701 708 \n34. Gilissen L.P. Derijks L.J. Bos L.P. Bus P.J. Hooymans P.M. Engels L.G. Therapeutic drug monitoring in patients with inflammatory bowel disease and established azathioprine therapy Clin. Drug Investig. 2004 24 479 486 10.2165/00044011-200424080-00006 17523708 \n35. Chande N. Patton P.H. Tsoulis D.J. Thomas B.S. MacDonald J.K. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease Cochrane Database Syst. Rev. 2015 Cd000067 10.1002/14651858.CD000067.pub3 26517527 \n36. Timmer A. Patton P.H. Chande N. McDonald J.W. MacDonald J.K. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis Cochrane Database Syst. Rev. 2016 CD000478 10.1002/14651858.CD000478.pub4 27192092 \n37. Broekman M. Coenen M.J.H. van Marrewijk C.J. Wanten G.J.A. Wong D.R. Verbeek A.L.M. Klungel O.H. Hooymans P.M. Guchelaar H.J. Scheffer H. More Dose-dependent Side Effects with Mercaptopurine over Azathioprine in IBD Treatment Due to Relatively Higher Dosing Inflamm. Bowel Dis. 2017 23 1873 1881 10.1097/MIB.0000000000001163 28644183 \n38. Pruijt J.F. Haanen J.B. Hollander A.A. den Ottolander G.J. Azathioprine-induced pure red-cell aplasia Nephrol. Dial. Transpl. 1996 11 1371 1373 10.1093/ndt/11.7.1371 \n39. Logan J.K. Yapa S.W.S. Harinstein L. Saluja B. Munoz M. Sahajwalla C. Neuner R. Seymour S. Drug Interaction Between Febuxostat and Thiopurine Antimetabolites: A Review of the FDA Adverse Event Reporting System and Medical Literature Pharmacotherapy 2020 40 125 132 10.1002/phar.2362 31885095 \n40. Beigel F. Steinborn A. Schnitzler F. Tillack C. Breiteneicher S. John J.M. Van Steen K. Laubender R.P. Goke B. Seiderer J. Risk of malignancies in patients with inflammatory bowel disease treated with thiopurines or anti-TNF α antibodies Pharmacoepidemiol. Drug Saf. 2014 23 735 744 10.1002/pds.3621 24788825 \n41. Fraser A.G. Orchard T.R. Robinson E.M. Jewell D.P. Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine Aliment. Pharmacol. Ther. 2002 16 1225 1232 10.1046/j.1365-2036.2002.01297.x 12144571 \n42. McGovern D.P. Jewell D.P. Risks and benefits of azathioprine therapy Gut 2005 54 1055 1059 10.1136/gut.2004.053231 16009676 \n43. Lewis J.D. Schwartz J.S. Lichtenstein G.R. Azathioprine for maintenance of remission in Crohn’s disease: Benefits outweigh the risk of lymphoma Gastroenterology 2000 118 1018 1024 10.1016/S0016-5085(00)70353-2 10833475 \n44. de Jong D.J. Goullet M. Naber T.H. Side effects of azathioprine in patients with Crohn’s disease Eur. J. Gastroenterol. Hepatol. 2004 16 207 212 10.1097/00042737-200402000-00014 15075996 \n45. Liu Y.P. Xu H.Q. Li M. Yang X. Yu S. Fu W.L. Huang Q. Association between Thiopurine S-Methyltransferase Polymorphisms and Azathioprine-Induced Adverse Drug Reactions in Patients with Autoimmune Diseases: A Meta-Analysis PLoS ONE 2015 10 e0144234 10.1371/journal.pone.0144234 26633017 \n46. Kreijne J.E. Seinen M.L. Wilhelm A.J. Bouma G. Mulder C.J. van Bodegraven A.A. de Boer N.K. Routinely Established Skewed Thiopurine Metabolism Leads to a Strikingly High Rate of Early Therapeutic Failure in Patients With Inflammatory Bowel Disease Ther. Drug Monit. 2015 37 797 804 10.1097/FTD.0000000000000213 25853923 \n47. Smith M.A. Blaker P. Marinaki A.M. Anderson S.H. Irving P.M. Sanderson J.D. Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol J. Crohns Colitis 2012 6 905 912 10.1016/j.crohns.2012.02.007 22386736 \n48. Moon W. Loftus E.V. Jr. Review article: Recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease Aliment. Pharmacol. Ther. 2016 43 863 883 10.1111/apt.13559 26876431 \n49. Keats B.J.B. Sherman S.L. Chapter 13—Population Genetics Emery and Rimoin’s Principles and Practice of Medical Genetics 6th ed. Academic Press Oxford, UK 2013 1 12 \n50. Hawwa A.F. Millership J.S. Collier P.S. Vandenbroeck K. McCarthy A. Dempsey S. Cairns C. Collins J. Rodgers C. McElnay J.C. Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine Br. J. Clin. Pharmacol. 2008 66 517 528 10.1111/j.1365-2125.2008.03248.x 18662289 \n51. Kham S.K. Soh C.K. Aw D.C. Yeoh A.E. TPMT*26 (208F-->L), a novel mutation detected in a Chinese Br. J. Clin. Pharmacol. 2009 68 120 123 10.1111/j.1365-2125.2009.03405.x 19660010 \n52. McLeod H.L. Siva C. The thiopurine S-methyltransferase gene locus -- implications for clinical pharmacogenomics Pharmacogenomics 2002 3 89 98 10.1517/14622416.3.1.89 11966406 \n53. Tamm R. Oselin K. Kallassalu K. Magi R. Anier K. Remm M. Metspalu A. Thiopurine S-methyltransferase (TPMT) pharmacogenetics: Three new mutations and haplotype analysis in the Estonian population Clin. Chem. Lab. Med. 2008 46 974 979 10.1515/CCLM.2008.187 18605963 \n54. Lennard L. Implementation of TPMT testing Br. J. Clin. Pharmacol. 2014 77 704 714 10.1111/bcp.12226 23962279 \n55. Krynetski E.Y. Evans W.E. Genetic polymorphism of thiopurine S-methyltransferase: Molecular mechanisms and clinical importance Pharmacology 2000 61 136 146 10.1159/000028394 10971199 \n56. Iu Y.P.H. Helander S. Kahlin A.Z. Cheng C.W. Shek C.C. Leung M.H. Wallner B. Martensson L.G. Appell M.L. One amino acid makes a difference-Characterization of a new TPMT allele and the influence of SAM on TPMT stability Sci. Rep. 2017 7 46428 10.1038/srep46428 28462921 \n57. Appell M.L. Berg J. Duley J. Evans W.E. Kennedy M.A. Lennard L. Marinaki T. McLeod H.L. Relling M.V. Schaeffeler E. Nomenclature for alleles of the thiopurine methyltransferase gene Pharmacogenet. Genom. 2013 23 242 248 10.1097/FPC.0b013e32835f1cc0 23407052 \n58. Tai H.L. Krynetski E.Y. Schuetz E.G. Yanishevski Y. Evans W.E. Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): Mechanisms for the genetic polymorphism of TPMT activity Proc. Natl. Acad. Sci. USA 1997 94 6444 6449 10.1073/pnas.94.12.6444 9177237 \n59. Szumlanski C. Otterness D. Her C. Lee D. Brandriff B. Kelsell D. Spurr N. Lennard L. Wieben E. Weinshilboum R. Thiopurine methyltransferase pharmacogenetics: Human gene cloning and characterization of a common polymorphism DNA Cell Biol. 1996 15 17 30 10.1089/dna.1996.15.17 8561894 \n60. Wang L. Sullivan W. Toft D. Weinshilboum R. Thiopurine S-methyltransferase pharmacogenetics: Chaperone protein association and allozyme degradation Pharmacogenetics 2003 13 555 564 10.1097/00008571-200309000-00004 12972954 \n61. Loennechen T. Utsi E. Hartz I. Lysaa R. Kildalsen H. Aarbakke J. Detection of one single mutation predicts thiopurine S-methyltransferase activity in a population of Saami in northern Norway Clin. Pharmacol. Ther. 2001 70 183 188 10.1067/mcp.2001.117445 11503013 \n62. Adam L. Phulukdaree A. Soma P. Effective long-term solution to therapeutic remission in Inflammatory Bowel Disease: Role of Azathioprine Biomed. Pharmacother. 2018 100 8 14 10.1016/j.biopha.2018.01.152 29421584 \n63. Ichida K. Matsumura T. Sakuma R. Hosoya T. Nishino T. Mutation of human molybdenum cofactor sulfurase gene is responsible for classical xanthinuria type II Biochem. Biophys. Res. Commun. 2001 282 1194 1200 10.1006/bbrc.2001.4719 11302742\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2073-4425",
"issue": "11(10)",
"journal": "Genes",
"keywords": "TPMT; azathioprine; mutation; targeted therapies; ulcerative colitis",
"medline_ta": "Genes (Basel)",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D001379:Azathioprine; D003093:Colitis, Ulcerative; D004351:Drug Resistance; D006801:Humans; D008780:Methyltransferases; D009154:Mutation; D010597:Pharmacogenetics",
"nlm_unique_id": "101551097",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33081236",
"pubdate": "2020-10-16",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "29421584;15075996;9931346;26517527;11503013;18662289;19660010;12972954;9177237;23962279;32542562;31562236;30927276;12172211;10971199;25789922;27192092;22386736;20393175;31813937;24512909;27660341;31290039;17499605;12144571;26072396;24788825;16009676;2758725;28507448;8688098;8881811;28462921;19160175;18605963;30349479;28513805;23407052;3905317;30863001;31885095;26876431;11966406;26323879;28498350;28644183;8561894;10833475;26633017;11302742;6578834;8672045;17523708;15354273;27703193;3832014;29050646;23514635;28839871;25248004;25853923",
"title": "Thiopurine Drugs in the Treatment of Ulcerative Colitis: Identification of a Novel Deleterious Mutation in TPMT.",
"title_normalized": "thiopurine drugs in the treatment of ulcerative colitis identification of a novel deleterious mutation in tpmt"
} | [
{
"companynumb": "FR-BAUSCH-BL-2020-032105",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": null,
... |
{
"abstract": "Fever is a common early complication after infusion of stem cells in patients undergoing T-replete HLA haploidentical transplantation using post-transplant cyclophosphamide (PTCY). We analyzed the records of 172 haploidentical transplant patients to identify risk factors and to assess the impact of such fevers on transplant morbidity and mortality. One hundred and seventy-two patients received haploidential hematopoietic stem cell transplantation (haplo-HSCT) using PBSC (n = 103) or marrow (n = 69) grafts. One hundred and forty patients (81%) experienced fever (T ≥ 100.5 °F or >38 °C) with median onset on d + 2. Compared to patients who did not develop fevers, patients with fevers received higher median CD34+ cell dose (5.00 vs. 3.08 × 106/kg, p < 0.001), CD3+ cell dose (12.8 vs. 4.5 × 107/kg), were more likely to have received a myeloablative regimen (50% vs. 9%, p < 0.001), and PBSC source (71% vs. 9%, p < 0.001). Cox model showed that fever had no impact on TRM, GVHD, OS, and DFS. In the logistic regression to identify correlation with fevers, higher degree of HLA mismatches and use of PBSC were all predictors of developing fever. Fevers between infusion of the T-Cell replete graft and administration of PTCY are very common in Haplo-HSCT. This complication is transient and had no impact on post-transplant morbidity and mortality.",
"affiliations": "Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA. msolh@bmtga.com.;Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA.;Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA.;Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA.;Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.;Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA.;Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA.",
"authors": "Solh|Melhem M|MM|;Dickhaus|Elizabeth|E|;Solomon|Scott R|SR|;Morris|Lawrence E|LE|;Zhang|Xu|X|;Holland|H Kent|HK|;Bashey|Asad|A|",
"chemical_list": "D006680:HLA Antigens",
"country": "England",
"delete": false,
"doi": "10.1038/s41409-019-0522-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "54(11)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D064591:Allografts; D005260:Female; D005334:Fever; D006680:HLA Antigens; D006801:Humans; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D012189:Retrospective Studies; D012307:Risk Factors; D013601:T-Lymphocytes",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "1756-1763",
"pmc": null,
"pmid": "30953027",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Fevers post infusion of T-cell replete hla mismatched haploidentical hematopoietic stem cells with post-transplant cyclophosphamide: risk factors and impact on transplant outcomes.",
"title_normalized": "fevers post infusion of t cell replete hla mismatched haploidentical hematopoietic stem cells with post transplant cyclophosphamide risk factors and impact on transplant outcomes"
} | [
{
"companynumb": "US-AMGEN-USASP2019202302",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nAfter several visits with unrelated complaints, a 16-year-old female patient disclosed symptoms of unwanted genital arousal and was diagnosed with persistent genital arousal disorder (PGAD).\n\n\nMETHODS\nA 16-year-old female patient with history of depression, sexual abuse, and dysmenorrhea insistently requested etonogestrel rod removal. At 2 visits after implant removal, the patient disclosed the reason for her insistence: PGAD symptoms developed after implant insertion, although they worsened with removal. Chart review revealed selective serotonin reuptake inhibitor discontinuation before symptom onset. Normalization of sexual arousal occurred with counseling, selective serotonin reuptake inhibitor treatment, and hormonal contraception.\n\n\nCONCLUSIONS\nThis case highlights the importance of clinician recognition of PGAD symptoms, which adolescents might not openly disclose. Clinicians must nonjudgmentally collect medication history and sexual history, including sexual arousal and satisfaction, to make this diagnosis.",
"affiliations": "Section of Adolescent Medicine, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Electronic address: Kelly-Curran@ouhsc.edu.",
"authors": "Curran|Kelly A|KA|",
"chemical_list": "D003278:Contraceptives, Oral, Hormonal; D017367:Serotonin Uptake Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpag.2018.11.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-3188",
"issue": "32(2)",
"journal": "Journal of pediatric and adolescent gynecology",
"keywords": "Adolescence; Childhood sexual abuse; Libido; Medication side effect; Orgasm; PGAD; Persistent genital arousal disorder; Sexual arousal; Sexual dysfunction; Sexual history",
"medline_ta": "J Pediatr Adolesc Gynecol",
"mesh_terms": "D000293:Adolescent; D003278:Contraceptives, Oral, Hormonal; D003863:Depression; D003937:Diagnosis, Differential; D005260:Female; D005835:Genitalia; D006801:Humans; D017367:Serotonin Uptake Inhibitors; D020018:Sexual Dysfunctions, Psychological",
"nlm_unique_id": "9610774",
"other_id": null,
"pages": "186-188",
"pmc": null,
"pmid": "30513343",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case Report: Persistent Genital Arousal Disorder in an Adolescent Woman.",
"title_normalized": "case report persistent genital arousal disorder in an adolescent woman"
} | [
{
"companynumb": "US-009507513-1803USA010400",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BUPROPION HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "A 73-year-old man (164cm height 51 kg body weight) with a history of Parkinson's disease and dementia was scheduled for a cervical lymph node biopsy under general anesthesia. We induced anesthesia with thiamylal and fentanyl, and maintained with sevoflurane and remifentanil without any incident. The patient did not emerge from anesthesia after the surgery. He developed coma and did not respond to painful stimuli. However, his breathing was spontaneous with stable hemodynamics. Although naloxone was given, he was still comatose. His clinical neurological findings showed no organic abnormalities. Forty minutes after the surgery, he suddenly woke up and followed instructions. We learned that previously he had been diagnosed with dementia with Lewy bodies.",
"affiliations": null,
"authors": "Takebe|Sawako|S|;Inoue|Kazuyoshi|K|;Kawanishi|Hiroyuki|H|;Nakamura|Hitoshi|H|;Ohnishi|Ai|A|;Ohnishi|Junji|J|;Yatsu|Yuichi|Y|;Nagai|Akihiro|A|;Matsuda|Rikiya|R|;Hirasaki|Akihito|A|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-4892",
"issue": "64(1)",
"journal": "Masui. The Japanese journal of anesthesiology",
"keywords": null,
"medline_ta": "Masui",
"mesh_terms": "D000368:Aged; D000768:Anesthesia, General; D001364:Awareness; D003704:Dementia; D006801:Humans; D016631:Lewy Bodies; D008297:Male",
"nlm_unique_id": "0413707",
"other_id": null,
"pages": "81-3",
"pmc": null,
"pmid": "25868207",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Delayed emergence from general anesthesia in a dementia patient with Lewy bodies.",
"title_normalized": "delayed emergence from general anesthesia in a dementia patient with lewy bodies"
} | [
{
"companynumb": "JP-BAXTER-2015BAX037342",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SEVOFLURANE"
},
"drugadditional": null,
... |
{
"abstract": "Transplant-associated thrombotic microangiopathy (TMA) in the post-organ transplantation setting occurs from a number of potential inciting factors, such as the use of calcineurin inhibitors, ischemic injury, infections, or antibody-mediated rejection leading to unchecked complement activation and end-organ damage. Delayed recognition of this condition can result in allograft loss. In this case description, we describe the first case of de novo TMA in a patient with polycystic kidney disease that occurred immediately after kidney transplantation. The diagnosis was made promptly on the basis of clinical and laboratory characteristics by a multidisciplinary team and confirmed through kidney biopsy, which showed acute TMA. The patient was successfully managed by replacing tacrolimus with belatacept, which targets cytotoxic T lymphocyte antigen 4, and use of eculizumab, a C5 inhibitor. Eculizumab treatment was discontinued after 3 months of complement inhibition on the patient's request, and relapse of TMA has not been encountered after more than 1 year of follow-up.",
"affiliations": "Department of Hematology-Oncology, Tufts Medical Center, Boston, MA.;Kidney Transplant Team, Division of Nephrology, Tufts Medical Center, Boston, MA.;Division of Pathology, Tufts Medical Center, Boston, MA.;Kidney Transplant Team, Division of Nephrology, Tufts Medical Center, Boston, MA.;Department of Hematology-Oncology, Tufts Medical Center, Boston, MA.;Division of Nephrology, Tufts Medical Center, Boston, MA.",
"authors": "Godara|Amandeep|A|;Migliozzi|Daniel R|DR|;Pilichowska|Monika|M|;Goyal|Nitender|N|;Varga|Cindy|C|;Gordon|Craig E|CE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.xkme.2020.06.007",
"fulltext": "\n==== Front\nKidney Med\nKidney Med\nKidney Medicine\n2590-0595 Elsevier \n\nS2590-0595(20)30161-8\n10.1016/j.xkme.2020.06.007\nCase Report\nUse of Eculizumab in Transplant-Associated Thrombotic Microangiopathy in a Patient With Polycystic Kidney Disease Immediately Post–Kidney Transplant: A Case Report\nGodara Amandeep ramandeepgodara@gmail.com1∗ Migliozzi Daniel R. 2 Pilichowska Monika 3 Goyal Nitender 2 Varga Cindy 1 Gordon Craig E. 4 1 Department of Hematology-Oncology, Tufts Medical Center, Boston, MA\n2 Kidney Transplant Team, Division of Nephrology, Tufts Medical Center, Boston, MA\n3 Division of Pathology, Tufts Medical Center, Boston, MA\n4 Division of Nephrology, Tufts Medical Center, Boston, MA\n∗ Address for Correspondence: Amandeep Godara, MD, Hematology-Oncology fellow, Tufts Medical Center, 800 Washington St, Boston, MA 02111. ramandeepgodara@gmail.com\n05 8 2020 \nSep-Oct 2020 \n05 8 2020 \n2 5 652 656\n© 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Transplant-associated thrombotic microangiopathy (TMA) in the post–organ transplantation setting occurs from a number of potential inciting factors, such as the use of calcineurin inhibitors, ischemic injury, infections, or antibody-mediated rejection leading to unchecked complement activation and end-organ damage. Delayed recognition of this condition can result in allograft loss. In this case description, we describe the first case of de novo TMA in a patient with polycystic kidney disease that occurred immediately after kidney transplantation. The diagnosis was made promptly on the basis of clinical and laboratory characteristics by a multidisciplinary team and confirmed through kidney biopsy, which showed acute TMA. The patient was successfully managed by replacing tacrolimus with belatacept, which targets cytotoxic T lymphocyte antigen 4, and use of eculizumab, a C5 inhibitor. Eculizumab treatment was discontinued after 3 months of complement inhibition on the patient’s request, and relapse of TMA has not been encountered after more than 1 year of follow-up.\n\nIndex Words\nThrombotic microangiopathykidney transplantpolycystic kidney diseaseeculizumabbelatacept\n==== Body\nIntroduction\nTransplant-associated thrombotic microangiopathy (TMA) is a rare complication encountered after kidney transplantation. Incidence rates are estimated at 0.8% to 15%, with allograft loss in up to 33% to 50% of cases.1,2 Key findings associated with this condition include thrombocytopenia, reduced haptoglobin and elevated lactate dehydrogenase (LDH) levels, and either lack of improvement or decline (once stabilized) in glomerular filtration rate, a set of laboratory findings that can arise from several other conditions in the usual posttransplantation course.\n\nCalcineurin inhibitors (CNIs) are frequently implicated in transplant-associated TMA, especially in the early period (3-6 months) after transplantation.3,4 Mammalian target of rapamycin inhibitors have also been associated with TMA and only belatacept (cytotoxic T lymphocyte antigen 4–immunoglobulin fusion protein that inhibits T-cell function) exists as an alternative to these agents.5,6 Withdrawal of CNI treatment alone may not be sufficient to fully reverse the adverse effects of the alternative pathway of complement activation associated with this condition.2,3 To adequately reverse complement activation, eculizumab (C5 inhibitor) has been successfully used in a number of resistant cases of de novo transplant-associated TMA.7, 8, 9 We describe the successful use of eculizumab in a transplant recipient with kidney failure secondary to polycystic kidney disease (PKD) who developed de novo transplant-associated TMA in the immediate postsurgical setting.\n\nCase Report\nAn unsensitized (panel-reactive antibody, 0%) 63-year-old woman of Korean ethnicity with kidney failure secondary to PKD underwent deceased donor kidney transplantation (HLA antigen match, 3/10). Donation was performed after cardiac death and Kidney Donor Profile Index was 51%. On the day of the transplantation she started her immunosuppressive regimen, which included 3 doses of thymoglobulin, tacrolimus, mycophenolate, and a rapid steroid taper. The patient experienced delayed graft function but also anemia and thrombocytopenia. Hematologic evaluation (Table 1) on postoperative day (POD) 2 revealed an elevated LDH level (1,359 IU/L), undetectable haptoglobin (<8 mg/dL), and the presence of schistocytes (2-5/high-power field) on review of the peripheral smear. These findings were concerning for posttransplantation TMA and tacrolimus treatment was discontinued on POD 3. Tacrolimus 12-hour trough levels decreased from 6.0 (POD 3) to 2.3 ng/mL (POD 4).Table 1 Laboratory Test Results During the Pre- and Postoperative Period\n\n\tPresurgery\tPOD 0\tPOD 2\tPOD 3\tPOD 4\tPOD 5\tPOD 7\tPOD 14\tPOD 28\t3 mo Later\t\nWBC, K/μL\t6.4\t4.4\t3.3\t3.2\t2.1\t3.9\t6\t7.6\t8.1\t5.2\t\nHemoglobin, g/dL\t12\t10\t8.1\t7.5\t6.4\t8.5\t8.6\t6.8\t10.1\t9.9\t\nPlatelets, K/μL\t154\t107\t56\t40\t32\t26\t65\t145\t239\t167\t\nCreatinine, mg/dL\t5.59\t5.88\t6.49\t7.27\t8.54\t5.48\t7.83\t7.72\t1.54\t1.30\t\nLDH, IU/L\t\t\t1,359\t1,260\t1,106\t1,173\t1,043\t396\t181\t167\t\nHaptoglobin, mg/dL\t\t\t<8\t<8\t<8\t<8\t<8\t145\t186\t122\t\nCH50 (complement total), U/mL\t\t\t\t\t\t56\t\t\t<10\t<10\t\nTacrolimus, ng/mL\t\t\t4.3\t6\t2.3\t\t\t\t\t\t\nInfectious workup\tEBV IgG: positive; EBV IgM negative; CMV IgG positive; CMV IgM negative; HIV: negative\t\t\t\t\tCMV DNA: negative; Parvo IgM: negative; EBV PCR: negative\t\t\tBK virus DNA: negative\t\t\nAutoimmune\t\t\tCoombs: negative\tAnti-PF4: negative\t\t\t\t\t\t\t\nStart of treatment\t\t\t\t\t\tEculizumab\tEculizumab\tEculizumab\tEculizumab\tEculizumab\t\nAbbreviations: Anti-PF4, anti–platelet factor 4 antibody; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; IgG, immunoglobulin G; LDH, lactate dehydrogenase; PCR, polymerase chain reaction; POD, postoperative day; WBC, white blood cells.\n\n\n\nDespite these interventions, the patient’s serum creatinine and LDH levels remained elevated and hemoglobin level (nadir, 6.4 g/dL) and platelet count (nadir, 26 K/μL) continued to decline (Fig 1A). Kidney biopsy was not performed initially because of the degree of thrombocytopenia. The PLASMIC (platelet count, combined hemolysis variable, absence of active cancer, absence of stem-cell or solid-organ transplant, mean corpuscular volume, international normalized ratio, creatinine) score was 4, which is consistent with a low likelihood of thrombotic thrombocytopenic purpura, which was confirmed by ADAMTS13 (von Willebrand factor protease) activity of 55% (reference value ,>67%). Negative anti–platelet factor 4 antibody test results ruled out heparin-induced thrombocytopenia as a cause for thrombocytopenia. Coombs test was performed to investigate an autoimmune cause for the anemia and results were negative. The initial workup included testing for infections such as bacterial, Epstein-Barr virus, cytomegalovirus, and parvovirus. Epstein-Barr virus and cytomegalovirus polymerase chain reaction did not detect any viral reactivation. Serum protein electrophoresis did not detect monoclonal protein. After a comprehensive evaluation by the members of our multidisciplinary TMA team constituting experts from hematology, nephrology, and transplant surgery, a diagnosis of transplant-associated TMA was made in the absence of any other alternative diagnoses.Figure 1 Laboratory results and kidney biopsy findings are consistent with thrombotic microangiopathy involving the transplanted kidney. (A-D) Laboratory parameters show improvement after complement inhibition with eculizumab was initiated on postoperative day 5, with creatinine, hemoglobin, platelet, and lactate dehydrogenase (LDH) levels returning to normal range. Filled triangle marks the day of discontinuation of tacrolimus therapy, arrow marks the start of eculizumab therapy followed by the introduction of belatacept therapy on the following day. (E-F) Light microscopy of the kidney biopsy specimen (hematoxylin and eosin stain) is shown. Occluded arteriole (indicated by arrow) can be seen along with reactive endothelium and expanded subendothelial space. Red blood cell fragmentation can be seen beneath the endothelium. (G) Periodic acid–Schiff and (H) trichrome stain show similar findings.\n\n\n\nOn POD 5 (36 hours after discontinuation of tacrolimus therapy), eculizumab, 900 mg, was administered for 4 weekly doses followed by 1,200 mg every 2 weeks. On POD 7, hemoglobin level improved to 8.6 g/dL, LDH level decreased to 1,043 IU/L, and platelet count improved to 65 K/μL. After the second dose of eculizumab, urine output increased further and serum creatinine level decreased from 8.5 to 4.06 mg/dL. Total complement activity was sent before and after the first dose to assess complement inhibition.\n\nAfter the improvement in platelet count, a kidney biopsy was pursued and confirmed a diagnosis of acute TMA with no evidence of rejection. Evaluation of glomeruli showed no evidence of necrosis, but arterioles showed reactive endothelium and expanded subendothelial space (1 arteriole with red blood cells and fibrin beneath the endothelium) with minimal mononuclear infiltrate in the interstitium (Fig 1E-H). C3 and C4d deposition was noted on intimal staining in the arteriole.\n\nProphylaxis against meningococcal infections was accomplished with penicillin VK (250 mg twice daily) for antibacterial prophylaxis, along with meningococcal group B and meningococcal (groups A, C, Y, and W-135) vaccines. In the absence of a CNI, immunosuppression was maintained with the aid of belatacept, while mycophenolate mofetil therapy was continued and low-dose prednisone was added (5 mg daily). The belatacept dosing protocol was based on the package insert: 10 mg/kg on days 1 and 5 and weeks 2, 4, 8, and 12, followed by 5 mg/kg monthly.10 By POD 30, serum creatinine and hemoglobin levels improved to 1.78 mg/dL and 9.6 g/dL, respectively, while both platelet count and LDH level normalized (Fig 1A).\n\nThe aHUS Genetic Panel (Machaon Diagnostics Inc) revealed a stop-loss variant (c.1708T>C, p.Ter570ArgextTer37) in exon 10, the last exon of the CFHR5 gene. No previously reported cases of transplant-associated TMA are associated with this variant. Three polymorphisms were also detected in the CFH gene (homozygous change in the promoter 2, homozygous silent variant in exon 13 [c.2016A>G, p.Gln672Gln], and homozygous missense variant in exon 18 [c.2808G>T, p.Glu936Asp]), which occur commonly in healthy individuals but are statistically enriched in patients with atypical hemolytic uremic syndrome (aHUS). There was no family history of TMA or consanguinity. Overall, this analysis was equivocal because no strong genetic risk for aHUS was identified.\n\nThree months post–kidney transplantation, this patient continues on an immunosuppressive regimen of belatacept, mycophenolate mofetil, and prednisone with no ongoing evidence of TMA.\n\nThe patient discontinued eculizumab after 3 months of treatment and was followed up with clinical and laboratory assessment at monthly intervals. Laboratory monitoring has confirmed no TMA recurrence at 1 year posttransplantation.\n\nDiscussion\nThe development of hemolytic anemia and thrombocytopenia in the immediate post–kidney transplantation period should raise concern for a microangiopathic process. The diagnosis of posttransplantation TMA poses a diagnostic dilemma, especially in the immediate posttransplantation period in which a multitude of reasons, such as ischemia-reperfusion injury, use of CNIs, or antibody-mediated rejection, alone or together can cause delayed graft function.11,12 Early and accurate diagnosis of transplant-associated TMA facilitated by a TMA team followed by treatment with eculizumab, which is a recombinant C5 binding humanized antibody, can result in a quick TMA reversal, as seen in this case.7,8\n\nTransplant-associated TMA results from endothelial damage due to unregulated complement activation and requires sufficient clinical-pathologic correlation.13 In a survey of kidney transplantation centers across Japan, 1.5% of patients exhibited evidence of TMA within 1 week of kidney transplantation.14 A kidney biopsy can be confirmatory in this setting but carries a high risk in a thrombocytopenic patient. In this case, TMA occurred in the immediate posttransplantation course and failed to respond to discontinuation of tacrolimus therapy, suggesting an alternative mechanism, and was only subsequently confirmed by kidney biopsy. An underlying predisposing genetic mutation can be identified in >30% of patients with transplant-associated TMA, including after solid-organ transplantation, and use of conventional therapies such as plasmapheresis can be ineffective in the absence of any quantitative defects in ADAMTS13 or inhibitors of complement pathway or antibody-mediated rejection.15,16 For this patient, loss of kidney function from PKD was the reason for kidney transplantation and possibly the presence of a CFHR5 mutation in the setting of surgery triggered the complement activation. In such cases, early use of eculizumab can reverse the complement activation and prevent further organ damage, leading to rapid recovery of hematologic and kidney function.17\n\nThere is no prevailing consensus on the duration of eculizumab therapy in cases of TMA following solid-organ transplantation.18 The presence of a predisposing genetic mutation can help assess the recurrence risk and duration of therapy.19 Often, genetic analysis reveals variants of unknown significance , as evident in this case in which a rare stop-loss variant (c.1708T>C) in exon 10 of the CFHR5 gene was identified, which has also been reported in a case of immunoglobulin A glomerulopathy and 3 healthy controls, with no cases of TMA identified in relation to this mutation.20 Additionally, there were also 3 variants in the CFH gene. The possibility cannot be excluded that these variants in combination with an inciting event can increase the probability of developing transplant-associated TMA, but this pathogenicity cannot be confirmed at this time given the lack of additional information. As the understanding of variants of unknown significance further evolves, caution is required in its interpretation because it does not necessarily implicate or preclude involvement in the pathogenesis.21,22 As genetic testing makes inroads into everyday clinical practice, the association of rare genetic variants can be laid bare.\n\nThe duration of complement inhibition with eculizumab for transplant-associated TMA is unclear. It has been proposed that patients with pathogenic complement regulatory mutations should continue eculizumab treatment indefinitely to prevent TMA relapse, although it might be safe to discontinue it after 6 to 12 months of treatment in patients with no genetic predisposition.23, 24, 25, 26 In this case, the genetic association with complement gene variants cannot be confirmed as pathogenic and eculizumab treatment was discontinued after 3 months as per the patient’s preference and was followed by close monitoring of kidney function and hemolysis parameters on a monthly basis. When complications of TMA have completely resolved, consideration can be made for discontinuation of therapy on a case-by-case basis, especially in the absence of any ongoing or predisposing triggers.9 If TMA recurs, reinitiating eculizumab therapy has been successful in suppressing complement activation.27\n\nIn summary, this case highlights the importance of prompt diagnosis of kidney transplant–associated TMA by a multidisciplinary TMA team and early initiation of eculizumab therapy to allow recovery of renal graft and hematologic parameters.28 Genetic testing should also be incorporated in the workup of TMA to identify any predisposition and guide the duration of therapy.\n\nArticle Information\nAuthors’ Full Names and Academic Degrees\nAmandeep Godara, MD, Daniel R. Migliozzi, PharmD, Monika Pilichowska, MD, PhD, Nitender Goyal, MD, Cindy Varga, MD, and Craig E. Gordon MD, MS.\n\nSupport\nNone.\n\nFinancial Disclosure\nDr Gordon has received consulting fees and honoraria from Alexion, the manufacturer of eculizumab. The remaining authors declare that they have no relevant financial interests.\n\nPatient Consent\nThe authors declare that they have obtained consent from the patient discussed in the report.\n\nPeer Review\nReceived January 2, 2020. Evaluated by 3 external peer reviewers with editorial input from an Acting Editor-in-Chief (Editorial Board Member Michelle Rheault, MD). Accepted in revised form June 4, 2020. The involvement of an Acting Editor-in-Chief to handle the peer-review and decision-making processes was to comply with Kidney Medicine’s procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies.\n\nComplete author and article information provided before references.\n==== Refs\nReferences\n1 Schwimmer J. Nadasdy T.A. Spitalnik P.F. Kaplan K.L. Zand M.S. De novo thrombotic microangiopathy in renal transplant recipients: a comparison of hemolytic uremic syndrome with localized renal thrombotic microangiopathy Am J Kidney Dis 41 2 2003 471 479 12552512 \n2 Reynolds J.C. Agodoa L.Y. Yuan C.M. Abbott K.C. Thrombotic microangiopathy after renal transplantation in the United States Am J Kidney Dis 42 5 2003 1058 1068 14582050 \n3 Naesens M. Kuypers D.R. Sarwal M. Calcineurin inhibitor nephrotoxicity Clin J Am Soc Nephrol 4 2 2009 481 508 19218475 \n4 Trimarchi H.M. Truong L.D. Brennan S. Gonzalez J.M. Suki W.N. FK506-associated thrombotic microangiopathy: report of two cases and review of the literature Transplantation 67 4 1999 539 544 10071024 \n5 Nava F. Cappelli G. Mori G. Everolimus, cyclosporine, and thrombotic microangiopathy: clinical role and preventive tools in renal transplantation Transplant Proc 46 7 2014 2263 2268 25242766 \n6 Vincenti F. Belatacept and long-term outcomes in kidney transplantation N Engl J Med 374 26 2016 2600 2601 27355541 \n7 Dedhia P. Govil A. Mogilishetty G. Alloway R.R. Woodle E.S. Abu Jawdeh B.G. Eculizumab and belatacept for de novo atypical hemolytic uremic syndrome associated with CFHR3-CFHR1 deletion in a kidney transplant recipient: a case report Transplant Proc 49 1 2017 188 192 28104134 \n8 Yamamoto T. Watarai Y. Futamura K. Efficacy of eculizumab therapy for atypical hemolytic uremic syndrome recurrence and antibody-mediated rejection progress after renal transplantation with preformed donor-specific antibodies: case report Transplant Proc 49 1 2017 159 162 28104125 \n9 Ikeda T. Okumi M. Unagami K. Two cases of kidney transplantation-associated thrombotic microangiopathy successfully treated with eculizumab Nephrology (Carlton) 21 suppl 1 2016 35 40 \n10 FDA Belatacept prescribing information. 2011. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125288s070lbl.pdf. Accessed August 19, 2020.\n11 Satoskar A.A. Pelletier R. Adams P. De novo thrombotic microangiopathy in renal allograft biopsies-role of antibody-mediated rejection Am J Transplant 10 8 2010 1804 1811 20659088 \n12 Siedlecki A. Irish W. Brennan D.C. Delayed graft function in the kidney transplant Am J Transplant 11 11 2011 2279 2296 21929642 \n13 Zuber J. Le Quintrec M. Morris H. Fremeaux-Bacchi V. Loirat C. Legendre C. Targeted strategies in the prevention and management of atypical HUS recurrence after kidney transplantation Transplant Rev (Orlando) 27 4 2013 117 125 23937869 \n14 Satoh S. Saito K. Harada H. Okumi M. Saito M. Survey Committee for TA-TMA of the Japan Society for Transplantation Survey of thrombotic microangiopathy within 1 week after kidney transplantation between 2010 and 2015 in Japan Clin Exp Nephrol 23 4 2019 571 572 30539337 \n15 Ali M.N. Syed A. Bhandari S. Case series: hemolytic uremic syndrome--another cause of transplant dysfunction Transplant Proc 45 9 2013 3284 3288 24182801 \n16 Le Quintrec M. Lionet A. Kamar N. Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation Am J Transplant 8 8 2008 1694 1701 18557729 \n17 Legendre C.M. Campistol J.M. Feldkamp T. Outcomes of patients with atypical haemolytic uraemic syndrome with native and transplanted kidneys treated with eculizumab: a pooled post hoc analysis Transpl Int 30 12 2017 1275 1283 28801959 \n18 Abbas F. El Kossi M. Kim J.J. Sharma A. Halawa A. Thrombotic microangiopathy after renal transplantation: current insights in de novo and recurrent disease World J Transplant 8 5 2018 122 141 30211021 \n19 Le Quintrec M. Zuber J. Moulin B. Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome Am J Transplant 13 3 2013 663 675 23356914 \n20 Zhai Y.L. Meng S.J. Zhu L. Rare variants in the complement factor H-related protein 5 gene contribute to genetic susceptibility to IgA nephropathy J Am Soc Nephrol 27 9 2016 2894 2905 26825529 \n21 Hoffman-Andrews L. The known unknown: the challenges of genetic variants of uncertain significance in clinical practice J Law Biosci 4 3 2017 648 657 29868193 \n22 Richards S. Aziz N. Bale S. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genet Med 17 5 2015 405 424 25741868 \n23 Gonzalez Suarez M.L. Thongprayoon C. Mao M.A. Leeaphorn N. Bathini T. Cheungpasitporn W. Outcomes of kidney transplant patients with atypical hemolytic uremic syndrome treated with eculizumab: a systematic review and meta-analysis J Clin Med 8 7 2019, 919 \n24 Fakhouri F. Fila M. Provot F. Pathogenic variants in complement genes and risk of atypical hemolytic uremic syndrome relapse after eculizumab discontinuation Clin J Am Soc Nephrol 12 1 2017 50 59 27799617 \n25 Goodship T.H. Cook H.T. Fakhouri F. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference Kidney Int 91 3 2017 539 551 27989322 \n26 Zuber J. Fakhouri F. Roumenina L.T. Loirat C. Fremeaux-Bacchi V. French Study Group for aHUS/C3G Collaborators Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies Nat Rev Nephrol 8 11 2012 643 657 23026949 \n27 Macia M. de Alvaro Moreno F. Dutt T. Current evidence on the discontinuation of eculizumab in patients with atypical haemolytic uraemic syndrome Clin Kidney J 10 3 2017 310 319 28621343 \n28 Gordon C.E. Chitalia V.C. Sloan J.M. Thrombotic microangiopathy: a multidisciplinary team approach Am J Kidney Dis 70 5 2017 715 721 28720207\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2590-0595",
"issue": "2(5)",
"journal": "Kidney medicine",
"keywords": "Thrombotic microangiopathy; belatacept; eculizumab; kidney transplant; polycystic kidney disease",
"medline_ta": "Kidney Med",
"mesh_terms": null,
"nlm_unique_id": "101756300",
"other_id": null,
"pages": "652-656",
"pmc": null,
"pmid": "33089142",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "28720207;23937869;18557729;25741868;20659088;19218475;28104125;30539337;31252541;23356914;28801959;27989322;27799617;30211021;26970541;12552512;25242766;27355541;23026949;26825529;28104134;10071024;21929642;28621343;24182801;29868193;14582050",
"title": "Use of Eculizumab in Transplant-Associated Thrombotic Microangiopathy in a Patient With Polycystic Kidney Disease Immediately Post-Kidney Transplant: A Case Report.",
"title_normalized": "use of eculizumab in transplant associated thrombotic microangiopathy in a patient with polycystic kidney disease immediately post kidney transplant a case report"
} | [
{
"companynumb": "US-ASTELLAS-2020US031087",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
"drug... |
{
"abstract": "BACKGROUND\nPost-traumatic epilepsy after a traumatic brain injury occurs in 10%-20% of children. Unfortunately, a biomarker that could provide prognostic information about both post-traumatic epilepsy and cognitive development is lacking. In this first of a series of studies, we have reviewed and analyzed clinical variables in children following traumatic brain injury to understand the epidemiologic and clinical characteristics of post-traumatic epilepsy in our urban population.\n\n\nMETHODS\nWe performed a retrospective electronic chart review of patients who had suffered traumatic brain injury and subsequently evaluated at Children's Hospital of Michigan from 2002 to 2012. Various epidemiologic and clinical variables were analyzed.\n\n\nRESULTS\nPatients who had severe traumatic brain injury and post-traumatic epilepsy had an abnormal acute head computed tomography. These patients had increased number of different seizure types, increased risk of intractability of epilepsy, and were on multiple antiepileptic drugs. Hypomotor seizure was the most common seizure type in these patients. There was a high prevalence of patients who suffered nonaccidental trauma, all of whom had severe traumatic brain injury.\n\n\nCONCLUSIONS\nThis study demonstrates a need for biomarkers in children following traumatic brain injury to reliably evaluate the risk of post-traumatic epilepsy.",
"affiliations": "Division of Pediatric Epilepsy, Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, Ohio; Divison of Pediatric Neurology, Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, Michigan. Electronic address: jun.park@uhhospitals.org.;Divison of Pediatric Neurology, Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, Michigan.",
"authors": "Park|Jun T|JT|;Chugani|Harry T|HT|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-8994",
"issue": "52(2)",
"journal": "Pediatric neurology",
"keywords": "brain injury and seizures; epileptic spasms; hypomotor seizures; nonaccidental trauma (NAT); post-traumatic epilepsy (PTE); seizure semiology; traumatic brain injury (TBI)",
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D000293:Adolescent; D001930:Brain Injuries; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual; D004569:Electroencephalography; D004827:Epilepsy; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D012189:Retrospective Studies; D062606:Tertiary Care Centers; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "174-81",
"pmc": null,
"pmid": "25693582",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Post-traumatic epilepsy in children-experience from a tertiary referral center.",
"title_normalized": "post traumatic epilepsy in children experience from a tertiary referral center"
} | [
{
"companynumb": "US-ABBVIE-15P-163-1403518-00",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALPROATE SODIUM"
},
"drugadditional": nul... |
{
"abstract": "Background: Literature about torsade de pointes induced by azole antifungal agents is scarce, despite the well-known association. Furthermore, little is known about the latency time between commencing an azole antifungal agent and developing torsade de pointes. The objectives of the present study were therefore to identify all cases of torsade de pointes associated with systemic azole antifungal use reported to the WHO monitoring centre (Uppsala, Sweden) and to determine the latency times between commencing the azole and developing torsade de pointes. Methods: Investigator-driven, retrospective, descriptive analysis of post-marketing pharmacovigilance data regarding systemic azole antifungal agents and the development of torsade de pointes reported to the WHO monitoring centre 1995-2015. Results: 191 cases were reported as follows: fluconazole 130, itraconazole 22, ketoconazole 5, posaconazole 1, voriconazole 33. More than half of all cases involved concomitant suspected or interacting drugs. The median latency times between starting the azole and developing torsade de pointes ranged from 1 (posaconazole) - 9.5 days (itraconazole), range <1-250). Conclusions: Clinicians should be aware of these features of azole-associated torsade de pointes, avoid interacting drugs if at all possible and monitor at-risk patients.",
"affiliations": "Department of Clinical Pharmacology and Toxicology, University & University Hospital Basel, Switzerland.;Department of Cardiology, University Hospital Basel, Switzerland.;Department of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Switzerland.;Department of Clinical Pharmacology and Toxicology, University & University Hospital Basel, Switzerland.",
"authors": "Salem|M|M|;Reichlin|T|T|;Fasel|D|D|;Leuppi-Taegtmeyer|A|A|",
"chemical_list": null,
"country": "Qatar",
"delete": false,
"doi": "10.21542/gcsp.2017.11",
"fulltext": "\n==== Front\nGlob Cardiol Sci PractGlob Cardiol Sci PractGCSPGCSPGlobal Cardiology Science & Practice2305-7823Magdi Yacoub Heart Foundation UK gcsp.2017.1110.21542/gcsp.2017.11PharmacovigilanceTorsade de pointes and systemic azole antifungal agents: Analysis of global spontaneous safety reports Salem M. 1Reichlin T. 2Fasel D. 3Leuppi-Taegtmeyer A. 1anne.leuppi-taegtmeyer@usb.ch1 Department of Clinical Pharmacology and Toxicology, University & University Hospital Basel, Switzerland2 Department of Cardiology, University Hospital Basel, Switzerland3 Department of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Switzerland30 6 2017 30 6 2017 2017 2 1105 5 2017 29 5 2017 Copyright © 2017 The Author(s)2017The Author(s), licensee Magdi Yacoub Institute.This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.Background: Literature about torsade de pointes induced by azole antifungal agents is scarce, despite the well-known association. Furthermore, little is known about the latency time between commencing an azole antifungal agent and developing torsade de pointes. The objectives of the present study were therefore to identify all cases of torsade de pointes associated with systemic azole antifungal use reported to the WHO monitoring centre (Uppsala, Sweden) and to determine the latency times between commencing the azole and developing torsade de pointes.\n\nMethods: Investigator-driven, retrospective, descriptive analysis of post-marketing pharmacovigilance data regarding systemic azole antifungal agents and the development of torsade de pointes reported to the WHO monitoring centre 1995–2015.\n\nResults: 191 cases were reported as follows: fluconazole 130, itraconazole 22, ketoconazole 5, posaconazole 1, voriconazole 33. More than half of all cases involved concomitant suspected or interacting drugs. The median latency times between starting the azole and developing torsade de pointes ranged from 1 (posaconazole) – 9.5 days (itraconazole), range <1–250).\n\nConclusions: Clinicians should be aware of these features of azole-associated torsade de pointes, avoid interacting drugs if at all possible and monitor at-risk patients.\n==== Body\nBackground\nTorsade de pointes is a special type of ventricular tachycardia which is preceded by the development of a long QT-interval in a patient’s electrocardiogram1. Torsade de pointes can be self-terminating causing dizzy spells and syncope, or it can degenerate into ventricular fibrillation, cardiac arrest and sudden cardiac death1.\n\nAzole antifungal agents are known to cause QT-interval prolongation and in some cases subsequent torsade de pointes through inhibition of cardiac hERG (human ether receptor a go-go) potassium channels2. Literature about torsade de pointes induced by azole antifungal agents, however is scarce, despite this well-known association3. Furthermore, little is known about the latency time between commencing an azole antifungal agent and developing torsade de pointes.\n\nThe objectives of the present study were therefore to identify all cases of torsade de pointes associated with systemic azole antifungal use reported to the WHO monitoring centre (Uppsala, Sweden) and to determine the latency times between commencing the azole and developing torsade de pointes.\n\nMethods\nAn investigator-driven, retrospective, descriptive analysis of post-marketing pharmacovigilance data reported to the WHO monitoring centre 1995–2015 was performed. Data were available in the form of individual case safety reports (ICSRs) in the global database VigiBase™ which was accessed using the web-based platform Vigilyze™ (http://vigilyze.who-umc.org/. Accessed January 2016). The following drugs were searched for in conjunction with torsade de pointes: fluconazole, itraconazole, ketoconazole, posaconazole and voriconazole. The reaction term according to MedDRA (Medical Dictionary for Regulatory Activities) terminology was “Torsade de pointes”. The number of reports per drug, reporting countries, patient demographics and outcome were recorded. Where possible, the latency time between starting the drug and the development of torsade de pointes was also determined. As this data was not always available, the date of stopping the suspected drug was used as a surrogate for the date of occurrence of the reaction in some cases as it is usual clinical practice to withdraw a likely causative drug as soon as an adverse drug reaction is recognised.\n\nResults\nThere were 191 reports of torsade de pointes in association with systemic azole antifungal use present in the WHO VigiBase™ database. The ICRs are summarised in Table 1 and Figure 1 shows the age distribution of the patients.\n\n10.7717/gcsp.201711/table-1Table 1 Characteristics of individual case reports for systemic azole antifungal agents and torsades de pointes.\nDrug\tNumber\tPercent male, female, unknown (%)\tMedian age (years; range; number available)\tMain reporting continent (%)\t\nFluconazole\t130\t46, 49, 5\t60 (11–91; 119)\tAmericas (80)\t\nItraconazole\t22\t36, 59, 5\t50 (24–92; 20)\tAmericas (45), Europe (45)\t\nKetoconazole\t5\t40, 60, 0\t57 (37–75; 5)\tAmericas (80)\t\nPosaconazole\t1\t0, 100, 0\t15\tEurope (100)\t\nVoriconazole\t33\t53, 44, 3\t57 (15–81; 30)\tAmericas (50)\t\n10.7717/gcsp.201711/fig-1Figure 1. Age distribution of the 191 reported patients.\nTable 2 shows the data regarding the presence of co-suspected or interacting medication, latency time between starting azole antifungal agent and onset of reaction. Reported co-suspected or interacting medication included methadone, quinolone antibiotics, macrolide antibiotics, terfenadine, amiodarone and a number of different antiemetics (Figure 2 shows the top 20 co-reported substances). For itraconazole there were 2 cases where torsade de pointes occurred 7 and 4 days after stopping the drug, respectively. The single case where posaconazole was implicated had received voriconazole for 18 days prior to switching to posaconazole and then developing torsade de pointes within 24 hours.\n\n10.7717/gcsp.201711/table-2Table 2 Presence of co-suspected or interacting medication, latency time and outcome data.\nDrug\tCases with reported co-suspected or interacting medication (%)\tMedian latency time (days) (range; number available)\tPercentage of cases with data available occurring within 1 day and 1 week\tReported outcome (recovered, death, unknown %)\t\nFluconazole\t88 (68)\t4 (<1–250; 52)\t29, 59\t25, 5, 70\t\nItraconazole\t19 (86)\t9.5 (1–26; 12)\t8, 42\t50, 5, 45\t\nKetoconazole\t5 (100)\t8 (1–219; 4)\t25, 25\t0, 20, 80\t\nPosaconazole\t1 (100)\t1\t100, 100\t100, 0, 0\t\nVoriconazole\t17 (52)\t8 (1–173; 23)\t13, 48\t27, 4, 69\t\n10.7717/gcsp.201711/fig-2Figure 2. Top 20 co-reported substances (WHODrug).\nDiscussion\nThis analysis of cases of torsade de pointes associated with systemic azole antifungal agents found that the majority of cases were reported from the Americas, that co-suspected and interacting drugs were present in the majority of cases and that latency time was during the first week in approximately half of all cases.\n\nGeographic differences in reporting adverse drug reactions may reflect reporting habits of the different nations, the resources available for reporting or even genetic differences in predisposition to developing adverse drug reactions. Potential candidate genes for azole antifungal agents and the development of torsade de pointes are genes encoding drug-metabolising enzymes such as CYP2C19 and CYP2C9 which are involved in the metabolic clearance of azoles3 and genes encoding cardiac ion channels such as KCNH24.\n\nConcomitant treatment with other drugs known to be associated with QTc-prolongation and torsade de pointes or with drugs causing pharmacokinetic interactions leading to increased drug exposure are known risk factors for torsade de pointes1–3 and our study reconfirms that this is also true for systemic azole antifungal agents.\n\nThe latency time was found to be comparatively short in the majority of cases. This is in keeping with the nature of the adverse drug reaction which depends on drug binding to and inhibiting a receptor. This occurs rapidly after drug intake. A large longitudinal database study from The Netherlands also found that recent starters of non-cardiac QTc-prolonging agents were at increased risk of developing sudden cardiac death5. Schaffer and colleagues examined cases of torsade de pointes associated with macrolide use and found the mean time between commencing therapy and developing torsade de pointes to be 9 days (or 4 days if 3 outliers were excluded)6.\n\nThe fact that in some cases torsade de pointes occurred a number of days after stopping itraconazole can be explained by itraconazole’s long half-life of 42 hours, which may be increased further in the presence of hepatic impairment7.\n\nA number of important drug-safety aspects for clinicians and their patients can be drawn from these findings. Firstly, prescribing azole antifungal agents in combination with interacting drugs should be avoided if at all possible. Secondly torsade de pointes can occur soon after commencing the drug and QTc-monitoring after commencing therapy may be prudent in high-risk patients. There are no established guidelines, but on the basis of currently available data, close monitoring during the first week would seem prudent, particularly for patients at high risk. Risk factors for QTc-prolongation include various drugs, metabolic disorders (i.e., hypokalemia), bradyarrhythmias, myocardial ischemia, congenital factors and other rare causes. Finally, torsade de pointes is associated with significant mortality.\n\nLimitations of this study were that it is likely that not all cases of torsade de pointes present in the database were captured due to possible alternative coding such as “ventricular arrhythmia”, “ventricular tachycardia” or “cardiac arrest”. Furthermore, some cases may have been reported as being primarily due to another drug known to be associated with torsade de pointes with an azole classified as a concomitant, in which case they would not have been found by the search we performed. Pharmacovigilance data can also not deliver any information regarding the incidence of an adverse drug reaction because the total number of exposed people is not known. It is therefore not possible to determine which systemic azoles are more or less likely to cause torsade de pointes.\n\nConclusions\nCases of torsade de pointes associated with systemic azole antifungal agents reported to the WHO during the past 20 years were mainly from the Americas, in the majority of cases co-suspected and interacting drugs were present and torsade de pointes occurred within one week of starting the drug in approximately half the cases. Clinicians should be aware of these features of azole-induced torsade de pointes and avoid interacting drugs if at all possible and monitor at-risk patients for the development of QTc-prolongation.\n\nCompeting Interests\nThe authors have no competing interests to declare.\n\nAccompanying Statement\nThe data for this work were obtained from the WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden. Data from spontaneous reporting are inhomogeneous as a result of different reporting policies worldwide and are vulnerable to underreporting and reporting bias. The information contained in this work comes from a variety of different sources and the likelihood that the suspected adverse reaction is drug-related is not the same in all cases. The information does not represent the opinion of the World Health Organization.\n\nFunding sources\nNo specific funding was received for this work.\n\nAuthors’ contributions\nAll authors contributed to the conception and design of the study. MS and AT were involved in data acquisition and analysis. MS, DF, TR and AT interpreted the data, AT drafted the manuscript and MS, DF, TR and AT revised it critically for content. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1. Schwartz PJ Woosley RL 2016 Predicting the unpredictable: Drug-induced QT prolongation and Torsades de Pointes J Am Coll Cardiol 67 1639 1650 27150690 \n2. De Bruin ML Pettersson M Meyboom RH Hoes AW Leufkens HG 2005 Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death Eur Heart J 26 590 597 15637086 \n3. Owens Jr RC Nolin TD 2006 Antimicrobial-associated QT interval prolongation: Pointes of interest Clin Infect Dis 43 1603 1611 17109296 \n4. Yang P Kanki H Drolet B Yang T Wei J Viswanathan PC 2002 Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes Circulation 105 1943 1948 11997281 \n5. Straus SM Sturkenboom MC Bleumink GS Dieleman JP van der Lei J de Graeff PA 2005 Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death Eur Heart J 26 2007 2012 15888497 \n6. Shaffer D Singer S Korvick J Honig P 2002 Concomitant risk factors in reports of torsades de pointes associated with macrolide use: Review of the United States Food and Drug Administration Adverse Event Reporting System Clin Infect Dis 35 197 200 12087527 \n7. Product Information Sporanox® , Janssen-Cilag AG, Zug, ZG, Switzerland. 2015\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2305-7823",
"issue": "2017(2)",
"journal": "Global cardiology science & practice",
"keywords": null,
"medline_ta": "Glob Cardiol Sci Pract",
"mesh_terms": null,
"nlm_unique_id": "101613130",
"other_id": null,
"pages": "11",
"pmc": null,
"pmid": "29644223",
"pubdate": "2017-06-30",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "15637086;17109296;11997281;27150690;15888497;12087527",
"title": "Torsade de pointes and systemic azole antifungal agents: Analysis of global spontaneous safety reports.",
"title_normalized": "torsade de pointes and systemic azole antifungal agents analysis of global spontaneous safety reports"
} | [
{
"companynumb": "CH-MYLANLABS-2017M1067072",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMisoprostol, a synthetic prostaglandin E1 analog is labeled for the treatment of gastric and duodenal ulcers. In Brazil, where abortion is not a legal procedure, there is a widespread popular misuse of this drug in abortion attempts. This misuse and the fact that, in many cases the desired pregnancy termination does not occur, raise concerns about fetal safety. Case reports of congenital anomalies after maternal use of misoprostol have been published. The objective of this work was to compare pregnancy outcome following misoprostol exposure with a matched control group. This is the first prospective controlled study on fetal safety after misoprostol use.\n\n\nMETHODS\nA prospective, observational cohort study with 86 exposed and 86 pair-matched, non-exposed controls.\n\n\nRESULTS\nThere was no significant difference in the rates of major or minor birth between exposed compared to non-exposed infants (2/67 vs 2/81, major defects; 7/67 vs. 3/81, minor anomalies) There were significantly more miscarriages in the exposed group (17.1% vs. 5.8%; relative risk, 2.97; 95% confidence interval, 1.12 to 7.88). There was no statistical difference in gestational age at delivery, birth weight, sex ratio, rate of prematurity, low birth weight, or rates of cesarean section between groups.\n\n\nCONCLUSIONS\nOur study, despite its limited statistical power, does not suggest a potent teratogenic action of misoprostol exposure during pregnancy.",
"affiliations": "Genetics Department, Universidade Federal do Rio Grande do Sul, Brazil.",
"authors": "Schüler|L|L|;Pastuszak|A|A|;Sanseverino|T V|TV|;Orioli|I M|IM|;Brunoni|D|D|;Ashton-Prolla|P|P|;Silva da Costa|F|F|;Giugliani|R|R|;Couto|A M|AM|;Brandao|S B|SB|;Koren|G|G|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D000897:Anti-Ulcer Agents; D016595:Misoprostol",
"country": "United States",
"delete": false,
"doi": "10.1016/s0890-6238(98)00072-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-6238",
"issue": "13(2)",
"journal": "Reproductive toxicology (Elmsford, N.Y.)",
"keywords": null,
"medline_ta": "Reprod Toxicol",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000020:Abortifacient Agents, Nonsteroidal; D000024:Abortion, Criminal; D000028:Abortion, Induced; D000897:Anti-Ulcer Agents; D001938:Brazil; D005260:Female; D005313:Fetal Death; D005500:Follow-Up Studies; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D016595:Misoprostol; D010437:Peptic Ulcer; D011247:Pregnancy; D011256:Pregnancy Outcome; D011446:Prospective Studies",
"nlm_unique_id": "8803591",
"other_id": null,
"pages": "147-51",
"pmc": null,
"pmid": "10213522",
"pubdate": "1999",
"publication_types": "D016430:Clinical Trial; D018848:Controlled Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pregnancy outcome after exposure to misoprostol in Brazil: a prospective, controlled study.",
"title_normalized": "pregnancy outcome after exposure to misoprostol in brazil a prospective controlled study"
} | [
{
"companynumb": "CA-EAGLE PHARMACEUTICALS, INC.-ELL201602-000038",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DICLOFENAC SODIUM\\MISOPROSTOL"
... |
{
"abstract": "Oral anticoagulation is a widely used treatment and atrial fibrillation (AF) is the most frequent indication. We review the therapeutic options on an important clinical challenge: rapid reversal anticoagulation in the setting of an urgent invasive procedure. We report a case of a 71-year-old man treated with warfarin who was over-anticoagulated when presented to the emergency department for syncope due to severe bradiarrhythmia and needed temporary pacing. Intravenous infusion of vitamin-k was not adequate for rapid reversal over anticoagulation whereas the administration of a Prothrombin Complex Concentrate (PCC) was able to quickly reverse anticoagulant activity and allowed the performance of an urgent invasive procedure without hemorrhagic complication. The aim of this paper is to draw attention to possible therapeutic strategies to reduce the risk of bleeding related to over-anticoagulation with vitamin-K antagonists (VKAs) in case of urgent invasive procedure, emphasizing the role of PCC in keeping with national and international guidelines.",
"affiliations": null,
"authors": "Di Fusco|Stefania Angela|SA|;Aspromonte|Nadia|N|;Aquilani|Stefano|S|;Mele|Luca|L|;Colivicchi|Furio|F|",
"chemical_list": "D000925:Anticoagulants; D001779:Blood Coagulation Factors; D014812:Vitamin K; C025667:prothrombin complex concentrates; D014859:Warfarin",
"country": "Italy",
"delete": false,
"doi": "10.4081/monaldi.2013.5235",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1122-0643",
"issue": "80(4)",
"journal": "Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace",
"keywords": null,
"medline_ta": "Monaldi Arch Chest Dis",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D001779:Blood Coagulation Factors; D016063:Blood Loss, Surgical; D006801:Humans; D008297:Male; D010138:Pacemaker, Artificial; D014812:Vitamin K; D014859:Warfarin",
"nlm_unique_id": "9307314",
"other_id": null,
"pages": "184-8",
"pmc": null,
"pmid": "25087295",
"pubdate": "2013-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Emergency reversal of vitamin-K antagonists related over-anticoagulation: case report and brief overview on the role of prothrombin complex concentrate.",
"title_normalized": "emergency reversal of vitamin k antagonists related over anticoagulation case report and brief overview on the role of prothrombin complex concentrate"
} | [
{
"companynumb": "IT-IPCA LABORATORIES LIMITED-IPC201509-000586",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMIODARONE"
},
"drugaddi... |
{
"abstract": "Bleomycin electrochemotherapy (ECT) has emerged as a treatment modality for locally advanced metastatic melanoma over the past decade. The phenomenon of reversible electroporation enhances cell permeability when a pulsed electrical current is applied to tissues. This facilitates enhanced cytotoxicity of bleomycin with minimal systemic side effects. We present two case analyses of patients with advanced metastatic melanoma of lower limb which did not respond to alternative therapies, including immunotherapy and isolated limb perfusion, but had a positive clinical response to bleomycin ECT. Locoregional control of the tumour was gained along with positive functional outcomes for the patients including increased mobility and reduced malodour. Bleomycin ECT is an exciting new therapeutic modality in the armamentarium of the plastic surgeon. Operating parameters have been developed and refined which facilitate its safe use along with incorporation into international melanoma guidelines. Evidence in the literature supports its use in select cases, however, it is vital that we share our experiences in its use so that its role can be better defined. Particularly in the era of rapidly developing systemic treatments which are decreasing mortality and thereby increasing the number of patients requiring locoregional disease managment.",
"affiliations": "Department of Plastic Surgery, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, United Kingdom.;Ninewells Hospital, James Arrott Drive, Dundee, DD2 1SG, Scotland.;Department of Plastic Surgery, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, United Kingdom.",
"authors": "Gallagher|Michael|M|;Chin|Kuen Yeow|KY|;MacKenzie-Ross|Alastair|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jpra.2020.09.007",
"fulltext": "\n==== Front\nJPRAS Open\nJPRAS Open\nJPRAS Open\n2352-5878 Elsevier \n\nS2352-5878(20)30042-5\n10.1016/j.jpra.2020.09.007\nCase Report\nBleomycin electrochemotherapy for the management of locally advanced metastatic melanoma: Two notable clinical cases potentially indicating a greater therapeutic role in the era of targeted and immuno-therapy\nGallagher Michael michael.gallagher@doctors.org.ukab⁎ Chin Kuen Yeow c MacKenzie-Ross Alastair a a Department of Plastic Surgery, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, United Kingdom\nb Department of Surgery and Cancer, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom\nc Ninewells Hospital, James Arrott Drive, Dundee, DD2 1SG, Scotland\n⁎ Corresponding author. michael.gallagher@doctors.org.uk\n06 10 2020 \n12 2020 \n06 10 2020 \n26 43 48\n18 7 2020 28 9 2020 © 2020 The Authors. Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Summary\nBleomycin electrochemotherapy (ECT) has emerged as a treatment modality for locally advanced metastatic melanoma over the past decade. The phenomenon of reversible electroporation enhances cell permeability when a pulsed electrical current is applied to tissues. This facilitates enhanced cytotoxicity of bleomycin with minimal systemic side effects.\n\nWe present two case analyses of patients with advanced metastatic melanoma of lower limb which did not respond to alternative therapies, including immunotherapy and isolated limb perfusion, but had a positive clinical response to bleomycin ECT. Locoregional control of the tumour was gained along with positive functional outcomes for the patients including increased mobility and reduced malodour.\n\nBleomycin ECT is an exciting new therapeutic modality in the armamentarium of the plastic surgeon. Operating parameters have been developed and refined which facilitate its safe use along with incorporation into international melanoma guidelines. Evidence in the literature supports its use in select cases, however, it is vital that we share our experiences in its use so that its role can be better defined. Particularly in the era of rapidly developing systemic treatments which are decreasing mortality and thereby increasing the number of patients requiring locoregional disease managment.\n\nKeywords\nMelanomaElectrochemotherapyBleomycinCutaneous metastases\n==== Body\nIntroduction\nMelanoma Bleomycin electrochemotherapy (ECT) has emerged as a treatment modality for locally advanced metastatic melanoma over the past decade. The phenomenon of reversible electroporation enhances cell permeability when a pulsed electrical current is applied to tissues.1,2 This facilitates greater local cytotoxicity of chemotherapeutic agents such as Bleomycin, whilst reducing systemic side effects due to the lower systemic dose required. Indeed, the cytotoxicity of bleomycin is enhanced up to 700-fold in combination with reversible electroporation technology.2 Bleomycin ECT is predominantly indicated for accessible neoplastic lesions including palliative management of locally advanced metastatic melanoma.1,3 Despite this, many melanoma surgeons are still unfamiliar with this treatment modality and it is likely underutilised.\n\nIn this report we discuss our bleomycin ECT treatment regime and care pathway in the context of this new era of targeted therapy (TT) and immuno-therapy (IT). We present two case analyses of patients with advanced metastatic melanoma of lower limb where options for standard therapies, including isolated limb perfusion, had been exhausted but in which a dramatic clinical response to bleomycin ECT was observed.\n\nCase report\nThe device used for both cases was the Cliniporator™ (IGEA Clinical Biophysics, Italy), with a centred hexagonal needle electrode, and was used in concordance with published guidelines.4\n\nCase 1\nA 70-year-old woman with no other significant medical co-morbidities or regular medications was diagnosed with a 15 mm Breslow thickness left foot acral malignant melanoma (BRAF wild type). She had wide excision and a sentinel lymph node biopsy (SLNB) was positive. She declined groin dissection (preceded adjuvant therapy availability). A year later recurrent disease was identified on positron emission tomography (PET) in the popliteal fossa lymph nodes and adjacent to the graft site on the sole of the foot. She had six cycles of pembrolizumab followed by T-VEC (Talimogene laherparepvec oncolytic virus) and isolated limb perfusion (ILP) over the following year. In-transit metastases and lesions on her leg significantly impacted her quality of life with pain, bleeding and resultant reduced mobility. Whilst ILP did reduce the size of some of the lesions her symptoms did not improve significantly, and she was referred for consideration of ECT. She had debulking and bleomycin ECT to her extensive lesions with 171 sequences completed in total (see Table 1). The treatment resulted in considerable reduction in tumour mass with less bleeding and less painful mobilization with partial weight bearing on crutches (Figure 1). She had increased pain and wound care requirements for a period of several months following bleomycin ECT. She had a further round of bleomycin ECT five months later with good effect and remained independent in activities of daily living. Post-treatment pain recurred following the second round of bleomycin ECT and was managed with oral analgesia alone.Table 1 Bleomycin electrochemotherapy delivery.\n\nTable 1\tProbe Configuration\tFrequency (kilohertz, kHz)\tSequences (n)\tDuration (min)\t\nCase 1\tHexagonal\t5 kHz\tTotal: 171\t39 min\t\nCase 2\tHexagonal\t5 kHz\tTotal: 95\t12 min\t\nFigure 1 Case 1. Left lower leg and foot, medial aspect. (A) Pre-operative. (B) 6-months post-operative.\n\nFigure 1\n\nCase 2\nA 51-year-old gentleman with a background of coeliac disease was diagnosed with malignant melanoma (BRAF wild type) of the right calf. Wide excision was carried out. Six years later the disease recurred with regional lymph node involvement and local disease recurrence. He received immunotherapy (7 doses of nivolumab) and, following a groin dissection, this was changed to ipilimumab. A single cycle induced auto-immune meningitis which necessitated cessation of treatment and a protracted course of prednisolone. Cutaneous and subcutaneous recurrences were initially surgically excised. T-VEC therapy had a limited effect on local disease and he was referred for ECT. His main complaint was the size and growth of a single metastasis lateral to his knee. The malodour was disabling, its size prevented wearing trousers and he was experiencing significant pain requiring opioid analgesics (dihydrocodeine). He had debulking and bleomycin ECT, completing 95 sequences in total (see Table 1). The bleomycin ECT treatment was successful in reducing and maintaining the reduction in tumour bulk (Figure 2). Following bleomycin ECT the patient was able to wear trousers and the malodorous smell had resolved. There was increased pain following bleomycin ECT, however, at four months this significantly reduced. Of note, the patient developed common peroneal nerve palsy, 3/5 power (NRC scale), improving to 4/5 power which may have been due to bleomycin ECT or tumour invasion.Figure 2 Case 2. Left knee, medial aspect. (A) Pre-operative. (B) 1-month post-operative. (C) 3-months post-operative (proximal tumour recurrence subsequently treated with excision).\n\nFigure 2\n\nDiscussion\nManagement of locally advanced metastatic melanoma is challenging with a plethora of available treatment modalities including excisional and ablative surgery, systemic therapies, ILP, radiotherapy and ECT.3 Systemic therapies (TT and IT) are rapidly evolving and increasingly available, they significantly prolong the course of the disease, are potentially curative and increase the number of patients who may benefit from local disease management.5\n\nBleomycin ECT is now recognised as a safe treatment for cutaneous tumours and skin metastases with established standard operating procedures.4 This is evidenced by its incorporation into clinical guidelines internationally.3,6,7 The evidence base is growing and a recently published cohort study of by the InspECT research group including 394 melanoma lesions found that 78% (306) had a complete or partial response, and 58% (229) had a complete response to bleomycin ECT.8 Additionally, there is emerging evidence that bleomycin ECT may be particularly effective in combination with immunotherapies, acting synergistically and producing enhanced systemic anti-tumour effects (the ‘abscopal effect’).9,10 This is of particular importance to patients, such as those in this report, with a ‘wild-type’ BRAF gene precluding the use of TT to the BRAF and MEK pathway. These patients cannot benefit from the highly effective TT combination of BRAF and MEK inhibitors.5 Post-treatment pain is a recognised complication of bleomycin ECT, has a reported incidence of 39% and is manageable with oral analgesia in the majority of cases.8\n\nClinicians determine on a case-by-case basis, or regional availability of services, which local peripheral treatments are used. National and international guidelines do not currently specify an algorithmic approach to determine which modality should be considered first-line.3,7 This approach appropriately reflects the paucity of comparative studies evaluating peripheral treatment modalities for locally advanced metastatic melanoma.10 We have presented two cases with a dramatic response to electrochemotherapy resulting in improved symptoms and quality of life. In both cases bleomycin ECT was considered after other modalities were utilised based on local dogmatic practice in which ILP is generally first-line.\n\nConclusions\nThese cases highlight the clinical efficacy of bleomycin ECT in managing locally advanced metastatic melanoma in the context of a new era of systemic therapies and improved survival. More research, in particular comparative studies, are required to establish the relative efficacy of bleomycin ECT versus other modalities. As the evidence base evolves guidelines must be regularly updated to ensure that clinicians are aware of the options available for their patients and their efficacy. Additionally, if modalities are clinically non-inferior cost-effectiveness analysis is warranted.\n\nDeclaration of Competing Interest\nNone.\n\nAcknowledgments\nNone.\n\nFunding\nNone.\n==== Refs\nReferences\n1. Probst U. Fuhrmann I. Beyer L. Wiggermann P. Electrochemotherapy as a new modality in interventional oncology: a review Technol Cancer Res Treat 17 2018 1533033818785329 \n2. Mir L.M. Orlowski S. Belehradek J. Jr. Paoletti C. Electrochemotherapy potentiation of antitumour effect of bleomycin by local electric pulses Eur J Cancer 27 1991 68 72 1707289 \n3. National Institute for Health and Care Excellence Melanoma: assessment and management https://www.nice.org.uk/guidance/ng14/chapter/1-Recommendations#managing-stage-iv-melanoma (Accessed 01/03/2020).\n4. Gehl J. Sersa G. Matthiessen L.W. Updated standard operating procedures for electrochemotherapy of cutaneous tumours and skin metastases Acta Oncol 57 2018 874 882 29577784 \n5. Pasquali S. Hadjinicolaou A.V. Chiarion Sileni V. Rossi C.R. Mocellin S. Systemic treatments for metastatic cutaneous melanoma Cochrane Database Syst Rev 2 2018 Cd011123 \n6. National Institute for Health and Care Excellence Electrochemotherapy for metastases in the skin from tumours of non-skin origin and melanoma https://www.nice.org.uk/guidance/IPG446 (Accessed 01/05/2020).\n7. Garbe C. Amaral T. Peris K. European consensus-based interdisciplinary guideline for melanoma. Part 2: treatment – update 2019 Eur J Cancer 126 2020 159 177 31866016 \n8. Kunte C. Letule V. Gehl J. Electrochemotherapy in the treatment of metastatic malignant melanoma: a prospective cohort study by InspECT Br J Dermatol 176 2017 1475 1485 28118487 \n9. Goggins C.A. Khachemoune A. The use of electrochemotherapy in combination with immunotherapy in the treatment of metastatic melanoma: a focused review Int J Dermatol 58 2019 865 870 30479009 \n10. Read R.L. Thompson J.F. Managing in-transit melanoma metastases in the new era of effective systemic therapies for melanoma Expert Rev Clin Pharmacol 12 2019 1107 1119 31687857\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-5878",
"issue": "26()",
"journal": "JPRAS open",
"keywords": "Bleomycin; Cutaneous metastases; Electrochemotherapy; Melanoma",
"medline_ta": "JPRAS Open",
"mesh_terms": null,
"nlm_unique_id": "101680420",
"other_id": null,
"pages": "43-48",
"pmc": null,
"pmid": "33102675",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "29986632;30479009;29577784;31866016;28118487;31687857;1707289",
"title": "Bleomycin electrochemotherapy for the management of locally advanced metastatic melanoma: Two notable clinical cases potentially indicating a greater therapeutic role in the era of targeted and immuno-therapy.",
"title_normalized": "bleomycin electrochemotherapy for the management of locally advanced metastatic melanoma two notable clinical cases potentially indicating a greater therapeutic role in the era of targeted and immuno therapy"
} | [
{
"companynumb": "GB-AMGEN-GBRSP2021002776",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TALIMOGENE LAHERPAREPVEC"
},
"drugadditional":... |
{
"abstract": "Extra-axial haemorrhage following epidural anaesthesia is extremely rare. We present the case of an 18-year-old G1P0 woman with Alport syndrome who had a ventouse delivery for failure to progress that was complicated by a postpartum tonic-clonic seizure. Clinically, and confirmed radiologically, the patient was found to have experienced an extra-axial haemorrhage (extradural and subdural haemorrhage) secondary to a cerebrospinal fluid leak caused by a dural puncture during epidural anaesthesia. Differentiating between postdural puncture headache, subdural haemorrhage and extradural haemorrhage can be extremely challenging, but it is important to consider these rare conditions when evaluating patients presenting with postpartum headache and seizure.",
"affiliations": "Department of Obstetrics & Gynaecology, Ipswich Hospital, Ipswich, Queensland, Australia shanika.wijayanayaka@uq.net.au.;Department of Anaesthesia, Ipswich Hospital, Ipswich, Queensland, Australia.;Department of Obstetrics & Gynaecology, Ipswich Hospital, Ipswich, Queensland, Australia.;Department of Obstetrics & Gynaecology, Ipswich Hospital, Ipswich, Queensland, Australia.",
"authors": "Wijayanayaka|Shanika|S|http://orcid.org/0000-0001-8748-7509;Guha|Abir|A|;Sivanesan|Kanapathippillai|K|;Veerasingham|Mayooran|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-242160",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(6)",
"journal": "BMJ case reports",
"keywords": "anaesthesia; pregnancy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000293:Adolescent; D000767:Anesthesia, Epidural; D017217:Blood Patch, Epidural; D065634:Cerebrospinal Fluid Leak; D005260:Female; D006408:Hematoma, Subdural; D006801:Humans; D009394:Nephritis, Hereditary; D051299:Post-Dural Puncture Headache; D011247:Pregnancy",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34083183",
"pubdate": "2021-06-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Extra-axial haemorrhage in a patient with Alport syndrome after epidural anaesthesia.",
"title_normalized": "extra axial haemorrhage in a patient with alport syndrome after epidural anaesthesia"
} | [
{
"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-304635",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadd... |
{
"abstract": "OBJECTIVE\nPrevious research has proposed that the hypomethylating agent decitabine can sensitize ovarian cancer cells to chemical agents. In this open-label, phase I/II clinical study, we analyzed the toxicity and efficacy of low dose decitabine combined with taxol and platinum chemotherapy in treatment of refractory and recurrent ovarian cancer.\n\n\nMETHODS\nDecitabine was administered intravenously at 7 mg/m(2) for 30 minutes over five consecutive days and followed by reduced dose taxol and platinum chemotherapy treatment (TC) every 28 days for at least four cycles. Adverse events (AEs) were graded according to the Common Terminology Criteria for AEs (NCI-CTCAE), and efficacy was assessed using the Response Evaluation Criteria in Solid Tumors assessment (RECIST).\n\n\nRESULTS\nTwenty-one patients diagnosed with relapsed/refractory ovarian cancer were initially enrolled in this study, and 17 patients were able to be evaluated. The combination of low dose decitabine and TC was well-tolerated. The most common adverse effects were nausea (77.8%) and neutropenia (66.7%), and adverse events greater than Grade 4 were not observed. The clinical benefit rate (CBR) was 70.6% (12/17), and the partial response (PR) and stable disease (SD) rates were 17.6% (3/17) and 52.9% (9/17), respectively. A significant decrease in serum CA125 levels was observed in many of the responsive cases even after completing the first treatment cycle.\n\n\nCONCLUSIONS\nLow dose decitabine combined with taxol and platinum was well-tolerated and suitable for treating refractory/refractory ovarian cancer. The change in CA125 levels might be a potential predictor for patient clinical response. The efficacy of low dose decitabine for treatment of ovarian cancer requires more volunteers for further investigation.",
"affiliations": "Department of Bio-therapy, College of Life Sciences, Chinese PLA General Hospital, Beijing, 100853, China. hanwdrsw69@yahoo.com.",
"authors": "Fu|Xiaoyu|X|;Zhang|Yan|Y|;Wang|Xiaohui|X|;Chen|Meixia|M|;Wang|Yao|Y|;Nie|Jing|J|;Meng|Yuanguang|Y|;Han|Weidong|W|",
"chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010984:Platinum; D000077209:Decitabine; D001374:Azacitidine; D017239:Paclitaxel",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/138920371604150429155740",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1389-2037",
"issue": "16(4)",
"journal": "Current protein & peptide science",
"keywords": null,
"medline_ta": "Curr Protein Pept Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D014408:Biomarkers, Tumor; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms; D017239:Paclitaxel; D010984:Platinum; D012008:Recurrence; D012449:Safety",
"nlm_unique_id": "100960529",
"other_id": null,
"pages": "329-36",
"pmc": null,
"pmid": "25929868",
"pubdate": "2015",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Low Dose Decitabine Combined with Taxol and Platinum Chemotherapy to Treat Refractory/Recurrent Ovarian Cancer: An Open-Label, Single-Arm, Phase I/II Study.",
"title_normalized": "low dose decitabine combined with taxol and platinum chemotherapy to treat refractory recurrent ovarian cancer an open label single arm phase i ii study"
} | [
{
"companynumb": "CN-OTSUKA-2015_001486",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "To evaluate features and outcomes of eyes with retinal vasculitis and intraocular inflammation (IOI) after intravitreal injection (IVI) of brolucizumab 6 mg/0.05 ml for treatment of neovascular age-related macular degeneration.\n\n\n\nRetrospective case series.\n\n\n\nFifteen eyes from 12 patients identified from 10 United States centers.\n\n\n\nReview of patient demographics, ophthalmologic examination results, and retinal imaging findings.\n\n\n\nBaseline and follow-up visual acuity (VA), prior anti-vascular endothelial growth factor (VEGF) injections, clinical presentation, retinal findings, fluorescein angiography results, and treatment strategies.\n\n\n\nThe number of previous anti-VEGF IVIs ranged between 2 and 80 in the affected eye before switching to brolucizumab. Retinal vasculitis and IOI were diagnosed at a mean of 30 days after brolucizumab IVI. Mean VA before brolucizumab IVI was 0.426 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/53) and VA at diagnosis of retinal vasculitis was 0.981 logMAR (Snellen equivalent, 20/191; range, 20/25-20/1600; P = 0.008). All affected eyes showed IOI with variable combinations of focal or elongated segmental sheathing and discontinuity of small and large retinal arteries, sclerotic arteries, regions of vascular nonperfusion, cotton-wool spots, Kyrieleis plaques, irregular venous caliber with dilated and sclerotic segments, perivenular hemorrhages, and foci of phlebitis. Fluorescein angiography revealed delayed retinal arterial filling, retinal vascular nonperfusion, and variable dye leakage from affected vessels and the optic nerve. Systemic evaluation for embolic causes was unrevealing in 2 patients, and 3 patients showed negative laboratory assessment for uveitis. Treatment consisted of various combinations of corticosteroids (systemic, intravitreal, and topical), and 2 eyes underwent vitrectomy without improvement in vision. After a mean follow-up of 25 days, mean VA was 0.833 logMAR (Snellen equivalent, 20/136), which was reduced compared with baseline (P = 0.033).\n\n\n\nRetinal vasculitis and IOI after brolucizumab IVI are characterized by variable occlusion of large or small retinal arteries, or both, and perivenular abnormalities. It may span from peripheral vasculitis to occlusion of large retinal arteries around the optic nerve or macula with severe vision loss. A high index of suspicion is required because vitreous cells may obscure visualization of retinal details.",
"affiliations": "Tufts University School of Medicine, New England Eye Center, Boston, Massachusetts. Electronic address: cbaumal@tuftsmedicalcenter.org.;Vitreous, Retina, Macula Consultants of New York, New York, New York.;Duke University Eye Center, Durham, North Carolina.;Vitreous, Retina, Macula Consultants of New York, New York, New York; Department of Ophthalmology, New York University, New York, New York.;University of Connecticut, Farmington, Connecticut.;Vistar Eye Center, Virginia Tech Carilion School of Medicine, Roanoke, Virginia.;Retina Consultants of Southern Colorado PC, Colorado Springs, Colorado.;Department of Ophthalmology, Yale University School of Medicine, New Have, Connecticut.;The Retina Care Center, LLC, Associated Retinal Consultants, LLC, Union, New Jersey.;Retina-Vitreous Surgeons of Central New York, PC, Liverpool, New York.;Department of Ophthalmology, University of Washington, Seattle, Washington.;Retina-Vitreous Surgeons of Central New York, PC, Liverpool, New York.;Retina Consultants of Southern Colorado PC, Colorado Springs, Colorado.;Vitreous, Retina, Macula Consultants of New York, New York, New York.;Tufts University School of Medicine, New England Eye Center, Boston, Massachusetts.;The Retina Care Center, LLC, Associated Retinal Consultants, LLC, Union, New Jersey.;The Retina Group of Seattle, Seattle, Washington.;Bascom Palmer Eye Institute, University of Miami Leonard M. Miller School of Medicine, Miami, Florida.",
"authors": "Baumal|Caroline R|CR|;Spaide|Richard F|RF|;Vajzovic|Lejla|L|;Freund|K Bailey|KB|;Walter|Scott D|SD|;John|Vishak|V|;Rich|Ryan|R|;Chaudhry|Nauman|N|;Lakhanpal|Rohit R|RR|;Oellers|Patrick R|PR|;Leveque|Thellea K|TK|;Rutledge|Bryan K|BK|;Chittum|Mark|M|;Bacci|Tommaso|T|;Enriquez|Ana Bety|AB|;Sund|Newman J|NJ|;Subong|Eric N P|ENP|;Albini|Thomas A|TA|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C000622091:brolucizumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ophtha.2020.04.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0161-6420",
"issue": "127(10)",
"journal": "Ophthalmology",
"keywords": null,
"medline_ta": "Ophthalmology",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D058449:Intravitreal Injections; D008266:Macula Lutea; D008297:Male; D011379:Prognosis; D031300:Retinal Vasculitis; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence; D014605:Uveitis; D014792:Visual Acuity",
"nlm_unique_id": "7802443",
"other_id": null,
"pages": "1345-1359",
"pmc": null,
"pmid": "32344075",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Retinal Vasculitis and Intraocular Inflammation after Intravitreal Injection of Brolucizumab.",
"title_normalized": "retinal vasculitis and intraocular inflammation after intravitreal injection of brolucizumab"
} | [
{
"companynumb": "NVSC2020US036862",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BROLUCIZUMAB-DBLL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPerforation of the cornea is a rare finding in patients with rheumatoid arthritis (RA). Addressing a perforated cornea associated with RA is challenging, since its pathogenesis is not fully elucidated. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) were developed to prevent cystoid macular edema following cataract surgery in patients at risk. Their prescription in inflammation of the anterior segment of the eye may induce negative effects on the ocular surface. We bring into focus a corneal perforation in a patient with RA who used indomethacin eye drops to treat corneal ulceration, but responded promptly to drug discontinuation and initiation of topical cyclosporine 0.1%. Our aim is to emphasize two issues: the contraindication of topical indomethacin in corneal defects, and the immediate positive impact of topical cyclosporine 0.1% on corneal healing.\n\n\nMETHODS\nA 73-year-old Caucasian woman with a 13-year history of RA was treated for corneal ulceration in her oculus sinister (OS) with topical indomethacin and gentamicin. The patient was being treated with systemic immunosuppression and NSAIDs for the underlying RA and artificial tears in both eyes. No bandage contact lens was used. After 3 weeks of treatment, perforation of the left cornea occurred and the patient was referred to our hospital. Upon admission, visual acuity (VA) in the OS was 20/630. Slit lamp examination of the OS revealed paracentral corneal perforation, iris plugging the perforation site, shallow anterior chamber, clear aqueous humor, and clear lens. Anterior segment optical coherence tomography showed the inclavated iris in the perforation site and minimum corneal thickness of 101 µm. Topical NSAIDs were discontinued and topical treatment was initiated with tobramycin, tropicamide 1%, phenylephrine 10%, and artificial tears five times a day, and occlusive patch. For 5 days, there was no improvement, so topical cyclosporine 0.1% was started, one drop every evening. Within 7 days, the cornea had healed, the iris was liberated from the perforation site, the minimum corneal thickness increased to 250 µm, VA improved to 20/25, and the patient was free of symptoms.\n\n\nCONCLUSIONS\nThe main \"takeaway\" lessons from this case are that topical indomethacin should not be prescribed in cases of inflammation of the anterior segment of the eye, and that topical cyclosporine was efficacious in healing corneal perforation in our patient.",
"affiliations": "Department of Ophthalmology, Iuliu Hațieganu University of Medicine and Pharmacy, 8, V. Babes Street, 400012, Cluj-Napoca, Romania. simonanicoara1@gmail.com.;Department of Ophthalmology, Iuliu Hațieganu University of Medicine and Pharmacy, 8, V. Babes Street, 400012, Cluj-Napoca, Romania.",
"authors": "Nicoară|Simona Delia|SD|http://orcid.org/0000-0002-7886-2044;Damian|Ioana|I|",
"chemical_list": "D009883:Ophthalmic Solutions; D007213:Indomethacin",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-020-02600-9",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2600\n10.1186/s13256-020-02600-9\nCase Report\nControversy of indomethacin eye drops in the treatment of rheumatoid arthritis-induced corneal ulceration: a case report\nhttp://orcid.org/0000-0002-7886-2044\nNicoară Simona Delia simonanicoara1@gmail.com\n\n12\nDamian Ioana 1\n1 grid.411040.0 0000 0004 0571 5814 Department of Ophthalmology, Iuliu Hațieganu University of Medicine and Pharmacy, 8, V. Babes Street, 400012 Cluj-Napoca, Romania\n2 grid.452359.c Department of Ophthalmology, Emergency County Hospital, Cluj-Napoca, Romania\n4 3 2021\n4 3 2021\n2021\n15 11614 8 2019\n26 11 2020\n© The Author(s) 2021\nOpen 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\nPerforation of the cornea is a rare finding in patients with rheumatoid arthritis (RA). Addressing a perforated cornea associated with RA is challenging, since its pathogenesis is not fully elucidated. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) were developed to prevent cystoid macular edema following cataract surgery in patients at risk. Their prescription in inflammation of the anterior segment of the eye may induce negative effects on the ocular surface. We bring into focus a corneal perforation in a patient with RA who used indomethacin eye drops to treat corneal ulceration, but responded promptly to drug discontinuation and initiation of topical cyclosporine 0.1%. Our aim is to emphasize two issues: the contraindication of topical indomethacin in corneal defects, and the immediate positive impact of topical cyclosporine 0.1% on corneal healing.\n\nCase presentation\n\nA 73-year-old Caucasian woman with a 13-year history of RA was treated for corneal ulceration in her oculus sinister (OS) with topical indomethacin and gentamicin. The patient was being treated with systemic immunosuppression and NSAIDs for the underlying RA and artificial tears in both eyes. No bandage contact lens was used. After 3 weeks of treatment, perforation of the left cornea occurred and the patient was referred to our hospital. Upon admission, visual acuity (VA) in the OS was 20/630. Slit lamp examination of the OS revealed paracentral corneal perforation, iris plugging the perforation site, shallow anterior chamber, clear aqueous humor, and clear lens. Anterior segment optical coherence tomography showed the inclavated iris in the perforation site and minimum corneal thickness of 101 µm. Topical NSAIDs were discontinued and topical treatment was initiated with tobramycin, tropicamide 1%, phenylephrine 10%, and artificial tears five times a day, and occlusive patch. For 5 days, there was no improvement, so topical cyclosporine 0.1% was started, one drop every evening. Within 7 days, the cornea had healed, the iris was liberated from the perforation site, the minimum corneal thickness increased to 250 µm, VA improved to 20/25, and the patient was free of symptoms.\n\nConclusions\n\nThe main “takeaway” lessons from this case are that topical indomethacin should not be prescribed in cases of inflammation of the anterior segment of the eye, and that topical cyclosporine was efficacious in healing corneal perforation in our patient.\n\nKeywords\n\nCorneal perforation\nTopical cyclosporine\nTopical nonsteroidal anti-inflammatory eye drops\nRheumatoid arthritis\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nPerforation of the cornea is a rare finding in patients with rheumatoid arthritis (RA) [1, 2]. This paper reports the case of perforated corneal ulceration in a patient with RA that had been treated for 3 weeks with topical indomethacin prior to admission to our hospital. Although the pathogenesis of corneal perforation is complex [1, 2], we aim to call attention to the potentially devastating effects of topical indomethacin on the cornea, if not properly indicated [3, 4]. Topical nonsteroidal anti inflammatory drugs (NSAIDs) are designed to prevent cystoid macular edema after cataract surgery in patients at risk, not to treat inflammation of the anterior segment of the eye [3, 4]. Unfortunately, some eye care physicians prescribe them routinely for inflammation of the anterior segment of the eye, with potential side effects, among which corneal perforation is the most severe. We bring into focus a case of corneal perforation in a patient with RA with prolonged use of topical indomethacin, but who responded promptly to drug discontinuation and initiation of topical cyclosporine 0.1%. Our case joins a few other reports in the literature related to the occurrence of severe corneal lesions following prolonged topical treatment with NSAIDs, sounding a warning signal on their accurate indication [3, 4]. We also emphasize the immediate positive effect of topical cyclosporine 0.1% on the corneal healing process.\n\nInformed consent was obtained from the patient regarding the publication of this case and the related images.\n\nCase presentation\n\nA 73-year-old Caucasian woman with a 13-year history of RA complained of a marked decrease in visual acuity (VA) and intense pain in her oculus sinister (OS), which was red, accompanied by a sensation of hot leakage on her cheek, approximately 12 hours before admission to our hospital. For the past 3 weeks she had been treated in another service with gentamicin drops and indomethacin drops four times a day for a previously diagnosed corneal ulceration of the OS. No bandage contact lens was used. Before this episode, the patient did not have regular ophthalmological follow-ups. The patient had no history of hypertension or diabetes.\n\nThe patient was using methotrexate 2.5 mg three times a week for treatment of RA. For the dry eye syndrome, preservative-free lubricants were prescribed.\n\nUpon ophthalmic examination, visual acuity (VA) was 20/32 in the oculus dexter (OD) and 20/630 in the OS. Slit lamp examination revealed subtle conjunctival congestion with fine stromal opacities in the OD, and in the OS, moderate ciliary injection, a perforated paracentral corneal ulceration approximately 1 mm in diameter, with a dense perilesional infiltrate, stromal melting, and a few corneal new vessels and stromal opacities around it (Fig. 1). The pupil was peaked but reactive and the iris was plugging the perforation. A shallow, almost flat anterior chamber with clear aqueous humor and a clear lens were found (Fig. 1). No abnormality was noted in the fundus examination of the eyes. Anterior segment optical coherence tomography (OCT, Heidelberg Spectralis) revealed the inclavated iris in the ulceration zone and a thin cornea in the OS and an imminent 100 µm minimum corneal thickness at the site of perforation (Fig. 2).Fig. 1 Slit lamp examination: perforated paracentral corneal ulceration, with dense perilesional infiltrate, stromal melting, a few corneal new vessels and stromal opacities, shallow anterior chamber, clear aqueous humor, iris plugging the corneal perforation\n\nFig. 2 Anterior segment optical coherence tomography (Heidelberg Spectralis): corneal thinning (minimum corneal thickness 101 µm), iris plugging the perforation site\n\nOphthalmological evaluation led us to the diagnosis of paracentral corneal perforation.\n\nSystemic treatment with Ceftriaxone was initiated, 1 g every 12 hours, and topical medication was modified to tobramycin hourly, mydriasis with tropicamide and phenylephrine five times a day, lubricants, and occlusive patch.\n\nEvolution under treatment was stationary without signs of improvement. Therefore, 5 days after admission, cyclosporine 1 mg/ml was added to the topical treatment and it was administered 1 drop a day in the evening. Treatment with Methotrexate 7.5 mg/week was continued.\n\nThe danger of this sight-threatening situation required rheumatologist expertise. Taking into account the lack of general symptoms and the normal values of C reactive protein and ESR, neither pulse therapy with methylprednisolone, nor cyclophosphamide addition were taken into consideration.\n\nFortunately, visual acuity started to improve to 20/63, the perilesional infiltrate decreased in size and depth, the iris was liberated from the perforation site and the corneal transparency improved (Fig. 3). At discharge, VA in the OS was 20/25 and the patient was free of symptoms.Fig. 3. Slit lamp examination of the left eye 7 days following treatment: corneal perforation sealed, dense perilesional infiltrate, and stromal melting diminished considerably, anterior chamber has normal depth\n\nAnterior segment optical coherence tomography showed an increase in minimum corneal thickness to 250 µm (Fig. 4). We performed a Schirmer test without anesthesia in the OD, and the result was 1 mm at 5 minutes.Fig. 4. Anterior segment optical coherence tomography of the left eye 7 days after treatment (Heidelberg Spectralis): minimum corneal thickness of 250 µm, iris liberated from the perforation site\n\nAfter having been discharged, the patient continued topical treatment with tobramycin three times/day and cyclosporine 1mg/ml, one drop/day every evening and preservative-free eye lubricants; 6 months after this episode, the patient experienced no further ocular complains, her vision is 20/20 in both eyes, she is under rheumatologic and ophthalmological supervision and keeps using preservative-free ocular lubricants.\n\nDiscussion and conclusions\n\nRheumatoid arthritis (RA), a chronic systemic autoimmune inflammatory entity, is one of the most common collagen vascular diseases. It affects 3–5% of the adult population, more frequently women than men, with an average age at onset of 35–40 years [1]. RA can affect the eye at multiple levels: anterior segment (keratoconjunctivitis sicca, punctate keratopathy, keratitis, episcleritis, scleritis), extraocular muscles, and posterior segment (choroid, retina, optic nerve) [1]. About 90% of patients with RA suffer from dry eye syndrome, especially keratoconjunctivitis sicca, which seems to be correlated with a disease course longer than 10 years [2]. With regard to corneal involvement, many types of keratitis have been described in RA, including peripheral limbal furrow, peripheral or paracentral ulcerative keratitis, keratolysis, acute stromal keratitis, and sclerosing keratitis.\n\nWe bring into discussion a case of perforated corneal ulceration in a patient with RA that had been treated for 3 weeks with topical indomethacin, which we managed to treat satisfactorily using a medical approach. Establishing the etiological diagnosis was challenging in this case, and most likely there are several implicating factors: RA definitely plays the main role through modification of the corneal structure and the associated ocular dryness, but the prolonged treatment with topical indomethacin cannot be ruled out, at least at the secondary level.\n\nThe pathogenesis of RA-associated corneal ulceration is far from fully elucidated [1]. It seems to be an imbalance between matrix metalloproteinases (MMP) such as MMP-2 in the corneal stroma and MMP-9 in the lacrimal glands and tissue inhibitors of matrix metalloproteinases (TIMP-1) [1, 2, 4]. Reduced levels of TIMP-1 are responsible for high collagenase activity that leads to a keratolytic sterile process [2]. A resulting altered epithelial barrier facilitates the entrance of inflammatory mediators such as monocytes and macrophages in the stroma that subsequently leads to activation of T cells, resulting in production of antibodies and formation of immune complexes. There seems to be significant human leukocyte antigen–DR isotype (HLA-DR) expression by stromal keratocytes and epithelium determined by interferon gamma released by TH2 lymphocytes [1]. Local cytokines such as interleukin-1 and tumor necrosis factor-alpha induce production of collagenase and protease [1, 2, 5, 6]. Paracentral ulcerative keratitis develops in patients with severe dry eye but without marked conjunctival inflammation, such as our case [1, 2].\n\nThe initiation of topical cyclosporine therapy was the key to successful treatment given that it arrested the keratolysis and led to ulcer re-epithelialization [7]. There are several reports that recommend topical cyclosporine for corneal ulcer associated with RA [7, 8], as it may enable epithelial healing while reducing cell-mediated immune reactions in the cornea [9]. In our case, topical cyclosporine was initiated with a 5-day delay, as it is expensive and not immediately available. Before the administration of topical cyclosporine, the corneal ulcer did not show significant improvement. Regarding systemic chemotherapy in rheumatoid corneal perforations, there are no clear guidelines, but a strong collaboration between ophthalmologists and rheumatologists is essential to assess the systemic disease status and to determine the need to change or adjust the immunosuppressive therapy.\n\nAlthough the patient was on immunosuppressive treatment and free of systemic symptoms, she still developed corneal ulceration, highlighting the fact that there are several events initiating corneal lesions and others perpetuating them, such as infection that accelerates corneal melting [5].\n\nThe previously diagnosed dry eye syndrome in the context of RA, even under treatment with preservative-free lubricants, favored the ulceration development [8]. There are studies showing that the corneal central thickness and stromal thickness in patients with RA are statistically significantly lower than in controls [1, 2]. Additionally, there is evidence of proteolytic degradation in both corneas of patients ranging from early xerophthalmia to ulcerating xerophthalmia [1, 8].\n\nThe use of topical indomethacin in our case is questionable [4, 10]. There have been case reports with patients taking topical NSAIDs who developed corneal perforation that healed after discontinuation [3, 4]. Moreover, it has been shown that topical NSAIDs are associated with corneal hypoesthesia and may be responsible for corneal perforation [3, 4].\n\nEven if the clinical aspect was suggestive of sterile ulcerative keratitis (clear cornea and aqueous), treating the condition exclusively as an autoimmune corneal melt without antibiotic coverage could have resulted in a potentially blinding condition [5]. For logistical reasons we did not have the ability to perform corneal scraping, and therefore we chose topical and systemic treatment with broad-spectrum antibiotics.\n\nConsidering the positive outcome following topical cyclosporine, the role of inflammation proved to be essential.\n\nIn cases with perforation, the application of cyanoacrylate adhesive, lamellar grafting, or tarsorrhaphy is indicated, depending on ulceration size [1]. In our case, the presence of the iris at the ulceration site acted like a self-adhesive substance.\n\nNevertheless, photographs of the lesion were helpful in evaluating regression. Anterior segment OCT images were particularly important, highlighting the anatomical improvement.\n\nCorneal perforated ulceration is a rare complication secondary to RA. This case signals and demonstrates that even though the underlying disease was well controlled and monitored, and the dry eye was properly addressed, corneal ulceration still occurred in this RA patient. Indomethacin administered topically may have precipitated corneal perforation, but cyclosporine associated with antibiotics led to good visual outcome. However, since the patient had already been diagnosed with corneal ulcer in another service, there is a possibility that the corneal perforation was a natural course of peripheral ulcerative keratitis (PUK) and undertreatment, rather than due to indomethacin drops. Establishing a cause-effect relationship in this scenario when natural course of the disease is a major confounding factor is difficult and the assumption that indomethacin is the sole culprit here is questionable. Methotrexate 7.5 mg/week is the usual lowest prescribed dose in PUK. Therefore, we can assume that the progression of the ulcer might have been prevented by increasing the methotrexate dose or by adding systemic steroids.\n\nAnterior segment OCT has demonstrated its valuable role in monitoring the disease from a structural perspective.\n\nThe main “takeaway” lessons from this case are that topical indomethacin should not be used in corneal ulcers, and that topical cyclosporine was efficacious in healing corneal perforation in a patient with RA.\n\nAbbreviations\n\nESR Erythrocyte sedimentation rate\n\nHLA Human leukocyte antigen\n\nMMP Matrix metalloproteinases\n\nNSAIDs Nonsteroidal anti-inflammatory drugs\n\nOCT Optical coherence tomography\n\nOD Right eye (oculus dexter)\n\nOS Left eye (oculus sinister)\n\nRA Rheumatoid arthritis\n\nTIMP Tissue inhibitors of matrix metalloproteinases\n\nVA Visual acuity\n\nAcknowledgements\n\nNone.\n\nAuthors' contributions\n\nSDN made substantial contributions to the design and conceptualization of the work, analysis and interpretation of data, and substantively revised the manuscript. ID made substantial contributions to the design and conceptualization of the work, acquisition and interpretation of data, and drafted the manuscript. Both authors read and approved the final manuscript.\n\nFunding\n\nNone.\n\nAvailability of data and materials\n\nThe datasets used and analyzed during the current case report are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\n\nThe report of this case has been performed in accordance with the Declaration of Helsinki, and it was approved by the ethics committee of the Emergency County Hospital in Cluj-Napoca, 7688/21.03.2019.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Lin A Bouchard CS Yanoff M Duker JS Noninfectious keratitis: rheumatoid-associated corneal ulceration Ophthalmology 2014 4 London Elsevier Health Sciences 249 251\n2. Karampatakis V Konidaris V Michailidou M Gerofotis A Daniilidis M Peripheral corneal ulceration associated with rheumatoid arthritis Am J Case Rep. 2013 14 8 318 321 23986797\n3. Tatsuhiko A Tetsushi N Mina M Norimasa H Takako T Yoshihiro H Three cases of corneal melting after instillation of a new nonsteroidal antiinflammatory drug Cornea 2006 25 2 224 227 10.1097/01.ico.0000177835.93130.d4 16371788\n4. Reviglio VE Rana TS Li QJ Ashraf MF Daly MK O’Brien TP Effects of topical nonsteroidal antiinflammatory drugs on the expression of matrix metalloproteinases in the cornea J Cataract Refract Surg. 2003 29 5 989 997 10.1016/S0886-3350(02)01737-6 12781288\n5. Williams GP Denniston AKO Elamanchi SR Rauz S Rheumatoid corneal melt: autoimmunity or infection? JRSM Short Rep. 2011 2 1 1 10.1258/shorts.2010.010079 21286224\n6. Villani E Galimberti D Viola F Corneal involvement in rheumatoid arthritis: an in vivo confocal study Invest Ophthalmol Vis Sci. 2008 49 2 560 564 10.1167/iovs.07-0893 18234999\n7. Levy O Labbe A Borderie V Laroche L Bouheraoua N Topical cyclosporine in ophthalmology: pharmacology and clinical indications J Fr Ophtalmol. 2016 39 3 292 307 10.1016/j.jfo.2015.11.008 26997607\n8. Othman TM Mousa A Gikandi PW Abdelmabod M Abdelrahman AM Efficacy and safety of using topical cyclosporine A for treatment of moderate to severe dry eye disease Saudi J Ophthalmol. 2018 32 3 217 221 10.1016/j.sjopt.2018.06.001 30224886\n9. Acheampong AA Shackleton M Tang-Liu DDS Ding SL Stern ME Decker R Distribution of cyclosporin A in ocular tissues after topical administration to albino rabbits and beagle dogs Curr Eye R. 1999 18 2 91 103 10.1076/ceyr.18.2.91.5381\n10. Masuda I Matsuo T Okamoto K Two cases of corneal perforation after oral administration of nonsteroidal anti-inflammatory drugs: oral NSAID-induced corneal damage Eur J Ophthalmol 2010 20 2 454 456 10.1177/112067211002000230 20037896\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "15(1)",
"journal": "Journal of medical case reports",
"keywords": "Corneal perforation; Rheumatoid arthritis; Topical cyclosporine; Topical nonsteroidal anti-inflammatory eye drops",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D002387:Cataract Extraction; D057112:Corneal Perforation; D005260:Female; D006801:Humans; D007213:Indomethacin; D009883:Ophthalmic Solutions",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "116",
"pmc": null,
"pmid": "33663589",
"pubdate": "2021-03-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18234999;30224886;23986797;16371788;20037896;26997607;12781288;10223652;21286224",
"title": "Controversy of indomethacin eye drops in the treatment of rheumatoid arthritis-induced corneal ulceration: a case report.",
"title_normalized": "controversy of indomethacin eye drops in the treatment of rheumatoid arthritis induced corneal ulceration a case report"
} | [
{
"companynumb": "RO-ASSERTIO THERAPEUTICS, INC.-RO-2021AST000037",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GENTAMICIN"
},
"drugadd... |
{
"abstract": "The immune system has the potential to either attenuate tumor growth or to promote tumor progression. The goal of cancer immunotherapy is to shift the balance in favor of tumor immunosurveillance, so that the immune system can recognize the tumor, eliminate it, and prevent its recurrence. Bendamustine plus rituximab is generally considered effective and safe in patients with previously untreated chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphomas. To evaluate the effects of bendamustine-rituximab and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on the recuperation of immune system, we analyze the distribution of CD4+ and CD8+ T cells, B cells, and NK cells in peripheral blood of 18 patients who received 4-6 cycles of rituximab-bendamustine (BR) or six R-CHOP before therapy and 6 months after completing treatment. Our results indicate that lymphocyte recovery is impaired in patients with chronic lymphocytic leukemia and indolent lymphomas treated with bendamustine plus rituximab. Low CD4 T cells (<200 cells/μl) induced by bendamustine (BR) suggest prophylaxis should be applied against opportunistic infections. Asymptomatic EBV and CMV reactivations support a negative effect of BR on the immune system. If cellular immune therapy such as lymphokine-activated killer (LAK) or effector lymphocytes infusion is planned, regimes other than BR should be the first choice.",
"affiliations": "Hematology Department, Hospital San Pedro, c/Piqueras 98, 26006, Logroño, La Rioja, Spain, rgmunoz@riojasalud.es.",
"authors": "García Muñoz|Ricardo|R|;Izquierdo-Gil|Araceli|A|;Muñoz|Aura|A|;Roldan-Galiacho|Verónica|V|;Rabasa|Pilar|P|;Panizo|Carlos|C|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D018906:Antineoplastic Agents, Alkylating; D009588:Nitrogen Mustard Compounds; D000069283:Rituximab; D000069461:Bendamustine Hydrochloride",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-014-2135-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "93(11)",
"journal": "Annals of hematology",
"keywords": null,
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D018906:Antineoplastic Agents, Alkylating; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069461:Bendamustine Hydrochloride; D015496:CD4-Positive T-Lymphocytes; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008214:Lymphocytes; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D009588:Nitrogen Mustard Compounds; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1879-87",
"pmc": null,
"pmid": "24951124",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Lymphocyte recovery is impaired in patients with chronic lymphocytic leukemia and indolent non-Hodgkin lymphomas treated with bendamustine plus rituximab.",
"title_normalized": "lymphocyte recovery is impaired in patients with chronic lymphocytic leukemia and indolent non hodgkin lymphomas treated with bendamustine plus rituximab"
} | [
{
"companynumb": "ES-ROCHE-2882536",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BENDAMUSTINE HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "We present a case of urticaria caused by antihistamines in a patient with nonsteroidal anti-inflammatory drug (NSAID) sensitivity. A 35-year-old man experienced, on 2 separate occasions, immediate generalized urticaria during treatment with ibuprofen and naproxen, respectively. A single-blind, placebo-controlled oral challenge (SBPCOC) with piroxicam was carried out, and resulted in urticaria and angioedema 3 hours later. Two hours after initial clinical resolution, the patient developed multiple wheals on the trunk and upper limbs. He described similar delayed reactions after oral antihistamine administration on previous occasions. SBPCOCs with acetaminophen and etoricoxib were performed, with good tolerance. Skin prick and patch tests with loratadine and cetirizine were negative. After an SBPCOC with loratadine, the patient developed generalized urticaria 90 minutes after intake. Tolerance to fexofenadine 180 mg was confirmed. We describe the first case of a possible new subset of antihistamine urticaria, and suggest calling this NSAID-sensitive antihistamine-induced urticaria/angioedema.",
"affiliations": "Allergy Department, Hospital Virgen del Rocío, Seville, Spain. scimbollek@gmail.com",
"authors": "Cimbollek|S|S|;Ortega Camarero|M|M|;Avila|R|R|;Quiralte|J|J|;Prados|M|M|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D039563:Histamine H1 Antagonists, Non-Sedating; D009288:Naproxen; D017336:Loratadine; D007052:Ibuprofen",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-9068",
"issue": "21(6)",
"journal": "Journal of investigational allergology & clinical immunology",
"keywords": null,
"medline_ta": "J Investig Allergol Clin Immunol",
"mesh_terms": "D000328:Adult; D000799:Angioedema; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004342:Drug Hypersensitivity; D039563:Histamine H1 Antagonists, Non-Sedating; D006801:Humans; D007052:Ibuprofen; D017336:Loratadine; D008297:Male; D009288:Naproxen; D012882:Skin Tests; D014581:Urticaria",
"nlm_unique_id": "9107858",
"other_id": null,
"pages": "488-90",
"pmc": null,
"pmid": "21995184",
"pubdate": "2011",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "NSAID-sensitive antihistamine-induced urticaria/angioedema.",
"title_normalized": "nsaid sensitive antihistamine induced urticaria angioedema"
} | [
{
"companynumb": "ES-JNJFOC-20120305971",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "A 5-question telephone survey was administered to compare satisfaction between patients receiving vancomycin vs daptomycin outpatient parenteral antimicrobial therapy (OPAT). Twenty-seven patients completed the survey (40%). Vancomycin had higher daily interference score than daptomycin (P = .03). All patients receiving daptomycin reported a satisfaction score ≥8/10, as compared to 67% of patients who received vancomycin (P < .03). OPAT antibiotics with less cumbersome administration regimens may translate into higher patient satisfaction and quicker return to life normalcy.",
"affiliations": "Skaggs School of Pharmacy, University of California, San Diego, La Jolla, California, USA.;Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, California, USA.;Sharp Memorial Hospital, San Diego, California, USA.",
"authors": "Wu|Katherine H|KH|;Sakoulas|George|G|;Geriak|Matthew|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofab418",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957\nOxford University Press US\n\n10.1093/ofid/ofab418\nofab418\nBrief Reports\nAcademicSubjects/MED00290\nVancomycin or Daptomycin for Outpatient Parenteral Antibiotic Therapy: Does It Make a Difference in Patient Satisfaction?\nWu Katherine H 1\nSakoulas George 23\nGeriak Matthew 3\n1 Skaggs School of Pharmacy, University of California, San Diego, La Jolla, California, USA\n2 Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, California, USA\n3 Sharp Memorial Hospital, San Diego, California, USA\nCorrespondence: Matthew Geriak, PharmD, Research Pharmacy, Sharp Memorial Hospital, 7901 Frost St, San Diego, CA 92123, USA (matthew.geriak@sharp.com).\n8 2021\n30 8 2021\n30 8 2021\n8 8 ofab41810 6 2021\n28 7 2021\n16 8 2021\n30 8 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nA 5-question telephone survey was administered to compare satisfaction between patients receiving vancomycin vs daptomycin outpatient parenteral antimicrobial therapy (OPAT). Twenty-seven patients completed the survey (40%). Vancomycin had higher daily interference score than daptomycin (P = .03). All patients receiving daptomycin reported a satisfaction score ≥8/10, as compared to 67% of patients who received vancomycin (P < .03). OPAT antibiotics with less cumbersome administration regimens may translate into higher patient satisfaction and quicker return to life normalcy.\n\ndaptomycin\nMRSA\noutpatient infusion therapy\nvancomycin\nSharp Healthcare Foundation\n==== Body\nWith the development of new antimicrobials agents, outpatient parenteral antimicrobial therapy (OPAT) has increasingly been used to manage patients with serious bacterial infections [1]. OPAT allows for a more rapid and efficient transition from inpatient to outpatient settings, thus shortening costly lengths of hospital stay, allowing a quicker return to work, improving patient satisfaction, and reducing the likelihood of hospital-acquired infection [2–6].\n\nNumerous antibiotic options are available to clinicians in selecting OPAT [7], centered initially on spectrum of activity, but also involving characteristics specific to the antibiotics, including tolerability, infusion time, number of daily doses, drug concentration monitoring, and the possibility of self-administration. While these latter characteristics are less relevant in the inpatient setting, their importance looms larger in the OPAT setting. How important is it to the patient to have an antibiotic with decreased infusion time, reduced number of daily doses, and decreased blood draws? In this study, our main goal was to get patient feedback about whether or not the choice of antibiotic played a role in how satisfied they were with their treatment.\n\nThe treatment of resistant gram-positive infections has evolved considerably in the last 2 decades through the approval of several antibiotics [8]. While vancomycin has been the treatment standard for decades due to its low drug acquisition cost, it has cumbersome dosing characteristics of 2–3 doses per day in patients with normal renal function. With each vancomycin infusion being 60–90 minutes, it is extremely onerous for OPAT [9]. The need for therapeutic drug monitoring not only places an increased burden on providers, due to drug serum level concentration–predicated dose adjustment, but creates opportunity for dosing errors to occur. These factors create a medical need for less cumbersome antibiotics in OPAT that may improve productivity of both patients and providers, and reduce provider liability, the value of which cannot be quantified financially.\n\nVancomycin and daptomycin are commonly utilized antibiotics in OPAT [10–13]. At our OPAT treatment center, both groups require weekly renal monitoring. Daptomycin-treated patients require weekly creatine phosphokinase levels to be drawn, and vancomycin drug levels are also drawn weekly. The difference is that repeated vancomycin drug level monitoring often results in dose changes over the duration of treatment based on the pharmacokinetics. From a drug administration standpoint, vancomycin is usually infused twice per day, infused over 60–120 minutes. Daptomycin is a less cumbersome option [14, 15] requiring 1 dose every 24–48 hours (depending on renal function) that can be administered in 2 minutes. Surprisingly, there is a paucity of data in the literature examining the role of antibiotic therapy in impacting patient experience with OPAT.\n\nMETHODS\n\nThe treating physician conducted a brief 5-question survey with his patients post–OPAT treatment by phone as part of an internal quality assurance measure. The study team was given the surveys to analyze the results, retrospectively. The surveys were screened to meet the following criteria: Subjects were required to be ≥18 years of age and to have completed a course of either vancomycin or daptomycin OPAT at home. All those receiving care at the infusion center, nursing facility, or clinics were excluded. Subjects were excluded if complete data were unavailable.\n\nThe survey scores were summarized and analyzed using Stata version 16 software. The quantitative questions (1 and 2) were analyzed using Wilcoxon rank-sum test. The qualitative questions (3 and 4) were analyzed using Fisher exact test. For question number 5, patients who had an overall score ≥8 were said to have high satisfaction of the given antibiotic. Data were then analyzed by 2-tailed Fisher exact test. The comparison of the duration of treatment between the 2 arms was analyzed by the Mann-Whitney U test.\n\nRESULTS\n\nSixty-eight patients received the follow-up calls and 41 patients were excluded (60%). Reasons for exclusion were as follows: could not contact patient (n = 36), patient declined to participate (n = 3), and language barrier (n = 2). Twenty-seven patients completed the survey (40%). The daptomycin treatment group was 87% male and 63% white ethnicity and the vancomycin treatment group was 67% male and 67% white ethnicity. Infection types for the daptomycin treatment group included complicated soft tissue infection (n = 8 [53%]), bone/joint infection (n = 4 [27%]), and bacteremia/endocarditis (n = 3 [20%]). For the vancomycin group, infection types were bone/joint (n = 7 [58%]), complicated soft tissue infection (n = 3 [25%]), and bacteremia/endocarditis (n = 2 [17%]). The most common bacterial pathogens in the daptomycin arm were methicillin-resistant Staphylococcus aureus (MRSA) in 5 patients (33%), Enterococcus faecalis in 3 patients (20%), and methicillin-susceptible S aureus in 2 patients (13%). The most common bacterial pathogens in vancomycin OPAT patients were MRSA in 5 patients (41%), and Staphylococcus epidermidis in 4 patients (34%). The remaining 3 vancomycin patients (25%) did not have a specified pathogen.\n\nAll daptomycin-treated patients received once-daily dosing. Among the vancomycin treatment group, 5 patients received a dose every 24–48 hours, 5 patients received a dose every 12 hours, and 2 patients received a dose every 8 hours. The median time period between completion of OPAT and survey administration was 85 weeks (range, 4–127 weeks) and 56 weeks (range, 9–127 weeks) for the daptomycin and vancomycin treatment groups, respectively. The median duration of OPAT was 31 days (range, 14–71 days) and 16 days (range, 6–64 days) for the daptomycin and vancomycin treatment groups, respectively (P = .09, Mann-Whitney U test).\n\nThe survey questions and results are shown in Table 1. The median daily interference scores indicate a difference between treatment groups (P = .03). Patients reported having more daily interference while receiving vancomycin. Question 4 was excluded from analysis since all patients reported that the infection itself, not the antibiotic therapy, made them take time off work. All patients who received daptomycin reported high satisfaction, compared with 67% of patients who received vancomycin (Table 1, P = .03). The remaining scores did not indicate a difference between treatment groups.\n\nTable 1. Questionnaire Scores of Daptomycin and Vancomycin Outpatient Parenteral Antimicrobial Therapy\n\nQuestion\tDaptomycin (n = 15)\tVancomycin (n = 12)\tP Value\tZ Statistic\t\nAge, y, mean (SD)\t55 (16)\t58 (11)\tNA\tNA\t\nQuestion 1: How much did OPAT interfere with your daily routine? None = 0, mild = 2, moderate = 5, severe = 8; very severe = 10\nScore: Median (75th percentile)\t0 (2)\t5 (8)\t.03\t–2.14\t\nQuestion 2: How bad were the OPAT side effects? (0 to 10)\nNone = 0, very severe = 10\nScore: Median (75th percentile)\t0 (0)\t0 (5)\t.12\t–1.55\t\nQuestion 3: Did you need to go back to the hospital to treat the same infection (yes or no)\nScore: % readmitted (yes)\t13.3%\t8.33%\t1.00\tNA\t\nQuestion 4: Did the OPAT require you to take time off from work? (yes or no)\nScore: % yes\t100%\t100%\tNA\tNA\t\nQuestion 5: How would you score your overall satisfaction with OPAT? (0 to 10)\nUnsatisfied = 0; extremely satisfied = 10\nScore: % patient score ≥8\t100%\t67%\t.03\tNA\t\nAbbreviations: NA, not applicable; OPAT, outpatient parenteral antimicrobial therapy; SD, standard deviation.\n\nDISCUSSION\n\nVancomycin and daptomycin are commonly utilized in OPAT of infections caused by gram-positive organisms. While vancomycin has been the treatment standard for decades due to its low drug acquisition cost, its onerous dosing characteristics of 2–3 infusions every 60–90 minutes in patients with normal renal function renders it potentially very disruptive and inconvenient for patients when used in OPAT [9]. While all OPAT generally calls for weekly bloodwork to monitor for adverse drug effects (eg, creatinine phosphokinase for daptomycin, hematological studies for β-lactam myelotoxicity), the need for vancomycin therapeutic drug monitoring places an increased burden on physicians, pharmacists, and laboratory personnel to consider dose adjustment, opening up opportunities for medical errors and nephrotoxic overdosing to occur. These factors create a medical need for less cumbersome antibiotics in OPAT that may improve productivity for both patients and providers and reduce provider liability, the value of which cannot be quantified financially. While our study was too small to capture differences in adverse drug effects, prior studies show consistency in demonstrating that vancomycin is associated with significantly higher adverse drug events than daptomycin in OPAT [16, 17]. This would be anticipated to weigh on patient satisfaction differences in a larger study.\n\nWhile high acquisition cost of daptomycin has often been restrictive in its utilization, the expiration of patent, rendering daptomycin generic in the United States, has resulted in a significant drug acquisition price drop and convergence in price of vancomycin and daptomycin. Daptomycin is commonly utilized in OPAT as a much less cumbersome option, requiring only 1 dose every 24 hours (or every 48 hours for creatinine clearance <30 mL/minutes) that can be administered in as little as 2 minutes [10–15]. Such different properties in administration would suggest an impact on the patient OPAT experience, depending on which of the 2 agents is utilized. Such studies have never been performed, which is surprising, especially given that patient satisfaction is a metric of increasing relevance in clinical decision making.\n\nDespite the survey being extremely brief (generally administered over the phone in 2 minutes or less), only a 40% survey response was obtained. Patients receiving daptomycin had better satisfaction scores in this brief survey and had less life disruption and return to normal living. Adverse side effects and readmission rates were not significantly different between the 2 antibiotic treatment groups.\n\nThe results of this study confirm what has generally been assumed in that patient satisfaction in OPAT ties significantly into the ease of administration of therapy. Several years ago before daptomycin became generic in the United States, the acquisition cost of daily doses of daptomycin was several hundred dollars. In May 2021, the daptomycin cost was $31 per 500 mg [18] compared to vancomycin at $9/g. When adding up the vancomycin multiple doses per day, the therapeutic drug monitoring, laboratory blood draws, and ancillary supplies [19], the cost differential between daptomycin and vancomycin is becoming negligible. Therefore, selection of OPAT in daptomycin that is very close to vancomycin in price, yet much easier to administer, led to more satisfied patients in our sample population. Nevertheless, given great heterogeneity in insurance reimbursement, best practices still require confirmation with the patient’s third-party payor (frequently by a hospital case manager or discharge planner) to determine payments for OPAT that the patient is responsible for. In some instances, daptomycin may be accompanied by “copays” that are higher than those of vancomycin, which patients are unable, or unwilling, to cover for the sake of OPAT convenience.\n\nOur study has some very important limitations. First, the population sample was small, the fraction of captured patients was low, and data were collected in 1 geographical area. Second, recall bias needs to be considered given that some patients received and completed their treatment roughly 2 years prior to the survey. Third, overall satisfaction score may be artificially high because the treating physician verbally administered the survey over the phone and not anonymously. Finally, we deployed a survey that semi-quantitatively assessed patient experiences, but it has not been previously validated.\n\nIn summary, this study showed that antibiotics such as daptomycin with fewer doses per day and shorter infusion times led to higher patient satisfaction and less life disruption on OPAT. Larger studies are needed to further examine this issue to better evaluate the balance between higher drug acquisition costs, perceived patient satisfaction, and patient productivity.\n\nNotes\n\nAuthor contributions. K. H. W.: execution, data gathering and organization, data analysis, manuscript preparation. G. S.: study design, data analysis, statistics, data gathering, manuscript preparation. M. G.: research team oversight, IRB submission, study design, organization, data analysis, statistics, manuscript preparation and submission. All authors gave their approval for the final version of the manuscript to be published.\n\nAcknowledgments. We thank all of the patients who responded to the questions in our survey; Francisco Aldrete for his assistance in the data mining of patients treated with antibiotics in the outpatient setting; and the Sharp Institutional Review Board (IRB) for waiving the review fees.\n\nPatient consent statement. The design of the work has received approval by the local ethical committee (Sharp Healthcare IRB study number 1906805). The IRB of record determined that this research is not subject to regulation under 45 Code of Federal Regulations (CFR) part 46. Determination applies to the following documents: University of California, San Diego Summer Research Training Program Application, dated 19 February 2019; a HIPAA waiver was allowed per 45 CFR 164.512(i)(2)(ii). This study conformed to the Helsinki Declaration of 1964, as revised in 2013, concerning human and animal rights.\n\nFinancial support. This research was supported by the Sharp Healthcare Foundation (San Diego, California); the funding was only for the labor of the local IRB review and the Sharp Center of Research support staff.\n\nPotential conflicts of interest. G. S. has consulted for AbbVie, Ferring, and Paratek Pharmaceuticals and on the speaker’s bureaus for AbbVie and Paratek Pharmaceuticals. All other authors report no potential conflicts of interest.\n\nAll authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n\n1. BowlingJ, LewisJ, OwensA. Outpatient parenteral antimicrobial therapy. Hospital Medicine Clinics 2013; 2 :e45–56.\n2. WilliamsDN, BakerCA, KindAC, SannesMR. The history and evolution of outpatient parenteral antibiotic therapy (OPAT). Int J Antimicrob Agents 2015; 46 :307–12.26233483\n3. MitchellED, Czoski MurrayC, MeadsD, et al. Clinical and cost-effectiveness, safety and acceptability of community intravenous antibiotic service models: CIVAS systematic review. BMJ Open 2017; 7 :e013560.\n4. McCarthyMW, KeylounKR, GillardP, et al. Dalbavancin reduces hospital stay and improves productivity for patients with acute bacterial skin and skin structure infections: the ENHANCE trial. Infect Dis Ther 2020; 9 :53–67.31713130\n5. BukeC, Armand-LefevreL, LolomI, et al. Epidemiology of multidrug-resistant bacteria in patients with long hospital stays. Infect Control Hosp Epidemiol 2007; 28 :1255–60.17926276\n6. WyllieDH, WalkerAS, PetoTE, CrookDW. Hospital exposure in a UK population, and its association with bacteraemia. J Hosp Infect 2007; 67 :301–7.18022283\n7. TiceAD, RehmSJ, DalovisioJR, et al ; Infectious Diseases Society of America. Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines. Clin Infect Dis 2004; 38 :1651–72.15227610\n8. TabaeeA, AnandVK, YoonC. Outpatient intravenous antibiotics for methicillin-resistant Staphylococcus aureus sinusitis. Am J Rhinol 2007; 21 :154–8.17424870\n9. PolkRE, HealyDP, SchwartzLB, et al. Vancomycin and the red-man syndrome: pharmacodynamics of histamine release. J Infect Dis 1988; 157 :502–7.2449506\n10. CromptonJA, NorthDS, YoonM, et al. Outcomes with daptomycin in the treatment of Staphylococcus aureus infections with a range of vancomycin MICs. J Antimicrob Chemother 2010; 65 :1784–91.20554570\n11. KullarR, DavisSL, KayeKS, et al. Implementation of an antimicrobial stewardship pathway with daptomycin for optimal treatment of methicillin-resistant Staphylococcus aureus bacteremia. Pharmacotherapy 2013; 33 :3–10.23307539\n12. FowlerVGJr, BoucherHW, CoreyGR, et al ; S aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355 :653–65.16914701\n13. MoisePA, CulshawDL, Wong-BeringerA, et al. Comparative effectiveness of vancomycin versus daptomycin for MRSA bacteremia with vancomycin MIC >1 mg/L: a multicenter evaluation. Clin Ther 2016; 38 :16–30.26585355\n14. OlesonFBJr, BermanCL, KirkpatrickJB, et al. Once-daily dosing in dogs optimizes daptomycin safety. Antimicrob Agents Chemother 2000; 44 :2948–53.11036005\n15. CaulderCR, SloanA, YasirA, BookstaverPB. Infusion-related reaction following daptomycin two-minute rapid intravenous administration. Hosp Pharm 2014; 49 :644–6.25477584\n16. SchrankGM, WrightSB, Branch-EllimanW, LaSalviaMT. A retrospective analysis of adverse events among patients receiving daptomycin versus vancomycin during outpatient parenteral antimicrobial therapy. Infect Control Hosp Epidemiol 2018; 39 :947–54.29893658\n17. ShresthaNK, MasonP, GordonSM, et al. Adverse events, healthcare interventions and healthcare utilization during home infusion therapy with daptomycin and vancomycin: a propensity score-matched cohort study. J Antimicrob Chemother 2014; 69 :1407–15.24398341\n18. Drugs.com. Daptomycin prices, coupons and patient assistance programs. https://www.drugs.com/price-guide/daptomycin#:~:text=The%20cost%20for%20daptomycin%20intravenous,on%20the%20pharmacy%20you%20visit. Accessed 10 May 2021.\n19. ShahNP, ReddyP, PaladinoJA, et al. Direct medical costs associated with using vancomycin in methicillin-resistant Staphylococcus aureus infections: an economic model. Curr Med Res Opin 2004; 20 :779–90.15200734\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "8(8)",
"journal": "Open forum infectious diseases",
"keywords": "MRSA; daptomycin; outpatient infusion therapy; vancomycin",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofab418",
"pmc": null,
"pmid": "34476284",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": "26585355;29893658;18022283;11036005;20554570;26233483;15227610;23307539;17424870;15200734;28428184;2449506;25477584;16914701;31713130;24398341;17926276",
"title": "Vancomycin or Daptomycin for Outpatient Parenteral Antibiotic Therapy: Does It Make a Difference in Patient Satisfaction?",
"title_normalized": "vancomycin or daptomycin for outpatient parenteral antibiotic therapy does it make a difference in patient satisfaction"
} | [
{
"companynumb": "US-009507513-2111USA005189",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugadditional": "4",
... |
{
"abstract": "We report a 71-year-old woman with inferior acute myocardial infarction (AMI) due to type A acute aortic dissection. Emergency enhanced computed tomography (CT) did not show obvious aortic dissection. During emergency percutaneous coronary intervention (PCI), intravascular ultrasonography revealed type A aortic dissection. Hemodynamic stability was restored after PCI. 1 month later, CT revealed a sinus of Valsalva aneurysm, which was treated surgically. This case suggests that PCI could be a good initial treatment option for unstable patients with AMI due to type A aortic dissection. This is the first reported case of sinus of Valsalva aneurysm subsequent to aortic dissection.",
"affiliations": "Department of Cardiovascular Medicine, Asahi General Hospital, I-1326 Asahi, Chiba, 289-2511, Japan, kodera@tke.att.ne.jp.",
"authors": "Kodera|Satoshi|S|;Ikeda|Masayuki|M|;Sato|Kazutoshi|K|;Kushida|Syunichi|S|;Kanda|Junji|J|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12928-014-0250-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1868-4297",
"issue": "30(1)",
"journal": "Cardiovascular intervention and therapeutics",
"keywords": null,
"medline_ta": "Cardiovasc Interv Ther",
"mesh_terms": "D000368:Aged; D000784:Aneurysm, Dissecting; D001014:Aortic Aneurysm; D005260:Female; D006801:Humans; D009203:Myocardial Infarction; D062645:Percutaneous Coronary Intervention; D011183:Postoperative Complications; D014057:Tomography, X-Ray Computed; D018084:Ultrasonography, Interventional",
"nlm_unique_id": "101522043",
"other_id": null,
"pages": "61-7",
"pmc": null,
"pmid": "24691883",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Percutaneous coronary intervention is a useful bridge treatment for acute myocardial infarction due to acute type A aortic dissection.",
"title_normalized": "percutaneous coronary intervention is a useful bridge treatment for acute myocardial infarction due to acute type a aortic dissection"
} | [
{
"companynumb": "PHHY2015JP161278",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "Meralgia paresthetica is a condition caused by entrapment of the lateral femoral cutaneous nerve that leads to paresthesia along the anterolateral portion of the thigh. Because of advancements in neuromodulation, peripheral nerve stimulation (PNS) has been considered a new treatment option for meralgia paresthetica. Newer PNS technology targets peripheral nerves directly yet in a minimally invasive manner. We report a case in which a PNS device provided more than 12 months of complete pain relief in a patient with meralgia paresthetica and helped the patient avoid a neurolysis procedure.\n\n\n\nA 57-year-old male presented to clinic with a 6-year history of \"painful numbness [and] burning\" along the right lateral thigh. He rated his pain as 8 out of 10, which decreased to a rating of 2 out of 10 with the use of gabapentin, but unwanted side effects motivated him to seek alternative treatment. On the basis of his history, physical exam, and imaging results, he was diagnosed with meralgia paresthetica. He was offered neurolysis; however, after seeing a pain specialist, he agreed to the implantation of a SPRINT peripheral nerve stimulator. After the implantation procedure, his pain reduced to 0 out of 10, and his quality of life improved, with better sleep and less somnolence. The device was removed after 60 days, as planned. He continued to have complete resolution of pain at 12 months after the date of device implantation.\n\n\n\nWith recent advancements, PNS can be used to treat meralgia paresthetica in an effective yet minimally invasive manner. As newer PNS technology becomes more familiar to physicians and pain specialists, it is likely to be used as a mainstay treatment for meralgia paresthetica.",
"affiliations": "Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Department of Anesthesiology and Perioperative Medicine, Division of Pain Medicine, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Langford|Brendan|B|;Mauck|William D|WD|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/pm/pnaa326",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-2375",
"issue": "22(1)",
"journal": "Pain medicine (Malden, Mass.)",
"keywords": "Lateral Femoral Cutaneous Nerve; Meralgia Paresthetica; Neuromodulation; Peripheral Nerve Stimulation",
"medline_ta": "Pain Med",
"mesh_terms": "D005267:Femoral Nerve; D020428:Femoral Neuropathy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009408:Nerve Compression Syndromes; D010292:Paresthesia; D011788:Quality of Life",
"nlm_unique_id": "100894201",
"other_id": null,
"pages": "213-216",
"pmc": null,
"pmid": "33164097",
"pubdate": "2021-02-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Peripheral Nerve Stimulation: A New Treatment for Meralgia Paresthetica.",
"title_normalized": "peripheral nerve stimulation a new treatment for meralgia paresthetica"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2020GMK050553",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditiona... |
{
"abstract": "Corynebacterium macginleyi, a lipophilic diphtheroid from the genus Corynebacteria, is a known cause of conjunctivitis. It was recently reported as a cause of serious infections in immunocompromised individuals. It has never been reported as a cause of ventilator-associated pneumonia, that which carries a high burden and risk of mortality. Our report intends to increase awareness of a potentially lethal nosocomial bacterial infection.\n\n\nMETHODS\nThis case reports on a 73 year old lady with metastatic lung adenocarcinoma on chemotherapy, who was hospitalized for dyspnea and diffuse pulmonary infiltrates in 2011. Trans-bronchial biopsies revealed cryptogenic organizing pneumonia. The patient improved with steroids. Failure to wean ensued with a bronchopleural fistula, increase in secretions, oxygen requirements, and appearance of new infiltrates. Two mini-BAL cultures yielded gram positive pleomorphic rods with palisade arrangement, diagnosed as C. macginleyi. Vancomycin therapy was initiated. She improved and was successfully extubated.\n\n\nCONCLUSIONS\nNon-diphtheria Corynebacteria usually form normal flora. If isolated, they are often dismissed as contaminants. C. macginleyi has emerged as a life-threatening nosocomial infection. Prompt identification and treatment are required. It is resistant to quinolones. Thus far, vancomycin is the preferred treatment.",
"affiliations": "Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University at Buffalo, The State University of New York, 3495 Bailey Avenue, Buffalo, NY 14215, USA.;Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University at Buffalo, The State University of New York, 3495 Bailey Avenue, Buffalo, NY 14215, USA.",
"authors": "Kebbe|Jad|J|;Mador|M Jeffery|MJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2015.10.004",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(15)30047-210.1016/j.rmcr.2015.10.004Case ReportCorynebacterium macginleyi: A cause of ventilator associated pneumonia in an immunocompromised patient Kebbe Jad jadkebbe@buffalo.edu∗Mador M. Jeffery Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University at Buffalo, The State University of New York, 3495 Bailey Avenue, Buffalo, NY 14215, USA∗ Corresponding author. jadkebbe@buffalo.edu02 11 2015 2015 02 11 2015 16 154 156 28 9 2015 19 10 2015 © 2015 The Authors2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose and Importance\nCorynebacterium macginleyi, a lipophilic diphtheroid from the genus Corynebacteria, is a known cause of conjunctivitis. It was recently reported as a cause of serious infections in immunocompromised individuals. It has never been reported as a cause of ventilator-associated pneumonia, that which carries a high burden and risk of mortality. Our report intends to increase awareness of a potentially lethal nosocomial bacterial infection.\n\nObservations\nThis case reports on a 73 year old lady with metastatic lung adenocarcinoma on chemotherapy, who was hospitalized for dyspnea and diffuse pulmonary infiltrates in 2011. Trans-bronchial biopsies revealed cryptogenic organizing pneumonia. The patient improved with steroids. Failure to wean ensued with a bronchopleural fistula, increase in secretions, oxygen requirements, and appearance of new infiltrates. Two mini-BAL cultures yielded gram positive pleomorphic rods with palisade arrangement, diagnosed as C. macginleyi. Vancomycin therapy was initiated. She improved and was successfully extubated.\n\nConclusion and relevance\nNon-diphtheria Corynebacteria usually form normal flora. If isolated, they are often dismissed as contaminants. C. macginleyi has emerged as a life-threatening nosocomial infection. Prompt identification and treatment are required. It is resistant to quinolones. Thus far, vancomycin is the preferred treatment.\n\nKeywords\nCorynebacterium macginleyiVentilator-associated pneumoniaImmunocompromised\n==== Body\n1 Introduction\nThe Corynebacterium species are aerobic gram positive pleomorphic rods. The most important for human health is Corynebacterium diphtheriae, the pathogen chiefly responsible for diphtheria. The majority of Corynebacterium species are innocuous and ubiquitous in nature. Some can be found on mucosa or on skin in humans. When isolated from clinical samples, past practice habits had been to consider them as contaminants. However, there have been reports of non-diphtheria Corynebacteria causing nosocomial infections in certain at-risk populations, such as immunocompromised patients, or those with indwelling devices [1].\n\nAmong these is Corynebacterium macginleyi, first described in 1995 by Riegel et al. and named in honor of Kenneth John McGinley [2]. It is a lipophilic diphtheroid [3] that has been mainly isolated from ocular samples in conjunctivitis [4], [5]. More recently, there have been reports of non-ocular infections: a urinary tract infection associated with an indwelling bladder catheter [6], an intravenous catheter-related blood-stream infection [7], a case of septicemia [8], a case of endocarditis [9], a case of pneumonia in an HIV infected individual [10], a tracheostomy site infection in a patient with laryngeal carcinoma [11], and a case of surgical site infection following orthopedic surgery [12].\n\nWe hereby report a case of C. macginleyi as an emerging cause of ventilator-associated pneumonia in an immunocompromised individual.\n\n2 Case report\nA 73-year-old lady with a 40-pack-year smoking history, COPD and metastatic left lung adenocarcinoma, recently treated with erlotinib, gemcitabine and radiation therapy, was admitted for progressive dyspnea. A PET/CT Scan showed interval decrease in the lung mass (indicating a partial response to therapy), but interval development of diffuse bilateral (right greater than left) hypermetabolic ground glass reticular infiltrates. These were thought to be related to an atypical infection, an inflammatory process, or acute interstitial pneumonitis. Levofloxacin, cefepime and vancomycin were started after cultures were sent, and later showed no growth. The patient's condition deteriorated, resulting in hypoxemic respiratory failure and mechanical ventilation. She underwent bronchoscopy, transbronchial biopsy and bronchoalveolar lavage (BAL). The procedure was complicated by a right-sided pneumothorax, for which a chest tube was placed. Pathology showed a cryptogenic organizing pneumonia, likely related to erlotinib. Cultures were negative. Prednisone was started, resulting in clinical improvement. However the patient remained intubated due to persistence of the pneumothorax with formation of a broncho-pleural fistula. Furthermore, she developed zoster which subsequently resolved with acyclovir.\n\nWhile still intubated, there was an increase in secretions and oxygen requirements with leukocytosis. A chest X ray showed a new right middle lobe infiltrate (Fig. 1). A mini-BAL was submitted for culture and incubated for 24 h at 37 °C on 5% sheep blood agar and chocolate agar. Microscopic examination showed a few epithelial cells, many polymorphonuclear cells, and many gram positive rods in palisade arrangement (Fig. 2). The culture grew more than 105 of the lipophilic bacterium C. macginleyi solely, further identified with a 99.3% probability using the API Coryne System V3.0 (profile number 1100305; bioMérieux, France). Sensitivity testing was performed using the Etest, revealing susceptibility to vancomycin, but resistance to penicillins, cephalosporins and quinolones. These results were initially thought to represent contamination. No antibiotics were started. However, in view of continued worsening of the patient's respiratory status, another mini-BAL culture was sent two days later, yielding the same results. Hence a ten-day course of vancomycin was given and the patient improved clinically and radiographically. A subsequent mini-BAL culture, following the vancomycin course, was negative. The patient underwent a tracheotomy, was successfully weaned off of mechanical ventilation and was discharged to an extended-care facility.\n\n3 Discussion\nVentilator associated pneumonias can be hard to treat, particularly in the immunocompromised host. They are an immense burden on healthcare resources and a major cause of death. C. macginleyi, a gram positive pleomorphic rod is a normal inhabitant of mucous membranes. Although it had often been dismissed as a non-pathogenic contaminant, C. macginleyi has been more recently implicated in several cases of systemic infections. Furthermore, more recent and accurate identification methods using rpoB gene sequencing [13] have been enacted to improve detection (this was not available at our facility when this organism was discovered). This test separates C. macginleyi from Corynebacterium accolens with 100% certainty.\n\nNonetheless, neither C. macginleyi nor C. accolens has been reported as a cause of ventilator associated pneumonia in an immunocompromised host. A prior report demonstrated that C. macginleyi can cause pneumonia in individuals with HIV and advanced AIDS [10]. Another account implicated C. macginleyi as a cause of tracheostomy infection in a patient with laryngeal cancer [11]. In our patient, risk factors were lung cancer, prior treatment with chemotherapy and high dose steroids, radiation as well as lung inflammation from cryptogenic organizing pneumonia. To date, reports of ophthalmologic isolates have exhibited a high level resistance to antibiotics commonly used in the treatment of respiratory infections. For example high-level fluoroquinolone resistance has been seen in ophthalmic isolates [14], as well as in non-ocular cases [10]. The strain isolated in a previously reported urinary catheter-related infection was only sensitive to vancomycin, netilmycin and tetracycline [6]. In all the reported cases C. macginleyi has been sensitive to vancomycin while variably resistant to other antibiotics. In our account, the organism was exclusively sensitive to vancomycin, however it was not tested against linezolid or daptomycin.\n\nThe growing number of non-ocular infections with C. macginleyi in immunocompromised patients suggests this pathogen might be destined to be increasingly implicated in life-threatening infections. Therefore, rapidly dismissing it as a contaminant could be dangerous. In the absence of an alternative diagnosis, positive cultures from adequate samples in the appropriate host should be taken seriously and treatment should be promptly initiated. Given the limited data available in the literature, we recommend initiating therapy with vancomycin, and readjusting after susceptibility results become available.\n\nContributions\nJK collected the data, reviewed it, performed literature search and wrote the manuscript. JM supervised the above process and edited the manuscript. Both authors approved the final version.\n\nConflicts of interest\nNone to disclose; no funding was received for this work.\n\nFig. 1 Chest X ray showing the new right lung infiltrate.\n\nFig. 2 Light microscopy of BAL specimen showing the organism in palisade arrangement.\n==== Refs\nReferences\n1 Funke G. Von Graevenitz A. Clarridge J.E. 3rd Bernard K.A. Clinical microbiology of coryneform bacteria Clin. Microbiol. Rev. 10 1997 125 159 8993861 \n2 Riegel P. Ruimy R. De Briel D. Prevost G. Jehl F. Christen R. Monteil H. Genomic diversity and phylogenetic relationships among lipid-requiring diphtheroids from humans and characterization of Corynebacterium macginleyi spp. nov Int. J. Syst. Bacteriol. 45 1995 128 133 7857793 \n3 McGinley K.J. Labows J.N. Zechman J.M. Nordstrom K.M. Webster G.F. Leyden J.J. Analysis of cellular components, biochemical reactions and habitat of human cutaneous lipophilic diphtheroids J. Invest. Dermatol. 85 1985 374 377 3930617 \n4 Funke G. Pagano-Niederer M. Bernauer W. Corynebacterium macginleyi has to date been isolated exclusively from conjunctival swabs J. Clin. Microbiol. 36 1998 3670 3673 9817893 \n5 Giammanco G.M. Di Marco V. Priolo I. Intrivici A. Grimont F. Grimont P.A. Corynebacterium macginleyi isolation from conjunctival swab in Italy Diagn. Microbiol. Infect. Dis. 44 2002 205 207 12458130 \n6 Villanueva J.L. Dominguez A. Rios M.J. Iglesias C. Corynebacterium macginleyi isolated from urine in a patient with a permanent bladder catheter Scand. J. Infect. Dis. 34 2002 699 700 12374370 \n7 Dobler G. Braveny I. Highly resistant Corynebacterium macginleyi as cause of intravenous catheter-related infection Eur. J. Clin. Microbiol. Infect. Dis. 22 2003 72 73 12582751 \n8 Villamil-Cajoto I. Rodriguez-Otero L. Villacian-Vicedo M.J. Garcia-Zabarte M.A. Aguilera-Guirao A. Garcia-Riestra C. Reguero B.J. Villacián-Vicedo M.J. Septicemia caused by Corynebacterium macginleyi : a rare form of extra-ocular infection Int. J. Infect. Dis. 12 2008 333 335 17981483 \n9 Pubill Sucarrat M. Martinez-Costa X. Sauca Subias G. Capdevilla Morell J.A. Corynebacterium macginleyi as an exceptional cause of endocarditis: a case report An. Med. Interna. 20 2003 654 655 14697092 \n10 Hur J.A. Kim S. Pneumonia caused by Corynebacterium macginleyi in HIV-infected patient Infect. Chemother. 42 5 2010 319 322 \n11 Dias M. Shreevidya K. Rao S. Shet D. Corynebacterium macginleyi a rare bacteria causing infection in an immunocompromised patient J. Cancer Res. Ther. 6 3 2010 374 375 21119282 \n12 Cacopardo B. Stefani S. Cardì F. Cardì C. Pinzone M.R. Nunnari G. Surgical site infection by Corynebacterium macginleyi in a patient with neurofibromatosis Type 1 Case Rep. Infect. Dis. 2013 2013 970678 23819079 \n13 Khamis A. Raoult D. La Scola B. rpoB gene sequencing for identification of Corynebacterium species J. Clin. Microbiol. 42 9 2004 Sep 3925 3931 15364970 \n14 Eguchi H. Kuwahara T. Miyamoto T. Imaohji H.N. Ichimura M. Hayashi T. Shiota H. High level fluoroquinolone resistance in ophthalmic clinical isolates belonging to the species Corynebacterium macginleyi J. Clin. Microbiol. 46 2008 527 532 18077650\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "16()",
"journal": "Respiratory medicine case reports",
"keywords": "Corynebacterium macginleyi; Immunocompromised; Ventilator-associated pneumonia",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "154-6",
"pmc": null,
"pmid": "26744687",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "21119282;17981483;8993861;15364970;3930617;23819079;12582751;7857793;18077650;14697092;12374370;12458130;9817893",
"title": "Corynebacterium macginleyi: A cause of ventilator associated pneumonia in an immunocompromised patient.",
"title_normalized": "corynebacterium macginleyi a cause of ventilator associated pneumonia in an immunocompromised patient"
} | [
{
"companynumb": "US-ACCORD-037247",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERLOTINIB HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Acute flaccid paralysis is an uncommon, but potentially life threatening, sequel of severe hyperkalemia. Reported primary aetiologies include renal failure, Addison's disease, potassium sparing diuretics, potassium supplements, and dietary excess. Coconut water, when consumed in excess, has been reported to cause severe hyperkalemia. We report the case of acute ascending flaccid paralysis secondary to hyperkalemia induced by multiple trigger factors-king coconut water, renal failure, diabetes, metabolic acidosis, and potassium sparing diuretics.\nA 78-year-old man presented with acute ascending type flaccid paralysis over five-hour duration and subsequently developed preterminal cardiac arrhythmias secondary to severe hyperkalemia (serum potassium: 7.02 mEq/L). He was on Losartan and Spironolactone for ischemic heart disease. Dietary history revealed excessive intake of king coconut water (Cocos nucifera) over past one week. Electrocardiogram returned to normal rhythm and serum potassium was 6.1 mEq/L within 2 hours of institution of emergency management for life threatening hyperkalemia. Neurological symptoms completely recovered within twenty-four hours without the need for dialysis. Electromyogram three days after the initial presentation revealed normal findings.\nThe report describes a rare case of secondary hyperkalemic flaccid paralysis induced by multiple trigger factors. It is important that patients with risk factors for hyperkalemia are educated regarding avoiding excess dietary potassium. Regular follow-up of these patients is mandatory with review of medication related side effects and serum electrolytes.",
"affiliations": "Teaching Hospital Kandy, Kandy, Sri Lanka.;University Paediatrics Unit, Lady Ridgeway Hospital for Children, Colombo, Sri Lanka.;Teaching Hospital Kandy, Kandy, Sri Lanka.",
"authors": "Hemachandra|K H D Thilini|KHDT|;Chandimal Dayasiri|M B Kavinda|MBK|0000-0003-0438-9837;Kannangara|Thamara|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2018/6360381",
"fulltext": "\n==== Front\nCase Rep Neurol MedCase Rep Neurol MedCRINMCase Reports in Neurological Medicine2090-66682090-6676Hindawi 10.1155/2018/6360381Case ReportAcute Ascending Flaccid Paralysis Secondary to Multiple Trigger Factor Induced Hyperkalemia Hemachandra K. H. D. Thilini \n1\nhttp://orcid.org/0000-0003-0438-9837Chandimal Dayasiri M. B. Kavinda kavindadayasiri@gmail.com\n2\nKannangara Thamara \n1\n\n1Teaching Hospital Kandy, Kandy, Sri Lanka\n2University Paediatrics Unit, Lady Ridgeway Hospital for Children, Colombo, Sri LankaAcademic Editor: Dominic B. Fee\n\n2018 29 5 2018 2018 63603817 12 2017 19 3 2018 28 3 2018 Copyright © 2018 K. H. D. Thilini Hemachandra et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\n Acute flaccid paralysis is an uncommon, but potentially life threatening, sequel of severe hyperkalemia. Reported primary aetiologies include renal failure, Addison's disease, potassium sparing diuretics, potassium supplements, and dietary excess. Coconut water, when consumed in excess, has been reported to cause severe hyperkalemia. We report the case of acute ascending flaccid paralysis secondary to hyperkalemia induced by multiple trigger factors—king coconut water, renal failure, diabetes, metabolic acidosis, and potassium sparing diuretics.\n\n Case Presentation\n A 78-year-old man presented with acute ascending type flaccid paralysis over five-hour duration and subsequently developed preterminal cardiac arrhythmias secondary to severe hyperkalemia (serum potassium: 7.02 mEq/L). He was on Losartan and Spironolactone for ischemic heart disease. Dietary history revealed excessive intake of king coconut water (Cocos nucifera) over past one week. Electrocardiogram returned to normal rhythm and serum potassium was 6.1 mEq/L within 2 hours of institution of emergency management for life threatening hyperkalemia. Neurological symptoms completely recovered within twenty-four hours without the need for dialysis. Electromyogram three days after the initial presentation revealed normal findings.\n\n Conclusions\n The report describes a rare case of secondary hyperkalemic flaccid paralysis induced by multiple trigger factors. It is important that patients with risk factors for hyperkalemia are educated regarding avoiding excess dietary potassium. Regular follow-up of these patients is mandatory with review of medication related side effects and serum electrolytes.\n==== Body\n1. Background\nHyperkalemia is an uncommon cause of reversible flaccid paralysis. While primary hyperkalemic paralysis is secondary to a defective sodium channel, a number of aetiologies have been reported as leading to secondary hyperkalemic paralysis. The primary aetiology could be one of renal failure [1], Addison's disease [2, 3], potassium sparing diuretics [4], potassium supplements, and dietary excess [5]. Coconut water, when consumed in excess, has been reported to cause severe hyperkalemia [6]. Recent reports suggest that patients with diabetes are at higher risk of developing hyperkalemia following ingestion of coconut water [7].\n\nThe objective of this report is to describe the case of a 78-year-old man with previously diagnosed diabetes mellitus, who presented with acute ascending type flaccid paralysis and subsequently developed preterminal cardiac arrhythmias following severe hyperkalemia. Increased dietary intake of king coconut (Cocos nucifera) water may have precipitated severe hyperkalemia in this patient in the presence of multiple other risk factors for hyperkalemia.\n\n2. Case Report\nA 78-year-old Sri Lankan man presented to the emergency department with acute onset upper and lower limb weakness for several-hour duration. The patient denied any limb weakness on the night prior to admission and was otherwise healthy. Upon waking up in the morning he found difficulty in getting up with weakness involving all four limbs. He was able to lift limbs but was unable to walk or dress himself. The weakness persisted and remained the same until the time of admission five hours later. Weakness was symmetrical and nonprogressive and involved all four limbs. There was no pain, numbness, or abnormal movements in limbs. Swallowing and breathing were not impaired. Urinary and faecal incontinence were absent.\n\nPatient's past medical history consisted of type 2 diabetes, hypertension, ischemic heart disease, and systolic heart failure. Home medications included Mixtard 18 U mane and 8 U vesper, Losartan 50 mg twice daily, Nifedipine 20 mg twice daily, Spironolactone 50 mg daily, Frusemide 40 mg daily, Atorvastatin 20 mg daily, and Amiodarone 100 mg daily. Dietary history revealed that he was drinking king coconut water 2–4 servings almost every day for past one week.\n\nHe was overweight (height: 166 cm, weight: 70 kg, BMI: 25.4 kg/m2). Xanthelasma and arcus senilis were present. He had elevated blood pressure (140/90) with cardiac apex lying in 6th intercostal space. Examination of limbs revealed symmetrical weakness with more distal involvement (proximal 4/5, distal 3/5). Limb reflexes were not impaired except for absent bilateral ankle jerks. Impaired sensation of pain and temperature was present in a glove and stocking type distribution. Joint position sensation was diminished in both upper and lower limbs. Examination of central nervous, respiratory, and gastrointestinal systems was normal.\n\nInvestigations revealed renal dysfunction (serum creatinine: 3.66 mg/dl-, eGFR: 15 ml/min, blood urea: 20.32 mmol/l, and arterial blood HCO3−: 12.7 meq/l). He had severe hyperkalemia (serum potassium: 7.02 mmol/l) with electrocardiogram showing tall, tented T waves and sine waves. Serum sodium was 129 meq/l. Renal ultrasound showed increased cortical echogenicity and impaired corticomedullary demarcation. Noncontrast computerized tomography of brain revealed normal findings. Electromyogram did not reveal acute radiculopathy, plexopathy, or myopathy. Nerve conduction studies revealed distal segmental axonal neuropathy suggestive of diabetic polyneuropathy.\n\nStandard ward protocol for managing hyperkalemia was followed. Patient was initially given IV 10% calcium gluconate 10 ml over 10 minutes followed by a repeat dose. Spironolactone and Losartan were immediately withheld. He was given IV 50% Dextrose 50 ml with 10 U of Soluble Insulin. Patient was nebulized with Salbutamol 5 ml over 10 minutes and it was repeated twice. The interventions showed biochemical and electrocardiographic improvement in two hours (serum potassium: 6.1 meq/l). He was commenced on calcium resonium 15 g three times daily. Limb weakness showed rapid clinical improvement within 24 hours.\n\n3. Discussion\nSecondary hyperkalemic paralysis is characterized by vague muscle pain and ascending muscle weakness. Clinical manifestations occur only in the presence of a potential primary aetiology. Physical examination findings include absent limb reflexes and flaccid motor paralysis. Sphincter tone and sensory function are usually not deranged. Onset is usually rapid and resolves completely following correction of hyperkalemia [8].\n\nHyperkalemia is well recognized complication of chronic kidney disease and the patient described in this report had previously undetected chronic kidney disease secondary to diabetic nephropathy. Hyperkalemia is clinically significant since it is associated with severe complications including fatal cardiac arrhythmias [9] and seizures [10]. Paralysis is a rare complication of hyperkalemia [11].\n\nCoconut water, which is increasingly popular as sports drink, is reportedly a cause of fatal cardiac arrhythmia following severe hyperkalemia [12]. Eight ounces of coconut water contain 600 mg of potassium [13]. King coconut (Cocos nucifera “king”) is a species of coconut which is native to Sri Lanka. The recommended daily dietary intake of potassium by a person without chronic kidney disease is 4.7 g [14]. This patient had a history of short term dietary excessive intake of potassium via king coconut water and was on long term treatment with angiotensin receptor blockers and Spironolactone. Chronic kidney disease secondary to diabetic nephropathy was detected following the acute presentation. Increased dietary potassium most likely precipitated severe hyperkalemia in this patient while having other risk factors for hyperkalemia.\n\nThis presentation with ascending paralysis resembles the clinical presentation of Guillain-Barre syndrome [15]. The patient described in this report presented with rapid onset ascending type weakness over several hours without any other clinical features of Guillain-Barre syndrome. Electromyogram of this patient was normal and nerve conduction studies revealed only the long standing neuropathy. Long term hyperkalemia has been implicated as a contributing factor for neuropathy in chronic kidney disease [16]. Diabetic neuropathy is another contributing factor in this patient. Most previously reported patients had abnormal motor unit potentials in electromyograms [17] in the acute stage. This patient underwent electromyogram three days after the acute presentation since management of preterminal cardiac arrhythmias and stabilization of hyperkalemia was given priority over evaluation. Limb weakness had completely recovered by the time electromyogram was done. Electromyogram and nerve conduction velocity changes had been rapidly reversible following the correction of hyperkalemia in reported cases [18–20].\n\nPathophysiology and underlying genetic basis of hyperkalemic periodic paralysis are well known. There are only few case reports of secondary hyperkalemic paralysis and little is known about its underlying pathophysiology. Some reports suggest a direct influence of potassium on the muscle cell membrane/muscle fibers [15], while one report suggested a functional disturbance of the peripheral nerves [19]. Mechanism of muscle weakness and paralysis is likely due to constant and prolonged nerve membrane depolarization secondary to changes in potassium gradient and resting membrane potentials [21]. This leads to inactivation of sodium channels and impaired muscle membrane excitability. Cardiac and skeletal muscle can be adversely affected as a consequence [22].\n\nPatients with diabetes mellitus are at a higher risk of developing hyperkalemia following ingestion of coconut water and the adverse effects are related to renal microvascular changes of diabetic nephropathy and subsequent low glomerular filtration rate. Coconut water has been found to further compromise glomerular filtration in patients with diabetic nephropathy resulting in hyperkalemia at a lower threshold [7]. Up to date there is not enough literature on recommended safe limits of daily coconut water intake for patient with comorbidities including diabetes. It is therefore important that patients with diabetes are educated regarding potential harmful effects of excessive consumption of coconut water.\n\nThe reported patient presented acute flaccid paralysis in a background of multiple trigger factors for hyperkalemia. Given the worse outcomes due to delayed treatment and complete reversibility of clinical manifestations following timely and appropriate treatment, vigilance regarding hyperkalemia is of great benefit to the patient. Further it is crucial and lifesaving that secondary hyperkalemic paralysis must be looked into while a patient is being evaluated for differential diagnosis of flaccid paralysis.\n\n4. Conclusions\nThe reported patient had both preterminal cardiac rhythms and acute ascending flaccid paralysis following multiple trigger factor induced severe hyperkalemia. It is therefore crucial that patients with multiple risk factors for hyperkalemia are essentially educated regarding harmful effects of excess dietary potassium. Excessive consumption of coconut water can be detrimental in triggering off fatal hyperkalemia in these patients. Regular follow-up is mandatory with review of medication related side effects and serum electrolytes.\n\nData Availability\nThe data that support the findings of this case report are available from Medical Records Department, Kandy Teaching Hospital, but restrictions apply to the availability of these data, which were used under license for the current report and so are not publicly available. Data are, however, available from the authors upon reasonable request and with permission of Medical Records Department, Kandy Teaching Hospital, Sri Lanka.\n\nConsent\nWritten informed consent was obtained from the reported patient and the consent form is available with the first author of this report.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nAuthors' Contributions\nK. H. D. Thilini Hemachandra carried out data collection, analysed patient data, and wrote the manuscript. M. B. Kavinda Chandimal Dayasiri carried out data collection, analysed patient data, and wrote the manuscript. Thamara Kannangara analysed data and supervised manuscript writing process.\n==== Refs\n1 Maury E. Lemant J. Dussaule J.-C. Pénicaud Védrine A. Offenstadt G. A reversible paralysis The Lancet 2002 360 9346 p. 1660 2-s2.0-0037164332 10.1016/S0140-6736(02)11604-7 \n2 Vilchez J. J. Cabello A. Benedito J. Villarroya T. Hyperkalaemic paralysis, neuropathy and persistent motor neuron discharges at rest in Addison's disease Journal of Neurology, Neurosurgery & Psychiatry 1980 43 9 818 822 2-s2.0-0018949374 10.1136/jnnp.43.9.818 \n3 Sowden J. M. Borsey D. Q. Hyperkalaemic periodic paralysis: A rare presentation of Addison's disease Postgraduate Medical Journal 1989 65 762 238 240 2-s2.0-0024512983 10.1136/pgmj.65.762.238 2594601 \n4 Dutta D. Fischler M. McClung A. Angiotensin converting enzyme inhibitor induced hyperkalaemic paralysis Postgraduate Medical Journal 2001 77 904 114 115 2-s2.0-0035143157 10.1136/pmj.77.904.114 11161080 \n5 Tamm M. Ritz R. Thiel G. Der hyperkaliämische Notfall: Ursache, Diagnose und Therapie Schweiz Med Wochenschr 1990 120 1031 1036 2374893 \n6 Rees R. N. Barnett J. Marks D. J. B. George M. J. Coconut water-induced hyperkalaemia British Journal of Hospital Medicine 2012 73 9 p. 534 2-s2.0-84866710268 10.12968/hmed.2012.73.9.534 \n7 Devgun M. S. Coconut water drink and the risk of hyperkalaemia in diabetes Practical Diabetes 2016 33 3 87 89 2-s2.0-84964600618 10.1002/pdi.2009 \n8 Wilson N. S. Hudson J. Q. Cox Z. King T. Finch C. K. Hyperkalemia-induced paralysis Pharmacotherapy 2009 29 10 1270 1272 2-s2.0-70349655896 10.1592/phco.29.10.1270 19792996 \n9 Esposito C. Bellotti N. Fasoli G. Foschi A. Plati A. R. Dal Canton A. Hyperkalemia-induced ECG abnormalities in patients with reduced renal function Clinical Nephrology 2004 62 6 465 468 2-s2.0-10644276255 10.5414/CNP62465 15630907 \n10 Sakemi T. Ikeda Y. Rikitake O. Tonic convulsion associated with sinus arrest due to hyperkalemia in a chronic hemodialysis patient Nephron 1996 73 2 370 371 2-s2.0-0029688142 10.1159/000189093 8773397 \n11 Effiong C. Ahuja T. S. Wagner J. D. Singhal P. C. Mattana J. Reversible hemiplegia as a consequence of severe hyperkalemia and cocaine abuse in a hemodialysis patient The American Journal of the Medical Sciences 1997 314 6 408 410 2-s2.0-0031454732 10.1097/00000441-199712000-00010 9413348 \n12 Rees R. N. Barnett J. Marks D. J. George M. J. Coconut water-induced hyperkalaemia British Journal of Hospital Medicine 2012 73 9 534 534 10.12968/hmed.2012.73.9.534 23124410 \n13 Hakimian J. Goldbarg S. H. Park C. H. Kerwin T. C. Death by Coconut Circulation: Arrhythmia and Electrophysiology 2014 7 1 180 181 10.1161/CIRCEP.113.000941 24550410 \n14 National Nutrient Database for Standard Reference Daily Reference Intakes - Food and Nutrition Board 2017, http://fnic.nal.usda.gov/dietary-guidance/dietary-reference-intakes \n15 Livingstone I. R. Cumming W. J. K. Hyperkalaemic paralysis resembling Guillain-Barré syndrome The Lancet 1979 314 8149 963 964 10.1016/S0140-6736(79)92663-1 2-s2.0-0018780955 \n16 Kiernan M. C. Walters R. J. L. Andersen K. V. Taube D. Murray N. M. F. Bostock H. Nerve excitability changes in chronic renal failure indicate membrane depolarization due to hyperkalaemia Brain 2002 125 6 1366 1378 2-s2.0-0036260368 10.1093/brain/awf123 12023325 \n17 Sitprija V. Sribhibhadh R. Benyajati C. Haemodialysis in Poisoning by Sea-snake Venom British Medical Journal 1971 3 5768 218 219 2-s2.0-0015238520 10.1136/bmj.3.5768.218 5559044 \n18 Naumann M. Schalke B. Schneider C. Hyperkalaemia mimicking Guillain-Barre syndrome Journal of Neurology, Neurosurgery & Psychiatry 1994 57 11 1436 1437 2-s2.0-0028089748 10.1136/jnnp.57.11.1436-a \n19 Shinotoh H. Hattori T. Kitano K. Suzuki J. Hyperkalaemic paralysis following traumatic rupture of the urinary bladder Journal of Neurology, Neurosurgery & Psychiatry 1985 48 5 484 485 2-s2.0-0021885731 10.1136/jnnp.48.5.484 \n20 Naik K. R. Saroja A. O. Khanpet M. S. Reversible electrophysiological abnormalities in acute secondary hyperkalemic paralysis Annals of Indian Academy of Neurology 2012 15 4 339 343 2-s2.0-84871899439 10.4103/0972-2327.104354 23349611 \n21 Evers S. Engelien A. Karsch V. Hund M. Secondary hyperkalaemic paralysis Journal of Neurology, Neurosurgery & Psychiatry 1998 64 2 249 252 10.1136/jnnp.64.2.249 2-s2.0-0031923004 \n22 Mushiyakh Y. Dangaria H. Qavi S. Ali N. Pannone J. Tompkins D. Treatment and pathogenesis of acute hyperkalemia Journal of Community Hospital Internal Medicine Perspectives (JCHIMP) 2012 1 4 p. 7372 10.3402/jchimp.v1i4.7372\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6676",
"issue": "2018()",
"journal": "Case reports in neurological medicine",
"keywords": null,
"medline_ta": "Case Rep Neurol Med",
"mesh_terms": null,
"nlm_unique_id": "101576451",
"other_id": null,
"pages": "6360381",
"pmc": null,
"pmid": "30002937",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "23882341;91060;9413348;7964831;23124410;2374893;9489541;15630907;12023325;12457790;8773397;23349611;24550410;7420104;3998756;11161080;19792996;2594601;5559044",
"title": "Acute Ascending Flaccid Paralysis Secondary to Multiple Trigger Factor Induced Hyperkalemia.",
"title_normalized": "acute ascending flaccid paralysis secondary to multiple trigger factor induced hyperkalemia"
} | [
{
"companynumb": "LK-ACCORD-069933",
"fulfillexpeditecriteria": "1",
"occurcountry": "LK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SPIRONOLACTONE"
},
"drugadditional": "1",
"d... |
{
"abstract": "Rifampicin has been widely used due to its broad antibacterial spectrum. Acute haemolysis is a rarely encountered complication of rifampicin. A 58-year-old woman was admitted to our department because of high-grade fever with rigors, accompanied by abdominal and lumbar pain and laboratory evidence of acute haemolysis. She had been treated for brucellosis initially with doxycycline and streptomycin. Due to subsequent appearance of myositis, ciprofloxacin and rifampicin were added for treatment of localised brucellosis. After intravenous administration of rifampicin, the patient deteriorated significantly. After exclusion of other causes of haemolysis, autoimmune haemolytic anaemia related to rifampicin was established by strongly positive direct Coombs test. Drug withdrawal in conjunction with intravenous immune globulin and prednisolone resulted in resolution of haemolysis and no relapse in the ensuing 1-year period. Our case highlights the importance of recognising commonly administrative drugs as cause of haemolytic anaemia, that can often be life threatening.",
"affiliations": "Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece.;Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece.;Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece.;Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece.",
"authors": "Sveroni|Dafni|D|;Stefos|Aggelos|A|;Rigopoulou|Eirini I|EI|;Dalekos|Georgios N|GN|http://orcid.org/0000-0001-7075-8464",
"chemical_list": "D000900:Anti-Bacterial Agents; D016756:Immunoglobulins, Intravenous; D011239:Prednisolone; D012293:Rifampin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227356",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "11(1)",
"journal": "BMJ case reports",
"keywords": "haematology (drugs and medicines); haematology (incl blood transfusion); unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D015746:Abdominal Pain; D000744:Anemia, Hemolytic, Autoimmune; D000900:Anti-Bacterial Agents; D002006:Brucellosis; D023341:Chills; D005260:Female; D005334:Fever; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008875:Middle Aged; D011239:Prednisolone; D012293:Rifampin; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30567221",
"pubdate": "2018-12-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19224484;15043594;16041663;15157250;4704498;8184201;18284300;28369704;11766291;25247618;22502777;5314737;2293464;18680155;11972531;324964;28764592;3984005;9428460;22075310;22302861;10694089;24881740;3796143",
"title": "Rifampicin: not always an innocent drug.",
"title_normalized": "rifampicin not always an innocent drug"
} | [
{
"companynumb": "GR-PFIZER INC-2019022457",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "STREPTOMYCIN\\STREPTOMYCIN SULFATE"
},
"drugad... |
{
"abstract": "Previous studies have suggested that diuretic therapy for heart failure may lead to thiamine deficiency due to the increased urinary thiamine excretion. Herein, we present the case of a 61-year-old man with shoshin beriberi, a fulminant form of wet beriberi, induced by long-term diuretic therapy. The patient had a history of heart failure with preserved ejection fraction and was receiving furosemide and trichlormethiazide therapy. He presented with worsening exertional dyspnea and was admitted for heart failure exacerbation. His condition failed to improve even after intensive treatment. A hemodynamic evaluation with the Swan-Ganz catheter revealed high-output heart failure with low peripheral vascular resistance. Thiamine was administered for suspected shoshin beriberi; his hemodynamic status improved dramatically within the next six hours. The serum thiamine level was below the normal range; the patient was therefore diagnosed with shoshin beriberi. The common causes of thiamine deficiency were not identified. Long-term diuretic therapy with furosemide and thiazide was thought to have played a major role in the development of thiamine deficiency. This case illustrates the importance of considering wet beriberi as a possible cause of heart failure exacerbation in patients taking diuretics, even when the common thiamine deficiency causes are not identified with history-taking.",
"affiliations": "Department of Cardiology, Toyota Memorial Hospital, 1-1 Heiwa-cho, Toyota 471-8513, Japan ; Department of Medicine, Mount Sinai Beth Israel, First Avenue at 16th Street, New York, NY 10003, USA.;Department of Cardiology, Toyota Memorial Hospital, 1-1 Heiwa-cho, Toyota 471-8513, Japan.;Department of Cardiology, Toyota Memorial Hospital, 1-1 Heiwa-cho, Toyota 471-8513, Japan.",
"authors": "Misumida|Naoki|N|;Umeda|Hisashi|H|;Iwase|Mitsunori|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2014/878915",
"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi Publishing Corporation 10.1155/2014/878915Case ReportShoshin Beriberi Induced by Long-Term Administration of Diuretics: A Case Report Misumida Naoki \n1\n\n2\n*Umeda Hisashi \n1\nIwase Mitsunori \n1\n1Department of Cardiology, Toyota Memorial Hospital, 1-1 Heiwa-cho, Toyota 471-8513, Japan2Department of Medicine, Mount Sinai Beth Israel, First Avenue at 16th Street, New York, NY 10003, USA*Naoki Misumida: nmisumida@chpnet.orgAcademic Editor: Hajime Kataoka\n\n2014 3 7 2014 2014 87891519 5 2014 21 6 2014 Copyright © 2014 Naoki Misumida et al.2014This 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.Previous studies have suggested that diuretic therapy for heart failure may lead to thiamine deficiency due to the increased urinary thiamine excretion. Herein, we present the case of a 61-year-old man with shoshin beriberi, a fulminant form of wet beriberi, induced by long-term diuretic therapy. The patient had a history of heart failure with preserved ejection fraction and was receiving furosemide and trichlormethiazide therapy. He presented with worsening exertional dyspnea and was admitted for heart failure exacerbation. His condition failed to improve even after intensive treatment. A hemodynamic evaluation with the Swan-Ganz catheter revealed high-output heart failure with low peripheral vascular resistance. Thiamine was administered for suspected shoshin beriberi; his hemodynamic status improved dramatically within the next six hours. The serum thiamine level was below the normal range; the patient was therefore diagnosed with shoshin beriberi. The common causes of thiamine deficiency were not identified. Long-term diuretic therapy with furosemide and thiazide was thought to have played a major role in the development of thiamine deficiency. This case illustrates the importance of considering wet beriberi as a possible cause of heart failure exacerbation in patients taking diuretics, even when the common thiamine deficiency causes are not identified with history-taking.\n==== Body\n1. Introduction\nBeta-blockers and angiotensin converting enzyme inhibitors are now routinely used in the treatment of patients with chronic heart failure. Furthermore, nonpharmacological treatment has achieved marked progress. However, use of diuretics remains an important component of the treatment for moderate to severe chronic heart failure. Previous studies have suggested that diuretic therapy for heart failure may lead to thiamine deficiency due to the increased urinary thiamine excretion [1, 2]. Therefore, thiamine deficiency induced by furosemide is of particular interest beyond the spectrum of its well-known side effects. Thiamine is an essential cofactor in energy metabolism, and its deficiency may induce cardiovascular damage resulting in wet beriberi (beriberi heart disease), which is characterized by high-output heart failure with low peripheral vascular resistance. Herein, we present a case of shoshin beriberi, a fulminant form of wet beriberi, induced by long-term administration of the diuretics, furosemide, and thiazide.\n\n2. Case Presentation\nA 61-year-old man visited his primary care physician six months prior to admission with a complaint of exertional dyspnea for one month. Chest X-ray showed cardiomegaly and pulmonary vascular congestion. Echocardiography revealed a preserved ejection fraction with no significant valve disease. He was diagnosed as having congestive heart failure with preserved ejection fraction, and treatment was initiated six months prior to admission with medications including furosemide 40 mg/day, trichlormethiazide 1 mg/day, methyldigoxin 0.1 mg/day, and losartan 50 mg/day. His symptoms gradually resolved over the next several weeks. He developed slight myalgia in both thighs two months after the initiation of diuretics. Two weeks prior to admission, his exertional dyspnea recurred with gradual exacerbation; the patient therefore presented to our emergency department. His past medical history included diabetes mellitus and stage 3 chronic kidney disease secondary to diabetic nephropathy. He had no liver disease. The patient reported that he used to drink beer once a month and last consumed alcohol six months prior to admission. He also reported that he had consumed polished rice but had also been eating fruit and vegetables on a daily basis. The patient's family members endorsed his abstinence from alcohol and his daily fruit and vegetable consumption. The patient was not taking any vitamin supplements.\n\nAt the time of admission, he was in acute distress and was orthopneic. He was well nourished with BMI of 29. His blood pressure was 103/52 mmHg, which was lower than his usual approximate blood pressure of 140/90 mmHg. He had a heart rate of 92 bpm, respiratory rate of 30/min, and oxygen saturation of 98% on room air. Physical examination revealed jugular venous distention, but the heart sounds and breath sounds were unremarkable. Bilateral pitting edema was present throughout the legs, and prominent muscle tenderness was noted in both thighs. Chest X-ray revealed cardiomegaly and pulmonary vascular congestion (Figure 1). Electrocardiogram revealed downsloping ST depressions in left precordial and inferior leads (Figure 2). Echocardiography revealed a dilated left ventricle and preserved left ventricular ejection fraction of 58% without regional wall motion abnormalities (Figure 3). No other valvular lesions were found except for mild tricuspid regurgitation. Inferior vena cava was markedly dilated to 26.7 mm and the respiratory variation was diminished. Laboratory data are shown in Table 1. The atrial blood gas analysis revealed severe metabolic acidosis with a decreased HCO3\n− level of 7.7 mEq/L and an elevated lactate level of 8.6 mmol/L; pH was maintained by compensatory hyperventilation suggested by the pCO2 level of 12.8 mmHg. Acute kidney injury was evident by the blood urea nitrogen and creatinine levels, 65 mg/dL and 3.7 mg/dL, which were remarkably elevated compared to his baseline levels of 20 mg/dL and 1.3 mg/dL, respectively. The creatine kinase level was also elevated up to 1,643 IU/L. Serum troponin I level was slightly elevated to 0.25 ng/dL, and the brain natriuretic peptide level was remarkably elevated up to 1,030 pg/mL.\n\nThe patient was admitted for heart failure exacerbation. Intravenous furosemide was administered repeatedly, but his urine output remained less than 10 mL/hour. His systolic blood pressure ranged from 80 mmHg to 100 mmHg, and a continuous infusion of dopamine was initiated. The metabolic acidosis persisted despite frequent administration of sodium bicarbonate. His condition failed to improve in spite of the abovementioned treatment. On the second day of admission, his systolic blood pressure dropped to 70 mmHg, and shortness of breath was exacerbated. He was transferred to the intensive care unit. The hemodynamic evaluation using the Swan-Ganz catheter revealed a cardiac index of 8.0 L/min/m2, pulmonary capillary wedge pressure of 27 mmHg, systemic vascular resistance of 266 dyne-sec·cm−5 (normal range: 700–1600 dyne-sec·cm−5), and mixed venous oxygen saturation of 78%. These findings were consistent with high-output heart failure with low peripheral vascular resistance. Given this hemodynamic profile and the existence of lactic acidosis, shoshin beriberi was strongly suspected, and thiamine (100 mg) was administered intravenously. His hemodynamic status improved dramatically within the next six hours with normalized diuresis. His blood urea nitrogen and creatinine levels returned to baseline, and the creatine kinase level was normalized within the following 48 hours. The hemodynamic profile 60 hours after thiamine administration was as follows: cardiac index, 4.3 L/min/m2; pulmonary capillary wedge pressure, 18 mmHg; systemic vascular resistance, 728 dyne-sec·cm−5 (normal range: 700–1600 dyne-sec·cm−5); and mixed venous oxygen saturation, 64%. Septic shock was excluded based on his overall clinical picture, absence of fever and leukocytosis, and negative results of serial blood cultures. Thyroid function was normal. The diagnosis of shoshin beriberi was confirmed by a low plasma thiamine concentration of 11 mg/dL (normal range: 20–50 mg/dL). Repeated careful neurological examination revealed horizontal nystagmus and hyporeflexia of bilateral lower extremities, and the patient was diagnosed with Wernicke's encephalopathy. The common causes of thiamine deficiency were not identified even with thorough history-taking. Intestinal malabsorption syndrome was excluded after gastrointestinal investigations including esophagogastroduodenoscopy and colonoscopy. His myalgia and nystagmus resolved within the next ten days, and he was discharged on day 15 with oral vitamin pills.\n\n3. Discussion\nTo the best of our knowledge, this is the first case report of shoshin beriberi induced by long-term administration of diuretics. Although two cases of wet beriberi precipitated by diuretics have been reported previously, in both of these cases, the patient had a history of either gastrectomy or pancreaticoduodenectomy [3, 4]. In the present case, the common well-known causes of thiamine deficiency were not identified even with thorough history-taking and further investigations, and chronic diuretic therapy was thought to have played a major role in the development of thiamine deficiency.\n\nPrevious studies have suggested that diuretic therapy for heart failure may lead to thiamine deficiency due to the increased urinary thiamine excretion [1, 2]. The prevalence of thiamine deficiency in heart failure patients has been reported to range from 3% to 91% [5–10]. This wide variation is thought to stem from the differences in patients' background including their age, underlying diseases, and the assay validity of thiamine pyrophosphate activity. The prevalence is higher in patients of advanced age and with multiple comorbidities. A study that focused on outpatients with heart failure reported a very low prevalence of thiamine deficiency of 3% [8]. Interestingly, the largest cross-sectional observational study on 100 patients with heart failure found no relationship between thiamine deficiency and the furosemide dose [10].\n\nConsidering this high prevalence of thiamine deficiency in patients taking diuretics, it may seem odd that wet beriberi is not commonly seen in our daily practice and that there has been no reported case of shoshin beriberi induced solely by diuretics. This discrepancy may result from underrecognition of wet beriberi induced by diuretics due to the limited awareness of diuretic induced thiamine deficiency, and those cases might have been undiagnosed or diagnosed as shoshin beriberi of unknown etiology.\n\nUrinary thiamine loss due to diuretic therapy is not specific to loop diuretics, and it has been shown to occur with virtually all diuretics in an experimental rat model [11]. Two different types of diuretics, furosemide and thiazide, were used concomitantly in this case, and this combination usage might have predisposed the patient to an even higher risk of thiamine deficiency compared to that with the usual furosemide monotherapy. In addition, the patient had stage 3 chronic kidney disease. A study that evaluated thiamine status in patients with stage 4 and stage 5 chronic kidney disease revealed that a substantial proportion of these patients had a high erythrocyte transketolase activity indicating a thiamine deficient state [12]. In the present case, the patient's underlying chronic kidney disease was not severe compared to those evaluated in the aforementioned study, but it might have contributed to the development of thiamine deficiency. However, the definite mechanism that led to shoshin beriberi in this patient, beyond the subclinical thiamine deficient state, remains unclear.\n\nThe present case had another interesting clinical characteristic of thiamine deficiency. The patient developed myalgia two months after the initiation of diuretics, which preceded the onset of worsening exertional dyspnea. The elevation of the creatine kinase level found upon admission was thought to be derived from the skeletal muscle rather than the heart because the elevation of troponin I level was subtle compared with the extent of the creatine kinase elevation. Myalgia has been observed in patients with beriberi neuropathy [13]. Myopathy with creatine kinase elevation has also been reported to be accompanied by thiamine deficiency, in which case myalgia preceded the development of heart failure [14]. Because of the temporal association of the symptom onset and diuretic administration, as well as complete resolution of the myalgia after thiamine administration, a final diagnosis of myopathy secondary to thiamine deficiency was made.\n\nIn the light of the high prevalence of thiamine deficiency in patients taking diuretics and its potential adverse effect on the cardiovascular system, the question is whether thiamine administration offers any benefit for these patients. Several studies have examined the association between thiamine supplementation and cardiac function measured by left ventricular ejection fraction in patients with heart failure. A pilot study conducted by Seligmann and colleagues evaluated the effect of intravenous thiamine on left ventricular ejection fraction in six patients with heart failure. It showed an improvement of left ventricular ejection fraction by 13% (from 24% ± 4.3% to 37.0% ± 2.4%) [5]. The first randomized, double-blind, placebo-controlled study [15], in which 30 patients were randomly assigned to one-week therapy with either IV thiamine or placebo, showed significant improvement of left ventricular ejection fraction at one week (from 28% ± 11% to 32% ± 9%, P < 0.05). After discharge, both groups of patients received oral thiamine for six weeks. At the end of seven weeks of the study, the left ventricular ejection fraction increased by 22% compared to baseline (P < 0.01). Recently, another randomized, double-blind, placebo-controlled study also reported a significant improvement of left ventricular ejection fraction after 28 days of oral thiamine administration [16]. These studies showed a promising effect of thiamine on left ventricular function in heart failure patients taking diuretics. However, this issue remains controversial because of their small study sizes and lack of a long-term followup.\n\nWhile awaiting further studies and given the associated absence of toxicity and low cost, it would be reasonable to recommend a daily thiamine containing multivitamin to heart failure patients with a low thiamine level. Most importantly, heart failure caused by thiamine deficiency is treatable with thiamine administration, and a remarkable improvement can be expected as early as within 12 hours.\n\nIn conclusion, we report a case of shoshin beriberi induced by long-term administration of diuretics. This case illustrates the importance of considering wet beriberi as a possible cause of heart failure exacerbation in patients taking diuretics, even when the common causes of thiamine deficiency are not identified with history-taking.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Chest X-ray shows cardiomegaly and pulmonary vascular congestion.\n\nFigure 2 ECG shows downsloping ST depressions in left precordial and inferior leads.\n\nFigure 3 Echocardiography shows preserved left ventricular ejection fraction of 58% without regional wall motion abnormalities.\n\nTable 1 WBC\t11,000\t/μL\t\nRBC\t395\t104/μL\t\nMCV\t100\tfL\t\nMCHC\t34\t%\t\nHb\t11.1\tg/dL \t\nPlt\t23\t×104/μL\t\nBUN\t65\tmg/dL \t\nCre\t3.7\tmg/dL \t\nNa\t135\tmEq/L\t\nK\t5.0\tmEq/L\t\nCl\t95\tmEq/L \t\nCa\t8.8\tmEq/L \t\nCK\t1643\tIU/L\t\nTroponin I\t0.25\tIU/L\t\nAST\t35\tIU/L\t\nALT\t35\tIU/L\t\nT-bil\t0.6\tmg/dL \t\nLDH\t327\tIU/L\t\nALP\t114\tIU/L \t\nTP\t6.5\tg/dL \t\nAlb\t3.9\tg/dL\t\nCRP\t0.8\tmg/dL \t\nGlu\t217\tmg/dL \t\nHbA1c\t6.4\t%\t\nBNP\t1030\tpg/mL\t\npH\t7.399\t \t\n\npCO2\n\t12.8\tmmHg \t\npO2\n\t99.3\tmmHg \t\nHCO3\n−\n\t7.7\tmmol/L \t\nBase excess\t−14.4\tmmol/L \t\nAnion gap\t30.3\tmEq/L\t\nLactate \t8.6\tmmol/L\n==== Refs\n1 Yui Y Itokawa Y Kawai C Furosemide-induced thiamine deficiency Cardiovascular Research 1980 14 9 537 540 2-s2.0-0019165592 7214397 \n2 Rieck J Halkin H Almog S Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers Journal of Laboratory and Clinical Medicine 1999 134 3 238 243 2-s2.0-0033198706 10482308 \n3 Tsujino T Nakao S Wakabayashi K Loop diuretic precipitated beriberi in a patient after pancreaticoduodenectomy: a case report The American Journal of the Medical Sciences 2007 334 5 407 409 2-s2.0-38449107573 18004099 \n4 Akahori H Tsujino T Masutani M Postgastrectomy beriberi exaggerated by diuretic use : a case report Journal of Cardiology 2007 49 1 49 53 2-s2.0-33947511515 17269213 \n5 Seligmann H Halkin H Rauchfleisch S Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study American Journal of Medicine 1991 91 2 151 155 2-s2.0-0026046540 1867241 \n6 Zenuk C Healey J Donnelly J Vaillancourt R Almalki Y Smith S Thiamine deficiency in congestive heart failure patients receiving long term furosemide therapy Canadian Journal of Clinical Pharmacology 2003 10 4 184 188 2-s2.0-0842278743 14712323 \n7 Kwok T Falconer-Smith JF Potter JF Ives DR Thiamine status of elderly patients with cardiac failure Age & Ageing 1992 21 1 67 71 2-s2.0-0026567414 1553864 \n8 Levy WC Soine LA Huth MM Thiamine deficiency in congestive heart failure The American Journal of Medicine 1992 93 6 705 706 2-s2.0-0026446238 \n9 Brady JA Rock CL Horneffer MR Thiamin status, diuretic medications, and the management of congestive heart failure Journal of the American Dietetic Association 1995 95 5 541 544 2-s2.0-0029063313 7722187 \n10 Hanninen SA Darling PB Sole MJ Barr A Keith ME The prevalence of thiamin deficiency in hospitalized patients with congestive heart failure Journal of the American College of Cardiology 2006 47 2 354 361 2-s2.0-30344436715 16412860 \n11 Lubetsky A Winaver J Seligmann H Urinary thiamine excretion in the rat: effects of furosemide, other diuretics, and volume load Journal of Laboratory and Clinical Medicine 1999 134 3 232 237 2-s2.0-0033198785 10482307 \n12 Frank T Czeche K Bitsch R Stein G Assessment of thiamin status in chronic renal failure patients, transplant recipients and hemodialysis patients receiving a multivitamin supplementation International Journal for Vitamin and Nutrition Research 2000 70 4 159 166 2-s2.0-0033869002 10989764 \n13 Ohnishi A Tsuji S Igisu H Beriberi neuropathy: morphometric study of sural nerve Journal of the Neurological Sciences 1980 45 2-3 177 190 2-s2.0-0018877722 7365498 \n14 Koike H Watanabe H Inukai A Myopathy in thiamine deficiency: analysis of a case Journal of the Neurological Sciences 2006 249 2 175 179 2-s2.0-33750510674 16920153 \n15 Shimon I Almog S Vered Z Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy The American Journal of Medicine 1995 98 5 485 490 2-s2.0-0029026199 7733128 \n16 Schoenenberger AW Schoenenberger-Berzins R der Maur CA Suter PM Vergopoulos A Erne P Thiamine supplementation in symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled, cross-over pilot study Clinical Research in Cardiology 2012 101 3 159 164 2-s2.0-84860836891 22057652\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6404",
"issue": "2014()",
"journal": "Case reports in cardiology",
"keywords": null,
"medline_ta": "Case Rep Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101576452",
"other_id": null,
"pages": "878915",
"pmc": null,
"pmid": "25105030",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "16412860;7722187;17269213;22057652;1553864;7733128;1466372;10482307;10989764;14712323;7214397;16920153;10482308;18004099;7365498;1867241",
"title": "Shoshin beriberi induced by long-term administration of diuretics: a case report.",
"title_normalized": "shoshin beriberi induced by long term administration of diuretics a case report"
} | [
{
"companynumb": "JP-ROXANE LABORATORIES, INC.-2014-RO-01660RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditi... |
{
"abstract": "We report on the first pulmonary embolism treatment via the large-bore aspiration mechanical thrombectomy device (Inari FlowTriever®) outside the USA, in a resuscitated patient on veno-arterial extracorporeal membrane oxygenation (VA-ECMO) suffering from severe and acute right heart failure. In this particular high-risk patient population, where thrombolysis is mostly not applicable, this new technology could be a promising solution as the combination of large-bore thrombus aspiration and extraction successfully removes large emboli. In our case, right ventricular function improved rapidly after the procedure, ECMO could be weaned, and the patient was dismissed 2 weeks after. In summary, we provide a new therapeutic option for the often difficult treatment of pulmonary embolism in high-risk patients on VA-ECMO.",
"affiliations": "Department of Internal Medicine II, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, 93055, Germany.;Department of Internal Medicine II, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, 93055, Germany.;Department of General Surgery, Intensive Care Unit, University Hospital Regensburg, Regensburg, Germany.;Department of Internal Medicine II, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, 93055, Germany.;Department of Internal Medicine II, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, 93055, Germany.",
"authors": "Stadler|Stefan|S|;Debl|Kurt|K|;Ritzka|Markus|M|;Maier|Lars Siegfried|LS|;Sossalla|Samuel|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ehf2.13571",
"fulltext": "\n==== Front\nESC Heart Fail\nESC Heart Fail\n10.1002/(ISSN)2055-5822\nEHF2\nESC Heart Failure\n2055-5822\nJohn Wiley and Sons Inc. Hoboken\n\n34431236\n10.1002/ehf2.13571\nEHF213571\nESCHF-21-00482\nCase Report\nCase Reports\nBail‐out treatment of pulmonary embolism using a large‐bore aspiration mechanical thrombectomy device\nBail‐out treatment of pulmonary embolism using a large‐bore aspiration mechanical thrombectomy device\nS. Stadler et al.\nStadler Stefan 1\nDebl Kurt 1\nRitzka Markus 2\nMaier Lars Siegfried 1\nSossalla Samuel 1 samuel.sossalla@ukr.de\n\n1 Department of Internal Medicine II University Hospital Regensburg Franz‐Josef‐Strauss‐Allee 11 Regensburg 93055 Germany\n2 Department of General Surgery, Intensive Care Unit University Hospital Regensburg Regensburg Germany\n* Correspondence to: Samuel Sossalla, Department of Internal Medicine II, University Hospital Regensburg, Franz‐Josef‐Strauss‐Allee 11, 93055 Regensburg, Germany. Tel: +49‐941‐944‐7211; Fax +49‐941‐944‐7338. Email: samuel.sossalla@ukr.de\n24 8 2021\n10 2021\n8 5 10.1002/ehf2.v8.5 43184321\n01 7 2021\n11 5 2021\n04 8 2021\n© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ 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.\n\nAbstract\n\nWe report on the first pulmonary embolism treatment via the large‐bore aspiration mechanical thrombectomy device (Inari FlowTriever®) outside the USA, in a resuscitated patient on veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO) suffering from severe and acute right heart failure. In this particular high‐risk patient population, where thrombolysis is mostly not applicable, this new technology could be a promising solution as the combination of large‐bore thrombus aspiration and extraction successfully removes large emboli. In our case, right ventricular function improved rapidly after the procedure, ECMO could be weaned, and the patient was dismissed 2 weeks after. In summary, we provide a new therapeutic option for the often difficult treatment of pulmonary embolism in high‐risk patients on VA‐ECMO.\n\nPulmonary embolism\nLarge‐bore aspiration mechanical thrombectomy device\nFlowTriever\nVeno‐arterial ECMO\nProjekt DEAL source-schema-version-number2.0\ncover-dateOctober 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.8 mode:remove_FC converted:07.10.2021\nStadler, S. , Debl, K. , Ritzka, M. , Maier, L. S. , and Sossalla, S. (2021) Bail‐out treatment of pulmonary embolism using a large‐bore aspiration mechanical thrombectomy device. ESC Heart Failure, 8 : 4318–4321. 10.1002/ehf2.13571.\n==== Body\npmcIntroduction\n\nPulmonary embolism is a common cause of acute right heart failure. Even with bridging extracorporeal membrane oxygenation (ECMO), haemodynamic stability can often not be regained. As it is known, there exists a number of contraindications against lysis therapy itself. Due to these two facts, it is necessary to invent new methods for the recanalization of the pulmonary arteries.\n\nCase report\n\nWe report on a 55‐year‐old woman who suffered a car accident with multiple fractures of the ribs, the sternum, and the right lower extremity as well as a haemothorax and a diaphragmatic rupture. After emergency operation with diaphragmatic reconstruction and positioning of a thoracic drainage, the patient was successfully weaned from ventilation the day after. Surgical reposition and plate osteosynthesis of a tibial head impression fracture was successfully performed after 1 week. Two days later, the patient collapsed during physical therapy on the general ward and complained new onset dyspnoea. Computed tomography showed a massive bilateral pulmonary embolism (Figure 1 A ). Sonography revealed a thrombosis of the left popliteal vein. Repeated echocardiography showed an increasing dilatation of the right heart with a thrombus in the right atrium (Figure 1 B ). In spite of recent operations, lysis with 100 mg of alteplase was given, but the haemodynamic situation worsened and the patient was twice resuscitated before a veno‐arterial ECMO (VA‐ECMO; left femoral vein, right femoral artery, flow 3.8 L/min) was implanted. As signs of cardiogenic shock, the right heart was massively dilated and high doses of catecholamines were required.\n\nFigure 1 (A) Computed tomography scan of the central pulmonary embolism. (B) Echocardiography of right heart thrombus.\n\nTwenty hours after thrombolysis, we decided to use the large‐bore aspiration mechanical thrombectomy device FlowTriever® as a bail‐out strategy although this device has not been used before outside USA so far. 1 A 26 French sheath was carefully inserted into the right femoral vein using fluoroscopy in order to avoid complications concerning the venous ECMO cannula. The 24 French catheter (Triever24 Aspiration Catheter®) was carefully advanced after passing the right heart using a pigtail catheter to pulmonary artery over a stiff guide wire (Figure 2 A ). We managed to mobilize several clots from both sides under suction using the large‐bore syringe. A total of 50–70 mL of blood were aspirated at each suction attempt. Due to the fact that the removed thrombus appeared as well subacute (Figure 2 B ), we additionally applied the self‐expanding nitinol mesh disks (FlowTriever Catheter®), which is designed to engage, disrupt, and deliver clot to the aspiration catheter for extraction (Figure 2 C ).\n\nFigure 2 Position of the large lumen catheter (Triever Aspiration Catheter®) in the right lung (A) and of the self‐expanding nitinol mesh disks (FlowTriever Catheter®) in the left lung (B). Clots aspirated with the large‐bore syringe (C).\n\nEchocardiography before and immediately after the intervention in the cath lab revealed considerable improvement of right ventricular function and dimension: the end‐diastolic mid‐diameter of the right ventricle markedly declined from 53 to 36 mm, and tricuspid annular plane systolic excursion increased from 10 to 13 mm (Figure 3 ). The flow of the VA‐ECMO could be reduced from 3.8 to 2.7 L/min within the next 12 h. Finally, the device was explanted 60 h after the intervention using a Manta® system. Anticoagulation was performed with unfractionated heparin. Forty‐two hours later, the patient developed a heparin‐induced thrombocytopenia so that the anticoagulation was changed into Argatroban (activated partial thromboplastin time was 60–70 s). The patient was successfully extubated 7 days after the Inari FlowTriever® tool had been used. The discharge from the hospital was 19 days following intervention. At that time, a normalized right ventricular function was measured.\n\nFigure 3 Echocardiography focusing on the right heart immediately before (A) and after (B) aspiration of the pulmonary embolisms.\n\nDiscussion\n\nWe report on the first treatment of pulmonary embolism with acute right heart failure via the large‐bore aspiration mechanical thrombectomy device (Inari FlowTriever®) outside the USA. It has to be pointed out that the patient of our case report was a complex one with implanted VA‐ECMO and cardiopulmonary resuscitation. The use of the Inari FlowTriever® under these circumstances was safe, feasible, and very effective. Initial thrombolysis was not effective enough to restore the required pulmonary perfusion most likely due to the mixture of an acute and subacute event. Although in previous publications, even larger thrombi could be extracted by this particular device, 2 the patient benefitted most likely from thrombus aspiration as the need for catecholamines declined quickly, right ventricular function rapidly improved, and the VA‐ECMO could be explanted shortly after.\n\nPatients with haemodynamic instability due to a massive pulmonary embolism remain challenging for clinicians. On the one hand, thrombolytic agents are occasionally contraindicated due to their bleeding risk. On the other hand, they are often insufficient to restore haemodynamic stability. Surgical interventions for acute pulmonary embolism mainly have a poor prognosis. 3 VA‐ECMO can be a bridge to recovery for patients with massive pulmonary embolism, but vascular and bleeding problems are frequent, in particular if lysis was already administered or is necessary on top. However, even the combination of VA‐ECMO and thrombolytic agents may not be effective enough in severe cases of pulmonary embolism, as we have demonstrated in the aforementioned case.\n\nBy the combination of large‐bore thrombus aspiration and extraction, the removal of large and potentially subacute emboli seems to be possible. The Inari FlowTriever® might be a novel unique tool, which is helpful to have up one's sleeve in acute pulmonary embolism with haemodynamic instability. However, it is important to note that the large sheath and the catheter itself can potentially injure the femoral insertion site as well as the right ventricle and the pulmonary artery. In addition, the vascular access site has to be free of thrombosis, and large vascular sheaths should generally be avoided in the setting of severely impaired coagulation very early after thrombolysis.\n\nIt is well known that residual pulmonary vascular obstruction, as it often persists after ECMO in pulmonary embolism patients without thrombolysis, constitutes an independent predictor of mortality and chronic thromboembolic pulmonary hypertension (CTEPH). This unique large‐bore device can remove thrombus at the whole piece due to a higher rate of aspirational blood flow compared with common small lumen devices. Additionally, the wider catheter can carry more blood volume at a lower resistance.\n\nAs discussed earlier, it might be presumed that there probably exists a positive effect against the development of CTEPH in this particular patient collective by using this new Inari FlowTriever® tool. Therefore, it would be necessary and of particular interest to prospectively investigate whether this intervention is of prognostic benefit in patients with pulmonary embolism and particularly in those who are treated with ECMO. Moreover, it is of great necessity to further investigate the safety and efficacy of this new device in such particular patients.\n\nConflict of interest\n\nNone declared.\n\nFunding\n\nOpen Access funding is enabled and organized by Projekt DEAL.\n==== Refs\nReferences\n\n1 Tu T , Toma C , Tapson VF , Adams C , Jaber WA , Silver M , Khandhar S , Amin R , Weinberg M , Engelhardt T , Hunter M , Holmes D , Hoots G , Hamdalla H , Maholic RL , Lilly SM , Ouriel K , Rosenfield K . A prospective, single‐arm, multicenter trial of catheter‐directed mechanical thrombectomy for intermediate‐risk acute pulmonary embolism: the FLARE study. JACC Cardiovasc Interv 2019;12 : 859–869. 10.1016/j.jcin.2018.12.022 31072507\n2 Toma C , Khandhar S , Zalewski AM , D'Auria SJ , Tu TM , Jaber WA . Percutaneous thrombectomy in patients with massive and very high‐risk submassive acute pulmonary embolism. Catheter Cardiovasc Interv 2020; 96 : 1465–1470. 10.1002/ccd.29246 32866345\n3 Fukuda I , Taniguchi S . Embolectomy for acute pulmonary thromboembolism: from Trendelenburg's procedure to the contemporary surgical approach. Surg Today 2011; 41 : 1–6. 10.1007/s00595-010-4416-8 21191685\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2055-5822",
"issue": "8(5)",
"journal": "ESC heart failure",
"keywords": "FlowTriever; Large-bore aspiration mechanical thrombectomy device; Pulmonary embolism; Veno-arterial ECMO",
"medline_ta": "ESC Heart Fail",
"mesh_terms": "D015199:Extracorporeal Membrane Oxygenation; D006333:Heart Failure; D006801:Humans; D011655:Pulmonary Embolism; D017131:Thrombectomy; D016278:Ventricular Function, Right",
"nlm_unique_id": "101669191",
"other_id": null,
"pages": "4318-4321",
"pmc": null,
"pmid": "34431236",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": "21191685;31072507;32866345;34431236",
"title": "Bail-out treatment of pulmonary embolism using a large-bore aspiration mechanical thrombectomy device.",
"title_normalized": "bail out treatment of pulmonary embolism using a large bore aspiration mechanical thrombectomy device"
} | [
{
"companynumb": "DE-TEVA-2021-DE-1984904",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "4",
... |
{
"abstract": "OBJECTIVE\nThe efficacy of a partial agonist for the dopamine D2 receptor, aripiprazole, for catatonia in schizophrenia has been reported.\n\n\nMETHODS\nWe report distinct clinical courses in challenging aripiprazole to treat residual mutism after severe catatonic symptoms improved.\n\n\nRESULTS\nIn the first case, mutism was successfully treated when the patient was switched from olanzapine to aripiprazole. In contract, switching to aripiprazole from risperidone aggravated auditory hallucinations in the second case.\n\n\nCONCLUSIONS\nWe will discuss the benefits and risks of using aripiprazole for the treatment of catatonic schizophrenia and the possibility of dopamine supersensitivity psychosis.",
"affiliations": "Gakuji-Kai Kimura Hospital, Chiba, Japan; Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, Japan; Division of Medical Treatment and Rehabilitation, Center for Forensic Mental Health, Chiba University, Chiba, Japan.;Gakuji-Kai Kimura Hospital, Chiba, Japan.",
"authors": "Muneoka|Katsumasa|K|;Kanahara|Nobuhisa|N|;Kimura|Shou|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X17692936",
"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1769293610.1177_2050313X17692936Case ReportSwitching to aripiprazole for the treatment of residual mutism resulted in distinct clinical courses in two catatonic schizophrenia cases Muneoka Katsumasa 12Kanahara Nobuhisa 23Kimura Shou 11 Gakuji-Kai Kimura Hospital, Chiba, Japan2 Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, Japan3 Division of Medical Treatment and Rehabilitation, Center for Forensic Mental Health, Chiba University, Chiba, JapanKatsumasa Muneoka, Gakuji-Kai Kimura Hospital, 6-19 Higashihon-cho, Chuo-ku, Chiba 260-0004, Japan. Email: kmuneoka@med.showa-u.ac.jp08 2 2017 2017 5 2050313X1769293629 7 2016 13 1 2017 © The Author(s) 20172017SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page(https://us.sagepub.com/en-us/nam/open-access-at-sage).Objectives:\nThe efficacy of a partial agonist for the dopamine D2 receptor, aripiprazole, for catatonia in schizophrenia has been reported.\n\nMethods:\nWe report distinct clinical courses in challenging aripiprazole to treat residual mutism after severe catatonic symptoms improved.\n\nResults:\nIn the first case, mutism was successfully treated when the patient was switched from olanzapine to aripiprazole. In contract, switching to aripiprazole from risperidone aggravated auditory hallucinations in the second case.\n\nConclusions:\nWe will discuss the benefits and risks of using aripiprazole for the treatment of catatonic schizophrenia and the possibility of dopamine supersensitivity psychosis.\n\nMutismcatatoniaaripiprazoledopamine supersensitivity psychosiscover-dateJanuary-December 2017\n==== Body\nIntroduction\nMutism is defined as a functional inhibition of speech and vocalization. This symptom has been reported in various neuropsychiatric illnesses, including catatonic and paranoid schizophrenia,1,2 though the exact neurological mechanism is unknown. The efficacy of electroconvulsive therapy in mutism has been reported in case reports,3,4 which suggest that activation of the mesolimbic dopamine system is involved in the therapeutic outcomes.5 Case reports6–9 have shown that a partial agonist for the dopamine D2 receptor, aripiprazole,10 improves catatonia with7,8 or without other additional medication.6,9 Therefore, aripiprazole is expected to improve catatonic mutism due to its pharmacological property of partially activating dopaminergic neurotransmission. This report presents two schizophrenia cases with mutism as a residual symptom after severe catatonic symptoms were improved. They had distinct clinical outcomes after their pharmacotherapy was changed to the medication with aripiprazole. We will discuss the benefits and risks of using aripiprazole for the treatment of catatonic schizophrenia. In addition, we discuss the results from the perspective of a recent theory of drug-induced dopaminergic supersensitivity psychosis (DSP) because the recognition of DSP is useful to prevent the acquisition of treatment resistance in schizophrenia when prescribing antipsychotics parallel to the prevention of a well-known type of dopaminergic supersensitivity, tardive dyskinesia.11\n\nCase reports\nCase 1 was a 55-year-old woman with 14 years of education. She was married at 22 years of age and lived with her husband and three daughters. At the age of 47, she began to have persecutory delusions, and she stopped talking with her family and withdrew to her room. At 48 years of age, she visited a hospital, accompanied by her family, and she was admitted. She did not speak with anyone, but she indicated her intentions nonverbally. Organic brain disease, neurodegenerative disease, and psychosis due to systemic disease were excluded by a computerized tomography scan of the brain and a blood test. Her mutism and refusal to communicate were diagnosed as a symptom of schizophrenia, and she was successfully treated with olanzapine. After discharge, at 49 years of age, she lived with her family and started to work part-time. However, at 51 years of age, when the dosage of olanzapine was tapered down, due to overweight status, her mutism and refusal to communicate re-emerged. She was admitted to a hospital with a score of 18 on the Bush–Francis catatonia rating scale (BFCRS; 14 items). She was treated by increasing the dose of olanzapine to the original level. Abnormal symptoms improved within 3 months, and she was discharged with a BFCRS score of 7. She continued treatment as an outpatient with daily doses of 20 mg olanzapine, 1.5 mg lorazepam, and 150 mg amantadine. However, her mutism did not improve. In addition, she was overweight (161 cm, 84.9 kg). She agreed in writing to change treatment from olanzapine to aripiprazole. Thus, at 53 years of age, she started treatment with 24 mg aripiprazole daily. Shortly after adding the aripiprazole, she experienced a reduction in appetite and reduced her excessive eating. One month after starting aripiprazole, she reported difficulty urinating, and the daily dose of aripiprazole was reduced to 12 mg. Olanzapine was tapered off gradually, and aripiprazole was maintained at a daily dose of 15 mg. The patient began to speak vocally after 3 months of starting aripiprazole. Then, she began to take part in housekeeping when her BFCRS score dropped to 3. Finally, olanzapine was stopped at 8 months after introducing aripiprazole. Case 2 was a 55-year-old woman with 14 years of education. She was not married. She was diagnosed with schizophrenia when she began to exhibit catatonic symptoms, including immobility and mutism, at 32 years of age. She was treated with bromperidol, followed by risperidone. However, her catatonic symptoms recurred at 46 years of age when she learned that her mother had cancer, and then again at 48 years of age when her mother’s cancer relapsed. After treatment in a hospital, the next relapse of her mutism occurred at 53 years of age when her benzodiazepines were tapered without other severe symptoms. She was maintained without hospitalization, but her catatonic symptoms deteriorated at 55 years of age, when her mother’s dementia became severe in addition to her cancer. She was admitted to a hospital with catatonic symptoms, including immobility, mutism, and refusal to consume food and water when her mother moved to a care unit, and the patient was left alone at home. She scored 20 points on the BFCRS. She was treated with daily doses of 2 mg risperidone, 3 mg lorazepam, and 200 mg amantadine. Her catatonic symptoms gradually improved, except mutism. She communicated with gestures or writing on paper without vocalizing. To treat the mutism, aripiprazole was prescribed. Aripiprazole was started at a daily dose of 12 mg and then it was increased to 24 mg and maintained at that dose. Risperidone was tapered off and completely stopped at 4 weeks after starting aripiprazole. However, soon after the cessation of risperidone, the patient began to walk around the ward, attempting to leave the hospital; she told us (in writing) that she heard her mother’s voice calling her. We recognized this as an auditory hallucination, and we replaced aripiprazole with a dopamine D2 receptor antagonist, perospirone. After that replacement, the patient’s abnormal behavior stopped, but mutism was not cured.\n\nDiscussion\nIn both cases, mutism had continued for about 2 years. In Case 1, a successful course was achieved when the patient was switched from olanzapine to aripiprazole. Olanzapine targets multiple receptors, including dopamine D2 receptors, which it antagonizes with relatively low affinity. Classical antipsychotics with strong dopamine D2 antagonism have been known to exacerbate catatonic symptoms, due to excessive inhibition of dopaminergic activity.2 In accordance with previous reports that aripiprazole could successfully treat catatonia,6–9 the switch from olanzapine to aripiprazole had a favorable effect in Case 1, which suggested that the D2 partial agonist provided an advantage over the antagonist. Notably, the onset of psychosis occurred late in life in Case 1. Moreover, her social/occupational function recovered enough to work part-time during remission. Thus, paranoid schizophrenia or paranoia should be considered as a differential diagnosis. Mutism may emerge as a result of adaptive coping in the presence of a paranoid delusion.12 A catatonic state may emerge as an attempt to self-heal by escaping from a threatening psychiatric experience.2 A randomized study indicated that aripiprazole provided an advantage over a dopamine D2 antagonist, paliperidone, for improving subscale scores on the Quality of Life Scale; this improvement was associated with therapeutic efficacy for negative symptoms or cognitive function.13 Hence, in the present Case 1, the therapeutic effect might be attributed to an improvement in negative symptoms or cognitive function, which resulted in the normalization of excessive behavioral reactions associated with a psychiatric disturbance. In Case 2, switching to aripiprazole from risperidone aggravated the condition by causing auditory hallucinations. Risperidone is a potentially strong antagonist of dopamine D2 receptors. This finding supported the notion that dopamine D2 partial agonists can potentially exacerbate dopamine-related pathology, like hallucinations, as previously suggested, both theoretically10 and practically.14 In Case 2, the patient was vulnerable to stress, as indicated by the multiple episodes of deterioration after stressful life events and by the abrupt relapse triggered by the reduction or discontinuation of the usual medication. This vulnerability and the aggravation caused by switching antipsychotic treatments are proposed to be core elements in DSP.15 Furthermore, long-term treatment with a strong D2 receptor antagonist elevates the risk of DSP.14 Taken together, these considerations suggested that Case 2 represented a patient that had acquired DSP. This could explain why the partial agonist, aripiprazole, worsened the hallucinatory symptoms. This case study described two cases of mutism that persisted after treating catatonic schizophrenia. Although the application of aripiprazole is a valid choice for treating catatonic schizophrenia, the clinician must monitor the course carefully because the outcome appears to depend on the patient’s history with pharmacotherapy.\n\nDeclaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.M. received honoraria from Otsuka, Janssen, and Eli Lilly. N.K. received honoraria from Otsuka, Janssen, Eli Lilly, Meiji Parma, and Dainippon-Sumitomo. S.K. declares no conflict of interests.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n==== Refs\nReferences\n1 \nAltshuler LL Cummings JL Mills MJ \nMutism: review, differential diagnosis, and report of 22 cases . Am J Psychiatry \n1986 ; 143 (11 ): 1409 –1414 .3777229 \n2 \nBlumer D Mills MJ \nCatatonia and the neuroleptics: psychobiologic significance of remote and recent findings . Compr Psychiatry \n1997 ; 38 (4 ): 193 –201 .9202876 \n3 \nBasu A Singh P Gupta R \nElectroconvulsive therapy for long-term mutism in a case of noncatatonic paranoid schizophrenia . Innov Clin Neurosci \n2013 ; 10 (7–8 ): 10 –12 .\n4 \nDar MA Rather YH Shah MS \nRapid response of long-standing, treatment-resistant non-catatonic mutism in paranoid schizophrenia with single ECT session . N Am J Med Sci \n2014 ; 6 (11 ): 591 –594 .25535609 \n5 \nBaldinger P Lotan A Frey R \nNeurotransmitters and electroconvulsive therapy . J ECT \n2014 ; 30 (2 ): 116 –121 .24820941 \n6 \nBastiampillai T Dhillon R \nCatatonia resolution and aripiprazole . Aust N Z J Psychiatry \n2008 ; 42 (10 ): 907 .\n7 \nKirino E \nProlonged catatonic stupor successfully treated with aripiprazole in an adolescent male with schizophrenia: a case report . Clin Schizophr Relat Psychoses \n2010 ; 4 (3 ): 185 –188 .20880829 \n8 \nRoberto AJ Pinnaka S Mohan A \nAdolescent catatonia successfully treated with Lorazepam and aripiprazole . Case Rep Psychiatry \n2014 ; 2014 : 309517 .25184067 \n9 \nSasaki T Hashimoto T Niitsu T \nTreatment of refractory catatonic schizophrenia with low dose aripiprazole . Ann Gen Psychiatry \n2012 ; 11 (1 ): 12 .22553911 \n10 \nKim DH Maneen MJ Stahl SM \nBuilding a better antipsychotic: receptor targets for the treatment of multiple symptom dimensions of schizophrenia . Neurotherapeutics \n2009 ; 6 (1 ): 78 –85 .19110200 \n11 \nFallon P Dursun S Deakin B \nDrug-induced supersensitivity psychosis revisited: characteristics of relapse in treatment-compliant patients . Ther Adv Psychopharmacol \n2012 ; 2 (1 ): 13 –22 .23983951 \n12 \nSmith KP Penzner JB \nMutism in non-catatonic schizophrenia: psychotic symptom and adaptive behavioral strategy . Schizophr Res \n2015 ; 168 (1–2 ): 569 –570 .26144881 \n13 \nNaber D Hansen K Forray C \nQualify: a randomized head-to-head study of aripiprazole once-monthly and paliperidone palmitate in the treatment of schizophrenia . Schizophr Res \n2015 ; 168 (1–2) : 498 –504 .26232241 \n14 \nTakase M Kanahara N Oda Y \nDopamine supersensitivity psychosis and dopamine partial agonist: a retrospective survey of failure of switching to aripiprazole in schizophrenia . J Psychopharmacol \n2015 ; 29 (4 ): 383 –389 .25735995 \n15 \nChouinard G \nSevere cases of neuroleptic-induced supersensitivity psychosis. Diagnostic criteria for the disorder and its treatment . Schizophr Res \n1991 ; 5 (1 ): 21 –33 .1677263\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-313X",
"issue": "5()",
"journal": "SAGE open medical case reports",
"keywords": "Mutism; aripiprazole; catatonia; dopamine supersensitivity psychosis",
"medline_ta": "SAGE Open Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101638686",
"other_id": null,
"pages": "2050313X17692936",
"pmc": null,
"pmid": "28255444",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "18777237;22553911;25735995;25184067;25535609;20880829;3777229;26144881;26232241;23983951;24820941;1677263;9202876;24062967;19110200",
"title": "Switching to aripiprazole for the treatment of residual mutism resulted in distinct clinical courses in two catatonic schizophrenia cases.",
"title_normalized": "switching to aripiprazole for the treatment of residual mutism resulted in distinct clinical courses in two catatonic schizophrenia cases"
} | [
{
"companynumb": "JP-TEVA-2017-JP-838525",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMANTADINE HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "A 70-year-old previously independent man developed progressive proximal leg weakness resulting in a fall at home suffering traumatic brain injury. He was prescribed a statin medication two years prior, but this was discontinued on admission to the hospital due to concern for statin myopathy. His weakness continued to progress while in acute rehabilitation, along with the development of dysphagia requiring placement of gastrostomy tube and respiratory failure requiring tracheostomy. Corticosteroids and intravenous immunoglobulin were administered without response. Nerve conduction study demonstrated no evidence of neuropathy; electromyography revealed spontaneous activity suggestive of myopathy. A muscle biopsy was performed and demonstrated myonecrosis. Serology was positive for autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), verifying our diagnosis of statin-associated autoimmune myopathy (SAM). The patient was subsequently treated with rituximab and methotrexate and demonstrated mild clinical improvement. He was eventually liberated from the ventilator. However, later in the course of treatment, he developed respiratory distress and required ventilator support. The patient was discharged to long-term acute care two months after his initial presentation and died due to ventilator-acquired pneumonia three months later. Since their introduction 30 years ago, statin medications have been widely prescribed to prevent cardiovascular diseases. Myalgias and/or myopathic symptoms are among the most recognized side effects of the medication. Statin-associated autoimmune myopathy is a very rare complication of statin use and estimated to affect two to three for every 100,000 patients treated. Clinically, the condition presents as progressive symmetric weakness, muscle enzyme elevations, necrotizing myopathy on muscle biopsy, and the presence of autoantibodies to HMGCR. These findings will often persist and even progress despite discontinuation of the statin. Very few cases of SAM have been described in the literature. Describing this rare condition and the ultimately fatal outcome of our patient, we aim to further understanding of SAM, its presentation and clinical course to promote earlier diagnosis and prompt management.",
"affiliations": "St. Mary Medical Center, Department of Internal Medicine, Long Beach, CA, USA; UCLA, David Geffen School of Medicine, CA, USA.;St. Mary Medical Center, Department of Internal Medicine, Long Beach, CA, USA; UCLA, David Geffen School of Medicine, CA, USA.;St. Mary Medical Center, Department of Internal Medicine, Long Beach, CA, USA; UCLA, David Geffen School of Medicine, CA, USA.;St. Mary Medical Center, Department of Internal Medicine, Long Beach, CA, USA; UCLA, David Geffen School of Medicine, CA, USA.;St. Mary Medical Center, Department of Internal Medicine, Long Beach, CA, USA; UCLA, David Geffen School of Medicine, CA, USA.;St. Mary Medical Center, Department of Internal Medicine, Long Beach, CA, USA; UCLA, David Geffen School of Medicine, CA, USA.;St. Mary Medical Center, Department of Internal Medicine, Long Beach, CA, USA; UCLA, David Geffen School of Medicine, CA, USA.",
"authors": "Sweidan|Alexander J|AJ|;Leung|Anthony|A|;Kaiser|Cassandra J|CJ|;Strube|Sarah J|SJ|;Dokukin|Andrei N|AN|;Romansky|Stephen|S|;Farjami|Sassan|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1179547616688231",
"fulltext": "\n==== Front\nClin Med Insights Case RepClin Med Insights Case RepICRspicrClinical Medicine Insights. Case Reports1179-5476SAGE Publications Sage UK: London, England 2846949910.1177/117954761668823110.1177_1179547616688231ICR-41158Case ReportA Case of Statin-Associated Autoimmune Myopathy Sweidan Alexander J Leung Anthony Kaiser Cassandra J Strube Sarah J Dokukin Andrei N Romansky Stephen Farjami Sassan St. Mary Medical Center, Department of Internal Medicine, Long Beach, CA, USA; UCLA, David Geffen School of Medicine, CA, USAAlexander J Sweidan, Department of Internal Medicine, University of California, Los Angeles and St. Mary Medical Center, 1050 Linden Ave, Long Beach, CA 90813, USA. Email: ajsweidan@gmail.com30 3 2017 2017 10 117954761668823117 10 2016 5 12 2016 © The Author(s) 20172017SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).A 70-year-old previously independent man developed progressive proximal leg weakness resulting in a fall at home suffering traumatic brain injury. He was prescribed a statin medication two years prior, but this was discontinued on admission to the hospital due to concern for statin myopathy. His weakness continued to progress while in acute rehabilitation, along with the development of dysphagia requiring placement of gastrostomy tube and respiratory failure requiring tracheostomy. Corticosteroids and intravenous immunoglobulin were administered without response. Nerve conduction study demonstrated no evidence of neuropathy; electromyography revealed spontaneous activity suggestive of myopathy. A muscle biopsy was performed and demonstrated myonecrosis. Serology was positive for autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), verifying our diagnosis of statin-associated autoimmune myopathy (SAM). The patient was subsequently treated with rituximab and methotrexate and demonstrated mild clinical improvement. He was eventually liberated from the ventilator. However, later in the course of treatment, he developed respiratory distress and required ventilator support. The patient was discharged to long-term acute care two months after his initial presentation and died due to ventilator-acquired pneumonia three months later. Since their introduction 30 years ago, statin medications have been widely prescribed to prevent cardiovascular diseases. Myalgias and/or myopathic symptoms are among the most recognized side effects of the medication. Statin-associated autoimmune myopathy is a very rare complication of statin use and estimated to affect two to three for every 100,000 patients treated. Clinically, the condition presents as progressive symmetric weakness, muscle enzyme elevations, necrotizing myopathy on muscle biopsy, and the presence of autoantibodies to HMGCR. These findings will often persist and even progress despite discontinuation of the statin. Very few cases of SAM have been described in the literature. Describing this rare condition and the ultimately fatal outcome of our patient, we aim to further understanding of SAM, its presentation and clinical course to promote earlier diagnosis and prompt management.\n\nHMGCRstatin complicationsstatin myopathystatin failurestatin-associated autoimmune myopathycover-dateJanuary-December 2017\n==== Body\nIntroduction\nStatins (3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR] inhibitors), since their introduction more than 20 years ago, have been one of the most widely prescribed medications used to treat atherosclerotic disease. Treatment with statins has effectively reduced morbidity and mortality for both cardiovascular and cerebral vascular diseases. Millions of prescriptions are written annually for this class of medication. Given this number of prescriptions written, it is of major importance to closely observe patients for adverse and even life-threatening side effects. Herein, we examine a rare but serious case of statin-associated autoimmune myopathy (SAM).\n\nCase Report\nA 70-year-old man presented to the emergency department after sustaining a fall at home. The patient was admitted to the intensive care unit for a large subdural hematoma and required respiratory support with mechanical ventilation. Prior to his fall, the patient had noticed increasing pain and weakness located bilaterally in the proximal shoulder and hip girdle region, but no other focal symptoms. His home medications for the past two years included, atorvastatin 40 mg once daily and aspirin 81 mg once daily without adverse effects during that time.\n\nHis creatine kinase (CK) on presentation was found to be 12 300 IU/L, the statin was discontinued. Despite this, the CK remained persistently elevated, without clinical evidence of improvement in the patient’s weakness. The patient was evaluated by several specialists and underwent with extensive testing for neuromyopathies including autoimmune, paraneoplastic, and chronic viral infection—all with negative findings. Tests for autoantibodies were negative, including antinuclear antibody, rheumatoid factor, anti-Ro/SSA, anti-La/SSB, and anti-Jo-1. The myositis panel was negative for PL-7 Ab, PL-12Ab, EJ Ab, OJ Ab, SRP Ab, Mi-2 Ab, and Ku Ab. The patient was also seronegative for HIV and hepatitis A, B, and C infections. A computerized computed tomographic (CT) scan of the chest, abdomen, and pelvis with intravenous (IV) and oral (PO) contrast was unremarkable for malignancy. Nerve conduction study demonstrated no evidence of neuropathy. However, needle electromyography demonstrated features consistent with an active myopathic process with abnormal spontaneous activity. Prior to the initiation of corticosteroid and rituximab therapy, a muscle biopsy was performed and revealed a pauci-immune necrotizing myopathy with the absence of macrophage infiltration, inclusion bodies and vascular abnormalities (Figure 1). Serologic testing also revealed HMGCR autoantibodies consistent with an autoimmune process and established the diagnosis of statin -associated autoimmune myopathy.\n\nFigure 1. Severe myofiber atrophy with necrosis and myocytolysis not associated with endomysial inflammation. Frozen section (hematoxylin-eosin).\n\nInitially, the patient was treated with high-dose corticosteroids (IV methylprednisolone, 40 mg every 8hr) but required the addition of rituximab (IV 1000 mg for 3 doses) when no clinical improvement was seen. Of note, it was difficult to assess and quantify the patient’s strength, given his dependence on mechanical ventilation and sedation. However, the patient’s CK did improve to 1500 IU/L. While continuing rituximab a corticosteroid taper was attempted; however, the CK relapsed toward 9000 IU/L, and he subsequently required an increase in corticosteroid dosing (Figure 2).\n\nFigure 2. CK trend over the course of days including when particular treatments were implemented.\n\nThe patient had mild clinical improvement with the treatments as described above following the diagnosis of SAM, and was liberated from the ventilator. Unfortunately, he once again developed respiratory distress and ultimately required a tracheostomy and return to ventilator support. After 2 months of his initial presentation, he was discharged to a long-term acute care facility on a drug regime consisting of a high-dose corticosteroid, rituximab, and methotrexate. Eventually, corticosteroids were successfully tapered but rituximab and methotrexate were continued, given incomplete remission. Unfortunately, he died 3 months after being transferred due to ventilator-associated pneumonia.\n\nDiscussion\nDespite being one of the most commonly prescribed medications, the latest guidelines from the American College of Cardiology and the American Heart Association advocate for increase use; the number of prescriptions for statins is expected to increase substantially. Per the Centers for Disease Control and Prevention, 36.7% of US adults, 78.1 million people aged 21 years or older, are eligible for statin medication; however, approximately 40 million people are actually taking statins.1 Statins have been shown to have an acceptable side effect profile and have been found to be generally safe in their indicated patient population. Studies have shown that a wide range (5%-20%) of patients discontinue statin therapy due to intolerance of side effects.2,3 Muscle complaints are the most well-known and common side effect of statins and can range from asymptomatic with elevation in CK, mild elevation of CK with myalgia, and profound elevation of CK with frank rhabdomyolysis. In initial clinical trials of statins, myalgia and/or myopathic symptoms (muscle pain without elevation of muscle enzymes) were not identified as common adverse events, with only 1% to 5% of participants reporting muscle-related side effects. However, subsequent observational studies have estimated a much higher incidence of muscle complaints, ranging from 9% to 20%. This illustrates the point that the true side effect profile may not be captured by clinical trials, possibly given their restrictive inclusion criteria.4\n\nMyopathy or myositis is generally defined as muscle pain, cramps, soreness, and/or concomitant elevation in CK. It has been estimated to occur in 5 patients per 100 000 person-years, and the incidence of myopathy generally increases with higher dosage of statins.5\n\nRhabdomyolysis is defined as a marked increase in CK levels, more than 10 times the upper limit of normal, which results from massive destruction of muscle fibers and the corresponding release of their contents into the bloodstream. It can induce renal failure and death; however, the rate of occurrence is low, that is, ~1/100 000 or roughly 324 cases per year.6 A dose-response relationship is also observed in the incidence of rhabdomyolysis.\n\nRecently, a rare but unique entity has received increasing attention called statin-associated autoimmune myopathy; the clinical spectrum and presentation of statin-induced myotoxicity consist of asymptomatic elevation of CK, muscle pain or weakness, biopsy-proven myositis, and/or rhabdomyolysis with evidence of muscle-cell necrosis on biopsy and the presence of autoantibodies to HMGCR.7 The distinct histologic profile consists of profound necrotic, degenerating, or regenerating muscle fibers undergoing phagocytosis with macrophage predominance.8 The reported sensitivity and specificity of positive anti-HMGCR for autoimmune statin myopathy are 94.4% and 99.3%, respectively.9\n\nAlthough no prospective clinical trials have yet been completed to allow for evidence-based guidelines for diagnosis or treatment of SAM, the following approach has been advised. Initial workup for patients with current or past statin usage who present with proximal muscle weakness and/or muscle pain begins with obtaining CK levels. CK levels ⩾10 times the upper limit of normal are suggestive of SAM, whereas levels below this threshold should lead the clinician toward investigation of other causes of weakness and muscle. For patients with significantly elevated CK, discontinuation of the statin is indicated, allowing up to 8 weeks for observation of symptoms before repeating CK levels (sooner if symptoms progress). If CK levels remain ⩾10 times the upper limit of normal 8 weeks after discontinuation of the statin or if symptoms progress after statin discontinuation, the patient should be tested for anti-HMG-CoA reductase autoantibody. A positive test for anti-HMG-CoA reductase autoantibody yields presumptive diagnosis of SAM.7\n\nStatin-associated autoimmune myopathy may occur anytime and even long after initial exposure or statin cessation. This is evidenced by elevation of CK and relapse in patients despite discontinuation of the statin. This may occur even while on corticosteroid or immunomodulatory therapy. There are case reports of patients off statin therapy for more than 6 months and then develop the classic characteristic clinical features of SAM.9 Patients can have marked weakness, and electrodiagnostic evidence of an active myopathic process and this can be seen up to 11 years after statin cessation. A case series done by Ramanathan et al demonstrated that patients required multiple immunosuppressive agents to achieve clinical remission, and almost all of those that relapsed seemed to be related to de-escalation of high-dose corticosteroids.10 Therefore, suspicion and early recognition of this diagnosis, use of multiple immunomodulatory agents, and a cautious approach to corticosteroids taper are warranted. At this time, there are no prospective trials with long-term follow-up evaluating the duration and course of this myopathic process. There has yet to be an optimal definitive induction, maintenance, and remission therapy. Recommendations for treatment of SAM are as follows: first discontinue statin and observe symptoms. If symptoms remain unchanged or clinically worsen, begin initial therapy with oral prednisone. In cases of severe weakness, the clinician may consider a second agent at onset of treatment with prednisone, such as methotrexate, azathioprine, or mycophenolate mofetil. Rituximab or IVIG may be considered after 8 to 12 weeks if no response with prednisone with or without a second agent or sooner in more severe presentations of the condition. IVIG is typically reserved for severe or refractory cases but has been described to be effective as a first-line agent in patients. In a case series, three patients with SAM and underlying diabetes mellitus were treated with IVIG as monotherapy after declining corticosteroid treatment due to potential side effects—partial to full recovery of strength was demonstrated. The combination of prednisone, IVIG, and a steroid-sparing agent was used in nearly one-half of cases described in literature. Treatment of SAM with triple therapy has been recommended. There is also evidence of using IVIG as the sole treatment as depicted by Dr. Mammen in his review article on SAM in the New England Journal of Medicine.11 IVIG has been suggested to be first line therapy in severe cases, especially in those who present with an aggressive course.12\n\nIt is hypothesized that statins may increase the expression of HMGCR autoantibody in regenerating muscle fibers. This self-antigen would perpetuate an immune response. This may explain why patients have a propensity to relapse up on de-escalation of immunosuppression or immunomodulatory therapy.13 This is further evidenced in a recent study which demonstrated patients responded well to immunosuppressive treatment, but serum levels of the anti-HMGCR antibody remained high and did not correlate with disease activity.14\n\nConclusions\nStatin-associated autoimmune myopathy has a unique clinical, histologic, and therapeutic profile that separates it from other inflammatory myopathies. With the new Atherosclerotic Cardiovascular Disease (ASCVD) risk calculator in place and improving access to health care, we expect an increasing use of statin medications. With the benefits of statins with regard to reducing risk of both cardiovascular and cerebrovascular events far outweigh risk and potential adverse effects of these medications; it is crucial for providers to remain aware of possible and even rare side effects of these medications and how to test for them. Statin-associated autoimmune myopathy has been described as an exceedingly rare complication of statin use and is often underrecognized in clinical practice; we urge providers to educate patients to alert their physicians if any signs or symptoms of serious myopathy occur.\n\nPeer Review:Five peer reviewers contributed to the peer review report. Reviewers’ reports totaled 1195 words, excluding any confidential comments to the academic editor.\n\nFunding:The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nDeclaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1 \nGu Q Paulose-Ram R Burt VL Kit BK. \nPrescription Cholesterol-Lowering Medication Use in Adults Aged 40 and Over: United States, 2003–2012 (NCHS Data Brief No. 177). Hyattsville, MD : National Center for Health Statistics ; 2014 .\n2 \nCholesterol Treatment Trialists’ (CTT) Collaboration , Fulcher J O’Connell R \nEfficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials . Lancet . 2015 ;385 :1397 –1405 .25579834 \n3 \nBruckert E Hayem G Dejager S Yau C Bégaud B. \nMild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study . Cardiovasc Drugs Ther . 2005 ;19 :403 –414 .16453090 \n4 \nHamann PD Cooper RG McHugh NJ Chinoy H \nStatin-induced necrotizing myositis—a discrete autoimmune entity within the “statin-induced myopathy spectrum.” \nAutoimmun Rev . 2013 ;12 :1177 –\n1181 .23851103 \n5 \nLaw M Rudnicka AR. \nStatin safety: a systematic review . Am J Cardiol . 2006 ;97 :52C –\n60C .\n6 \nSirvent P Mercier J Lacampagne A. \nNew insights into mechanisms of statin-associated myotoxicity . Curr Opin Pharmacol . 2008 ;8 :333 –\n338 .18243052 \n7 \nBabu S1 Li Y2 \nStatin induced necrotizing autoimmune myopathy . Curr Opin\nRheumatol . 2014 Nov;26 (6 ):679-83. doi: 10.1097/BOR.0000000000000106 .\n8 \nDimachkie MM. \nIdiopathic inflammatory myopathies . J Neuroimmunol . 2011 ;231 :32 –42 .21093064 \n9 \nDrouot L Allenbach Y Jouen F \nExploring necrotizing autoimmune myopathies with a novel immunoassay for anti-3-hydroxy-3-methyl-glutaryl-CoA reductase autoantibodies . Arthritis Res Ther . 2014 ;16 :R39 .24484965 \n10 \nRamanathan S Langguth D Hardy TA \nClinical course and treatment of anti-HMGCR antibody–associated necrotizing autoimmune myopathy . Neurol Neuroimmunol Neuroinflamm . 2015 ;2 :e96 .25866831 \n11 \nMammen AL. \nStatin-associated autoimmune myopathy . N Engl J Med . 2016 ;374 :664 –669 . doi:10.1056/nejmra1515161 .26886523 \n12 \nMammen AL Tiniakou E \nIntravenous immunoglobulin for statin-triggered autoimmune myopathy . N Engl J Med \n2015 ; 373 :1680-2\n13 \nMammen AL Pak K Williams EK \nRarity of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies in statin users, including those with self-limited musculoskeletal side effects . Arthritis Care Res (Hoboken) . 2012 ;64 :269 –272 .21972203 \n14 \nGe Y Lu X Peng Q Shu X Wang G. \nClinical characteristics of anti-3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies in Chinese patients with idiopathic inflammatory myopathies . PLoS ONE . 2015 ;10 :e0141616 .26509687\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-5476",
"issue": "10()",
"journal": "Clinical medicine insights. Case reports",
"keywords": "HMGCR; statin complications; statin failure; statin myopathy; statin-associated autoimmune myopathy",
"medline_ta": "Clin Med Insights Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101531893",
"other_id": null,
"pages": "1179547616688231",
"pmc": null,
"pmid": "28469499",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "25536410;25579834;21972203;16453090;26509687;26886523;16581329;18243052;23851103;24484965;21093064;26488714;25866831",
"title": "A Case of Statin-Associated Autoimmune Myopathy.",
"title_normalized": "a case of statin associated autoimmune myopathy"
} | [
{
"companynumb": "US-CIPLA LTD.-2017US20102",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "1",... |
{
"abstract": "Immune checkpoint inhibitors are the most important new medications in oncology and include inhibitors of programmed cell death protein-1 (PD-1) such as Pembrolizumab, Nivolumab, and Cemiplimab. These anticancer agents prevent tumour immune evasion and have been associated with a range of immune-related adverse events (irAEs) including those involving the nervous system. In this case report and literature review, we present the first case of inflammatory myeloradiculitis secondary to Pembrolizumab. We also summarise the characteristics, treatment, and outcomes of other cases reported in the literature which include a component of myelitis. Finally, we make general recommendations on management.",
"affiliations": "Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.;Department of Medical Oncology, Redcliffe Hospital, Redcliffe, Queensland, Australia.;Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.;Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.;Herston Health Sciences Library, University of Queensland, Brisbane, Queensland, Australia.;Department of Medical Oncology, Redcliffe Hospital, Redcliffe, Queensland, Australia.;Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.;Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.",
"authors": "Vickers|M L|ML|https://orcid.org/0000-0002-2831-404X;Seidl|B|B|;Bigby|K|K|;Chern|B|B|;Eriksson|L|L|;Hartnett|G|G|;Gericke|C|C|;Chew|R|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/8819296",
"fulltext": "\n==== Front\nCase Rep Oncol Med\nCase Rep Oncol Med\nCRIONM\nCase Reports in Oncological Medicine\n2090-6706 2090-6714 Hindawi \n\n10.1155/2020/8819296\nCase Report\nInflammatory Myeloradiculitis Secondary to Pembrolizumab: A Case Report and Literature Review\nhttps://orcid.org/0000-0002-2831-404XVickers M. L. mark.vickers@uq.net.au\n1\n\n2\n\n3\n Seidl B. \n3\n Bigby K. \n1\n\n3\n Chern B. \n1\n\n3\n Eriksson L. \n4\n Hartnett G. \n3\n Gericke C. \n1\n\n5\n Chew R. \n1\n\n6\n \n1Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia\n\n2Biomedical Engineering and Clinical Sciences, Queensland University of Technology, Brisbane, Australia\n\n3Department of Medical Oncology, Redcliffe Hospital, Redcliffe, Queensland, Australia\n\n4Herston Health Sciences Library, University of Queensland, Brisbane, Queensland, Australia\n\n5Department of Neurology, The Prince Charles Hospital, Brisbane, Queensland, Australia\n\n6Infectious Disease, Redcliffe Hospital, Redcliffe, Queensland, Australia\nAcademic Editor: Jose I. Mayordomo\n\n\n2020 \n18 8 2020 \n2020 88192965 7 2020 1 8 2020 5 8 2020 Copyright © 2020 M. L. Vickers 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.Immune checkpoint inhibitors are the most important new medications in oncology and include inhibitors of programmed cell death protein-1 (PD-1) such as Pembrolizumab, Nivolumab, and Cemiplimab. These anticancer agents prevent tumour immune evasion and have been associated with a range of immune-related adverse events (irAEs) including those involving the nervous system. In this case report and literature review, we present the first case of inflammatory myeloradiculitis secondary to Pembrolizumab. We also summarise the characteristics, treatment, and outcomes of other cases reported in the literature which include a component of myelitis. Finally, we make general recommendations on management.\n==== Body\n1. Introduction\nWe report the first case of inflammatory myeloradiculitis following administration with the immune checkpoint inhibitor (ICI) Pembrolizumab. The development of ICIs has been the most notable advancement in cancer care in recent years. These medications act on immune inhibitory receptors including the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein-1 (PD-1) and its ligand (PD-L1) [1, 2]. The PD-1 receptor is an important pharmacological target because it inhibits T-lymphocyte proliferation and survival, induces apoptosis of tumour cells, and promotes differentiation of CD4+ T cells [3]. Inhibition of PD-1 limits tumour immune evasion by effectively taking the brakes off the immune system. In Australia, PD-1 inhibitors in common clinical use include Pembrolizumab and Nivolumab, which are approved for the treatment of multiple cancers including bladder and urothelial cancers, non-small-cell lung cancer, melanoma, lymphoma, and head and neck cancers [4]. The newer agent, Cemiplimab, is currently approved in the United States for use in squamous cell carcinoma and is undergoing clinical trial for further indications.\n\nWith the rapidly expanding use of ICIs such as Pembrolizumab, we have also seen growing recognition of the potential for immune-related adverse events (irAEs) [5]. These can impact any organ or body system and the more commonly encountered irAEs including hepatitis, colitis, pneumonitis, endocrine dysfunction, and dermatological disorders. In addition, neurological complications have been reported with a frequency of up to 4% and include encephalopathies, polyradiculopathies, Guillain-Barré-like syndromes, and myasthenic syndromes [6–15]. In order to summarise the relevant features, treatment, and outcomes of other myelitis cases with or without associated syndromes, we carried out a thorough systematic review of the literature and report the findings.\n\n2. Case Presentation\nA 73-year-old man presented to the emergency department with right leg swelling and an acute kidney injury. CT scans revealed a 6.2 mm unresectable right pelvic mass compressing the external iliac vein and ureters, a right acetabular metastasis, and external iliac vein thrombosis. Subsequent bladder biopsy led to the diagnosis of locally advanced transitional cell carcinoma. Malignant cells were positive for CK7, GATA3, and p40 with patchy positive staining for CK20. The patient had a background of benign prostatic hypertrophy, stage three chronic kidney disease, and melanoma of the right shin which had been excised several months prior. During a three-month period, he was treated with three cycles of gemcitabine on days one and eight in a 21-day cycle. Due to the lack of tumour response and multiple side effects, this was ceased, and one month later, he was commenced on Pembrolizumab. He received three 200 mg doses over a nine-week period. Three days prior to the final dose, he developed acute on chronic lumbar back pain with no inciting trauma. Over the following week, he developed an asymmetrical grade 3 paraesthesia of the upper and lower limbs, though retained brisk reflexes [16]. He also developed hypoesthesia and hypoalgesia in a banded distribution extending from the T10 to L1 dermatomes. Pembrolizumab was discontinued, and neurooncological investigations commenced. A Naranjo score of 7 was calculated, indicating a probable adverse drug reaction.\n\nBrain and spine magnetic resonance imaging (MRI) demonstrated no evidence of haemorrhagic, ischaemic, or metastatic events and no cord compression. An inversion sequence could not be administered due to significant renal impairment. Fat saturation sequencing demonstrated no evidence of radiculopathy. Nerve conduction studies demonstrated bilaterally reduced lower limb motor units with retained sensory responses and reduced F-waves in the upper limbs. F-waves compare the conduction in the proximal half of the nerve pathway to the distal and can be used to distinguish a root lesion from a distal neuropathy [17]. Nerve conduction findings assisted in the exclusion of axonal loss and demyelinating syndromes such as acute inflammatory demyelinating polyneuropathy. Cerebrospinal fluid (CSF) was clear with an elevated protein level (2100 mg/L, normal 150-500 mg/L) and raised white blood cell count (35 × 10 [6]/L). There were no malignant cells or organisms, and the glucose level was normal (3.2 mmol/L). Multiple kappa and lambda IgG bands were present in trace amounts. Additional laboratory tests for anti-acetylcholine receptor antibodies, anti-ganglioside antibodies, and an infectious screen were negative. Respiratory function tests were also performed and normal.\n\nTreatment included a course of intravenous immunoglobulin (IVIG) commenced at 30 g then 25 g daily for five days. The patient had been receiving 2 mg daily of dexamethasone for treatment of cancer symptoms, and this was left unchanged. Mild improvement in symptoms occurred one week following IVIG, and the patient was then transferred to a Rehabilitation Unit. After five weeks of multidisciplinary team input, he was discharged able to walk with a single point stick. A restaging CT scan was performed which demonstrated progression of acetabular cortical bone destruction adjacent to the malignancy compared to four months earlier, but no new metastatic disease or lymphadenopathy. No further immune treatment was offered for the primary malignancy.\n\n3. Discussion\nWe aimed to describe a rare case of inflammatory myeloradiculitis following Pembrolizumab therapy and to review the literature for similar cases of myelitis with or without associated features. Using predefined terms, a systematic review of the literature was performed with PubMed, Embase, Web of Science, Scopus, Cochrane Central, and CINAHL from inception to 24th March 2020. Results were screened and included if they reported myelitis following treatment with any PD-1 inhibitor. A total of ten cases were identified [18–27]. Four cases were not included because the authors provided no data on the patient, investigations, treatment, or outcomes [18, 19, 22, 26]. Two cases reported myelitis in the context of associated radiotherapy [20, 21]. All cases received steroid therapy [20, 21, 23–25, 27]. Four cases received plasmapheresis [21, 23, 24, 27], and two received intravenous immunoglobulin [21, 27]. Four of the six included cases demonstrated significant improvement in their symptoms [20, 21, 23, 27]. A summary of reported myelitis cases secondary to PD-1 inhibitor therapy is provided in Table 1. A summary of treatment and outcomes is provided in Table 2. A list of search terms are provided in Appendix A. A PRISMA flow chart of the case inclusion process is shown in Figure 1, and search results by database are provided in Table 3.\n\nThere are not enough cases in the literature to form specific management recommendations in the treatment of myelitis with or without associated syndromes in the context of PD-1 inhibitor therapy. Based on our experience, however, we suggest early interruption of the offending agent, neurological consult, and baseline investigations including inflammatory markers, autoimmune screen, nerve conduction studies, CSF analysis, and spinal MRI. We note that while all included cases used steroid therapy in their management, there was no clear consensus on the dose or regimen of therapy. Similarly, there were varied approaches to treatment with IVIG and plasmapheresis. We agree with Möhn et al. who suggests that clinicians should have a low threshold for early initiation of these modalities when neurological irAEs occur in the context of ICI therapy [28].\n\nPredicting the response to PD-1 inhibitor therapy is problematic. This is due to the lack of a single reliable biomarker, varied success based on cancer subtype and the complexity of factoring in patient tumour burden, lymphocyte infiltration, comorbidities, and baseline performance status [29, 30]. Despite this, in some patients, PD-1 inhibitors have been shown to dramatically improve outcomes and are also generally better tolerated than chemotherapy with multiple studies reporting lower rates of neutropenia, thrombocytopenia, anaemia, fatigue, nausea, gastrointestinal toxicity, and neuropathy [31, 32]. While clinical trials largely exclude participants at high risk of adverse events, the growing role of these agents in daily clinical practice has broadened their application and uncovered a number of potentially serious neurological irAEs. This case report of myeloradiculitis secondary to Pembrolizumab highlights one such example and the importance of early recognition and treatment.\n\nAppendix\nA. List of Search Terms\nPembrolizumab, nivolumab, cemiplimab, lambrolizumab, keytruda, MK-3475, SCH 900475, PD-1 inhibitor, opdivo, ONO-4538, BMS-936558, MDX-1106, Nivo, Libtayo, REGN2810, SAR439684 and myelopathy, myelopathies, myelitis, transverse myelitis, polyradiculoneuropathy, polyradiculoneuropathies, polyneuropathy, radiculopathy, polyneuropathies, radiculopathies, myeloradiculitis, polyradiculitis, polyneuropathies, and spinal cord diseases.\n\nData Availability\nThis is a single patient case report with data accessed through the electronic medical record system. Information on other cases discussed is freely accessible in the public domain.\n\nConflicts of Interest\nThe authors declare no conflicts of interest.\n\nFigure 1 Table 1 Reported cases and findings of myelitis-related adverse events secondary to PD-1 inhibitor therapy.\n\nAuthor\tDiagnosis\tCase\tImmune checkpoint inhibitor\tInvestigations and clinical findings\t\nCarausu et al. [20]\tRadiation myelitis\t68 male, metastatic non-small-cell lung cancer\tPembrolizumab 8 cycles over 24 weeks\tSpine MRI T1 hypointense signal and enhancement at site of prior radiation (30 Gray in 10 fractions), CSF protein 0.84 g/L\t\nLeft lower limb muscle weakness, paraesthesia, difficulty urinating, rapid bowel movements\t\nChang et al. [21]\tTransverse myelitis\t68 male, metastatic melanoma\tCombination ipilimumab and Nivolumab 3 cycles, then 1 dose Pembrolizumab\tT5 to T10 enhancement at site of prior radiation (30 Gray in 10 fractions to T7-T10), CSF protein 99 mg/dL\t\nIntermittent tingling and numbness at soles of feet with ascension to knees during 2 months of Nivolumab, rapid progression after Pembrolizumab to gait instability, ataxia, ascension of sensory loss to hips, urinary retention, and faecal incontinence\t\nDurães et al. [23]\tEncephalomyelitis\t58 female, metastatic melanoma\tPembrolizumab 2 cycles\tMRI T2 hyperintense lesions with gadolinium enhancement, CSF protein 292 mg/dL, oligoclonal IgG bands\t\nLeft hemiparesis, global hyporeflexia, distal hypoesthesia, and gate impairment without ataxia\t\nNarumi et al. [24]\tNeuromyelitis optica spectrum disorder\t75 male, squamous cell carcinoma of lung\tNivolumab 1 dose\tT2 hyperintense lesions C5-C6 and Th12-L1, CSF white cell count 1195 microL, CSF protein 381 mg/dL, and serum anti-aquaporin-4 antibody positive\t\nAcute paralysis lower limbs, sensory loss Th10 down, and urinary retention\t\nPoretto et al. [25]\tMyelitis\t73 male, clear cell renal carcinoma\tNivolumab\tSpine MRI demonstrated intensive contrast-enhancing intramedullary lesion with surrounding T2 hyperintensity, CSF protein 80 mg/dL\t\nLeft lower limb hypoesthesia and urinary incontinence\t\nWilson et al. [27]\tLongitudinally extensive transverse myelitis\t35 male, classical Hodgkin lymphoma\tPembrolizumab 2 cycles 3 weeks apart\tMRI myelitis from pons to lower thoracic spine, CSF demonstrated 24 mononuclear cells/m3, antihuman-IgG antibody bound to Tregs with high CD62L and CD25\t\nAcute urinary retention, constipation, spastic tetra paresis, and profound sensory level loss\t\nTable 2 Treatment and outcomes of reported cases of myelitis-related adverse events secondary to PD-L1 inhibitor therapy.\n\nAuthor\tTreatment\tOutcome\t\nCarausu et al. [20]\tOral steroid 60 mg/day tapered over 2 months\tComplete resolution, Pembrolizumab reinitiated without recurrence of myelitis\t\nChang et al. [21]\tDexamethasone 8 mg BD, bevacizumab 2 doses, 1000 mg daily methylprednisolone for 5 days, plasmapheresis, cyclophosphamide 100 mg/m3, and infliximab\tDramatic improvement post infliximab, however succumbed to malignancy soon after\t\nDurães et al. [23]\tCorticosteroid therapy for 5 days and plasma exchange for 7 sessions\tAlmost complete symptomatic recovery with residual mild sensory complaints\t\nNarumi et al. [24]\tPulse steroid therapy, plasmapheresis\tMinimal improvement\t\nPoretto et al. [25]\tHigh-dose steroid\tMild clinical and radiological improvement\t\nWilson et al. [27]\tIntravenous methylprednisolone followed by oral prednisolone taper, intravenous immunoglobulins, and plasma exchange\tNear complete remission, mild residual hypertonia\t\nTable 3 Database\tResults\t\nPubMed\t65\t\nEmbase\t234\t\nWeb of Science\t36\t\nScopus\t107\t\nCochrane Central\t4\t\nCINAHL\t10\t\nTotal\t456\t\nAfter duplicates removed\t281\n==== Refs\n1 Dubbs S. B. The latest cancer agents and their complications Emergency Medicine Clinics of North America 2018 36 3 485 492 10.1016/j.emc.2018.04.006 2-s2.0-85048278945 30037436 \n2 Kourie H. R. Klastersky J. Immune checkpoint inhibitors side effects and management Immunotherapy 2016 8 7 799 807 10.2217/imt-2016-0029 2-s2.0-84976863749 27349979 \n3 Zitvogel L. Kroemer G. Targeting PD-1/PD-L1 interactions for cancer immunotherapy Oncoimmunology 2014 1 8 1223 1225 10.4161/onci.21335 2-s2.0-84877896663 \n4 eviQ Cancer treatments online 2020 March 2020, https://www.eviq.org.au/ \n5 Kumar V. Chaudhary N. Garg M. Floudas C. S. Soni P. Chandra A. B. Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy Frontiers in Pharmacology 2017 8 p. 49 10.3389/fphar.2017.00049 2-s2.0-85014218501 \n6 Cuzzubbo S. Javeri F. Tissier M. Neurological adverse events associated with immune checkpoint inhibitors: review of the literature European Journal of Cancer 2017 73 1 8 10.1016/j.ejca.2016.12.001 2-s2.0-85008315530 28064139 \n7 Jin K. T. Wang S. B. Ying X. J. Immune-mediated adverse effects of immune-checkpoint inhibitors and their management in cancer Immunology Letters 2020 221 61 71 10.1016/j.imlet.2020.02.008 32097671 \n8 Kubo K. Wadasaki K. Yamane H. Doi M. Radiation myelitis after durvalumab administration following chemoradiotherapy for locally advanced non-small cell lung cancer: an illustrative case report and review of the literature International Cancer Conference Journal 2019 8 3 118 121 10.1007/s13691-019-00367-5 31218187 \n9 Sepúlveda M. Martinez-Hernandez E. Gaba L. Motor polyradiculopathy during pembrolizumab treatment of metastatic melanoma Muscle & Nerve 2017 56 6 E162 E167 10.1002/mus.25672 2-s2.0-85019569116 28439919 \n10 Tanaka R. Maruyama H. Tomidokoro Y. Nivolumab-induced chronic inflammatory demyelinating polyradiculoneuropathy mimicking rapid-onset Guillain–Barré syndrome: a case report Japanese Journal of Clinical Oncology 2016 46 9 875 878 10.1093/jjco/hyw090 2-s2.0-84994173292 27380808 \n11 Manam R. Martin J. L. Gross J. A. Case reports of pembrolizumab-induced acute inflammatory demyelinating polyneuropathy Cureus 2018 10 9, article e3371 10.7759/cureus.3371 30510881 \n12 Dalakas M. C. Neurological complications of immune checkpoint inhibitors: what happens when you 'take the brakes off' the immune system Therapeutic Advances in Neurological Disorders 2018 11 10.1177/1756286418799864 2-s2.0-85054787483 \n13 Hottinger A. F. Neurologic complications of immune checkpoint inhibitors Current Opinion in Neurology 2016 29 6 806 812 10.1097/WCO.0000000000000391 2-s2.0-84988602795 27653290 \n14 Kao J. C. Brickshawana A. Liewluck T. Neuromuscular complications of programmed cell death-1 (PD-1) inhibitors Current Neurology and Neuroscience Reports 2018 18 10 p. 63 10.1007/s11910-018-0878-7 2-s2.0-85051126491 \n15 Perrinjaquet C. Desbaillets N. Hottinger A. F. Neurotoxicity associated with cancer immunotherapy: immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy Current Opinion in Neurology 2019 32 3 500 510 10.1097/WCO.0000000000000686 2-s2.0-85065346263 30893101 \n16 Kaplow R. Iyere K. Grading chemotherapy-induced peripheral neuropathy in adults Nursing 2017 47 2 67 68 10.1097/01.NURSE.0000511823.41645.a1 2-s2.0-85012870215 28121792 \n17 Mallik A. Weir A. I. Nerve conduction studies: essentials and pitfalls in practice Journal of Neurology, Neurosurgery & Psychiatry 2005 76 Supplement 2 ii23 ii31 10.1136/jnnp.2005.069138 2-s2.0-20444398865 15961865 \n18 Anderson D. Beecher G. Nathoo N. Proposed diagnostic and treatment paradigm for high-grade neurological complications of immune checkpoint inhibitors Neuro-Oncology Practice 2019 6 5 340 345 10.1093/nop/npy039 2-s2.0-85072736483 31555448 \n19 Benjamini O. Lavie D. Dann E. J. Real-life experience of nivolumab in heavily pretreated relapsed and refractory classical hodgkin lymphoma Blood 2016 128 22 p. 3008 10.1182/blood.V128.22.3008.3008 \n20 Carausu M. Beddok A. Langer A. Radiation myelitis after pembrolizumab administration, with favorable clinical evolution and safe rechallenge: a case report and review of the literature Journal for Immunotherapy of Cancer 2019 7 1 p. 317 10.1186/s40425-019-0803-x 31753021 \n21 Chang V. A. Simpson D. R. Daniels G. A. Piccioni D. E. Infliximab for treatment-refractory transverse myelitis following immune therapy and radiation Journal for Immunotherapy of Cancer 2018 6 1 p. 153 10.1186/s40425-018-0471-2 2-s2.0-85058910473 30577851 \n22 Chen R. Zinzani P. L. Lee H. J. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087 Blood 2019 134 14 1144 1153 10.1182/blood.2019000324 2-s2.0-85072945199 31409671 \n23 Durães J. Silva B. Mendes S. Geraldo A. Do Carmo Macário M. Acute disseminated encephalomyelitis-like clinical presentation after therapy with pembrolizumab: a rare complication Sinapse 2017 17 1 165 166 \n24 Narumi Y. Yoshida R. Minami Y. Neuromyelitis optica spectrum disorder secondary to treatment with anti-PD-1 antibody nivolumab: the first report BMC Cancer 2018 18 1 p. 95 10.1186/s12885-018-3997-2 2-s2.0-85043460485 29361915 \n25 Poretto V. Buganza M. Filipponi S. Hunting the real culprit: a complex case of nivolumab-related myelitis Neurology 2019 92 15 \n26 Sato K. Mano T. Iwata A. Toda T. Neurological and related adverse events in immune checkpoint inhibitors: a pharmacovigilance study from the Japanese Adverse Drug Event Report database Journal of Neuro-Oncology 2019 145 1 1 9 10.1007/s11060-019-03273-1 2-s2.0-85071334461 31452071 \n27 Wilson R. Menassa D. A. Davies A. J. Seronegative antibody-mediated neurology after immune checkpoint inhibitors Annals of Clinical and Translational Neurology 2018 5 5 640 645 10.1002/acn3.547 2-s2.0-85044417362 29761126 \n28 Mohn N. Beutel G. Gutzmer R. Ivanyi P. Satzger I. Skripuletz T. Neurological immune related adverse events associated with nivolumab, ipilimumab, and pembrolizumab therapy–review of the literature and future outlook Journal of Clinical Medicine 2019 8 11, article 1777 10.3390/jcm8111777 \n29 Chen R. Tao Y. Xu X. The efficacy and safety of nivolumab, pembrolizumab, and atezolizumab in treatment of advanced non-small cell lung cancer Discovery Medicine 2018 26 143 155 166 30586539 \n30 Dogan V. Rieckmann T. Munscher A. Busch C. J. Current studies of immunotherapy in head and neck cancer Clinical Otolaryngology 2018 43 1 13 21 10.1111/coa.12895 2-s2.0-85040834321 28464441 \n31 Nishijima T. F. Shachar S. S. Nyrop K. A. Muss H. B. Safety and tolerability of PD-1/PD-L1 inhibitors compared with chemotherapy in patients with advanced cancer: a meta-analysis The Oncologist 2017 22 4 470 479 10.1634/theoncologist.2016-0419 2-s2.0-85017474192 28275115 \n32 Luo W. Wang Z. Tian P. Li W. Safety and tolerability of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer: a meta-analysis of randomized controlled trials Journal of Cancer Research and Clinical Oncology 2018 144 10 1851 1859 10.1007/s00432-018-2707-4 2-s2.0-85049957419 30019319\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2020()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
"mesh_terms": null,
"nlm_unique_id": "101581035",
"other_id": null,
"pages": "8819296",
"pmc": null,
"pmid": "32908747",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "29761126;31218187;28464441;27653290;29361915;32097671;30577851;31653079;30019319;23243584;28439919;28064139;31452071;15961865;31555448;30037436;30245744;28275115;30586539;28228726;27380808;30078154;28121792;27349979;31753021;30893101;30510881;31409671",
"title": "Inflammatory Myeloradiculitis Secondary to Pembrolizumab: A Case Report and Literature Review.",
"title_normalized": "inflammatory myeloradiculitis secondary to pembrolizumab a case report and literature review"
} | [
{
"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-268604",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"d... |
{
"abstract": "Acute transient parotid gland enlargement in association with general anesthesia is a rare complication and has also been called anesthesia mumps. Unilateral or bilateral parotid or submandibular swelling usually develops during surgery under anesthesia or, a few hours later and usually resolves in a few days with no sequelae. It has been reported as a complication after general anesthesia in patients undergoing spinal surgeries in prone and lateral decubitus position, even after cesarean section in the supine position and also reported in Intensive Care Unit patients. We present a case of a unilateral parotid swelling noticed in immediate postoperative course, in a patient who underwent spine surgery.",
"affiliations": "Department of Anesthesiology, Aga Khan University Hospital, Karachi, Pakistan.;Department of Anesthesiology, Aga Khan University Hospital, Karachi, Pakistan.;Department of Anesthesiology, Aga Khan University Hospital, Karachi, Pakistan.",
"authors": "Asghar|Ali|A|;Karam|Karima|K|;Rashid|Saima|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/1658-354X.154743",
"fulltext": "\n==== Front\nSaudi J AnaesthSaudi J AnaesthSJASaudi Journal of Anaesthesia1658-354X0975-3125Medknow Publications & Media Pvt Ltd India SJA-9-33210.4103/1658-354X.154743Case ReportA case of anesthesia mumps after sacral laminectomy under general anesthesia Asghar Ali Karam Karima Rashid Saima Department of Anesthesiology, Aga Khan University Hospital, Karachi, PakistanAddress for correspondence: Dr. Ali Asghar, Department of Anesthesiology, Aga Khan University Hospital, Karachi, Pakistan. E-mail: asghar.ashraf@aku.eduJul-Sep 2015 9 3 332 333 Copyright: © Saudi Journal of Anaesthesia2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Acute transient parotid gland enlargement in association with general anesthesia is a rare complication and has also been called anesthesia mumps. Unilateral or bilateral parotid or submandibular swelling usually develops during surgery under anesthesia or, a few hours later and usually resolves in a few days with no sequelae. It has been reported as a complication after general anesthesia in patients undergoing spinal surgeries in prone and lateral decubitus position, even after cesarean section in the supine position and also reported in Intensive Care Unit patients. We present a case of a unilateral parotid swelling noticed in immediate postoperative course, in a patient who underwent spine surgery.\n\nAnesthesiamumpspain\n==== Body\nINTRODUCTION\nAnesthesia mumps is characterized by an acute transient parotid gland swelling in association with general anesthesia.[1] It is a rare, but known entity that resolves spontaneously in some days without any complication.[2] It has been found to be associated with patients of all age groups and various surgical procedures. Majority of the cases were found after the patient underwent general anesthesia for a long time.[3] We present this case, as no case of anesthesia mumps, has been reported yet in Pakistan.\n\nCASE REPORT\nA 52-year-old, 88 kg man scheduled for sacral laminectomy and excision of the sacral mass for sacral chordoma, under general anesthesia. His past medical history revealed no specific findings. The preoperative results of biochemical studies, chest X-ray and electrocardiography, were normal. Physical examination revealed limitation of movement of the left thigh. General anesthesia was induced with intravenous propofol 2 mg/kg, morphine 0.1 mg/kg, atracurium 0.6 mg/kg and maintained with isoflurane/oxygen/nitrous oxide mixture under standard monitoring. After oral tracheal intubation, an endotracheal tube was fixed on the right side of the mouth and kept at 22 cm in depth. After intubation, the patient was placed in the prone position with the neck flexed at approximately 10°. The head was turned to the right side, and the left side of the face was placed on a soft gel rolling pad. The surgery proceeded for about 7 h. The total blood loss was about 1000 ml. After endotracheal extubation, patient was shifted to postanesthesia care unit, where swelling of the left parotid gland was noted. The swelling of the parotid gland increased in size and hardness. Painful sensations were complained of after the patient was sent to the room after 4 h stay at postanesthesia care unit.\n\nENT consulted, examination revealed firm, mildly erythematous swelling starting from the left per auricular face to the angle of the mandible, no parotid secretions noted. Patient was reassured, and pain was managed with nonsteroidal anti-inflammatory drugs. Patient was discharged to home at 7th postoperative day after complete recovery with a follow-up visit at ENT clinic.\n\nDISCUSSION\nAnesthesia mumps is an acute transient sialadenitis of the major salivary glands in the early postoperative period.[1] It is a rare, but known complication of general anesthesia, it is usually unilateral, transient swelling of the parotid gland which may last for several minutes to several days, resolving spontaneously without requiring any specific treatment.[2] It has been reported in a wide range of age groups and in different surgical procedures.[3] The majority of cases were found after the patient who underwent anesthesia for a long time.[4] Incidence of anesthesia mumps was reported that 5 in 3000 following endotracheal anesthesia by Matsuki et al.[5]\n\nThe etiology and the mechanism behind the anesthesia mumps are still not clear. Among the implicated mechanisms suggested in literature are trauma, head and neck positioning, straining and coughing during anesthesia, vascular congestion and venous engorgement of head and neck,[1] overactive pharyngeal reflex stimulation of the salivary gland via the parasympathetic nerves, succinylcholine-stimulated copious secretions,[1] dehydration, and mechanical blockage of the parotid duct by intubation and fixation of the endotracheal tube or head stripping and obstruction of glandular excretory ducts by position, calculi, or thickened secretion[6] were the major causes of acute salivary glands enlargement during induction of anesthesia.\n\nLiu et al.[1] believe the presence of the patient's underlying disease (obesity), choice of anesthetic drugs (succinylcholine, atropine), surgical position (prone, lateral decubitus), operative site (such as head and neck surgery) and induction methods (such as endotracheal tube, laryngeal mask inadequate insertion and fixation) may all contribute to the development of acute swelling of the parotid glands after general anesthesia. In our patient, prone positioning, endotracaheal intubation and prolong surgery may be the contributing factors to the development of acute unilateral transient swelling of the parotid gland.\n\nAnesthesia mumps is uncommon postoperative complication but, fortunately, it is commonly self-limited condition, which rapidly improves with symptomatic therapy. Symptomatic therapy includes reassurance, observation, rehydration therapy and anti-inflammatory drugs such as nonsteroidal anti-inflammatory drugs;[17] dehydration is one of the most common causes of anesthesia mumps. Therefore, adequate rehydration therapy is fundamental for the treatment of anesthesia mumps.[17] Our patient was treated with nonsteroidal anti-inflammatory drugs, and the swelling subsided gradually within a week.\n\nTo prevent this complication, we suggest the use of an adaptive shaped soft pad for proper padding of face, to avoid direct compression of the parotid gland and ducts. Minimum turning of neck should be allowed to keep normal venous blood circulation, especially when the patient is placed in the prone position, or the duration of surgery is long. Premedication with anticholinergic drugs to decrease secretions, smooth intubation and extubation without disturbance or straining of the patient to avoid mechanical stimulation and occurrence of this unusual complication. Moreover, keeping an optimum hydration status during surgery is another important point in the prevention of this complication. In conclusion, proper use of anesthetic medication and technique, with adequate patient protection may help decrease this complication.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Liu FC Liou JT Li AH Chiou H Jr Day YJ Acute unilateral parotid glands enlargement following endotracheal general anesthesia: Report of two cases Chang Gung Med J 2007 30 453 7 18062177 \n2 Kati I Kurdoğlu Z Göktaş U Aytekin OC Avcu S Anesthesia mumps after cesarean section in pregnant woman Eur J Gen Med 2011 8 342 4 \n3 Ghatak T Gurjar M Samanta S Baronia AK A case of “Anesthesia mumps” from ICU Saudi J Anaesth 2013 7 222 3 23956735 \n4 Mutaf M Büyükgüral B An unusual postoperative complication: Anesthesia mumps Eur J Plast Surg 2007 29 335 8 \n5 Matsuki A Wakayama S Oyama T Acute transient swelling of the salivary glands during and following endotracheal anesthesia Anesthesist 1975 24 125 8 \n6 Kiran S Lamba A Chhabra B Acute pansialadenopathy during induction of anesthesia causing airway obstruction Anesth Analg 1997 85 1052 3 9356098 \n7 Kim LJ Klopfenstein JD Feiz-Erfan I Zubay GP Spetzler RF Postoperative acute sialadenitis after skull base surgery Skull Base 2008 18 129 34 18769650\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": null,
"issue": "9(3)",
"journal": "Saudi journal of anaesthesia",
"keywords": "Anesthesia; mumps; pain",
"medline_ta": "Saudi J Anaesth",
"mesh_terms": null,
"nlm_unique_id": "101500601",
"other_id": null,
"pages": "332-3",
"pmc": null,
"pmid": "26240559",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "23956735;18769650;9356098;1147203;18062177",
"title": "A case of anesthesia mumps after sacral laminectomy under general anesthesia.",
"title_normalized": "a case of anesthesia mumps after sacral laminectomy under general anesthesia"
} | [
{
"companynumb": "PK-FRESENIUS KABI-FK201600035",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ISOFLURANE"
},
"drugadditional": null,
... |
{
"abstract": "Interindividual variability in analgesic effects of nonsteroidal anti-inflammatory drugs prescribed for sickle cell disease (SCD) pain is attributed to polymorphisms in the CYP2C8 and CYP2C9 enzymes. We described CYP2C8 and CYP2C9 genotype/phenotype profiles and frequency of emergency department (ED) visits for pain management in an African American SCD patient cohort. DNA from 165 unrelated patients was genotyped for seven CYP2C8 and 15 CYP2C9 alleles using the iPLEX ADME PGx multiplexed panel. CYP2C8*1 (0.806),*2 (0.164), *3 (0.018), and *4 (0.012) alleles were identified. Genotype frequencies were distributed as homozygous wild type (66.7%), heterozygous (27.8%), and homozygous variant/compound heterozygous (5.4%), respectively. CYP2C9*1 (0.824), *2 (0.027), *3 (0.012), *5 (0.009), *6 (0.009), *8 (0.042), *9 (0.061), and *11(0.015) were observed with extensive (68.5%), intermediate (18.1%) and poor predicted metabolizers (0.6%), respectively. Fifty-two and 55 subjects, respectively had at least one variant CYP2C8 or CYP2C9 allele. Although the distribution of the CYP2C9 (p = 0.0515) phenotypes was marginally significantly in high and low ED users; some CYP2C8 and CYP2C9 allelic combinations observed in 15.2% (25) of the cohort are associated with higher risks for analgesic failure. CYP2C8 and CYP2C9 preemptive genotyping could potentially enable clinicians to identify patients with impaired metabolic phenotypes.",
"affiliations": "College of Nursing, University of Cincinnati, Cincinnati, Ohio, USA.;Department of Medicine, Georgia Regents University, Augusta, Georgia, USA.;Department of Medicine, Georgia Regents University, Augusta, Georgia, USA.;Department of Medicine, Georgia Regents University, Augusta, Georgia, USA.;Department of Biostatistics, Georgia Regents University, Augusta, Georgia, USA.;Department of Emergency Medicine Georgia Regents University, Augusta, Georgia, USA.;Department of Medicine, Georgia Regents University, Augusta, Georgia, USA.",
"authors": "Jaja|Cheedy|C|;Bowman|Latanya|L|;Wells|Leigh|L|;Patel|Niren|N|;Xu|Hongyan|H|;Lyon|Matt|M|;Kutlar|Abdullah|A|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D065729:Cytochrome P-450 CYP2C9; D065727:Cytochrome P-450 CYP2C8",
"country": "United States",
"delete": false,
"doi": "10.1111/cts.12260",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1752-8054",
"issue": "8(4)",
"journal": "Clinical and translational science",
"keywords": "CYP2C8; CYP2C9; NSAIDs; pharmacogenetics; sickle cell disease",
"medline_ta": "Clin Transl Sci",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000483:Alleles; D000755:Anemia, Sickle Cell; D000894:Anti-Inflammatory Agents, Non-Steroidal; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D059408:Pain Management",
"nlm_unique_id": "101474067",
"other_id": null,
"pages": "272-80",
"pmc": null,
"pmid": "25640739",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "15229460;15606441;21980265;11829203;22430884;16719391;19295432;24581091;23163547;24043992;11668219;18216720;19761371;19416438;19954515;22491019;18992652;20949441;22739144;19357842;15289789;17681167;23726390;23619115;23962911;19280158;24251363;21395648;22923496;24047136;22992667;10904451;20173083;21692610;14616425;15194568;19663669;19925388;24329188;11809254;17517247;24062210;19422321;14707031",
"title": "Preemptive Genotyping of CYP2C8 and CYP2C9 Allelic Variants Involved in NSAIDs Metabolism for Sickle Cell Disease Pain Management.",
"title_normalized": "preemptive genotyping of cyp2c8 and cyp2c9 allelic variants involved in nsaids metabolism for sickle cell disease pain management"
} | [
{
"companynumb": "US-JNJFOC-20150915134",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
"... |
{
"abstract": "Primary hepatic rhabdomyosarcoma is rare, making decisions regarding locoregional management with resection and/or conventional radiation difficult. We present a novel treatment approach for a pediatric patient diagnosed with rhabdomyosarcoma diffusely involving the liver. This patient underwent treatment with yttrium-90 (Y-90) microspheres followed by external beam radiation therapy (EBRT ) to residual disease, interdigitated with systemic chemotherapy. Initial post-radiation imaging showed significant response to treatment, and she experienced minimal acute toxicities and no long-term toxicities. She developed recurrent PET-avid disease 23 months after Y-90 treatment, necessitating further local and continued systemic therapies. We report on the tumor control following Y-90 and EBRT treatment.",
"affiliations": "Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, United States.;Department of Radiation Oncology, Stony Brook University Hospital, Stony Brook, NY, United States.;Division of Pediatric Hematology Oncology, Stony Brook Children's Hospital, Stony Brook, NY, United States.;Division of Pediatric Hematology Oncology, Stony Brook Children's Hospital, Stony Brook, NY, United States.;Division of Pediatric Hematology Oncology, Stony Brook Children's Hospital, Stony Brook, NY, United States.;Division of Pediatric Hematology Oncology, Stony Brook Children's Hospital, Stony Brook, NY, United States.;Department of Radiology, Stony Brook University Hospital, Stony Brook, NY, United States.;Department of Radiation Oncology, Stony Brook University Hospital, Stony Brook, NY, United States.;Department of Radiation Oncology, Stony Brook University Hospital, Stony Brook, NY, United States.",
"authors": "Patel|Rushil|R|;Roberson|John|J|;Prakash|Devina|D|;Meyer|Rina|R|;Hogan|Laura|L|;Azmy|Christeen|C|;Suprenant|Valmore|V|;Ryu|Samuel|S|;Stessin|Alexander|A|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5603/RPOR.a2021.0008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1507-1367",
"issue": "26(1)",
"journal": "Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology",
"keywords": "external beam radiation therapy; pediatrics; rhabdomyosarcoma; yttrium-90",
"medline_ta": "Rep Pract Oncol Radiother",
"mesh_terms": null,
"nlm_unique_id": "100885761",
"other_id": null,
"pages": "143-148",
"pmc": null,
"pmid": "34046225",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "21602502;28480066;20171502;30406959;20214218;19157721;29293557;19766639;7884423;32695311;18650514;19552767;25914774;23212597;14874125;26357620;25120955",
"title": "Potential alternative treatment approach for pediatric patient with diffusely infiltrative primary rhabdomyosarcoma of the liver.",
"title_normalized": "potential alternative treatment approach for pediatric patient with diffusely infiltrative primary rhabdomyosarcoma of the liver"
} | [
{
"companynumb": "US-CIPLA LTD.-2021US06480",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Mucormycosis is a life-threatening infection. This is the first report of transdiaphragmatic mucormycosis in a series of 3 patients. We observed this phenomenon in 11% of patients. Clinicians should be aware of this possibly underreported entity, and as a consequence we envision more comprehensive imaging studies in patients with mucormycosis.",
"affiliations": "Faculty of Medicine, Department I of Internal Medicine, University Hospital of Cologne, University of Cologne.;Department of Diagnostic and Interventional Radiology, University of Cologne, Germany.;Department of General, Visceral and Cancer Surgery, University of Cologne, Germany.;Institute of Pathology, University Hospital of Cologne, University of Cologne, Germany.;Faculty of Medicine, Department I of Internal Medicine, University Hospital of Cologne, University of Cologne.",
"authors": "Koehler|Philipp|P|;Reimer|Robert|R|;Wahba|Roger|R|;Schömig-Markiefka|Birgid|B|;Cornely|Oliver A|OA|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciz533",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "70(5)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "isavuconazole; liposomal amphotericin B; posaconazole; radiology; zygomycosis",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000935:Antifungal Agents; D006801:Humans; D009091:Mucormycosis; D014230:Triazoles",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "940-942",
"pmc": null,
"pmid": "31222210",
"pubdate": "2020-02-14",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Transdiaphragmatic Mucormycosis.",
"title_normalized": "transdiaphragmatic mucormycosis"
} | [
{
"companynumb": "DE-ASTELLAS-2019US023659",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": "3",
... |
{
"abstract": "The COVID-19 pandemic has raised questions about the management of systemic immunosuppressive treatments for rheumatic conditions. It is well known that rheumatic patients are at risk of developing infections because of their immunocompromised state. Moreover, drugs such as hydroxychloroquine or tocilizumab that are widely used to treat rheumatic diseases are now being used to treat COVID-19. The aim of this multicentre retrospective study of rheumatic patients in the Italian regions of Lombardy and Marche was to determine whether patients receiving biological or small molecules treatment are more susceptible to the development of COVID-19 than the general population.\n\n\n\nThe local registry data of 10,260 rheumatic patients being treated with bDMARDs or small molecules were evaluated from 15 March to 23 April 2020. The final analysis was based on the registry data relating to 7.204, telephone contacts and/or outpatient visits.\n\n\n\nForty-seven of the 7.204 patients were diagnosed with COVID-19, seven of whom died; the patients who had symptoms resembling those of COVID-19 but had negative swabs were considered negative for the disease. The overall infection rate was 0.65, and the crude case fatality risk (CFR) in the patients with COVID-19 was 14.9%. There was no difference in the mortality rate among the patients receiving the different individual biological drugs or small molecules.\n\n\n\nOur findings suggest that the susceptibility of rheumatic patients to COVID-19 is the same as that of the general population, but confirm that age, disease duration, and the number of co-morbidities are associated with an increased risk of a severe form of the disease. It seems that immunosuppressants drugs do not effectively represent a risk factor for COVID- 19.",
"affiliations": "Rheumatology Unit, ASST-Fatebenefratelli L. Sacco University Hospital, University of Milan, Italy. Electronic address: piercarlo.sarziputtini@gmail.com.;Rheumatology Unit, ASST-Fatebenefratelli L. Sacco University Hospital, University of Milan, Italy. Electronic address: daniela.marotto@tiscali.it.;Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, Milan, Italy. Electronic address: roberto.caporali@unimi.it.;Rheumatology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Electronic address: c.montecucco@smatteo.pv.it.;Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, Milan, Italy. Electronic address: ennio.favalli@gmail.com.;Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. Electronic address: franco.franceschini@unibs.it.;Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. Electronic address: fredi.micaela@gmail.com.;Rheumatology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Electronic address: silvia.balduzzi@hotmail.it.;Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. Electronic address: bazzani.reumatologia@gmail.com.;Rheumatology Unit, ASST-Fatebenefratelli L. Sacco University Hospital, University of Milan, Italy. Electronic address: sara.bongiovanni@unimi.it.;Rheumatology Unit, ASST-Fatebenefratelli L. Sacco University Hospital, University of Milan, Italy. Electronic address: vale.gio@fastwebnet.it.;Rheumatology Unit Ospedale di Circolo - Fondazione Macchi, ASST dei Sette Laghi, Varese, Italy. Electronic address: battic@tiscali.it.;Rheumatology Unit Ospedale di Circolo - Fondazione Macchi, ASST dei Sette Laghi, Varese, Italy. Electronic address: antonella.cappelli@asst-settelaghi.it.;Rheumatology Unit Ospedale di Circolo - Fondazione Macchi, ASST dei Sette Laghi, Varese, Italy. Electronic address: patrizia.balzarini@asst-settelaghi.it.;Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR) IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address: dagna.lorenzo@unisr.it.;Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR) IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address: sartorelli.silvia@hsr.it.;SSD Allergologia e Immunologia Clinica, ASST Mantova, Italy. Electronic address: viviana.ravagnani@asst-mantova.it.;SSD Allergologia e Immunologia Clinica, ASST Mantova, Italy. Electronic address: silvia.tamanini@asst-mantova.it.;Rheumatological Clinic, Ospedale \"Carlo Urbani\", Università Politecnica delle Marche, Jesi, Ancona, Italy. Electronic address: sonia.farah91@gmail.com.;Department of Internal Medicine ASST Ovest Milanese, Legnano, Italy; Rheumatology Department ASST Ovest Milanese, Magenta, Italy. Electronic address: faggioli.paola@gmail.com.;Department of Internal Medicine ASST Ovest Milanese, Legnano, Italy. Electronic address: laura.castelnuovo@gmail.com.;Rheumatology Department ASST Ovest Milanese, Magenta, Italy. Electronic address: alfredomarialurati@asst-ovestmi.it.;Department of Clinical and Biomedical Sciences \"Luigi Sacco\", University of Milano, Milano, Italy; III Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milano, Italy. Electronic address: massimo.galli@unimi.it.;Rheumatological Clinic, Ospedale \"Carlo Urbani\", Università Politecnica delle Marche, Jesi, Ancona, Italy. Electronic address: fausto.salaffi@gmail.com.",
"authors": "Sarzi-Puttini|Piercarlo|P|;Marotto|Daniela|D|;Caporali|Roberto|R|;Montecucco|Carlo Maurizio|CM|;Favalli|Ennio Giulio|EG|;Franceschini|Franco|F|;Fredi|Michela|M|;Balduzzi|Silvia|S|;Bazzani|Chiara|C|;Bongiovanni|Sara|S|;Giorgi|Valeria|V|;Batticciotto|Alberto|A|;Cappelli|Antonella|A|;Balzarini|Patrizia|P|;Dagna|Lorenzo|L|;Sartorelli|Silvia|S|;Ravagnani|Viviana|V|;Tamanini|Silvia|S|;Farah|Sonia|S|;Faggioli|Paola|P|;Castelnovo|Laura|L|;Lurati|Alfredo Maria|AM|;Galli|Massimo|M|;Salaffi|Fausto|F|",
"chemical_list": "D018501:Antirheumatic Agents",
"country": "England",
"delete": false,
"doi": "10.1016/j.jaut.2020.102545",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0896-8411",
"issue": "116()",
"journal": "Journal of autoimmunity",
"keywords": "Biologics; COVID 19; Dmards; Infections; Registries; Rheumatic disease; Small molecules",
"medline_ta": "J Autoimmun",
"mesh_terms": "D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents; D000086382:COVID-19; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007558:Italy; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D012189:Retrospective Studies; D012216:Rheumatic Diseases; D000086402:SARS-CoV-2",
"nlm_unique_id": "8812164",
"other_id": null,
"pages": "102545",
"pmc": null,
"pmid": "32972804",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Prevalence of COVID infections in a population of rheumatic patients from Lombardy and Marche treated with biological drugs or small molecules: A multicentre retrospective study.",
"title_normalized": "prevalence of covid infections in a population of rheumatic patients from lombardy and marche treated with biological drugs or small molecules a multicentre retrospective study"
} | [
{
"companynumb": "IT-AMGEN-ITASP2021009595",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Dexrazoxane(DXZ)is a drug used for treating extravasation(EV)of anthracycline antitumor antibiotics based on 2 of its mechanisms of action through Topo II. In Japan, it has been used in approximately 150 patients as of January 2016, but there is no detailed report. Three DXZ treatments were carried out for 2 cases in our facilities. One case involved a patient's right forearm while 2 cases occurred involved the left and right forearms of each of the patients, and both were Grade 2(CTCAE v4.0). The EV healed in all cases, and surgical procedures were not needed. Moreover, chemotherapy was performed without extending the treatment period. One year 8 months after administration there was no recurrence in both cases, and skin disorders did not develop. In our hospital, DXZ is managed based on the regimen as well as the anticancer agents, and administration within 6 hours from extravasation was made possible by the cooperation of pharmaceutical wholesalers. Nurses and pharmacists who engage in chemotherapy are encouraged to participate in the study sessions of the hospital, it has been the effort to learn the day-to-day knowledge and technology. DXZ is effective in treating the EV of anthracycline antitumor antibiotics and may be well tolerated. To properly use DXZ by integrating these cases, it is necessary to verify its effectiveness and safety.",
"affiliations": "Pharmaceutical Dept. Chibanishi General Hospital.",
"authors": "Kawamoto|Satoshi|S|;Shirahata|Takuya|T|;Katori|Tetsuya|T|;Izumo|Takafumi|T|;Kadono|Hitomi|H|;Fujita|Hiroaki|H|;Okamoto|Rumiko|R|",
"chemical_list": "D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D064730:Dexrazoxane",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D064730:Dexrazoxane; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005260:Female; D006761:Hospitals; D006801:Humans; D008875:Middle Aged; D009369:Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2517-2521",
"pmc": null,
"pmid": "28028257",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Effectiveness of Dexrazoxane for Extravasation of Anthracycline Antitumor Antibiotics - Reporting Measures Developed against Extravasation in the Hospital.",
"title_normalized": "effectiveness of dexrazoxane for extravasation of anthracycline antitumor antibiotics reporting measures developed against extravasation in the hospital"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1033463",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nInfants born with tuberous sclerosis complex, a genetic condition resulting from a mutation in TSC1 or TSC2, are at increased risk for intellectual disability and/or autism. Features of epilepsy, neuropathology, genetics, as well as timing and type of mechanism-based medications have been proposed as risk factors. Neurodevelopmental outcomes have been reported among these studies; however, few include data about the individuals' early neurodevelopmental profile, a factor that may contribute significantly to these outcomes. Further, there is no clinical standard for the neurodevelopmental assessment of these infants. The paucity of data regarding the natural history of neurodevelopment in infants with tuberous sclerosis complex and the lack of a gold standard for neurodevelopmental evaluation present a significant challenge for clinicians and researchers.\n\n\nMETHODS\nDuring the first year of life, we tracked the onset of infantile spasms, the type and timing of antiepileptic treatments, and the associated response of two age-matched infants with tuberous sclerosis complex. We also employed Capute Scales as a part of a structured neurodevelopmental evaluation to characterize and compare their neurodevelopmental profiles.\n\n\nRESULTS\nInfant 1 developed infantile spasms with confirmed hypsarrhythmia at 4 months of age. Treatment with vigabatrin was initiated within 24 hours with near immediate cessation of seizures and no further seizures to date. Expressive language delay was detected at 12 months and treated with speech and/or language therapy. Infant 2 developed complex partial seizures at 1 month. Treatment included levetiracetam, oxcarbazepine, and the ketogenic diet. Vigabatrin was initiated on detection of hypsarrhythmia after 4 months. Intractable epilepsy persists to date. Global developmental delay was evident by 8 months and treated with physical, occupational, and speech and/or language therapy.\n\n\nCONCLUSIONS\nMany risk factors have been associated with intellectual disability and/or autism in individuals with tuberous sclerosis complex; however, few data are available regarding practical clinical tools for early identification. In our case series, inclusion of the Capute Scales as a part of routine medical care led to the identification of developmental delays in the first 12 months of life and selection of targeted neurodevelopmental interventions. Development of a risk-based assessment using this approach will be the focus of future studies as it may provide a potential window of opportunity for both research and clinical purposes. In research, it may serve as an objective outcome measure. Clinically, this type of assessment has potential for informing clinical treatment decisions and serving as a prognostic indicator of long-term cognitive and psychiatric outcomes.",
"affiliations": "Tuberous Sclerosis Clinic, Kennedy Krieger Institute, Baltimore, Maryland; Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, Maryland; Clinical Trials Unit, Hugo W. Moser Research Institute, Inc., Kennedy Krieger Institute, Baltimore, Maryland; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: tsclinic@kennedykrieger.org.;Tuberous Sclerosis Clinic, Kennedy Krieger Institute, Baltimore, Maryland; Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, Maryland; Clinical Trials Unit, Hugo W. Moser Research Institute, Inc., Kennedy Krieger Institute, Baltimore, Maryland.;Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, Maryland.;Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Neuropsychology, Kennedy Krieger Institute, Baltimore, Maryland; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Neurology, The John M. Freeman Pediatric Epilepsy Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Tuberous Sclerosis Clinic, Kennedy Krieger Institute, Baltimore, Maryland; Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, Maryland; Clinical Trials Unit, Hugo W. Moser Research Institute, Inc., Kennedy Krieger Institute, Baltimore, Maryland; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, Maryland.",
"authors": "Gipson|Tanjala T|TT|;Gerner|Gwendolyn|G|;Srivastava|Siddharth|S|;Poretti|Andrea|A|;Vaurio|Rebecca|R|;Hartman|Adam|A|;Johnston|Michael V|MV|",
"chemical_list": "D000927:Anticonvulsants",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-8994",
"issue": "51(3)",
"journal": "Pediatric neurology",
"keywords": "Capute Scales; cognition; development; everolimus; mTOR inhibitors; sirolimus; tuberous sclerosis; vigabatrin",
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D000927:Anticonvulsants; D001921:Brain; D002657:Child Development; D018450:Disease Progression; D042241:Early Diagnosis; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D015997:Neonatal Screening; D014402:Tuberous Sclerosis",
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "398-402",
"pmc": null,
"pmid": "25160545",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "23733802;21204819;21959128;15254843;22695035;24053982;17304050;22189265;9075016;16417883;24417555;15155396;12622312;18801034;8132114;8889388;19369101;21668442;21507691;3817315;8603782;16566871;23437388;22021912",
"title": "Early neurodevelopmental screening in tuberous sclerosis complex: a potential window of opportunity.",
"title_normalized": "early neurodevelopmental screening in tuberous sclerosis complex a potential window of opportunity"
} | [
{
"companynumb": "US-UCBSA-2014012193",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "Azole prophylaxis has been shown to be effective in preventing invasive fungal infections (IFIs) and increasing survival in patients with prolonged neutropenia after myelosuppressive chemotherapy for haematological malignancies. Similarly, empirical antifungal therapy for persistent neutropenic fever has been shown to reduce IFI-related mortality. However, to date, there is little information with regard to the outcome of patients who receive both strategies. Here, we present our retrospective data on three cohorts of patients receiving empirical or targeted antifungal therapy after different antifungal prophylaxis regimens. All records from patients who received myelosuppressive induction chemotherapy for acute myelogenous leukemia (AML) in our centre from 2004-2010 were analysed. From 2004-2006, itraconazole was used as antifungal prophylaxis; for the first 6 months in 2007, local polyenes and from mid-2007 till 2010, posaconazole. Data of 315 courses of chemotherapy in 211 patients were analysed. Antifungal therapy (empirical or targeted, time point and antifungal agent at the physician's discretion) was initiated in 50/174 (29 %), 7/18 (39 %) and 34/123 courses (28 %, p = 0.615) in the itra cohort, the cohort without systemic prophylaxis and the posa cohort, respectively, and was effective in 24/50 (48 %), 5/7 (71 %) and 22/34 courses (65 %, p = 0.221), respectively. IFI occurred in 25/174 (14 %), 4/18 (22 %) and 16/123 (13 %) courses, respectively (p = 0.580). IFI-related survival was not different in the three cohorts. Antifungal treatment in patients with AML who received azole prophylaxis resulted in the expected efficacy-importantly, prior posaconazole prophylaxis did not render subsequent antifungal treatment less effective than prior itraconazole prophylaxis.",
"affiliations": "Medizinische Klinik und Poliklinik III, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany. corinna.hahn-ast@ukb.uni-bonn.de.;Medizinische Klinik und Poliklinik III, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.;Medizinische Klinik und Poliklinik III, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.;Medizinische Klinik und Poliklinik III, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.;Paracelsus-Klinik Osnabrück, Osnabrück, Germany.;Institut für Medizinische Statistik, Informatik und Epidemiologie, Universität zu Köln, Köln, Germany.;Institut für Medizinische Statistik, Informatik und Epidemiologie, Universität zu Köln, Köln, Germany.;Medizinische Klinik und Poliklinik III, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.;Klinik für Innere Medizin II, Abteilung für Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany.;Medizinische Klinik und Poliklinik III, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.;Medizinische Klinik und Poliklinik III, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.",
"authors": "Hahn-Ast|C|C|;Felder|L|L|;Mayer|K|K|;Mückter|S|S|;Ruhnke|M|M|;Hein|R|R|;Hellmich|M|M|;Schwab|K|K|;Rachow|T|T|;Brossart|P|P|;von Lilienfeld-Toal|M|M|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; D017964:Itraconazole; C101425:posaconazole",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-016-2630-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "95(6)",
"journal": "Annals of hematology",
"keywords": "Antifungal prophylaxis; Antimycotic chemotherapy; Empirical antifungal therapy; Febrile neutropenia; Invasive fungal infections",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D015331:Cohort Studies; D016503:Drug Delivery Systems; D036262:Empirical Research; D064147:Febrile Neutropenia; D005260:Female; D006801:Humans; D017964:Itraconazole; D008297:Male; D008875:Middle Aged; D056990:Post-Exposure Prophylaxis; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D014230:Triazoles",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1001-9",
"pmc": null,
"pmid": "27021301",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcome of empirical or targeted antifungal therapy after antifungal prophylaxis in febrile neutropenia.",
"title_normalized": "outcome of empirical or targeted antifungal therapy after antifungal prophylaxis in febrile neutropenia"
} | [
{
"companynumb": "DE-JNJFOC-20160512634",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CASPOFUNGIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe objective of this study was to present a case and review serotonin syndrome and the risk of occurrence in children and adolescents on multiple psychotropic medications.\n\n\nMETHODS\nThe clinical history of a patient in the University of South Florida's child and adolescent psychiatry clinic is presented. Literature review on serotonin syndrome, attention-deficit/hyperactivity disorder (ADHD), and psychostimulants was conducted through PubMed.\n\n\nCONCLUSIONS\nWe have presented a case of possible serotonin-related abnormal movements in an adolescent girl prescribed stimulants and multiple serotonergic medications. Serotonin syndrome may be precipitated through drug interactions that increase serum levels of psychotropic medications. Patients with ADHD often have comorbid psychiatric illness requiring treatment with medication. Amphetamine salts are an often-overlooked agent that potentiates serotonin through monoamine oxidase inhibitor (MAO) inhibition and neurotransmitter release. Children and adolescents on multiple psychotropic medications should be closely monitored for the triad of altered mental status, neuromuscular abnormalities, and autonomic hyperactivity.\n\n\nCONCLUSIONS\nPatients with ADHD often have comorbid psychiatric illness and are treated with multiple psychotropic medications. Given the effects of drug-drug interactions and the serotonergic effects of psychostimulants, clinicians should remain vigilant for the triad of altered mental status, neuromuscular abnormalities, and autonomic hyperactivity seen in serotonin syndrome.",
"affiliations": "University of South Florida Health, Morsani College of Medicine, Tampa, FL.",
"authors": "Davis|Chemar R|CR|;Hernandez|Michael|M|;Stock|Saundra|S|",
"chemical_list": "D000697:Central Nervous System Stimulants",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000375",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "43(1)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity; D000697:Central Nervous System Stimulants; D005260:Female; D006801:Humans; D019338:Polypharmacy; D020230:Serotonin Syndrome",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "28-30",
"pmc": null,
"pmid": "31934921",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Adolescent Polypharmacy and Serotonin Syndrome.",
"title_normalized": "adolescent polypharmacy and serotonin syndrome"
} | [
{
"companynumb": "US-BION-008518",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo determine whether treatment of attention-deficit/hyperactivity disorder (ADHD) with osmotic-release oral system (OROS) methylphenidate promotes abstinence from smoking among smokers with ADHD who have greater severity of ADHD symptoms at baseline or greater improvement in ADHD during treatment.\n\n\nMETHODS\nThis is a secondary analysis of data from a randomized, double-blind, 11-week trial conducted between December 2005 and January 2008 at 6 clinical sites; the original trial was sponsored by the National Drug Abuse Clinical Trials Network. Adult cigarette smokers (aged 18-55 years) who met DSM-IV criteria for ADHD were randomly assigned to OROS methylphenidate (72 mg/d) (n = 127) or matching placebo (n = 128). All participants received nicotine patches (21 mg/d) and weekly individual smoking cessation counseling. Logistic regression was used to model prolonged abstinence from smoking (ascertained by self-report and breath carbon monoxide testing) as a function of treatment, baseline ADHD Rating Scale-IV (ADHD-RS) score, change in ADHD-RS score during treatment, and their interactions.\n\n\nRESULTS\nTreatment interacted with both ADHD-RS score at baseline (P = .01) and change in ADHD-RS score during treatment (P = .008). Among patients with higher ADHD-RS scores (> 36) at baseline and the most improvement in ADHD during treatment (ADHD-RS change score ≥ 24), 70.0% of those who took OROS methylphenidate achieved abstinence from smoking compared to 36.8% of those who took placebo (P = .02). In contrast, among patients with the lowest ADHD-RS baseline scores (≤ 30), 30.3% of those who took OROS methylphenidate achieved abstinence from smoking compared to 60.7% of those who took placebo (P = .02).\n\n\nCONCLUSIONS\nOROS methylphenidate, in combination with nicotine patch, may be an effective treatment for nicotine dependence among smokers with more severe ADHD and more robust response of ADHD symptoms to medication. OROS methylphenidate may be counterproductive among smokers with lower severity of ADHD.\n\n\nBACKGROUND\nClinicalTrials.gov identifier: NCT00253747.",
"affiliations": "New York State Psychiatric Institute, 1051 Riverside Drive, Unit 51, Room 3717, New York, NY 10032 nunesed@nyspi.columbia.edu.",
"authors": "Nunes|Edward V|EV|;Covey|Lirio S|LS|;Brigham|Gregory|G|;Hu|Mei-Chen|MC|;Levin|Frances R|FR|;Somoza|Eugene C|EC|;Winhusen|Theresa M|TM|",
"chemical_list": "D000697:Central Nervous System Stimulants; D008774:Methylphenidate",
"country": "United States",
"delete": false,
"doi": "10.4088/JCP.12m08155",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-6689",
"issue": "74(10)",
"journal": "The Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "J Clin Psychiatry",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity; D001682:Biological Availability; D000697:Central Nervous System Stimulants; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004311:Double-Blind Method; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008774:Methylphenidate; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D016540:Smoking Cessation; D061485:Tobacco Use Cessation Devices; D014029:Tobacco Use Disorder; D016896:Treatment Outcome",
"nlm_unique_id": "7801243",
"other_id": null,
"pages": "983-90",
"pmc": null,
"pmid": "24229749",
"pubdate": "2013-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "20071099;21652734;5042823;15983792;10591283;19917596;1932883;15769553;15063992;3904487;12745503;16585449;22406192;20051569;15100209;21679263;17447052;12325108;22364776;11605079;12684732;21854289;17485608;17679638;8611060;18838643;8507351;19023824;20554984;11255931;16085513;7285484;17624979;8927677;20492837;11967475;20219292;3661797;8749796;18640914;17290726;16055769;9477929;19395647;17606817;16203959",
"title": "Treating nicotine dependence by targeting attention-deficit/ hyperactivity disorder (ADHD) with OROS methylphenidate: the role of baseline ADHD severity and treatment response.",
"title_normalized": "treating nicotine dependence by targeting attention deficit hyperactivity disorder adhd with oros methylphenidate the role of baseline adhd severity and treatment response"
} | [
{
"companynumb": "US-JNJFOC-20131114087",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Second-generation antipsychotic agents are commonly used by clinicians for the treatment of various psychiatric and medical conditions. Despite their presumed safety, an overdose with olanzapine may lead to the development of anticholinergic toxicity. The anticholinergic toxidrome is characterized by both central and peripheral physical findings. Central anticholinergic syndrome, a term used to describe the symptoms that arise from reduced cholinergic activity in the central nervous system, is characterized primarily by signs and symptoms consistent with hyperactive delirium. Signs of peripheral anticholinergia include mydriasis and blurred vision, tremors, ataxia, fever/hyperthermia, flushed and dry skin, dry oral mucosa, decreased bowel sounds, constipation, and urinary retention, among other symptoms. In extreme cases, central anticholinergic syndrome can be associated with seizures, coma, respiratory failure, and cardiovascular collapse.\n\n\n\nTo provide scientific evidence regarding the efficacy and safety of physostigmine use in cases of anticholinergic toxicity.\n\n\n\nWe conducted a comprehensive review of the published literature on the symptoms, diagnosis, and treatment of anticholinergic toxicity.\n\n\n\nCurrently the recommended treatment for olanzapine overdose, as is the case of most severe anticholinergic toxicity cases, involves supportive care, along with cardiac, neurological, and respiratory status monitoring. In addition, we detail the symptoms characteristic of anticholinergic toxicity, using the case of a patient experiencing central anticholinergic syndrome after an overdose with olanzapine.\n\n\n\nPhysostigmine, a tertiary acetylcholinesterase inhibitor, can be used to assist in the both the diagnosis and management of severe anticholinergic toxicity associated with an olanzapine overdose, which might be applicable to the antimuscarinic toxidrome associated with the ingestion of agents with significant anticholinergic activity.",
"affiliations": "Department of Psychiatry & Behavioral Sciences, Stanford University 401 Quarry Road, Stanford, CA.;Department of Psychiatry & Behavioral Sciences, Stanford University 401 Quarry Road, Stanford, CA. Electronic address: jrm@stanford.edu.",
"authors": "Serrano|Wilmarie Cidre|WC|;Maldonado|Jose|J|",
"chemical_list": "D018680:Cholinergic Antagonists; D010830:Physostigmine; D000110:Acetylcholinesterase; D000077152:Olanzapine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jaclp.2020.12.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2667-2960",
"issue": "62(3)",
"journal": "Journal of the Academy of Consultation-Liaison Psychiatry",
"keywords": "anticholinergic toxicity; antimuscarinic toxidrome; consultation liaison psychiatry; delirium; olanzapine overdose; psychopharmacology",
"medline_ta": "J Acad Consult Liaison Psychiatry",
"mesh_terms": "D000110:Acetylcholinesterase; D064807:Anticholinergic Syndrome; D018680:Cholinergic Antagonists; D006801:Humans; D000077152:Olanzapine; D010830:Physostigmine",
"nlm_unique_id": "101775059",
"other_id": null,
"pages": "285-297",
"pmc": null,
"pmid": "34102130",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "The Use of Physostigmine in the Diagnosis and Treatment of Anticholinergic Toxicity After Olanzapine Overdose: Literature Review and Case Report.",
"title_normalized": "the use of physostigmine in the diagnosis and treatment of anticholinergic toxicity after olanzapine overdose literature review and case report"
} | [
{
"companynumb": "US-QILU PHARMACEUTICAL CO.LTD.-QLU-000148-2021",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugaddi... |
{
"abstract": "Background and aims: Patients with COVID-19 frequently present abnormal elevated liver function tests of unknown clinical significance. We aimed to investigate the characteristics and factors influencing outcome in patients with confirmed SARS-CoV-2 infection and liver injury on admission.Methods: This is a retrospective observational study of patients hospitalized in two COVID units in Romania. Relevant data on clinical and laboratory parameters and medication administered during the admission were analyzed to identify predictors of a negative outcome. Patients with confirmed COVID-19 and liver function tests (LFTs) above the upper limit of normal were included in the analysis.Results: From 1,207 patients, we identified 134 patients (11%) with abnormal LFTs during hospitalization. The majority of patients had mildly elevated levels and a predominantly cholestatic pattern of liver injury. Patients who received lopinavir/ritonavir were more likely to have increased ALAT levels (p<0.0001). Sixteen patients had pre-existing chronic liver disease, and they were more likely to suffer from severe COVID-19 (p=0.009) and have a negative outcome (p<0.001), but on multivariate analysis, only the severity of COVID-19 was predictive of death (OR 69.9; 95% CI 6.4-761.4).Conclusions: Mild liver injury is relatively common in COVID-19 and possibly influenced by medication. Patients with chronic liver disease are at high risk for negative outcome, but the severity of the infection is the only predictor of death.",
"affiliations": "Gastroenterology Department, Colentina Clinical Hospital, Bucharest, Romania.;Gastroenterology Department, Mureș County Clinical Hospital, Romania.;Gastroenterology Department, Colentina Clinical Hospital, Bucharest, Romania.;Gastroenterology Department, Mureș County Clinical Hospital, Romania.;Pathology Department, Colentina Clinical Hospital, Bucharest, Romania.;Pathology Department, Colentina Clinical Hospital, Bucharest, Romania.;Gastroenterology Department, Colentina Clinical Hospital, Bucharest, Romania.;Gastroenterology Department, Mureș County Clinical Hospital, Romania.;Gastroenterology Department, Colentina Clinical Hospital, Bucharest, Romania.",
"authors": "Voiosu|Andrei|A|;Roman|Adina|A|;Pop|Ruxandra|R|;Boeriu|Alina|A|;Popp|Cristiana|C|;Zurac|Sabina|S|;Voiosu|Theodor|T|;Dobru|Daniela|D|;Mateescu|Bogdan|B|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.2478/rjim-2021-0027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1220-4749",
"issue": null,
"journal": "Romanian journal of internal medicine = Revue roumaine de medecine interne",
"keywords": "COVID-19; SARS-CoV-2; antiviral therapy; drug-induced liver injury; hepatitis; hydroxychloroquine; liver injury; lopinavir/ritonavir",
"medline_ta": "Rom J Intern Med",
"mesh_terms": null,
"nlm_unique_id": "9304507",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34253002",
"pubdate": "2021-07-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Characteristics and outcomes of patients with COVID-19 and liver injury: a retrospective analysis and a multicenter experience.",
"title_normalized": "characteristics and outcomes of patients with covid 19 and liver injury a retrospective analysis and a multicenter experience"
} | [
{
"companynumb": "RO-ABBVIE-21K-135-4096733-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOCILIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "To determine whether the diameter of intrahepatic and extrahepatic bile ducts and pancreatic ducts in patients on methadone maintenance therapy is increased when compared with control subjects.\n\n\n\nBetween January 1, 2000 and March 15, 2013, a total of 97 patients (mean age 49.9, range 22-79, 65 male, 32 female) were identified who were receiving chronic methadone maintenance therapy (MMT) when they underwent imaging with abdominal MRI or a contrast-enhanced abdominopelvic CT. A group of 97 consecutive non-MMT control patients (mean age 51.4, range 21-86, 45 male, 52 female) who underwent imaging with abdominal MRI or contrast-enhanced abdominopelvic CT were identified. Patients with known pancreaticobiliary pathology that may confound biliary ductal measurements were excluded. Blinded interpretation was performed, documenting the diameters of the intrahepatic and extrahepatic bile ducts and pancreatic ducts. Descriptive statistics were performed.\n\n\n\nPatients on MMT demonstrated increased bile duct diameter, with an average increase in duct diameter of 2.39 mm for the common bile duct (p < 0.001; 95% CI 1.88-2.90 mm), 1.43 mm for the intrahepatic bile ducts (p < 0.001; 95% CI 1.12-1.74 mm), and 0.90 mm for the pancreatic duct (p < 0.001; 95% CI 0.64-1.16 mm). No statistically significant correlation was found between ductal diameters and the daily dose of methadone.\n\n\n\nPatients on methadone maintenance therapy demonstrate significantly increased intra- and extrahepatic bile duct and pancreatic duct diameter when compared with controls. There was no correlation between the dose of methadone and ductal diameter.",
"affiliations": "Department of Radiology, Boston University Medical Center, 820 Harrison Ave, FGH Building, 3rd Floor, Boston, MA, 02118, USA. DBBATES@mgh.harvard.edu.;Department of Radiology, Boston University Medical Center, 820 Harrison Ave, FGH Building, 3rd Floor, Boston, MA, 02118, USA.;Renaissance Imaging Medical Associates, 18436 Roscoe Boulevard, Northridge, CA, 91325, USA.;Department of Radiology, Stanford University Medical Center, 300 Pasteur Drive, 5621, Stanford, CA, 94305-5105, USA.;Department of Radiology, Boston University Medical Center, 820 Harrison Ave, FGH Building, 3rd Floor, Boston, MA, 02118, USA.;Department of Radiology, Boston University Medical Center, 820 Harrison Ave, FGH Building, 3rd Floor, Boston, MA, 02118, USA.;Department of Radiology, Boston University Medical Center, 820 Harrison Ave, FGH Building, 3rd Floor, Boston, MA, 02118, USA.",
"authors": "Bates|David D B|DD|0000-0002-3105-156X;Tamayo-Murillo|Dorathy|D|;Kussman|Steven|S|;Luce|Adam|A|;LeBedis|Christina A|CA|;Soto|Jorge A|JA|;Anderson|Stephan W|SW|",
"chemical_list": "D003287:Contrast Media; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1007/s00261-016-0946-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "42(3)",
"journal": "Abdominal radiology (New York)",
"keywords": "Bile duct; Hepatobiliary; Methadone; Opiate; Opioid; Pancreatic duct",
"medline_ta": "Abdom Radiol (NY)",
"mesh_terms": "D000328:Adult; D000368:Aged; D001652:Bile Ducts; D016022:Case-Control Studies; D003287:Contrast Media; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008691:Methadone; D008875:Middle Aged; D009293:Opioid-Related Disorders; D010183:Pancreatic Ducts; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101674571",
"other_id": null,
"pages": "884-889",
"pmc": null,
"pmid": "27770163",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Biliary and pancreatic ductal dilation in patients on methadone maintenance therapy.",
"title_normalized": "biliary and pancreatic ductal dilation in patients on methadone maintenance therapy"
} | [
{
"companynumb": "PHHY2017US074375",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Adult guidelines recommend BEP (bleomycin, etoposide, cisplatin) for all ovarian germ cell tumours, causing debilitating toxicities in young patients who will survive long term. Paediatricians successfully reduce toxicities by using lower bleomycin doses and substituting carboplatin for cisplatin, while testicular and paediatric immature teratomas (ITs) are safely managed with surgery alone.\n\n\n\nThe aim was to determine whether reduced-toxicity treatment could rationally be extended to patients older than 18 years.\n\n\n\nMulticentre cohort study was carried out in four large UK cancer centres over 12 years.\n\n\n\nOne hundred thirty-eight patients were enrolled. Overall survival was 93%, and event-free survival (EFS) was 72%. Neoadjuvant/adjuvant chemotherapy (82% BEP) caused 27 potentially chronic toxicities, and one patient subsequently died from acute lymphoblastic leukaemia. There was no difference in histology, stage or grade in patients ≤/>18 years, and EFS was not different in these age groups (≤18:28% and >18:28%; log-rank P = 0.96). Histological subtype powerfully predicted EFS (log-rank P = 4.9 × 10-7). Neoadjuvant/adjuvant chemotherapy reduced future relapse/progression in dysgerminoma (n = 37, chemo:0% vs. no chemo:20%), yolk sac tumour (n = 23, 26.3% vs.75%) and mixed germ cell tumour (n = 32, 40%vs.70%) but not in IT (n = 42, 33% vs.15%). Additionally, we observed no radiological responses to chemotherapy in ITs, pathological IT grade did not predict EFS (univariate hazard ratio 0.82, 95% confidence interval: 0.57-1.19, P = 0.94) and there were no deaths in this subtype.\n\n\n\nSurvival was excellent but chemotherapy toxicities were severe, implying significant overtreatment. Our data support the extension of reduced-toxicity, paediatric regimens to adults. Our practice-changing findings that IT was chemotherapy resistant and pathological grade uninformative strongly endorse exclusive surgical management of ovarian ITs at all ages.",
"affiliations": "Barts Health NHS Trust, West Smithfield, London, EC1A 7BE, UK; University College Hospital, 235 Euston Road London, NW1 2BU, UK; University Hospitals Bristol NHS Foundation Trust, Upper Maudlin Street, Bristol, BS2 8HW, UK; University of Bristol, Senate House, Tyndall Avenue, Bristol BS8 1TH, UK.;The Royal Marsden Hospital, 203 Fulham Rd, Chelsea, London SW3 6JJ, UK.;The Wolfson Institute, CRUK Barts Cancer Centre, Queen Mary University London, Charterhouse Square, London EC1M 6BQ, UK; Cancer Intelligence, Cancer Research UK, Angel Building, 407 St John Street, London EC1V 4AD, UK.;Barts Health NHS Trust, West Smithfield, London, EC1A 7BE, UK; Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.;University College Hospital, 235 Euston Road London, NW1 2BU, UK.;University College Hospital, 235 Euston Road London, NW1 2BU, UK.;Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Research Department of Medical Education, UCL Medical School, Royal Free Campus, Hampstead, London NW3 2PR, UK.;University College Hospital, 235 Euston Road London, NW1 2BU, UK.;Barts Health NHS Trust, West Smithfield, London, EC1A 7BE, UK; Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.;Barts Health NHS Trust, West Smithfield, London, EC1A 7BE, UK.;The Royal Marsden Hospital, 203 Fulham Rd, Chelsea, London SW3 6JJ, UK.;University College Hospital, 235 Euston Road London, NW1 2BU, UK.;Barts Health NHS Trust, West Smithfield, London, EC1A 7BE, UK; University College Hospital, 235 Euston Road London, NW1 2BU, UK; Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: m.lockley@qmul.ac.uk.",
"authors": "Newton|C|C|;Murali|K|K|;Ahmad|A|A|;Hockings|H|H|;Graham|R|R|;Liberale|V|V|;Sarker|S-J|SJ|;Ledermann|J|J|;Berney|D M|DM|;Shamash|J|J|;Banerjee|S|S|;Stoneham|S|S|;Lockley|M|M|",
"chemical_list": "D001761:Bleomycin; D005047:Etoposide; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2019.03.001",
"fulltext": "\n==== Front\nEur J CancerEur. J. CancerEuropean Journal of Cancer0959-80491879-0852Elsevier Science Ltd S0959-8049(19)30177-710.1016/j.ejca.2019.03.001ArticleA multicentre retrospective cohort study of ovarian germ cell tumours: Evidence for chemotherapy de-escalation and alignment of paediatric and adult practice Newton C. abci1Murali K. d1Ahmad A. ef1Hockings H. agGraham R. bLiberale V. bSarker S.-J. ghLedermann J. bBerney D.M. agShamash J. aBanerjee S. dStoneham S. bLockley M. m.lockley@qmul.ac.ukabg∗a Barts Health NHS Trust, West Smithfield, London, EC1A 7BE, UKb University College Hospital, 235 Euston Road London, NW1 2BU, UKc University Hospitals Bristol NHS Foundation Trust, Upper Maudlin Street, Bristol, BS2 8HW, UKd The Royal Marsden Hospital, 203 Fulham Rd, Chelsea, London SW3 6JJ, UKe The Wolfson Institute, CRUK Barts Cancer Centre, Queen Mary University London, Charterhouse Square, London EC1M 6BQ, UKf Cancer Intelligence, Cancer Research UK, Angel Building, 407 St John Street, London EC1V 4AD, UKg Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UKh Research Department of Medical Education, UCL Medical School, Royal Free Campus, Hampstead, London NW3 2PR, UKi University of Bristol, Senate House, Tyndall Avenue, Bristol BS8 1TH, UK∗ Corresponding author: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. m.lockley@qmul.ac.uk1 These authors contributed equally to this work.\n\n1 5 2019 5 2019 113 19 27 10 12 2018 14 2 2019 2 3 2019 © 2019 The Author(s)2019This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Background\nAdult guidelines recommend BEP (bleomycin, etoposide, cisplatin) for all ovarian germ cell tumours, causing debilitating toxicities in young patients who will survive long term. Paediatricians successfully reduce toxicities by using lower bleomycin doses and substituting carboplatin for cisplatin, while testicular and paediatric immature teratomas (ITs) are safely managed with surgery alone.\n\nAim\nThe aim was to determine whether reduced-toxicity treatment could rationally be extended to patients older than 18 years.\n\nMethods\nMulticentre cohort study was carried out in four large UK cancer centres over 12 years.\n\nResults\nOne hundred thirty-eight patients were enrolled. Overall survival was 93%, and event-free survival (EFS) was 72%. Neoadjuvant/adjuvant chemotherapy (82% BEP) caused 27 potentially chronic toxicities, and one patient subsequently died from acute lymphoblastic leukaemia. There was no difference in histology, stage or grade in patients ≤/>18 years, and EFS was not different in these age groups (≤18:28% and >18:28%; log-rank P = 0.96). Histological subtype powerfully predicted EFS (log-rank P = 4.9 × 10−7). Neoadjuvant/adjuvant chemotherapy reduced future relapse/progression in dysgerminoma (n = 37, chemo:0% vs. no chemo:20%), yolk sac tumour (n = 23, 26.3% vs.75%) and mixed germ cell tumour (n = 32, 40%vs.70%) but not in IT (n = 42, 33% vs.15%). Additionally, we observed no radiological responses to chemotherapy in ITs, pathological IT grade did not predict EFS (univariate hazard ratio 0.82, 95% confidence interval: 0.57–1.19, P = 0.94) and there were no deaths in this subtype.\n\nConclusion\nSurvival was excellent but chemotherapy toxicities were severe, implying significant overtreatment. Our data support the extension of reduced-toxicity, paediatric regimens to adults. Our practice-changing findings that IT was chemotherapy resistant and pathological grade uninformative strongly endorse exclusive surgical management of ovarian ITs at all ages.\n\nHighlights\n• BEP (bleomycin, etoposide, cisplatin) chemotherapy caused multiple, severe and even life-threatening toxicities.\n\n• Ovarian germ cell tumour subtypes were distinct diseases, requiring different management.\n\n• Immature teratomas (ITs) were chemotherapy resistant.\n\n• The World Health Organisation pathological grade of ITs did not predict outcome.\n\n• There was no clinical difference in patients aged ≤/>18 years, but survival was worse in women >40 years (P < 0.02).\n\n\n\nKeywords\nOvarian germ cell cancerDysgerminomaYolk sac tumourImmature teratomaMixed germ cell tumourBEP\n==== Body\n1 Introduction\nOvarian germ cell tumours (OvGCTs) are very rare, comprising only 1–2% of ovarian malignancies [1], [2]. They usually present at an early stage in children and young adults, are generally chemotherapy sensitive and outcomes are excellent even in metastatic disease [3], [4]. Fertility-sparing surgery is established as standard of care [5], [6], [7], but clinical trial data are severely lacking regarding the adjuvant management of these rare tumours in adult women, and progress has lagged behind other cancers [8].\n\nOvGCTs are divided into histological subtypes according to the World health Organisation pathological classification: primitive germ cell tumours (dysgerminoma [Dys], yolk sac tumour [YST] and mixed germ cell tumour [MGCT]) and the teratomas (immature teratoma [IT] and mature teratoma [MT]) [9]. IT is further divided into three grades based on the amount of primitive neuroectodermal tumour (PNET). Prognosis varies by subtype, Dyss and teratomas having particularly favourable outcomes [10], [11]. Despite these differences, the National Comprehensive Cancer Network [6] recommends adjuvant BEP chemotherapy (bleomycin, etoposide and cisplatin) for all histologies in adults, except stage I Dys and stage I, grade 1 ITs. Recent European Society of Medical Oncology (ESMO) guidelines [7] describe active surveillance protocols for subsets of patients with stage I disease and normal postoperative tumour markers. BEP toxicities are significant, including pulmonary fibrosis, hypertension, permanent hearing damage, chronic kidney disease, Raynaud's phenomenon and an increase in secondary cancers such as leukaemia [12]. Late effects are particularly concerning in these young women with a very high likelihood of cure and some advocate close surveillance for all stage I OvGCTs, regardless of histology, with chemotherapy salvage if progression occurs [13], [14].\n\nReduced-toxicity treatments are already established in paediatric and male GCTs. JEB (carboplatin, etoposide and bleomycin) has replaced BEP in children [15], while adjuvant treatment of male seminomas (Dys equivalent) is with either carboplatin (AUC 7) or radiotherapy (20 Gy/10 fractions) [16], [17]. These strategies have not been tested in women. The most obvious discrepancy is in the management of ovarian ITs: adjuvant BEP is recommended for adults (except grade 1, stage IA) [6], whereas in children, evidence supports postoperative surveillance for all IT stages and grades [18]. This clearly presents a dilemma in the treatment of 18-year-old females [19]. The Malignant Germ Cell International Collaborative (MaGIC) conducted a retrospective analysis of IT data from paediatric (Children's Oncology Group and Children's Cancer and Leukaemia Group) and adult (Gynecologic Oncology Group) clinical trials [20]. Adults had higher stage, higher grade and lower complete debulking rates, and their overall survival (OS) was marginally lower (93% vs 99%), despite much higher administration of adjuvant chemotherapy (81 of 81 adult patients vs 8 of 98 children). Although it was not possible to determine whether the survival difference was due to trial eligibility or to disease biology, this analysis does question the overall efficacy of chemotherapy in ovarian ITs.\n\nIn view of the marked differences in adult and paediatric practice, the serious toxicities associated with current chemotherapy regimens and the paucity of available clinical data, we conducted a multicentre retrospective cohort study of adult and paediatric patients treated in four large UK cancer centres over 12 years. We interrogated the efficacy and toxicity of chemotherapy in the initial management of OvGCTs presenting in patients of all ages.\n\n2 Methods\n2.1 Patient selection\nWe analysed all OvGCTs at Barts Health NHS Trust, University College Hospital and University Hospitals Bristol NHS Foundation Trust, as well as adult patients presenting to the Royal Marsden Hospital, between 01 January 2005 and 31 December 2016. Hospital ethical approval was obtained, and data sharing agreements were established between partner organisations in accordance with the European General Data Protection Regulations. All primary gynaecological Dys, YST, IT and MGCT were identified from pathology and surgical databases. We excluded only one patient because of insufficient clinical information. Patient details were obtained via extensive review of hospital notes and computer records. Histology was reviewed centrally by supraregional specialists in each of the four individual cancer centres. All pathology reports were then reviewed again by an expert germ cell tumour pathologist (D.M.B.) to ensure accurate interpretation of local specialist pathology reports.\n\n2.2 Statistical analysis\nStatistical methods were documented in a prespecified statistical analysis plan. Univariable and multivariable Cox regression models were used to analyse the effects of covariates (age, Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stage, histology, grade, and chemotherapy) on the primary end-point, event-free survival (EFS). In the multivariable analysis, grade was excluded as it was not statistically significant and chemotherapy was also excluded as it was a non-randomised intervention rather than a baseline tumour characteristic. EFS was defined as the time from primary surgery until the date of documented relapse or progression of any germ cell histology (including disease progression while awaiting adjuvant chemotherapy). The age cut-off of paediatric and adult practice was ≤18 and > 18 years. The accepted upper age limit for adolescent and young adult (AYA) practice is 39 years, and thus, we defined a second age cut-off at ≥40 years to distinguish older adults from AYA. In view of the small patient numbers, neoadjuvant and adjuvant chemotherapies were combined for the purposes of statistical analysis and are collectively referred to here as ‘first-line chemotherapy’. Patients were censored on the date of the last follow-up or death. Schoenfeld residuals were examined to determine if Cox modelling was an appropriate analytical approach. Spearman's rank correlation was estimated pairwise for all variables. Kaplan–Meier survival curves were plotted, and P-values from the log-rank or Mantel–Haenszel test were reported. All applied statistical tests were two sided, and P < 0.05 was considered significant. Analyses were performed in R version 3.4.3 [21].\n\n3 Results\n3.1 Patient characteristics\nWe enrolled 138 patients (Table 1). One patient had primary endometrial MGCT, but the remainder had primary OvGCTs. Two patients with raised αFP (1178kIU/L and 42,000kIU/L) received neoadjuvant chemotherapy without diagnostic biopsy. Both were found to have MT at surgery after completion of chemotherapy and were grouped with MGCT for subsequent statistical analysis. There was a preponderance of early-stage disease, with only 38 stage III/IV patients (28% total). All but one patient had surgery, which was fertility sparing in 88% cases (120 of 137). The small number of patients who had bilateral salpingo-oophorectomy or hysterectomy were either older (≥40 years: 6 of 17 patients) or had undergone prophylactic surgery for underlying genetic syndromes (5 of 17 patients). A further six patients all had disease that had spread beyond the ovaries (FIGO II/III/IV).Table 1 Baseline patient characteristics.\n\nTable 1Histology\tNumber\t\n Dysgerminoma\t37\t\n Yolk sac tumour\t23\t\n Immature teratoma\t42\t\n PNET\t4\t\n Mixed germ cell tumour\t32\t\n Total\t138\t\nAge of patients\tMedian (range)\t\n Dysgerminoma\t21 (11–47)\t\n Yolk sac tumour\t27 (14–69)\t\n Immature teratoma\t26 (11–44)\t\n PNET\t23 (9–32)\t\n Mixed germ cell tumour\t24.5 (8–76)\t\n All patients\t23.5 (8–76)\t\nFirst-line chemotherapy\tn (%)\t\n Dysgerminoma\t22 (59%)\t\n Yolk sac tumour\t19 (82%)\t\n Immature teratoma\t9 (21%)\t\n PNET\t4 (100%)\t\n Mixed germ cell tumour\t22 (69%)\t\n All patients\t76 (55%)\t\nFIGO stage\tNumber\t\n IA/B\t59\t\n IC\t27\t\n II\t11\t\n III\t23\t\n IV\t15\t\n Not known\t3\t\n Total\t138\t\nFirst-line chemotherapy\tn (%)\t\n IA/B\t10 (17%)\t\n IC\t18 (66%)\t\n II\t9 (82%)\t\n III\t23 (100%)\t\n IV\t14 (93%)\t\n Not known\t2 (67%)\t\n Total\t76\t\n\n\n3.2 Overall and event-free survival\nMedian follow-up was 56.6 months (range: 11 days-16.5 years). The OS rate was 93%. Nine patients (7%) died of disease and one died of acute lymphoblastic leukaemia (ALL), which was presumed to be treatment related. EFS was 72%, and relapse/progression events occurred in 39 patients (28%). As expected, residual disease after surgery was associated with disease relapse (Suppl. Fig. 3; log-rank test P = 3.0 × 10−5). In the Cox regression analysis (Table 2), neither age (univariable hazard ratio [HR] 1.03, 95% confidence interval [CI] 1.0–1.05, P = 0.09; multivariable P = 0.25) nor FIGO stage (univariable HR 1.31, 95% CI 1.00–1.704, P = 0.051; multivariable P = 0.53) was significantly associated with EFS, although EFS was significantly different when FIGO stage I was compared with all other stages combined (Fig. 1A; log-rank test P = 0.03). In contrast, histological subtype strongly predicted outcome (Table 2; univariable P = 5.8 × 10−5 and Fig. 1B; log-rank test P = 4.9e-07).Table 2 Univariable and multivariable Cox regression analysis.\n\nTable 2Predictor\tUnivariable\tMultivariable\t\nHR (95% CI)\tLR χ2 test\td.f., p-value\tc-index\tHR (95% CI)\tΔχ2 (d.f.)\tp-value\t\nHistology, Dys\t1 Ref.\t24.68\t4, 5.8e-05\t0.73\t1 Ref.\t24.69 (4)\t5.8e-05\t\nHistology, IT\t3.02 (0.80, 11.46)\t\t\t\t3.15 (0.82, 12.06)\t\t\t\nHistology, YST\t5.06 (1.34, 19.09)\t\t\t\t5.56 (1.41, 21.96)\t\t\t\nHistology, MGCT\t8.87 (2.57, 30.55)\t\t\t\t10.73 (2.79, 41.21)\t\t\t\nHistology, PNET\t19.69 (4.35, 89.10)\t\t\t\t26.093 (5.27, 129.18)\t\t\t\nAge (years)\t1.03 (1.0, 1.05)\t2.84\t1, 0.09\t0.53\t0.934 (0.87, 1.00)\t1.32 (1)\t0.25\t\nChemotherapy, yes\t0.84 (0.45, 1.58)\t0.29\t1, 0.59\t0.53\t\t\t\t\nStage (linear)\t1.31 (1.01, 1.70)\t3.82\t1, 0.05\t0.59\t0.45 (0.22, 0.94)\t0.40 (1)\t0.53\t\nGrade\t0.824 (0.570, 1.193)\t1.17\t1, 0.28\t0.55\t\t\t\t\nAge*stage\t\t\t\t\t1.03 (1.01, 1.05)\t6.86 (1)\t0.01\t\nLR χ2 test (d.f., p)\t\t33.265 (7, 2.4e-05)\t\nc-index (95% CI)\t\t0.770 (0.677, 0.864)\t\nHR, hazards ratio, CI, confidence interval, LR χ2, log-rank chi-squared test, d.f., degrees of freedom, c-index, Harrell's c-index; Dys, dysgerminoma; IT, teratoma; YST, yolk sac tumour; MGCT, mixed germ cell tumour; PNET, primitive neuroectodermal tumour.\n\nFig. 1 Kaplan–Meier event-free survival. Event-free survival according to (A) FIGO stage, (B) histological OvGCT subtype, (C) patient age at diagnosis and (D) grade of immature teratoma. OvGCT, ovarian germ cell tumour; Dys, dysgerminoma; IT, teratoma; YST, yolk sac tumour; MGCT, mixed germ cell tumour; PNET, primitive neuroectodermal tumour; HR, hazard ratio; CI, confidence interval.\n\nFig. 1\n\n3.3 Age\nAdult patients (>18 years) made up 72% of cases (99 of 138). A greater proportion of women older than 18 years received chemotherapy (46% ≤ 18 vs. 59% > 18), despite there being no difference in the disease stage (Table 3; proportions test χ2 = 5.87, d.f. = 3, P = 0.12) or histological subtype (Table 3; proportions test χ2 = 4.06, d.f. = 4, P = 0.40) when patients ≤18 and > 18 years were compared. There was no significant difference in EFS between these age groups (log-rank P = 0.96, not shown).Table 3 Patient characteristics by predefined age cut-off.\n\nTable 3\tPatient's age\t\n≤18 years, N (%)\t>18 years, N (%)\t≥40 years, N (%)\t\nTotal patient number (138)\t39 patients\t99 patients\t11 patients\t\nStage\t\n I\t25 (64%)\t61 (62%)\t3 (27%)\t\n II, III, IV\t14 (36%)\t35 (35%)\t7 (64%)\t\n NK\t0\t3 (3%)\t1 (9%)\t\nProportions test\tχ2 = 4.06, d.f. = 3, p-value = 0.12\t\t\nHistology\t\n Dys\t12 (31%)\t25 (25%)\t1 (9%)\t\n IT (total)\t15 (38%)\t27 (27%)\t1 (9%)\t\n Gd 1\t7\t7\t1\t\n Gd 2\t2\t13\t0\t\n Gd 3\t6\t7\t0\t\n YST\t6 (15%)\t17 (17%)\t2 (18%)\t\n PNET\t1\t3\t0\t\n MT\t1\t1\t0\t\n MGCT\t4 (10%)\t26 (26%)\t7 (64%)\t\nProportions test\tχ2 = 4.06, d.f. = 4, p-value = 0.40\t\t\nχ2 ,chi-squared test, d.f., degrees of freedom; Dys, dysgerminoma; IT, teratoma; YST, yolk sac tumour; MGCT, mixed germ cell tumour; PNET, primitive neuroectodermal tumour; MT, mature teratoma.\n\n\n\nOnly 11 women were ≥40 years old. Most women ≥40 years presented with higher stage disease (Table 3), and they were more likely to receive first-line chemotherapy (73% ≥ 40 compared with 55% overall). Despite this, their EFS was significantly worse than younger patients (Fig. 1C; HR 3.30, 95% CI 1.26–8.67, P = 0.02) and OS rate was only 55% (5 of 11 women ≥40 years died of their disease) compared with 93% for the entire cohort.\n\n3.4 Chemotherapy use and toxicity\nFirst-line chemotherapy (neoadjuvant or adjuvant) was administered to 55% patients (76 of 138) and was more likely to be given in higher stage disease (Table 1). Chemotherapy was most commonly adjuvant (79%). Only 16 patients received neoadjuvant chemotherapy, 12 of whom had stage III/IV disease (Suppl. Fig. 1). BEP was used most frequently, accounting for 82% (62 of 76) of cases, 11% received JEB (8 of 76, all aged ≤18 years) and only one patient with IIIC PNET received a non-platinum–containing regimen (VIDE: vincristine, ifosfamide, doxorubicin and etoposide).\n\nChemotherapy caused significant short- and long-term toxicity (Table 4). This retrospective review will have only identified severe, clinically significant toxicities and so likely underestimates the true extent of treatment-related side-effects. Nonetheless, we observed 27 potentially chronic toxicities in 22 patients including kidney injury (n = 2), cardiac failure (n = 1), tinnitus or hearing loss (n = 9), bleomycin lung toxicity (n = 4) and peripheral neuropathy (n = 11). One 14-year-old patient died of ALL 2 years after surgery and adjuvant JEB for stage IIIA MGCT (Dys and YST). In view of these severe toxicities, and the powerful influence of histology on EFS (Table 2 and Fig. 1B), we investigated the use and efficacy of chemotherapy according to histological subtype.Table 4 The number of occurrences of potentially chronic chemotherapy treatment–related toxicities.\n\nTable 4Potentially chronic toxicity\tNumber\t\nKidney injury\t2\t\nCardiac failure\t1\t\nTinnitus/hearing loss\t9\t\nBleomycin lung\t4\t\nPeripheral neuropathy\t11\t\ndied of ALL\t1\t\nTotal\t27\t\nALL, acute lymphoblastic leukaemia.\n\n\n\n3.5 Immature teratoma\nIT was the most common histology (Table 1; 42 cases), and this subtype was overwhelmingly low stage (32 of 42 patients stage IA/B) (Suppl. Fig. 2A). Most patients were safely managed with surgery alone, and there were no deaths in this group. Only nine of 42 patients with ITs received first-line chemotherapy (Table 1), three preoperatively (stage III, IV and unknown; discussed in the following section) and six postoperatively (four stage IA and two stage IC) treated patients. The incidence of any teratoma recurrence (IT, MT and gliomatosis peritonei) was not reduced by first-line chemotherapy, occurring in three of nine (33%) chemotherapy-treated patients compared with five of 33 (15%) chemotherapy-naïve patients (Suppl. Tables 1 and 2). Because this could be explained by the higher disease stage of chemotherapy-treated patients (only three patients with ITs did not have stage I disease and all three received chemotherapy, Suppl. Fig. 2A), we examined chemotherapy efficacy in the four patients with ITs with measurable disease prior to chemotherapy. This included the three neoadjuvant patients listed previously and one chemotherapy-naïve patient who relapsed after initial surgery.\n\nA 34-year-old woman relapsed in the brain and two other distant sites one year after initial surgery for stage IA, grade 2 ITs. The brain mass was resected (grade 2 ITs) with residual disease at the operation site. She received EP-OMB chemotherapy (etoposide, cisplatin, vincristine, methotrexate and bleomycin) and intrathecal methotrexate with minor response on MRI brain but no radiological response in the other two metastatic sites. Both these metastases were resected (again grade 2 ITs), and she received postoperative ACE chemotherapy (actinomycin, cyclophosphamide, etoposide). Her most recent MRI brain was stable, and she was well at censor, four years after her most recent surgery.\n\nThe other three patients (stage III, IV and unknown) were all treated preoperatively. Two had no radiological response to chemotherapy, and IT was confirmed on subsequent surgical debulking. The only evidence of any chemotherapy response in ITs was in a 37-year-old individual presenting with abdominal pain, a rapidly growing pelvic mass and urinary sepsis. Presentation lactate dehydrogenase was 916, and a scanty diagnostic biopsy of the mass revealed PNET elements consistent with grade 3 ITs and a possible accompanying Dys, suggesting that this patient might have actually had a MGCT. Three cycles of BEP achieved only a 25% radiological reduction and surgical debulking revealed MT.\n\n3.6 IT grade\nRelapse and progression with any teratoma histology (immature, mature and gliomatosis) occurred in all grades of ITs (Gd1: 3/14, Gd2: 2/15 and Gd3: 3/13). Additionally, immature elements were found at recurrence in patients who initially presented with all three grades of ITs (Gd1: 1/14, Gd2:1/15 and Gd3: 1/13). Strikingly, pathological IT grade did not predict EFS (Table 2; univariable HR 0.82, 95% CI 0.57–1.19, P = 0.28: Fig. 1D; log-rank P = 0.94).\n\n3.7 Primitive germ cell tumours (Dys, YST and MGCT)\nIn marked contrast to the chemotherapy resistance of ITs, radiological responses were observed in 10 of 10 pure Dys and four of five pure YST chemotherapy-naïve patients. Dys outlook was exceptionally good, with no patient deaths and no relapses in any patient after first-line chemotherapy (Suppl. Fig. 2B; 22 of 22 patients). Relapse did occur in three of 15 patients with stage IA/B Dys who were initially treated with surgery alone. All three were salvaged with platinum-containing chemotherapy (Suppl. Table 1), and all were alive and disease free 16, 65 and 117 months after relapse. Only four patients with YST did not receive first-line chemotherapy: two stage IA and two stage IC (Suppl. Fig. 2C). Of these four, three progressed very rapidly after initial surgery at 53, 68 and 103 days. As with Dys, chemotherapy response in YST was excellent with all three of these chemotherapy-naïve relapses being successfully salvaged with BEP. All three patients were disease free 31, 28 and 26 months after diagnosis of recurrence.\n\nFurther evidence of chemotherapy sensitivity in YST came from the observation that relapse/progression appeared to be reduced by chemotherapy overall (5 of 19; 26% chemo-treated vs. 3 of 4; 75% chemo-naïve; Suppl. Table 1) and that median time to relapse was increased by first-line chemotherapy treatment (344 days in chemotherapy-treated patients compared with 68 days in chemotherapy-naive patients; unpaired t-test, P = 0.07). Re-treatment of the five patients with YST who relapsed after BEP treatment was less successful. Only two of these five patients were salvaged by further surgery and chemotherapy but both were still in remission at the censor date, two and eight years after diagnosis of relapse. The remaining three relapsed patients eventually died of their disease. Two of these three deaths occurred in the only two patients with YST who were aged ≥40 years.\n\nAll but one MGCT had a yolk sac component to their histology (29 of 30). Most patients (20 of 30) received first-line chemotherapy (Suppl. Fig. 2D). Eight of these chemotherapy-treated patients subsequently relapsed (Suppl. Table 1), but the pathology of six of these relapses revealed MTs and mature glial tissue only and these patients were all salvaged with surgery alone. Four MGCT patients died of disease. One 19-year-old patient with stage IV disease died of rapid disease progression postoperatively before initiation of adjuvant chemotherapy. The other three deaths were all in women aged ≥40 years. Two of these patients relapsed with confirmed YST (αFP rise ± biopsy) and were not salvaged by second-line treatment, while the third declined further chemotherapy.\n\n3.8 Primitive neuroectodermal tumours\nSomatic transformation of ovarian teratomas is associated with a poor outcome. Five patients had PNET, four at diagnosis and one at relapse. Only one was successfully treated to complete remission with surgical resection followed by GAMEC chemotherapy (GCSF, actinomycin, methotrexate, etoposide, cisplatin). She was disease free 5 years after diagnosis, confirming that PNET can be salvaged with intensive combination treatment [22].\n\n4 Discussion\nOvGCTs are a heterogenous group of rare diseases. Clinical data are severely lacking, and progress has lagged behind other cancers [8]. Paediatricians aim to reduce late effects in these patients with a near certainty of long-term cure, but until now, treatment-induced toxicities have not been prioritised in adult practice, and international guidelines still recommend BEP in nearly all cases.\n\nThis cohort study is one of the few large studies to investigate these exceptionally rare ovarian cancers. The OS rate was excellent at 93% with a median follow-up of 56.6 months. However, we recorded 27 potentially chronic toxicities in 76 chemotherapy-treated patients and one probable chemotherapy-related death. Together, this implies widespread overtreatment, and so, reduction of BEP use is a priority. Recent ESMO guidelines [7] now support surveillance of subsets of patients with stage I OvGCTs. Four of the 22 patients who experienced potentially chronic toxicities had stage I disease and thus might have been spared chemotherapy altogether according to these new guidelines. This approach appeared safe in our series. We identified 25 patients with stage I Dys, YST and MGCT who were initially managed without chemotherapy. Although 10 of these subsequently relapsed, all were salvaged with platinum-containing chemotherapy (BEP/JEB in nine patients) with or without further surgery. In agreement with others [23], our study therefore endorses and extends this expectant policy by advocating the avoidance of chemotherapy in all FIGO stage I patients.\n\nIn higher stage disease, paediatricians have already reduced chemotherapy toxicity by the widespread and accepted use of JEB in preference to BEP. We identified no statistically significant differences in OvGCTs presenting in patients younger and older than 18 years. Comparable series have made similar observations [24], [25], providing a compelling rationale for also using carboplatin-based chemotherapy in adult patients. This approach has already been shown to be equivalent in Dys [26] and is currently being tested in other patients aged 11–25 years with other ovarian germ cell histologies in the AGCT1531 study [27]. In contrast, women older than 40 years appeared to present with higher stage disease and were more likely to receive first-line chemotherapy, and their EFS and OS were significantly worse than younger adults. Age over 40 years has previously been identified as a poor prognostic factor [28], and clinical trials should now determine whether this reflects suboptimal treatment or underlying disease biology with the ultimate aim of improving the survival of this group of women.\n\nOur most important and practice-changing finding was that, compared to the excellent responses to chemotherapy observed in the primitive germ cell tumours, we found little evidence of response to chemotherapy in ITs. Although IT relapse and progression occurred frequently, there were no deaths either in pure ITs or in teratomatous relapse of MGCT and both were effectively managed with surgery alone. Eight of the nine patients with ITs who received chemotherapy were >18 years. We now propose that these adult patients might be spared the risks of BEP chemotherapy and managed safely with surgery as is currently the case in paediatric practice and for MT at all ages.\n\nThis clinical overlap between IT and MT is supported by frequent genetic homozygosity in IT and MT, but not in MGCT, indicating a common cellular origin of IT and MT with likely biological similarities in these histologies [29]. Developmental differences between ITs and other OvGCT subtypes can also be inferred from their more stable copy number profile and absence of 12p gain [30]. Furthermore, the observation that copy number profiles do not differ according to the grade of ITs [30] provides a biological explanation for our intriguing observation that EFS was identical regardless of the IT grade. This provocative finding differs from a previous pooled analysis of clinical trial data by MaGIC in which IT grade did predict future relapse [20]. This discrepancy could be explained by small numbers and retrospective analysis in both studies, and clinical trials are required to resolve this issue. Nonetheless, we agree with MaGIC that there was little evidence of chemotherapy response in any grade of ITs and thus question the utility of the World Health Organisation pathological IT grade as a biomarker to direct patient care.\n\nFinally, we confirmed that Dys was exquisitely chemotherapy sensitive with clear evidence of radiological response to chemotherapy, no relapses after chemotherapy and no deaths at a median follow-up of 6.38 years. Later relapse of this histology is possible with a high expectation of chemotherapy salvage as was the case for one patient in our cohort. Single-agent, high-dose carboplatin may therefore be an appropriate and less toxic treatment for Dys, as is already established in the histologically equivalent testicular seminoma.\n\nIn summary, our large, multicentre retrospective cohort study has exposed significant overtreatment with excellent survival but frequent debilitating and potentially life-threatening toxicities. We have shown that platinum-containing chemotherapy can safely be avoided in stage I disease and that the role of chemotherapy in the management of ovarian ITs should be reviewed. Treatment-induced toxicities would be further reduced by using single-agent carboplatin in Dys, and based on the clinical similarity between patients older and younger than 18 years, we propose that clinical trials should now compare BEP with carboplatin-based chemotherapy, such as JEB, in YST-containing histologies at all ages. These practice-changing recommendations will herald a new era in the management of these inherently good prognosis cancers.\n\nConflicts of interest statement\nNone declared.\n\nAppendix A Supplementary data\nThe following are the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 Multimedia component 2\nMultimedia component 2 Multimedia component 3\nMultimedia component 3 Multimedia component 4\nMultimedia component 4 Multimedia component 5\nMultimedia component 5 \n\nAcknowledgements\nThe authors thank patients and clinical staff. Also, the information governance teams at participating sites (Madalyn Hardaker; QMUL, Martyn Steers; Barts Health, Alan Ball; RMH, Jessica Bisset; UHB, Deborah Dillon; UCH). They also thank Prof Iain McNeish, Prof Martin Gore, Dr Sarah Martin, Dr Paulo Ribeiro, Prof Tyson Sharp, Prof Andrew Lister, Prof Kairbaan Hodivala-Dilke and Prof Jude Fitzgibbon for reviewing the final manuscript. D.M.B. acknowledges support from Orchid. K.M. and S.B. acknowledge the Royal Marsden and Institute of Cancer Research NIHR Biomedical Research Centre. M.L. is funded by Cancer Research UK, C41405/A19694.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.ejca.2019.03.001.\n==== Refs\nReferences\n1 Smith H.O. Berwick M. Verschraegen C.F. Wiggins C. Lansing L. Muller C.Y. Incidence and survival rates for female malignant germ cell tumors Obstet Gynecol 107 5 2006 1075 1085 16648414 \n2 Matz M. Coleman M.P. Sant M. Chirlaque M.D. Visser O. Gore M. The histology of ovarian cancer: worldwide distribution and implications for international survival comparisons (CONCORD-2) Gynecol Oncol 144 2 2017 405 413 27931752 \n3 Gershenson D.M. Management of ovarian germ cell tumors J Clin Oncol 25 20 2007 2938 2943 17617525 \n4 Murray M.J. F.L. and E.T. Stark D.P. Nicholson J.C. Breaking down barriers: improving outcomes for teenagers and young adults with germ cell tumours Onco Rev 3 2009 201 206 \n5 Morice P. Denschlag D. Rodolakis A. Reed N. Schneider A. Kesic V. Recommendations of the fertility task force of the european society of gynecologic Oncology about the conservative management of ovarian malignant tumors Int J Gynecol Cancer 21 5 2011 951 963 21697684 \n6 NCCN Ovarian cancer including fallopian tube cancer and primary peritoneal cancer Version 4 NCCN clinical practice guidelines in Oncology (NCCN Guidelines®) 2017 National Comprehensive Cancer Network 2017 \n7 Ray-Coquard I. Morice P. Lorusso D. Prat J. Oaknin A. Pautier P. Non-epithelial ovarian cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2018 \n8 Stoneham S.J. Hale J.P. Rodriguez-Galindo C. Dang H. Olson T. Murray M. Adolescents and young adults with a \"rare\" cancer: getting past semantics to optimal care for patients with germ cell tumors Oncol 19 7 2014 689 692 \n9 Tavassoli F.A. Devilee P.E. Pathology and genetics of tumors of the breast and female genital tract. World health organization classification of tumors 2003 International Agency for Research in Cancer Press Lyon France \n10 Norris H.J. Zirkin H.J. Benson W.L. Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases Cancer 37 5 1976 2359 2372 1260722 \n11 Brown J. Friedlander M. Backes F.J. Harter P. O'Connor D.M. de la Motte Rouge T. Gynecologic Cancer Intergroup (GCIG) consensus review for ovarian germ cell tumors Int J Gynecol Cancer 24 9 Suppl 3 2014 S48 S54 25341580 \n12 Howard R. Gilbert E. Lynch C.F. Hall P. Storm H. Holowaty E. Risk of leukemia among survivors of testicular cancer: a population-based study of 42,722 patients Ann Epidemiol 18 5 2008 416 421 18433667 \n13 Patterson D.M. Murugaesu N. Holden L. Seckl M.J. Rustin G.J. A review of the close surveillance policy for stage I female germ cell tumors of the ovary and other sites Int J Gynecol Cancer 18 1 2008 43 50 17466047 \n14 Mangili G. Sigismondi C. Lorusso D. Cormio G. Candiani M. Scarfone G. The role of staging and adjuvant chemotherapy in stage I malignant ovarian germ cell tumors (MOGTs): the MITO-9 study Ann Oncol 28 2 2017 333 338 27803008 \n15 Mann J.R. Raafat F. Robinson K. Imeson J. Gornall P. Sokal M. The United Kingdom Children's Cancer Study Group's second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity J Clin Oncol 18 22 2000 3809 3818 11078494 \n16 Oldenburg J. Fossa S.D. Nuver J. Heidenreich A. Schmoll H.J. Bokemeyer C. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 24 6 2013 vi125 vi132 24078656 \n17 Oliver R.T. Mead G.M. Rustin G.J. Joffe J.K. Aass N. Coleman R. Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214) J Clin Oncol 29 8 2011 957 962 21282539 \n18 Marina N.M. Cushing B. Giller R. Cohen L. Lauer S.J. Ablin A. Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: a Pediatric Oncology Group/Children's Cancer Group Intergroup Study J Clin Oncol 17 7 1999 2137 2143 10561269 \n19 Hurteau J.A. Febbraro T. Germ cell tumors: treatment consensus across all age groups through MaGIC [malignant germ cell international collaborative] Cancer 122 2 2016 181 183 26485495 \n20 Pashankar F. Hale J.P. Dang H. Krailo M. Brady W.E. Rodriguez-Galindo C. Is adjuvant chemotherapy indicated in ovarian immature teratomas? A combined data analysis from the Malignant Germ Cell Tumor International Collaborative Cancer 122 2 2016 230 237 26485622 \n21 R: a language and environment for statistical computing 2017 [cited 2017 2018] https://www.R-project.org._R_Core_Team \n22 Ehrlich Y. Beck S.D. Ulbright T.M. Cheng L. Brames M.J. Andreoiu M. Outcome analysis of patients with transformed teratoma to primitive neuroectodermal tumor Ann Oncol 21 9 2010 1846 1850 20231305 \n23 Mangili G. Sigismondi C. Lorusso D. Pignata S. Surveillance policy for stage IA malignant ovarian germ cell tumors in children and young adults J Clin Oncol 32 25 2014 2814 2815 25071128 \n24 Faure Conter C. Xia C. Gershenson D. Hurteau J. Covens A. Pashankar F. Ovarian yolk sac tumors; does age Matter? Int J Gynecol Cancer 28 1 2018 77 84 29194189 \n25 Meisel J.L. Woo K.M. Sudarsan N. Eng J. Patil S. Jacobsen E.P. Development of a risk stratification system to guide treatment for female germ cell tumors Gynecol Oncol 138 3 2015 566 572 26115974 \n26 Shah R. Xia C. Krailo M. Amatruda J.F. Arul S.G. Billmire D.F. Is carboplatin-based chemotherapy as effective as cisplatin-based chemotherapy in the treatment of advanced-stage dysgerminoma in children, adolescents and young adults? Gynecol Oncol 150 2 2018 253 260 29884437 \n27 AGCT 1531 2018 [cited 2018 29/11/2018]; Available from: https://clinicaltrials.gov/ct2/show/NCT03067181?term=AGCT1531&rank=1 \n28 Solheim O. Gershenson D.M. Trope C.G. Rokkones E. Sun C.C. Weedon-Fekjaer H. Prognostic factors in malignant ovarian germ cell tumours (The Surveillance, Epidemiology and End Results experience 1978-2010) Eur J Cancer 50 11 2014 1942 1950 24857045 \n29 Snir O.L. DeJoseph M. Wong S. Buza N. Hui P. Frequent homozygosity in both mature and immature ovarian teratomas: a shared genetic basis of tumorigenesis Mod Pathol 30 10 2017 1467 1475 28664933 \n30 Van Nieuwenhuysen E. Busschaert P. Neven P. Han S.N. Moerman P. Liontos M. The genetic landscape of 87 ovarian germ cell tumors Gynecol Oncol 151 1 2018 61 68 30170975\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0959-8049",
"issue": "113()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "BEP; Dysgerminoma; Immature teratoma; Mixed germ cell tumour; Ovarian germ cell cancer; Yolk sac tumour",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D017024:Chemotherapy, Adjuvant; D002648:Child; D002945:Cisplatin; D015331:Cohort Studies; D004407:Dysgerminoma; D018240:Endodermal Sinus Tumor; D005047:Etoposide; D005260:Female; D013509:Gynecologic Surgical Procedures; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009373:Neoplasms, Germ Cell and Embryonal; D016609:Neoplasms, Second Primary; D010051:Ovarian Neoplasms; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D000077982:Progression-Free Survival; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D013724:Teratoma; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "19-27",
"pmc": null,
"pmid": "30954883",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "10561269;11078494;1260722;16648414;17466047;17617525;18433667;20231305;21282539;21697684;24078656;24857045;24899644;25071128;25341580;26115974;26485495;26485622;27803008;27931752;28664933;29194189;29697741;29884437;30170975",
"title": "A multicentre retrospective cohort study of ovarian germ cell tumours: Evidence for chemotherapy de-escalation and alignment of paediatric and adult practice.",
"title_normalized": "a multicentre retrospective cohort study of ovarian germ cell tumours evidence for chemotherapy de escalation and alignment of paediatric and adult practice"
} | [
{
"companynumb": "GB-PFIZER INC-2019156098",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "Cyclosporine therapy for Stevens-Johnson syndrome-toxic epidermal necrolysis (SJSTEN) was first reported in the literature by Renfro et al. in 1989. Herein we report an additional 4 cases of SJS-TEN treated with cyclosporine.\n\n\n\nCase information was collected retroactively at the University of Louisville Hospital in Louisville, KY. All cases had a diagnosis of SJS or TEN by a dermatologist. All patients were ≥18 years of age and treated with cyclosporine during their admission.\n\n\n\nThree of four patients re-epithelialized within an average of 3.67 days of starting 3-4 mg/kg/day of cyclosporine. One patient passed away, likely due to advanced endometrial cancer.\n\n\n\nWe provide a review of the literature on cyclosporine use for SJS/TEN, including various outcome measures - stabilization (cessation of new lesions), time to re-epithelialization, mortality rate, and hospital length of stay and, where available, comparison to other systemic agents.\n\n\n\nThe outcomes appear to be consistent with rapid re-epithelialization and low mortality as seen in many previous reports. Treating SJS-TEN with systemic agents including cyclosporine will remaincontroversial because the vast majority of data comes from case reports, case series, or small open prospective trials.",
"affiliations": "Division of Dermatology, University of Louisville School of Medicine, Louisville, Kentucky. ceowen01@louisville.edu.",
"authors": "Conner|Clayton D|CD|;McKenzie|Emily|E|;Owen|Cindy E|CE|;Callen|Jeffrey P|JP|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D065095:Calcineurin Inhibitors; D016572:Cyclosporine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "24(1)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents; D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29469760",
"pubdate": "2018-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "The use of cyclosporine for Stevens-Johnson syndrome-toxic epidermal necrolysis spectrum at the University of Louisville: A case series and literature review.",
"title_normalized": "the use of cyclosporine for stevens johnson syndrome toxic epidermal necrolysis spectrum at the university of louisville a case series and literature review"
} | [
{
"companynumb": "US-APOTEX-2016AP009402",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": "3",
... |
{
"abstract": "A 73-year-old man with a petroclival tumor (metastatic renal cell carcinoma) presented with a progressive consciousness disturbance attributed to tension pneumocephalus during molecular-targeted therapy following low-dose fractionated radiotherapy for a petroclival tumor. The skull base defect was successfully reconstructed vi an endoscopic endonasal approach.",
"affiliations": "Department of Neurosurgery, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Neurosurgery, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Neurosurgery, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Neurosurgery, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Neurosurgery, Shinshu University School of Medicine, Matsumoto, Japan.",
"authors": "Nagm|Alhusain|A|;Ogiwara|Toshihiro|T|;Nishikawa|Akihiro|A|;Ichinose|Shunsuke|S|;Hongo|Kazuhiro|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/02688697.2018.1457772",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-8697",
"issue": "35(3)",
"journal": "British journal of neurosurgery",
"keywords": "Tension pneumocephalus; molecular-targeted therapy; oncology team; petroclival tumor; radiotherapy",
"medline_ta": "Br J Neurosurg",
"mesh_terms": "D000368:Aged; D002292:Carcinoma, Renal Cell; D006801:Humans; D007680:Kidney Neoplasms; D008297:Male; D011007:Pneumocephalus; D011183:Postoperative Complications; D019291:Skull Base",
"nlm_unique_id": "8800054",
"other_id": null,
"pages": "361-363",
"pmc": null,
"pmid": "29607683",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Petroclival tension pneumocephalus: an unrivalled life threatening complication linked to molecular-targeted therapy.",
"title_normalized": "petroclival tension pneumocephalus an unrivalled life threatening complication linked to molecular targeted therapy"
} | [
{
"companynumb": "JP-PFIZER INC-202101103378",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AXITINIB"
},
"drugadditional": "3",
... |
{
"abstract": "Golimumab efficacy data in ulcerative colitis (UC) are limited to anti-tumor necrosis factor α (TNF)-naive patients. The aim of this study was to assess the short-term and long-term efficacy of golimumab used as first, second, or third anti-TNF in UC in a real-life clinical setting.\n\n\n\nThis retrospective multicenter cohort study included patients with moderate-to-severe UC treated with golimumab. The primary efficacy endpoints were short-term partial Mayo score response, long-term golimumab failure-free survival, and colectomy-free survival.\n\n\n\nIn 142 patients with UC, golimumab was administered as first (40%), second (23%), or third anti-TNF (37%). Ninety-two patients (65%, 95% confidence interval 56.6-73) achieved short-term clinical response. Forty-five patients (32%, 95% confidence interval 23.7-39.7) achieved clinical remission. Response rates for golimumab were 75% as first anti-TNF, 70% as second anti-TNF (ns versus first anti-TNF), and 50% as third anti-TNF (P = 0.007 versus first anti-TNF). After 12 months median follow-up (interquartile range 6-18), 60 patients (42%, 95% confidence interval 34-51) had golimumab failure, and 15 patients (11%) needed colectomy. Thirty-one patients (22%) needed golimumab dose escalation, and 71% of these regained response after escalation. Starting maintenance with 100 mg golimumab doses and short-term nonresponse were independent predictors of golimumab failure.\n\n\n\nIn this real-life cohort of patients with UC, golimumab therapy was effective for inducing and maintaining clinical response. Although anti-TNF-naive patients had better outcomes, golimumab was also effective in anti-TNF-experienced patients. Only the patients given golimumab after previous failure of 2 anti-TNF agents had significantly worse outcomes. Golimumab dose escalation was beneficial and safe.",
"affiliations": "1Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Clínico San Carlos and Instituto de Investigación del Hospital Clínico San Carlos (IdISSC), Madrid, Spain; 2Department of Gastroenterology, Complejo Hospitalario de Navarra, Pamplona, Spain; 3Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 4Department of Gastroenterology, Hospital Gregorio Marañón and Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain; 5Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; 6Department of Gastroenterology, Hospital Ramón y Cajal, Madrid, Spain; 7Department of Gastroenterology, Complejo Asistencial Universitario de León, León, Spain; 8Department of Gastroenterology, Hospital Universitario de Burgos, Burgos, Spain; 9Department of Gastroenterology, Hospital 12 de Octubre, Madrid, Spain; 10Department of Gastroenterology, Hospital Germans Trias i Pujol, Badalona, Spain; 11Department of Gastroenterology, Hospital Reina Sofía, Córdoba, Spain; 12Department of Gastroenterology, Hospital de Fuenlabrada, Madrid, Spain; 13Department of Gastroenterology, Hospital Infanta Sofía, Madrid, Spain; 14Department of Gastroenterology, Hospital Marqués de Valdecilla, Santander, Spain; 15Department of Gastroenterology, Hospital Clínico de Santiago, Santiago de Compostela, Spain; 16Department of Gastroenterology, Hospital Universitario Fundación Alcorcón, Madrid, Spain; 17Department of Gastroenterology, Hospital Universitario Virgen Macarena, Sevilla, Spain; 18Department of Gastroenterology, Hospital General Universitario de Alicante, Alicante, Spain; 19Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; 20Department of Gastroenterology, Hospital Universitari Doctor Josep Trueta, Girona, Spain; 21Department of Gastroenterology, Hospital de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; and 22Department of Gastroenterology, Hospital Puerta de Hierro, Madrid, Spain.",
"authors": "Taxonera|Carlos|C|;Rodríguez|Cristina|C|;Bertoletti|Federico|F|;Menchén|Luís|L|;Arribas|Julia|J|;Sierra|Mónica|M|;Arias|Lara|L|;Martínez-Montiel|Pilar|P|;Juan|Alba|A|;Iglesias|Eva|E|;Algaba|Alicia|A|;Manceñido|Noemí|N|;Rivero|Montserrat|M|;Barreiro-de Acosta|Manuel|M|;López-Serrano|Pilar|P|;Argüelles-Arias|Federico|F|;Gutierrez|Ana|A|;Busquets|David|D|;Gisbert|Javier P|JP|;Olivares|David|D|;Calvo|Marta|M|;Alba|Cristina|C|;|||",
"chemical_list": "D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; C529000:golimumab",
"country": "England",
"delete": false,
"doi": "10.1097/MIB.0000000000001144",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0998",
"issue": "23(8)",
"journal": "Inflammatory bowel diseases",
"keywords": null,
"medline_ta": "Inflamm Bowel Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D003093:Colitis, Ulcerative; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012074:Remission Induction; D012189:Retrospective Studies; D012720:Severity of Illness Index; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "9508162",
"other_id": null,
"pages": "1394-1402",
"pmc": null,
"pmid": "28671873",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Clinical Outcomes of Golimumab as First, Second or Third Anti-TNF Agent in Patients with Moderate-to-Severe Ulcerative Colitis.",
"title_normalized": "clinical outcomes of golimumab as first second or third anti tnf agent in patients with moderate to severe ulcerative colitis"
} | [
{
"companynumb": "ES-JNJFOC-20170816865",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": "054",
"drugauthoriz... |
{
"abstract": "OBJECTIVE\nThis is the first case report where 1.25mg intravitreal bevacizumab (IVB) correlated with choroidal mass resolution from metastatic breast cancer given concurrently with chemotherapy demonstrating, at best, disease stability in other organs.\n\n\nMETHODS\nCase report.\n\n\nMETHODS\nUpon confirmation of choroidal, liver and bone metastasis from breast carcinoma, a 72-year-old female received four intravitreal bevacizumab 1.25mg injections based on the presence of subretinal and intraretinal fluid. Visual outcomes were analyzed by ophthalmologic evaluation, B-scan, fluorescein angiography, and optical coherence tomography.\n\n\nRESULTS\nAfter 3 treatments of 1.25mg intravitreal bevacizumab, visual acuity improved from 20/125 OD to 20/30 OD. These results were maintained for 5 months, after which a 4th IVB injection was given to try to further improve visual outcomes. Following this, complete resolution of the mass was observed with remaining pigmentary changes and vision improved to 20/25 one month following this. IVB was administered concurrently to systemic chemotherapy that demonstrated at best disease stability in metastases in other organs.\n\n\nCONCLUSIONS\nIn this case 1.25mg intravitreal bevacizumab proved to be a safe, effective and relatively easy treatment for choroidal metastasis from breast cancer. An important benefit of intravitreal bevacizumab therapy for choroidal metastasis is the ease of administration and minimal time commitment required as compared to other therapies. Further studies should be conducted to confirm the appropriate dosing and long-term outcomes of intravitreal bevacizumab to treat choroidal metastasis.",
"affiliations": "Dalhousie University, Halifax, N.S.;University of Calgary, University of Calgary, Calgary, Alta.;University of Calgary, University of Calgary, Calgary, Alta.;Tom Baker Cancer Center, University of Calgary, Calgary, Alta.;Calgary Retina Consultants, University of Calgary, Calgary, Alta.. Electronic address: mpfielden@gmail.com.",
"authors": "Augustine|Haley|H|;Munro|Monique|M|;Adatia|Feisal|F|;Webster|Marc|M|;Fielden|Michael|M|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-4182",
"issue": "49(5)",
"journal": "Canadian journal of ophthalmology. Journal canadien d'ophtalmologie",
"keywords": null,
"medline_ta": "Can J Ophthalmol",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001859:Bone Neoplasms; D001943:Breast Neoplasms; D002285:Carcinoma, Intraductal, Noninfiltrating; D002830:Choroid Neoplasms; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D058449:Intravitreal Injections; D008113:Liver Neoplasms; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity",
"nlm_unique_id": "0045312",
"other_id": null,
"pages": "458-63",
"pmc": null,
"pmid": "25284103",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Treatment of ocular metastasis with anti-VEGF: a literature review and case report.",
"title_normalized": "treatment of ocular metastasis with anti vegf a literature review and case report"
} | [
{
"companynumb": "PHHY2015CA030205",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LETROZOLE"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to evaluate the short- and long-term safety of infliximab in patients with Crohn's disease in clinical practice.\n\n\nMETHODS\nThe medical records of 500 consecutive patients treated with infliximab at the Mayo Clinic were reviewed and abstracted for demographic features and adverse events. The likelihood of a causal relationship to infliximab for each adverse event was determined by calculating an intrinsic likelihood (imputability) score.\n\n\nRESULTS\nThe 500 patients received a median of 3 infusions and had a median follow-up of 17 months. Forty-three patients (8.6%) experienced a serious adverse event, of which 30 (6%) were related to infliximab. Acute infusion reactions occurred in 19 of 500 patients (3.8%). Serum sickness-like disease occurred in 19 of 500 patients and was attributed to infliximab in 14 (2.8%). Three patients developed drug-induced lupus. One patient developed a new demyelination disorder. Forty-eight patients had an infectious event, of which 41 (8.2%) were attributed to infliximab. Twenty patients had a serious infection: 2 had fatal sepsis, 8 had pneumonia (of which 2 cases were fatal), 6 had viral infections, 2 had abdominal abscesses requiring surgery, one had arm cellulitis, and one had histoplasmosis. Nine patients had a malignant disorder, 3 of which were possibly related to infliximab. A total of 10 deaths were observed. For 5 of these patients (1%), the events leading to death were possibly related to infliximab.\n\n\nCONCLUSIONS\nShort- and long-term infliximab therapy is generally well tolerated. However, clinicians must be vigilant for the occurrence of infrequent but serious events, including serum sickness-like reaction, opportunistic infection and sepsis, and autoimmune disorders.",
"affiliations": "Division of Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA.",
"authors": "Colombel|Jean-Frederic|JF|;Loftus|Edward V|EV|;Tremaine|William J|WJ|;Egan|Laurence J|LJ|;Harmsen|W Scott|WS|;Schleck|Cathy D|CD|;Zinsmeister|Alan R|AR|;Sandborn|William J|WJ|",
"chemical_list": "D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1053/j.gastro.2003.10.047",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5085",
"issue": "126(1)",
"journal": "Gastroenterology",
"keywords": null,
"medline_ta": "Gastroenterology",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D001327:Autoimmune Diseases; D002648:Child; D002675:Child, Preschool; D003424:Crohn Disease; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D007239:Infections; D000069285:Infliximab; D016013:Likelihood Functions; D008177:Lupus Vulgaris; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D012189:Retrospective Studies; D012713:Serum Sickness",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "19-31",
"pmc": null,
"pmid": "14699483",
"pubdate": "2004-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients.",
"title_normalized": "the safety profile of infliximab in patients with crohn s disease the mayo clinic experience in 500 patients"
} | [
{
"companynumb": "US-JNJFOC-20130807626",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCritically ill patients with coronavirus disease-2019 (COVID-19) are at the theoretical risk of invasive pulmonary aspergillosis (IPA) due to known risk factors.\n\n\nMETHODS\nWe aimed to describe the clinical features of COVID-19-associated pulmonary aspergillosis at a single centre in New York City. We performed a retrospective chart review of all patients with COVID-19 with Aspergillus isolated from respiratory cultures.\n\n\nRESULTS\nA total of seven patients with COVID-19 who had one or more positive respiratory cultures for Aspergillus fumigatus were identified, all of whom were mechanically ventilated in the ICU. Four patients were classified as putative IPA. The median age was 79 years, and all patients were male. The patients had been mechanically ventilated for a mean of 6.8 days (range: 1-14 days) before Aspergillus isolation. Serum galactomannan level was positive for only one patient. The majority of our cases received much higher doses of glucocorticoids than the dosage with a proven mortality benefit. All four patients died.\n\n\nCONCLUSIONS\nVigilance for secondary fungal infections will be needed to reduce adverse outcomes in critically ill patients with COVID-19.",
"affiliations": "Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA.",
"authors": "Mitaka|Hayato|H|https://orcid.org/0000-0003-0765-3955;Perlman|David C|DC|;Javaid|Waleed|W|https://orcid.org/0000-0002-1213-4677;Salomon|Nadim|N|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1111/myc.13185",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0933-7407",
"issue": "63(12)",
"journal": "Mycoses",
"keywords": "COVID-19; SARS-CoV-2; acute respiratory distress syndrome; pulmonary aspergillosis",
"medline_ta": "Mycoses",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001232:Aspergillus fumigatus; D000086382:COVID-19; D018352:Coronavirus Infections; D017809:Fatal Outcome; D006801:Humans; D007362:Intensive Care Units; D055744:Invasive Pulmonary Aspergillosis; D008297:Male; D009519:New York City; D058873:Pandemics; D011024:Pneumonia, Viral; D012121:Respiration, Artificial; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "8805008",
"other_id": null,
"pages": "1368-1372",
"pmc": null,
"pmid": "32965042",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D064888:Observational Study",
"references": "32445626;23711529;28446576;32396381;32965042;22895826;32339350;32343223;30076119;32754626;30629998;32678530;18462102;32585069;22517788",
"title": "Putative invasive pulmonary aspergillosis in critically ill patients with COVID-19: An observational study from New York City.",
"title_normalized": "putative invasive pulmonary aspergillosis in critically ill patients with covid 19 an observational study from new york city"
} | [
{
"companynumb": "US-MYLANLABS-2020M1101961",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHomologous recombination deficiency is a marker of response to poly(ADP-ribose) polymerase inhibitors in different cancer types including ovary, prostate, and pancreatic cancer. To date, no report about poly(ADP-ribose) polymerase inhibitors has been published on cervical cancer.\n\n\nMETHODS\nHere we present the case of a patient with cervical cancer treated in this setting. A 49-year-old woman diagnosed with International Federation of Obstetricians and Gynecologists stage 2018 IIIC2 locally advanced undifferentiated cervical cancer received first-line chemoradiotherapy followed by carboplatin, paclitaxel, and bevacizumab with partial response. Because of a family history of cancers, the patient was tested and found positive for a pathogenic BRCA1 germline and somatic mutation, which motivated bevacizumab plus olaparib maintenance treatment. A simple hysterectomy was performed after 2 years stable disease; pathological report showed complete pathological response, and 12 months follow-up showed no recurrence.\n\n\nCONCLUSIONS\nPoly(ADP-ribose) polymerase inhibitors could be an alternative maintenance treatment for patients with persistent advanced cervical cancer previously treated with platinum, especially when familial history of cancers is reported. Clinical trials using poly(ADP-ribose) polymerase inhibitors for advanced cervical cancer are warranted.",
"affiliations": "Department of Gynaecologic and Breast Oncological Surgery, European Georges-Pompidou Hospital, APHP. Centre, 20, rue Leblanc, 75908, Paris Cedex 15, France.;Department of Gynaecologic and Breast Oncological Surgery, European Georges-Pompidou Hospital, APHP. Centre, 20, rue Leblanc, 75908, Paris Cedex 15, France. anne-sophie.bats@aphp.fr.;Faculty of Medicine, Paris University, Paris, France.;Department of Pathology, European Georges-Pompidou Hospital, APHP. Centre, Paris, France.;Faculty of Medicine, Paris University, Paris, France.;Department of Gynaecologic and Breast Oncological Surgery, European Georges-Pompidou Hospital, APHP. Centre, 20, rue Leblanc, 75908, Paris Cedex 15, France.;Faculty of Medicine, Paris University, Paris, France.;Centre Universitaire des Saints-Pères, INSERM UMR-S 1147, Université de Paris, Paris, France.;Department of Gynaecologic and Breast Oncological Surgery, European Georges-Pompidou Hospital, APHP. Centre, 20, rue Leblanc, 75908, Paris Cedex 15, France.;Faculty of Medicine, Paris University, Paris, France.;Faculty of Medicine, Paris University, Paris, France.;Faculty of Medicine, Paris University, Paris, France.;Department of Gynaecologic and Breast Oncological Surgery, European Georges-Pompidou Hospital, APHP. Centre, 20, rue Leblanc, 75908, Paris Cedex 15, France.",
"authors": "Montero-Macias|Rosa|R|;Koual|Meriem|M|http://orcid.org/0000-0002-4318-7894;Crespel|Céline|C|;Le Frére-Belda|Marie Aude|MA|;Hélène|Hélène Blons|HB|;Nguyen-Xuan|Huyen-Thu|HT|;Garinet|Simon|S|;Perkins|Géraldine|G|;Balay|Vincent|V|;Durdux|Catherine|C|;Florin|Marie|M|;Péré|Hélène|H|;Bats|Anne-Sophie|AS|",
"chemical_list": "D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D010793:Phthalazines; D010879:Piperazines; D000068258:Bevacizumab; C531550:olaparib",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-02767-9",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2767\n10.1186/s13256-021-02767-9\nCase Report\nComplete pathological response to olaparib and bevacizumab in advanced cervical cancer following chemoradiation in a BRCA1 mutation carrier: a case report\nMontero-Macias Rosa 1\nhttp://orcid.org/0000-0002-4318-7894\nKoual Meriem anne-sophie.bats@aphp.fr\n\n123\nCrespel Céline 24\nLe Frére-Belda Marie Aude 5\nHélène Hélène Blons 267\nNguyen-Xuan Huyen-Thu 12\nGarinet Simon 267\nPerkins Géraldine 78\nBalay Vincent 12\nDurdux Catherine 29\nFlorin Marie 210\nPéré Hélène 21112\nBats Anne-Sophie 127\n1 Department of Gynaecologic and Breast Oncological Surgery, European Georges-Pompidou Hospital, APHP. Centre, 20, rue Leblanc, 75908 Paris Cedex 15, France\n2 grid.508487.6 0000 0004 7885 7602 Faculty of Medicine, Paris University, Paris, France\n3 grid.508487.6 0000 0004 7885 7602 Centre Universitaire des Saints-Pères, INSERM UMR-S 1124, Université de Paris, Paris, France\n4 grid.414093.b Department of Medical Oncology, European Georges-Pompidou Hospital, APHP. Centre, Paris, France\n5 grid.414093.b Department of Pathology, European Georges-Pompidou Hospital, APHP. Centre, Paris, France\n6 grid.414093.b Department of Biochemistry, European Georges-Pompidou Hospital, APHP. Centre, Paris, France\n7 grid.508487.6 0000 0004 7885 7602 Centre Universitaire des Saints-Pères, INSERM UMR-S 1147, Université de Paris, Paris, France\n8 grid.414093.b Department of Biology, European Georges-Pompidou Hospital, APHP. Centre, Paris, France\n9 grid.414093.b Department of Radiotherapy, European Georges-Pompidou Hospital, APHP. Centre, Paris, France\n10 grid.414093.b Department of Radiology, European Georges-Pompidou Hospital, APHP. Centre, Paris, France\n11 grid.414093.b Department of Virology, European Georges-Pompidou Hospital, APHP. Centre, Paris, France\n12 grid.414093.b INSERM 970, Paris Centre de Recherche Cardiovasculaire (PARCC), European Georges-Pompidou Hospital, APHP. Centre, Paris, France\n23 4 2021\n23 4 2021\n2021\n15 2102 4 2020\n1 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\nHomologous recombination deficiency is a marker of response to poly(ADP-ribose) polymerase inhibitors in different cancer types including ovary, prostate, and pancreatic cancer. To date, no report about poly(ADP-ribose) polymerase inhibitors has been published on cervical cancer.\n\nCase presentation\n\nHere we present the case of a patient with cervical cancer treated in this setting. A 49-year-old woman diagnosed with International Federation of Obstetricians and Gynecologists stage 2018 IIIC2 locally advanced undifferentiated cervical cancer received first-line chemoradiotherapy followed by carboplatin, paclitaxel, and bevacizumab with partial response. Because of a family history of cancers, the patient was tested and found positive for a pathogenic BRCA1 germline and somatic mutation, which motivated bevacizumab plus olaparib maintenance treatment. A simple hysterectomy was performed after 2 years stable disease; pathological report showed complete pathological response, and 12 months follow-up showed no recurrence.\n\nConclusion\n\nPoly(ADP-ribose) polymerase inhibitors could be an alternative maintenance treatment for patients with persistent advanced cervical cancer previously treated with platinum, especially when familial history of cancers is reported. Clinical trials using poly(ADP-ribose) polymerase inhibitors for advanced cervical cancer are warranted.\n\nKeywords\n\nAdvanced cervical cancer\nBRCA1\nPARP inhibitor\nOlaparib\nPrecision oncology\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nCervical cancer (CC) is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women worldwide [1]. Squamous cell carcinomas is the most common histological type, and although the difference in survival outcomes with adenocarcinoma remains controversial, there are studies that have shown a significantly greater response to adjuvant treatment in squamous cell subtype compared with adenocarcinomas, as well as difference in immunological microenvironments and tumor escape mechanisms [2].\n\nThirteen percent of CC cases are diagnosed at an advanced stage, and even if patients are treated with curative intent, responses are of short duration and prognosis is very poor with recurrent and metastatic disease. Five-year survival rate in advanced stages is about 20–60% [3]. Treatment of locally advanced CC is based on chemoradiation, and recurrent, persistent, or metastatic disease is treated first-line with chemotherapy and bevacizumab [4, 5]. There are currently no clear recommendations for second-line treatment in these cases. A retrospective study showed that 70% of women treated for recurrent or metastatic CC with systemic therapy for recurrent or metastatic CC subsequently received second-line therapy with an overall response rate (ORR) of 13.2%, a median progression-free survival (PFS) of 3.2 months, and a median overall survival of 9.3 months [6]. Recent advances in molecular biology of cancer have led to the development of targeted therapies in gynecological cancers, including poly(ADP-ribose) polymerase inhibitors (PARPi) [7–9]. This novel class of anticancer drug is approved in various indications, such as high-grade serous ovarian cancer and metastatic breast cancer, and is under investigation in many other types of malignancies [10]. To date, no report about PARPi has been published on CC.\n\nHere, we report the case of a 49-year-old BRCA1 mutated woman diagnosed with advanced CC treated by chemoradiation, followed by the combination olaparib/bevacizumab with complete pathological response.\n\nCase presentation\n\nA Caucasian 49-year-old patient was referred to our center in January 2016 with a uterine mass of 6 cm discovered during an ultrasound examination performed for lumbar pain. Clinical examination showed a friable suspect cervix with bilateral parametrial involvement. Pelvic magnetic resonance imaging (MRI) revealed a 91-mm cervical and uterine mass, with involvement of the uterine serosa, left distal parametrium, left pelvic wall, and left hydronephrosis. Imaging revealed close contact with the rectal wall and bladder trigone without transmural invasion and a suspicious left external iliac adenomegaly. Positron emission tomography/computed tomography (PET/CT) showed no evidence of paraaortic lymph node involvement or distant metastasis. Cervical biopsy found a poorly differentiated cervical carcinoma human papilloma virus (HPV) 16 positive.\n\nA laparoscopic extraperitoneal paraaortic lymphadenectomy was performed in February 2016. Pathological report showed two nonmetastatic left external iliac nodes (2N-/2) and 23 paraaortic lymph nodes including five metastatic nodes (5N+/23): International Federation of Obstetricians and Gynecologists (FIGO) 2018 stage IIIC2.\n\nThe patient received two cycles of capecitabine/cisplatin and subsequent concurrent chemoradiation (64,8 Gy in 36 fractions in the pelvic area, 45 Gy in 25 fractions in iliac and paraaortic area, and 8 concurrent cycles of cisplatin). The treatment was completed in June 2016.\n\nAt 3 months follow-up (September 2016), MRI showed partial response. The decision of the multidisciplinary meeting was to propose carboplatin, paclitaxel, plus bevacizumab adjuvant chemotherapy with partial response at 3 months.\n\nPatient received genetic counseling because of family history of cancers, and results returned positive in April 2017 showing a deleterious BRCA1 germline mutation (BRCA1 p.His1006Glnfs*17.c.3018_3021delTTCA) that motivated the use of PARPi. Olaparib was started (800 mg twice daily) in maintenance associated with bevacizumab. Somatic tumor testing showed that the BRCA1 germline mutation was associated with loss of heterozygosity and with a TP53 mutation p.Arg248Gln; c.743 G>A validating homologous recombination deficiency (HRD) in this tumor. The treatment was well tolerated, despite nausea, grade 1 asthenia, and grade 4 anemia leading to dose reduction (400 mg twice daily).\n\nIn January 2019, pelvis MRI showed a decrease of nearly 50% in size of the tumor residue compared with previous examinations, with persistence of a left proximal infiltration of the parametrium and fibrous retraction of the left ureter. A timeline of treatment received and corresponding pelvic magnetic resonance imaging is shown in Fig. 1.Fig. 1 Timeline of treatment received and corresponding pelvic magnetic resonance imaging. The Arrow is pointing the cervix tumoral mass\n\nThere was no argument on PET/CT for distant disease, and clinical benefit was reported.\n\nThe multidisciplinary meeting (multidisciplinary tumor board) discussed the option of surgery at that time. After reevaluation of patient’s medical record, we proposed surgery. A simple hysterectomy was performed in March 2019 without ureteral resection as parametrium appeared normal. No intra- or postoperative complications were noticed. Histological results showed no residual malignancy. After 1 year follow-up, clinical and radiological examinations do not show any recurrence without maintenance therapy.\n\nDiscussion and conclusions\n\nWe report the first case of a BRCA1 mutated patient with persistent advanced CC following chemoradiation and chemotherapy showing a complete tumor response after olaparib/bevacizumab adjuvant treatment and 12 months disease-free survival after surgery. The understanding of the molecular changes involved in the development of cancer led to the development of a new anticancer therapy known as targeted therapy and to a more personalized management of patients. In CC, therapies targeting different molecular pathways are investigated, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), and poly(ADP-ribose) polymerase (PARP). An analysis of 592 samples of cervical cancer in a tumor library in the US using a combination of sequencing (that is, next-generation sequencing), gene amplification (that is, in situ hybridization), and protein expression (that is, immunohistochemistry) identified mutations in 224 specimens (BRCA1 in 10%). These biomarkers could help guide therapy in clinical trials for patients with PARPi; mitogen-activated protein kinase, cell cycle checkpoint, and PI3K/AKT/mTOR pathway inhibitors; EGFR- and HER2-directed therapy; immunotherapy; and hormonal therapy, mainly in patients who have progressed with bevacizumab [11].\n\nPARPi are being tested in different cancer trials. PARP are enzymes involved in different DNA repair pathways, most notably in the base excision repair pathway (BER) to repair single DNA strand breaks (SSBs). PARP inhibitors (PARPi) block PARP activity, resulting in increased DNA damage. Cells with HRD depend on PARP-mediated repair for survival. The dual blockade repairs pathways when PARPi are used in a background of HRD, resulting in synthetic lethality and cell death. The BRCA genes (BRCA1 and BRCA2) are major players of the HR repair pathway, and mutations in both genes predict response to PARPi in different cancer types [8, 9]. Currently, olaparib, rucaparib, and niraparib have been approved by the FDA and/or European Medicines Agency (EMA) for the treatment of ovarian cancer, while veliparib is in the late stage of clinical development. Talazoparib has been approved by the FDA for the treatment of metastatic germline BRCA1/2 mutated breast cancers in October 2018. The discovery and characterization of talazoparib as a potent, PARP1/2 inhibitor provides an important addition to the field of PARP inhibitors. Its potency in PARP trapping is early evidence that talazoparib could potentially lead to improved clinical outcomes in BRCA mutant malignancies [12].\n\nPARP-1 is overexpressed in cancer cells, and higher expression of PARP-1 has been associated with chemoresistance [13]; other studies suggest that PARPi could sensitize cancer cells to chemotherapy [14]. In vitro, PARPi increase apoptosis in the HeLa CC cell line and sensitize cancer cells to cisplatin [15]. Prasad et al. showed that CC cells exhibit high amounts of PARP1 and that expression level is significantly higher in stages IIB and IIIB as compared with IIA (FIGO 2009) [16]. In this study, authors have proven that the replication stress caused by cisplatin induces PARP1 expression in a dose-dependent manner and determined the effect of olaparib on PARP1 activity in a PARP1 cisplatin-induced model. They showed that PARP1 inhibition enhanced cisplatin-induced DNA damage and apoptosis in CC cells and had a suppressive effect on metastasis. Altogether, olaparib increased cisplatin-induced lethality in CC cells. The authors hypothesized that combination of olaparib with cisplatin could enhance the efficacy of cisplatin in CC and improve the results of platinum-based therapy, and we believe that this hypothesis can explain the complete pathological response observed in our report, especially in the case of BRCA mutation.\n\nBianchi et al. explored the preclinical activity of olaparib in vitro and in vivo against nine primary CC cells [17]. PARP1 enzyme plays a key role in the recruitment of DNA repair factors and is also involved in the PARylation of nuclear proteins, a posttranslational modification process by which polymers of ADP-ribose (poly(adenosine diphosphate-ribose)) are covalently attached to proteins by PAR polymerase enzymes [18]. In this study, none of the cell lines demonstrated HRD but 33% showed strong PARylation activity associated with high sensitivity to the PARPi olaparib in vitro. In this subset of CC primary cells, olaparib significantly impaired CC xenograft tumor growth (p = 0.0017) and increased animal overall survival (p = 0.008). Authors suggest the use of the level of PARylation as a biomarker to predict for which patients PARPi would be the most efficient. PARP expression/activity is suggested to be mediated by chronic inflammation and HPV infection through oxidative stress that may result in DNA single-strand breaks [19–21]. HPV infection may promote progression by creating a vicious circle of inflammation and PARP activation. Thereby, PARPi may limit the role of PARP and consequently CC progression, whatever the BRCA or HRD status.\n\nAt a clinical level, the majority of data on PARPi in gynecological malignancies has been specifically focused on ovarian cancer, but PARPi are also under evaluation in the treatment of cervical and uterine cancers [9]. In CC, data from a phase I/II study assessing veliparib with cisplatin and paclitaxel in the treatment of advanced, recurrent, or persistent CC showed a promising overall response rate [22]. In this trial conducted by the Gynecologic Oncology Group including 34 patients, an overall response rate of 34% was observed for all dose levels and 60% for the maximum dose level. These results were not observed in another phase I study using veliparib and topotecan, which reinforces the idea of a synergic effect of PARPi and cisplatin [14]. A phase II randomized placebo-controlled double-blind study started in October 2019 to evaluate the efficacy and safety of rucaparib, another PARPi, as adjuvant treatment for patients with locally advanced CC who are responding to chemoradiation (ClinicalTrials.gov identifier: NCT03795272).\n\nIn conclusion, PARPi could be an alternative maintenance treatment for patients with persistent advanced CC previously treated with platinum. More studies are necessary to confirm the association between HRD in CC and response to PARPi, but it opens the way for personalized treatments in this type of cancer, especially when familial history of cancers is reported.\n\nAbbreviations\n\nCC Cervical cancer\n\nPARP Poly(ADP-ribose) polymerase\n\nPARPi Poly(ADP-ribose) polymerase inhibitors\n\nHRD Homologous recombination deficiency\n\nMRI Magnetic resonance imaging\n\nPET/CT Positron emission tomography/computed tomography\n\nHPV Human papilloma virus\n\nAcknowledgements\n\nNone\n\nAuthors’ contributions\n\nASB designed the paper. RMM and MK wrote the paper. CD performed the chemoradiation. HB and SG performed the molecular research of BRCA mutation. GP performed the genetic counseling. HP performed human papilloma virus research. ASB, HTNX, and VB performed surgery. MF performed radiological examinations. MALFB provided pathological evaluation. All authors are members of our multidisciplinary tumor board and approved the final manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nNone\n\nAvailability of data and materials\n\nThe patient consent is available upon request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors have no conflicts of interest to declare.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nRosa Montero-Macias and Meriem Koual contributed equally to this work\n==== Refs\nReferences\n\n1. Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2018 68 6 394 424 10.3322/caac.21492 30207593\n2. Boussios S Seraj E Zarkavelis G Petrakis D Kollas A Kafantari A Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: Where do we stand? A literature review Crit Rev Oncol Hematol 2016 108 164 174 10.1016/j.critrevonc.2016.11.006 27931835\n3. Quinn M Benedet J Odicino F Maisonneuve P Beller U Creasman W Carcinoma of the cervix uteri Int J Gynecol Obstet 2006 95 S43 103 10.1016/S0020-7292(06)60030-1\n4. Marth C Landoni F Mahner S McCormack M Gonzalez-Martin A Colombo N Cervical cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Ann Oncol 2017 28 suppl_4 iv72 83 10.1093/annonc/mdx220 28881916\n5. Tewari KS Sill MW Long HJ Penson RT Huang H Ramondetta LM Improved survival with bevacizumab in advanced cervical cancer N Engl J Med 2014 370 8 734 743 10.1056/NEJMoa1309748 24552320\n6. McLachlan J Boussios S Okines A Glaessgen D Bodlar S Kalaitzaki R The impact of systemic therapy beyond first-line treatment for advanced cervical cancer Clin Oncol (R Coll Radiol) 2017 29 3 153 160 10.1016/j.clon.2016.10.002 27838135\n7. Basu P Mukhopadhyay A Konishi I Targeted therapy for gynecologic cancers: toward the era of precision medicine Int J Gynecol Obstet 2018 143 131 136 10.1002/ijgo.12620\n8. Liu FW Tewari KS New targeted agents in gynecologic cancers: synthetic lethality, homologous recombination deficiency, and PARP inhibitors Curr Treat Options Oncol 2016 17 3 12 10.1007/s11864-015-0378-9 26931795\n9. Lheureux S Mirza M Coleman R The DNA repair pathway as a target for novel drugs in gynecologic cancers J Clin Oncol 2019 37 27 2449 2459 10.1200/JCO.19.00347 31403862\n10. Sachdev E Tabatabai R Roy V Rimel BJ Mita MM PARP inhibition in cancer: an update on clinical development Targ Oncol 2019 14 6 657 679 10.1007/s11523-019-00680-2\n11. Feldman R Gatalica Z Reddy SK Tewari KS Paving the road to personalized medicine in cervical cancer: theranostic biomarker evaluation in a 592-specimen library Gynecol Oncol 2015 137 141 10.1016/j.ygyno.2015.01.351\n12. Boussios S Abson C Moschetta M Rassy E Karathanasi A Bhat T Poly (ADP-ribose) polymerase inhibitors: talazoparib in ovarian cancer and beyond Drugs R D 2020 20 2 55 73 10.1007/s40268-020-00301-8 32215876\n13. Fukushima M Kuzuya K Ota K Ikai K Poly(ADP-ribose) synthesis in human cervical cancer cell—diagnostic cytological usefulness Cancer Lett 1981 14 3 227 236 10.1016/0304-3835(81)90148-8 6277470\n14. Kunos C Deng W Dawson D Lea JS Zanotti KM Gray HJ A phase I-II evaluation of Veliparib (NSC #737664), topotecan, and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix: an NRG Oncology/Gynecologic Oncology Group Study Int J Gynecol Cancer 2015 25 3 484 492 10.1097/IGC.0000000000000380 25594147\n15. Ghosh U Bhattacharyya NP Induction of apoptosis by the inhibitors of poly(ADP-ribose)polymerase in HeLa cells Mol Cell Biochem 2009 320 1–2 15 23 10.1007/s11010-008-9894-2 18695944\n16. Prasad CB Prasad SB Yadav SS Pandey LK Singh S Pradhan S Olaparib modulates DNA repair efficiency, sensitizes cervical cancer cells to cisplatin and exhibits anti-metastatic property Sci Rep 2017 7 1 12876 10.1038/s41598-017-13232-3 28993682\n17. Bianchi A Lopez S Altwerger G Bellone S Bonazzoli E Zammataro L PARP-1 activity (PAR) determines the sensitivity of cervical cancer to olaparib Gynecol Oncol 2019 155 1 144 150 10.1016/j.ygyno.2019.08.010 31434613\n18. Ba X Garg NJ Signaling mechanism of poly(ADP-ribose) polymerase-1 (PARP-1) in inflammatory diseases Am J Pathol 2011 178 3 946 955 10.1016/j.ajpath.2010.12.004 21356345\n19. Hegan DC Lu Y Stachelek GC Crosby ME Bindra RS Glazer PM Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130 Proc Natl Acad Sci 2010 107 5 2201 2206 10.1073/pnas.0904783107 20133863\n20. Weaver AN Cooper TS Rodriguez M Trummell HQ Bonner JA Rosenthal EL DNA double strand break repair defect and sensitivity to poly ADP-ribose polymerase (PARP) inhibition in human papillomavirus 16-positive head and neck squamous cell carcinoma Oncotarget 2015 6 29 26995 27007 10.18632/oncotarget.4863 26336991\n21. Hassumi-Fukasawa MK Miranda-Camargo FA Zanetti BR Galano DF Ribeiro-Silva A Soares EG Expression of BAG-1 and PARP-1 in precursor lesions and invasive cervical cancer associated with human papillomavirus (HPV) Pathol Oncol Res 2012 18 4 929 937 10.1007/s12253-012-9523-y 22454210\n22. Thaker PH Salani R Brady WE Lankes HA Cohn DE Mutch DG A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852) Ann Oncol 2017 28 3 505 511 10.1093/annonc/mdw635 27998970\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "15(1)",
"journal": "Journal of medical case reports",
"keywords": "Advanced cervical cancer; BRCA1; Olaparib; PARP inhibitor; Precision oncology",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D019313:BRCA1 Protein; D000068258:Bevacizumab; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D010793:Phthalazines; D010879:Piperazines; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "210",
"pmc": null,
"pmid": "33888155",
"pubdate": "2021-04-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25594147;31403862;28881916;28993682;30306576;27838135;18695944;27931835;21356345;17161167;24552320;26336991;20133863;27998970;22454210;32215876;31625002;26931795;31434613;30207593;6277470",
"title": "Complete pathological response to olaparib and bevacizumab in advanced cervical cancer following chemoradiation in a BRCA1 mutation carrier: a case report.",
"title_normalized": "complete pathological response to olaparib and bevacizumab in advanced cervical cancer following chemoradiation in a brca1 mutation carrier a case report"
} | [
{
"companynumb": "FR-PFIZER INC-2021542804",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "OLAPARIB"
},
"drugadditional": null,
... |
{
"abstract": "The cytochrome P450 is a superfamily of isoenzymes that are responsible for the metabolism of many drugs. Significant changes in pharmacokinetics and drug interactions may be due to induction of hepatic cytochrome P450 enzymes. Rifampicin is a common inducer of CYP3A4. We report a case of a 57-year-old woman who was suspected for endocarditis and therefore treated with rifampicin. Due to previous mechanical aortic valve replacement, she also received phenprocoumon for anticoagulation. Although continuing anticoagulant therapy, antibiotic coadministration led to normal international normalised ratio (INR) level. Fifteen days after the treatment with rifampicin ended, INR returned to therapeutic level.",
"affiliations": "Klinik für Kardiologie und Kreislauferkrankungen, Universitätsklinikum Tübingen, Tuebingen, Germany.;Klinik für Kardiologie und Kreislauferkrankungen, Universitätsklinikum Tübingen, Tuebingen, Germany.;Department fur Experimentelle und Klinische Pharmakologie und Toxikologie, Eberhard Karls Universitat Tubingen, Tübingen, Germany.;Klinik für Kardiologie und Kreislauferkrankungen, Universitätsklinikum Tübingen, Tuebingen, Germany.;Klinik für Kardiologie und Kreislauferkrankungen, Universitätsklinikum Tübingen, Tuebingen, Germany.",
"authors": "Mizera|Lars|L|;Geisler|Tobias|T|;Mörike|Klaus|K|;Gawaz|Meinrad|M|;Steeg|Martin|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D014812:Vitamin K; D003577:Cytochrome P-450 Enzyme System; D010644:Phenprocoumon; D012293:Rifampin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-215155",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "drug interactions; valvar diseases",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D001022:Aortic Valve Insufficiency; D003577:Cytochrome P-450 Enzyme System; D004347:Drug Interactions; D004696:Endocarditis; D005260:Female; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D019934:International Normalized Ratio; D008875:Middle Aged; D010644:Phenprocoumon; D012293:Rifampin; D016896:Treatment Outcome; D014812:Vitamin K",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29440136",
"pubdate": "2018-02-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24530864;17031720;23991661;15358623;19713420;22922415;14765194;28157069;23974699;18698879;9727070;24657899;10770721;24224579;17708140;21110013",
"title": "Problems in anticoagulation of a patient with antibiotic treatment for endocarditis: interaction of rifampicin and vitamin K antagonists.",
"title_normalized": "problems in anticoagulation of a patient with antibiotic treatment for endocarditis interaction of rifampicin and vitamin k antagonists"
} | [
{
"companynumb": "DE-SA-2018SA065763",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GENTAMICIN"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nCarnobacterium species are lactic acid-producing Gram-positive bacteria that have been approved by the US Food and Drug Administration and Health Canada for use as a food bio-preservative. The use of live bacteria as a food additive and its potential risk of infections in immunocompromised patients are not well understood.\n\n\nMETHODS\nAn 81-year-old male with a history of metastatic prostate cancer on androgen deprivation therapy and chronic steroids presented to our hospital with a 2-week history of productive cough, dyspnea, altered mentation, and fever. Extensive computed tomography imaging revealed multifocal pneumonia without other foci of infection. He was diagnosed with pneumonia and empirically treated with ceftriaxone and vancomycin. Blood cultures from admission later returned positive for Carnobacterium inhibens. He achieved clinical recovery with step-down to oral amoxicillin/clavulanic acid for a total 7-day course of antibiotics.\n\n\nCONCLUSIONS\nThis is the fourth reported case of bacteremia with Carnobacterium spp. isolated from humans. This case highlights the need to better understand the pathogenicity and disease spectrum of bacteria used in the food industry for bio-preservation, especially in immunocompromised patients.",
"affiliations": "Division of Infectious Diseases, Juravinski Cancer Centre, McMaster University Infectious Diseases Residency Program, 699 Concession Street, Hamilton, Ontario, L8V 5C2, Canada. carson.lo@medportal.ca.;Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada. prameet.sheth@queensu.ca.",
"authors": "Lo|Carson Ka-Lok|CK|http://orcid.org/0000-0002-1620-2868;Sheth|Prameet M|PM|",
"chemical_list": "D000726:Androgen Antagonists; D000900:Anti-Bacterial Agents; D014640:Vancomycin; D019980:Amoxicillin-Potassium Clavulanate Combination; D002443:Ceftriaxone",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-021-06095-7",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect Dis\nBMC Infectious Diseases\n1471-2334\nBioMed Central London\n\n6095\n10.1186/s12879-021-06095-7\nCase Report\nCarnobacterium inhibens isolated in blood culture of an immunocompromised, metastatic cancer patient: a case report and literature review\nhttp://orcid.org/0000-0002-1620-2868\nLo Carson Ka-Lok carson.lo@medportal.ca\n\n1\nSheth Prameet M. prameet.sheth@queensu.ca\n\n23\n1 grid.25073.33 0000 0004 1936 8227 Division of Infectious Diseases, Juravinski Cancer Centre, McMaster University Infectious Diseases Residency Program, 699 Concession Street, Hamilton, Ontario L8V 5C2 Canada\n2 grid.410356.5 0000 0004 1936 8331 Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario Canada\n3 Division of Microbiology, Kingston Health Sciences Centre, 76 Stuart Street, Kingston, Ontario K7L 2V7 Canada\n1 5 2021\n1 5 2021\n2021\n21 4033 2 2021\n20 4 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\nCarnobacterium species are lactic acid-producing Gram-positive bacteria that have been approved by the US Food and Drug Administration and Health Canada for use as a food bio-preservative. The use of live bacteria as a food additive and its potential risk of infections in immunocompromised patients are not well understood.\n\nCase presentation\n\nAn 81-year-old male with a history of metastatic prostate cancer on androgen deprivation therapy and chronic steroids presented to our hospital with a 2-week history of productive cough, dyspnea, altered mentation, and fever. Extensive computed tomography imaging revealed multifocal pneumonia without other foci of infection. He was diagnosed with pneumonia and empirically treated with ceftriaxone and vancomycin. Blood cultures from admission later returned positive for Carnobacterium inhibens. He achieved clinical recovery with step-down to oral amoxicillin/clavulanic acid for a total 7-day course of antibiotics.\n\nConclusions\n\nThis is the fourth reported case of bacteremia with Carnobacterium spp. isolated from humans. This case highlights the need to better understand the pathogenicity and disease spectrum of bacteria used in the food industry for bio-preservation, especially in immunocompromised patients.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s12879-021-06095-7.\n\nKeywords\n\nBacteremia\nCarnobacterium inhibens\nCarnobacterium species\nCase report\nImmunocompromised\nSepsis\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nCarnobacterium species are lactic acid-producing, Gram-positive rod-shaped bacteria that are rarely isolated in humans and often regarded as non-pathogenic [1]. Instead, they are frequently isolated from the environment and are currently approved for use as a bio-preservative in the food industry [1]. The use of live bacteria as food additives poses a potential risk for immunocompromised patients, including several studies highlighting cases of bacteremia/sepsis associated with lactic acid bacteria used in probiotics (e.g., Lactobacillus spp.) [2–5].\n\nWe report a case of Carnobacterium inhibens isolated in blood culture of an immunocompromised cancer patient with pneumonia. We also reviewed published reports on human infections with Carnobacterium spp.\n\nCase presentation\n\nAn 81-year-old male presented to the Emergency Department with a 2-week history of productive cough, exertional dyspnea, general malaise, altered mental status, and subjective fevers and chills. He had no recent sick contact exposures or travel history. He had no (farm) animal exposures and no history of the handling of, or heavy consumption of fish, dairy or meat products. His past medical history included castrate-resistant prostate cancer with liver and bone metastases on enzalutamide, leuprolide, and oral prednisone (10 mg daily) for at least 1 year. He also had triple-bypass cardiac surgery for a previous myocardial infarction. He had a previous history of smoking but no alcohol or recreational drug use.\n\nOn examination, his body temperature was 37.5 °C, with sinus tachycardia at 135 beats per minute, and blood pressure of 95/62 mmHg which improved to 121/79 mmHg with intravenous fluid resuscitation. He had a resting pulse oximeter saturation (SpO2) nadir of 93% on room air, but continued to require supplemental oxygen by nasal cannula due to intermittent episodes of desaturations. Lung auscultation demonstrated decreased air entry to the bases with diffuse crackles bilaterally. No murmurs on cardiac auscultation or other stigmata of endocarditis.\n\nSepsis workup showed peripheral white blood cell count of 10.7 × 109/L with neutrophil count of 9.49 × 109/L and elevated inflammatory markers (erythrocyte sedimentation rate 90 mm/hr., C-reactive protein 195.9 mg/L). Blood cultures were obtained prior to antibiotic administration on admission. Chest radiograph followed by a full-body computerized tomography revealed multifocal pneumonia without other foci of infection. Transthoracic echocardiography did not show any vegetations or hemodynamically significant valvular dysfunctions. A bone scintigraphy revealed prior known bony metastases without other foci of infection.\n\nGiven concerns for clinical deterioration and sepsis, he was admitted to hospital and started on empiric antibiotics of ceftriaxone and vancomycin for pneumonia, potentially secondary to aspiration. Two of 4 blood culture bottles (i.e., both aerobic and anaerobic bottles) flagged positive at 18 h with a Gram-positive bacillus that failed to identify by the VITEK-MS MALDI-TOF (Matrix-Assisted Laser Desorption Time-Of-Flight Mass Spectrometry, bioMérieux Clinical Diagnostics, Canada). The isolate was forwarded to the provincial reference laboratory (Public Health Ontario Laboratory, PHOL) for further testing and identification. The isolate was identified by PHOL to be C. inhibens with homology of 99% using 16S rRNA gene sequence analysis (Fig. 1a-d), though this information was only available after the patient was discharged home. Fig. 1 Carnobacterium inhibens isolated after incubation at 37 °C for 18 h. a, b 1–2 mm diameter, grey-colored, round, alpha-hemolytic colonies on 5% sheep blood agar. c Grey-colored, flat colonies surrounded by greenish discoloration around the colonies on chocolate agar. d Gram staining of blood culture isolate of C. inhibens depicting Gram-positive, asporogenous, lactobacillus-like rods, 100x\n\nThe patient clinically improved with the empiric antibiotic regimen and was stepped down to oral amoxicillin/clavulanic acid for a total 7-day course of antibiotics. He achieved complete clinical recovery upon finishing antibiotics and did not require any supplemental oxygen at the time of discharge. Repeat blood cultures obtained both while on antibiotics and after discharge from hospital were negative.\n\nDiscussion and conclusions\n\nCarnobacterium spp. belong to the order of lactic acid bacteria known as Lactobacillales, which includes genera such as Lactobacillus often seen in probiotic use [6]. Carnobacterium spp. are non-spore-forming, lactic acid-producing, Gram-positive rod-shaped bacteria [7, 8]. Most species can be found in both polar and temperate environments due to their cryophilic and cryotolerant properties; they can tolerate, grow, and reproduce at low temperatures (i.e., − 20 to + 10 °C) [1, 7, 8]. They are also known to tolerate high-pressure environments, such as the vacuum-packing process in food preservation [9–11].\n\nThe use of live lactic acid-producing bacteria such as Carnobacterium spp. in food and bio-preservation continues to be a growing area of research in the meat, dairy and seafood industry. Bacteriocins produced by these bacteria have antimicrobial properties that limit or inhibit the growth of foodborne pathogens [1]. In particular, bacteriocins produced by the species C. divergens and C. maltaromaticum are shown to inhibit the growth of Listeria monocytogenes in various food products [1, 12]. The additional unique properties of Carnobacterium spp. to survive under high-pressure vacuum-packing and grow at refrigeration temperatures make them the ideal candidate as an additive to prevent food spoilage, especially in the meat and seafood industry [1]. Both C. divergens and C. maltaromaticum are currently approved by Health Canada as food additives for bio-preservation of ready-to-eat smoked fish and vacuum-packed meat and poultry, respectively [13, 14]. Carnobacterium spp. are also used in the dairy industry and have been shown to reduce the growth of both L. monocytogenes and Pseudomonas spp. in soft unpasteurized cheeses, improving the safety and shelf-life of selected dairy products [15, 16].\n\nCarnobacterium spp. are often considered non-pathogenic to humans [1]. Although the use of live lactic acid bacteria (e.g., Lactobacillus spp.) in probiotics has been approved by organizations such as the US Food and Drug Administration, current studies on its safety outcomes in immunocompromised populations remain limited [4]. Despite historical evidence of its safe use, recent studies have reported cases of infections associated with lactic acid bacteria used in probiotics [2–5]. For example, Lactobacillus spp. have been identified as the causal pathogen in several case reports, ranging from local (e.g., pneumonia, abscesses) to systemic infections (e.g., infective endocarditis, bacteremia and/or sepsis) [2–5]. To date, there are few studies on infections associated with Carnobacterium spp. in humans.\n\nWe performed a comprehensive search of all English-written articles published on human infections with Carnobacterium spp. isolated from any body site or culture. We searched for articles from inception to December 2020 using databases including OvidMEDLINE, EMBASE (Additional files 1 and 2 for search strategy), and Google Scholar. To date, only 5 cases of Carnobacterium spp. isolated from humans have been reported (Table 1). Two cases had Carnobacterium spp. identified amongst mixed flora containing other aerobic and anaerobic bacteria from traumatic wounds, in the setting of water exposure [17, 18]. Three cases were isolated from blood cultures; one was reported as suspected gastrointestinal source of infection in an immunocompetent man with 1 positive blood culture set who presented with fever and an extensive history of handling and consuming fish [19]. The remaining 2 cases were likely suspected gastrointestinal source or central line-associated bloodstream infection: a woman with diabetes and chronic alcohol use requiring parenteral nutrition post-esophagectomy for necrotizing esophagitis complicated by post-operative cardiac arrest and septic shock, with multiple positive blood cultures for C. divergens [20], and; a man receiving chemotherapy and parenteral nutrition presenting with febrile neutropenia and extensive oral mucositis with 1 positive blood culture set for C. divergens [21]. Table 1 Literature review of human infections with Carnobacterium spp. isolated in cultures\n\nCase\tAge/Sex\tCountry\tPossible risk factors\tType of culture/body Site\tIsolate\tPresentation\tTreatment\tOutcome\tReference\t\n1\t35/M\tCzech Republic\tNone\tWound swab of abscess\tMixed flora with C. piscicola\tTraumatic hand from water sawmill\tAmputation, debridement; Abx\tCured\t[17]\t\n2\t13/F\tChina\tNone\tWound swab of gangrene\tMixed flora with Carnobacterium spp.\tTraumatic hand with pool water exposure\tAmputation, debridement; IPM\tCured\t[18]\t\n3\t43/M\tAustria\tExtensive hx of handling and consuming fish\t½ blood culture sets\tC. mobile or C. funditum\tSepsis suspected from GI source\tCRO/AMP ➔ MXF\tCured\t[19]\t\n4\t57/F\tFrance\tDM; EtOH; TPN; post-cardiac arrest\t4 blood culture sets\tC. divergens\tSeptic shock post-cardiac arrest; esophagectomy for necrotizing esophagitis on TPN/EN\tBroad spectrum Abx ➔ AMX\tCured\t[20]\t\n5\t65/M\tSouth Korea\tCancer; neutropenia on etoposide\t½ blood culture sets\tC. divergens\tFebrile neutropenia with oral mucositis on TPN\tTZP/VAN\tCured\t[21]\t\n6\t81/M\tCanada\tCancer; chronic steroid use\t½ blood culture sets\tC. inhibens\tSepsis with multifocal pna\tCRO/VAN ➔ AMC\tCured\tOur case\t\nAge (years old) and sex (F, female; M, male). Abbreviations: Abx antibiotics (not specified), AMC amoxicillin/clavulanic acid, AMP ampicillin, AMX amoxicillin, CRO ceftriaxone, DM diabetes mellitus, EN enteral nutrition, EtOH chronic alcohol use, GI gastrointestinal, hx history, IPM imipenem, MXF moxifloxacin, pna pneumonia, TPN total parenteral nutrition, TZP piperacillin-tazobactam, VAN vancomycin, ½ 1 of 2 positive culture sets\n\nOur case described an immunocompromised cancer patient on chronic steroids presenting with multifocal pneumonia with C. inhibens isolated in 2 of 4 blood culture bottles. Given the lack of clinical experience with this pathogen and its ability to cause disease in humans, as well the fact that C. inhibens was only isolated in 1 of 2 blood culture sets (with negative repeat blood cultures on antibiotics), there remained uncertainty whether it was the causative pathogen for the patient’s pneumonia or a contaminant. Our case was unique as unlike other published cases, there was no clear exposure history, prior traumatic wounds, central venous catheter access (for parenteral nutrition), or excessive consumption of meat, dairy or seafood products. Extensive investigations by imaging confirmed pneumonia as the primary infection, without other foci of infection. Given the altered mentation, we suspect our patient aspirated giving rise to multifocal pneumonia, due to mixed aerobic and anaerobic bacteria from oral and/or gastric flora. We postulate the mixed flora likely included C. inhibens, which was later isolated in blood culture during transient bacteremia secondary from aspiration pneumonia. Although invasive procedures for culture (e.g., bronchoalveolar lavage) were not pursued to confirm our hypothesis as patient improved on empiric antibiotic therapy, we believe the pneumonia was likely polymicrobial as opposed to C. inhibens as sole pathogen responsible for causing infection.\n\nTo date, there are no recommended interpretative criteria or breakpoints established by the Clinical and Laboratory Standards Institute (CLSI) for the susceptibility testing of antimicrobial agents against Carnobacterium spp. causing human infections. Some of the cases reported the minimum inhibitory concentration (MIC) of their isolates, which seemed to suggest susceptibility to penicillins, carbapenems, macrolides, but resistance to cephalosporins [19, 20]. Certain Carnobacterium spp. isolates such as C. piscicola demonstrated intrinsic resistance to many antibiotics including fluoroquinolones, aminoglycosides, trimethoprim, though the mechanisms of resistance remain not well understood [22]. In vitro susceptibilities to antibiotic classes including penicillins also varied across different Carnobacterium spp. strains [22–24]. Drug susceptibility testing performed on a C. inhibens strain in a 2002 study appeared to show in vitro sensitivity to several antibiotics including, but not limited to, penicillins, tetracycline, and vancomycin [24]. No susceptibility testing was performed for our isolate; our patient responded well to empiric parenteral followed by oral step-down antibiotics for aspiration pneumonia, prior to confirmation of the C. inhibens isolate as it required identification at a reference laboratory. Future considerations of antibacterial susceptibility breakpoints can be revisited once a better understanding of the infections associated with Carnobacterium spp. has been established.\n\nThe pathogenicity and disease spectrum of Carnobacterium spp. in humans remain unknown. The use of Gram-positive bacteria in the food industry for their bio-preservative or fermentative capacity presents a potential source of unique organisms leading to disease, especially in immunocompromised patients.\n\nSupplementary Information\n\nAdditional file 1. Database: OVID Medline Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present – Search Strategy. Compilation of search strategy, search key terms, and full list of journal article titles and abstracts from initial literature search of Ovid MEDLINE database (inception to December 2020); list was used for screening of relevant articles for subsequent literature review (Table 1).\n\nAdditional file 2. Database: Embase <1974 to 2020 December 29> – Search Strategy. Compilation of search strategy, search key terms, and full list of journal article titles and abstracts from initial literature search of EMBASE database (inception to December 2020); list was used for screening of relevant articles for subsequent literature review (Table 1).\n\nAbbreviations\n\nC. divergens Carnobacterium divergens\n\nC. funditum Carnobacterium funditum\n\nC. inhibens Carnobacterium inhibens\n\nC. maltaromaticum Carnobacterium maltaromaticum\n\nC. mobile Carnobacterium mobile\n\nC. piscicola Carnobacterium piscicola\n\nCLSI Clinical and Laboratory Standards Institute\n\nL. monocytogenes Listeria monocytogenes\n\nMALDI-TOF-MS Matrix-Assisted Laser Desorption Time-Of-Flight Mass Spectrometry\n\nMIC Minimum inhibitory concentration\n\nPHOL Public Health Ontario Laboratory\n\n16S rRNA gene sequence analysis 16S ribosomal RNA gene sequence analysis\n\nAcknowledgements\n\nWe would like to thank our colleagues from the Division of Microbiology, Kingston Health Sciences Centre, for kindly preparing and isolating the Carnobacterium spp. strain for visualization.\n\nAuthors’ contributions\n\nCKL performed the literature review and drafted the manuscript. CKL and PMS critically reviewed and substantively revised the manuscript. PMS provided supervision and academic advice for CKL. All authors have read and approved the final manuscript.\n\nFunding\n\nThis research did not receive any specific funding.\n\nAvailability of data and materials\n\nAll data generated and/or analysed during this study are included in this published article [and its supplementary information files]. Please see Table 1 for data extracted from literature review and Additional file 1 and Additional file 2 for our literature search strategies from databases.\n\nDeclarations\n\nEthics approval and consent to participate\n\nEthical approval was obtained from Queen’s University Health Sciences & Affiliated Teaching Hospitals Research Ethics Board (HSREB). Written informed consent was obtained from the patient’s family.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient’s family for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\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. Leisner JJ Laursen BG Prévost H Drider D Dalgaard P Carnobacterium: positive and negative effects in the environment and in foods FEMS Microbiol Rev 2007 31 5 592 613 10.1111/j.1574-6976.2007.00080.x 17696886\n2. Castro-González JM, Castro P, Sandoval H, Castro-Sandoval D. Probiotic lactobacilli precautions. Front Microbiol. 2019;10(375):1–5. 10.3389/fmicb.2019.00375.\n3. Costa RL Moreira J Lorenzo A Lamas CC Infectious complications following probiotic ingestion: a potentially underestimated problem? A systematic review of reports and case series BMC Complement Altern Med 2018 18 1 329 10.1186/s12906-018-2394-3 30541524\n4. Doron S, Snydman DR. Risk and safety of probiotics. Clin Infect Dis. 2015;60(suppl_2):S129–S34. 10.1093/cid/civ085.\n5. Kothari D Patel S Kim S-K Probiotic supplements might not be universally-effective and safe: a review Biomed Pharmacother 2019 111 537 547 10.1016/j.biopha.2018.12.104 30597307\n6. Makarova KS Koonin EV Evolutionary genomics of lactic acid bacteria J Bacteriol 2007 189 4 1199 1208 10.1128/JB.01351-06 17085562\n7. Collins MD Farrow JAE Phillips BA Ferusu S Jones D Classification of lactobacillus divergens, lactobacillus piscicola, and some catalase-negative, asporogenous, rod-shaped bacteria from poultry in a new genus, carnobacterium Int J Syst Evol Microbiol 1987 37 4 310 316 10.1099/00207713-37-4-310\n8. Jöborn A Dorsch M Olsson JC Westerdahl A Kjelleberg S Carnobacterium inhibens sp. nov., isolated from the intestine of Atlantic salmon (Salmo salar) Int J Syst Evol Microbiol 1999 49 4 1891 1898 10.1099/00207713-49-4-1891\n9. Lakshmanan R, Dalgaard P. Effects of high-pressure processing on Listeria monocytogenes, spoilage microflora and multiple compound quality indices in chilled cold-smoked salmon. J Appl Microbiol. 2004;96(2):398–408. 10.1046/j.1365-2672.2004.02164.x.\n10. Lauro FM Chastain RA Blankenship LE Yayanos AA Bartlett DH The unique 16S rRNA genes of piezophiles reflect both phylogeny and adaptation Appl Environ Microbiol 2007 73 3 838 845 10.1128/AEM.01726-06 17158629\n11. Paarup T Sanchez JA Peláez C Moral A Sensory, chemical and bacteriological changes in vacuum-packed pressurised squid mantle (Todaropsis eblanae) stored at 4 °C Int J Food Microbiol 2002 74 1 1 12 10.1016/S0168-1605(01)00701-2 11929163\n12. Brillet A, Pilet M-F, Prevost H, Bouttefroy A, Leroi F. Biodiversity of Listeria monocytogenes sensitivity to bacteriocin-producing Carnobacterium strains and application in sterile cold-smoked salmon. J Appl Microbiol. 2004;97(5):1029–37. 10.1111/j.1365-2672.2004.02383.x.\n13. Notice of Health Canada’s proposal to enable the use of a new food additive, Carnobacterium divergens M35, as an antimicrobial preservative in sliced ready-to-eat cold-smoked salmon and sliced ready-to-eat cold-smoked trout - NOP/AVP-0018 [https://www.canada.ca/en/health-canada/services/food-nutrition/public-involvement-partnerships/proposal-use-new-food-additive-carnobacterium-divergens-antimicrobial-preservative-sliced-ready-cold-smoked-salmon-sliced.html]. Accessed 4 July 2020.\n14. Notice of modification to the list of permitted preservatives to enable the use of Carnobacterium maltaromaticum CB1 as an antimicrobial preservative in certain meat and poultry meat products reference number: NOM/ADM-0097. [https://www.canada.ca/en/health-canada/services/food-nutrition/public-involvement-partnerships/notice-modification-list-permitted-preservatives-enable-use-carnobacterium-maltaromaticum-cb1-antimicrobial-preservative-certain-meat-poultry-meat.html]. Accessed 4 July 2020.\n15. Hammi I Delalande F Belkhou R Marchioni E Cianferani S Ennahar S Maltaricin CPN, a new class IIa bacteriocin produced by Carnobacterium maltaromaticum CPN isolated from mould-ripened cheese J Appl Microbiol 2016 121 5 1268 1274 10.1111/jam.13248 27489131\n16. Spanu C Piras F Mocci AM Nieddu G De Santis EPL Scarano C Use of Carnobacterium spp protective culture in MAP packed ricotta fresca cheese to control Pseudomonas spp Food Microbiol 2018 74 50 56 10.1016/j.fm.2018.02.020 29706337\n17. Chmelař D Matušek A Korger J Durnová E Steffen M Chmelařová E Isolation of Carnobacterium piscicola from human pus—case report Folia Microbiol (Praha) 2002 47 4 455 457 10.1007/BF02818708 12422528\n18. Xu J Yang H Lai X Fu X Wu J Huang L Yu X Wu Y Wu Y Liu B Etiological study for a case of multi-bacterial synergistic gangrene Chin Sci Bull 1997 42 6 511 517 10.1007/BF02882606\n19. Hoenigl M Grisold AJ Valentin T Leitner E Zarfel G Renner H Krause R Isolation of Carnobacterium sp. from a human blood culture J Med Microbiol 2010 59 4 493 495 10.1099/jmm.0.016808-0 20075110\n20. Smati M Palacios C Cohen Y Méchaï F Tankovic J Le Flèche-Mateos A Carnobacterium divergens bacteremia in woman Emerg Infect Dis 2015 21 6 1081 1082 10.3201/eid2106.141799 25988484\n21. Jeong I-H, Ahn G-D, Kim N-H, Kim K-H, Shin S-D, Han J-Y, et al. Isolation of Carnobacterium divergens from blood culture in Korea: a case report and literature review. Ann Clin Microbiol. 2020;23(3):209–13. 10.5145/ACM.2303.23.3.4.\n22. Baya AM Toranzo AE Lupiani B Li T Roberson BS Hetrick FM Biochemical and serological characterization of Carnobacterium spp. isolated from farmed and natural populations of striped bass and catfish Appl Environ Microbiol 1991 57 11 3114 3120 10.1128/AEM.57.11.3114-3120.1991 1781676\n23. Lai S Manchester LN Numerical phenetic study of the genus Carnobacterium Antonie Van Leeuwenhoek 2000 78 1 73 85 10.1023/A:1002723609675 11016698\n24. Ringø E Seppola M Berg A Olsen RE Schillinger U Holzapfel W Characterization of Carnobacterium divergens strain 6251 isolated from intestine of Arctic charr (Salvelinus alpinus L.) Syst Appl Microbiol 2002 25 1 120 129 10.1078/0723-2020-00080 12086178\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "21(1)",
"journal": "BMC infectious diseases",
"keywords": "Bacteremia; Carnobacterium inhibens; Carnobacterium species; Case report; Immunocompromised; Sepsis",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000369:Aged, 80 and over; D019980:Amoxicillin-Potassium Clavulanate Combination; D000726:Androgen Antagonists; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D000071997:Blood Culture; D002170:Canada; D056573:Carnobacterium; D002443:Ceftriaxone; D005516:Food Microbiology; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D018410:Pneumonia, Bacterial; D011471:Prostatic Neoplasms; D014640:Vancomycin",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "403",
"pmc": null,
"pmid": "33933029",
"pubdate": "2021-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "17696886;30541524;30597307;17085562;17158629;11929163;27489131;29706337;20075110;25988484;1781676;11016698;12086178",
"title": "Carnobacterium inhibens isolated in blood culture of an immunocompromised, metastatic cancer patient: a case report and literature review.",
"title_normalized": "carnobacterium inhibens isolated in blood culture of an immunocompromised metastatic cancer patient a case report and literature review"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-301667",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Excluding ethanol, cannabis is the most commonly used drug in the United States and worldwide. Several published case series and reports have demonstrated an association between cannabis use and acute coronary syndrome (ACS). We report the first ever published case of ACS precipitated by cannabis use that was confirmed with concomitant rising quantitative plasma levels of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol, a secondary metabolite of cannabis. A 63-year-old non-tobacco smoking male with no prior medical history presented to the emergency department with chest pain immediately after smoking cannabis, and anterior ST-segment elevation pattern was observed on his electrocardiogram. He was taken to the cardiac catheterization lab for percutaneous coronary intervention (PCI) of his left anterior descending artery, whereupon he developed hemodynamically significant accelerated idioventricular rhythm necessitating intra-aortic balloon pump placement. He underwent two further PCI procedures during his inpatient stay and was discharged in improved condition after eight days. Two sequential quantitative plasma cannabis metabolite assays at time of arrival then 6 h later were 24 ng/mL then 39 ng/mL, an increase of 63%, which implicated the patient's acute cannabis use as a precipitant of ACS. We also discuss the putative pharmacologic mechanisms behind cannabis use and ACS. Clinicians caring for patients using cannabis who have vascular disease and/or risk factors should be aware of this potentially deleterious association, as cessation of cannabis use could be important for their cardiac rehabilitation and long-term health.",
"affiliations": "Department of Emergency Medicine, University of California Davis Medical Center, Sacramento, CA, United States of America. Electronic address: jrrichards@ucdavis.edu.;Department of Internal Medicine, Division of Cardiovascular Medicine, University of California Davis Medical Center, Sacramento, CA, United States of America.;Department of Emergency Medicine, University of California Davis Medical Center, Sacramento, CA, United States of America.;Department of Internal Medicine, Division of Cardiovascular Medicine, University of California Davis Medical Center, Sacramento, CA, United States of America.",
"authors": "Richards|John R|JR|;Singh|Gagan D|GD|;Parikh|Aman K|AK|;Venugopal|Sandhya|S|",
"chemical_list": "C009411:delta(6)-tetrahydrocannabinol-7-oic acid; D013759:Dronabinol",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2019.02.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "37(5)",
"journal": "The American journal of emergency medicine",
"keywords": "Acute coronary syndrome; Cannabis; Chest pain; Marijuana; Myocardial infarction; STEMI; Toxicology",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D054058:Acute Coronary Syndrome; D013759:Dronabinol; D006801:Humans; D008297:Male; D008385:Marijuana Smoking; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D000072657:ST Elevation Myocardial Infarction",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1007.e1-1007.e4",
"pmc": null,
"pmid": "30777374",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute coronary syndrome after cannabis use: Correlation with quantitative toxicology testing.",
"title_normalized": "acute coronary syndrome after cannabis use correlation with quantitative toxicology testing"
} | [
{
"companynumb": "US-MYLANLABS-2020M1009631",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAstrocytomas are the most common malignant glial tumors. With improved prognosis, it is possible for patients to pursue pregnancy post-treatment. However, with potential gonadotoxicity of oncology treatments, fertility preservation prior to chemotherapy and/or radiation therapy should be considered. This requires close collaboration between the oncologist and reproductive endocrinologist. To our knowledge this is the first report of successful pregnancies following fertility preservation for AA.\n\n\nMETHODS\n33-year-old nulligravid woman with newly diagnosed anaplastic astrocytoma (AA; WHO grade III, IDH1-negative) sought fertility preservation. Prior to chemotherapy and radiation for AA, the patient underwent in vitro fertilization (IVF) for fertility preservation, resulting in 8 vitrified embryos. Following chemo-radiation, the patient underwent two rounds of frozen embryo transfers (FET), each resulting in a successful singleton pregnancy.\n\n\nCONCLUSIONS\nThis case illustrates the realistic possibility, in carefully selected patients with brain tumors, of oocyte or embryo cryo-preservation prior to chemo-radiation and subsequent pregnancies.",
"affiliations": "Department of Obstetrics and Gynecology, Northwell Health, Division of Reproductive Endocrinology, 300 Community Drive, Manhasset, NY, 11030, USA.;Department of Obstetrics and Gynecology, Northwell Health, Division of Reproductive Endocrinology, 300 Community Drive, Manhasset, NY, 11030, USA.;Department of Obstetrics and Gynecology, Northwell Health, Division of Reproductive Endocrinology, 300 Community Drive, Manhasset, NY, 11030, USA. zymania1@northwell.edu.",
"authors": "Peyser|Alexandra|A|;Bristow|Sara L|SL|;Hershlag|Avner|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12885-018-4472-9",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 447210.1186/s12885-018-4472-9Case ReportTwo successful pregnancies following fertility preservation in a patient with anaplastic astrocytoma: a case report Peyser Alexandra apeyser@northwell.edu 12Bristow Sara L. spalen@northwell.edu 1Hershlag Avner (516) 562-2229zymania1@northwell.edu 121 0000 0001 2168 3646grid.416477.7Department of Obstetrics and Gynecology, Northwell Health, Division of Reproductive Endocrinology, 300 Community Drive, Manhasset, NY 11030 USA 2 0000 0001 2284 9943grid.257060.6Hofstra-Northwell School of Medicine, 500 Hofstra Blvd, Hempstead, NY 11549 USA 9 5 2018 9 5 2018 2018 18 54427 2 2018 1 5 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAstrocytomas are the most common malignant glial tumors. With improved prognosis, it is possible for patients to pursue pregnancy post-treatment. However, with potential gonadotoxicity of oncology treatments, fertility preservation prior to chemotherapy and/or radiation therapy should be considered. This requires close collaboration between the oncologist and reproductive endocrinologist. To our knowledge this is the first report of successful pregnancies following fertility preservation for AA.\n\nCase presentation\n33-year-old nulligravid woman with newly diagnosed anaplastic astrocytoma (AA; WHO grade III, IDH1-negative) sought fertility preservation. Prior to chemotherapy and radiation for AA, the patient underwent in vitro fertilization (IVF) for fertility preservation, resulting in 8 vitrified embryos. Following chemo-radiation, the patient underwent two rounds of frozen embryo transfers (FET), each resulting in a successful singleton pregnancy.\n\nConclusion\nThis case illustrates the realistic possibility, in carefully selected patients with brain tumors, of oocyte or embryo cryo-preservation prior to chemo-radiation and subsequent pregnancies.\n\nKeywords\nFertility preservationAnaplastic astrocytomaGliomaBrain cancerissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nAstrocytomas are the most common malignant glial tumors originating from small star- shaped glial cells (astrocytes) within the central nervous system. Anaplastic astrocytomas (AA) are defined as grade III glial tumors according to the WHO 2000 classification [1]. The incidence of AA is approximately 0.48 per 100,000 person/years. They occur more often in younger adults ages 30–50 and account for 17% of primary malignant brain tumors [2]. Prognosis in historical studies, which include both IDH (Isocitrate dehydrogenase)-mutant and IDH-wild type AAs, ranges from 3 to 5 five-year-survival. Prognosis is better for a genetically-defined subset of IDH-mutant tumors, with a median survival closer to 10 years [3]. The mainstay of therapy is surgery followed by radiotherapy. Multiple protocols, including various combinations of high dose radiotherapy, chemotherapy, alternative fraction regimens, heavy particle treatment, interstitial brachytherapy and radiosurgery have been proposed to extend survival [3].\n\nDetermining the safety of fertility preservation and subsequent pregnancy after treatment of gliomas is difficult due to the lack of data in the literature. Most studies have been done in patients where the glioma was diagnosed during pregnancy; in these cases there have been reports of changes in the growth of the tumors throughout the pregnancy [4–8]. Significantly, it seems that the same hormones and growth factors required for fetal development may also enhance tumor growth [9]. Currently, no guidelines exist for the medical management and treatment of gliomas diagnosed prior to or during pregnancy. Therefore, it is recommended that women with treated gliomas who want to pursue pregnancy should be followed by a high-risk obstetrician as well as a neuro-oncologist and monitored throughout pregnancy.\n\nCase presentation\nA 33-year-old nulligravid woman with newly diagnosed AA (WHO grade III, IDH1 negative) presented to our office for fertility preservation. The patient had undergone a craniotomy with complete resection of her right parietal lobe tumor one month prior, and was scheduled to start chemotherapy and radiation in the next month. Her neuro-oncologist recommended that she undergo fertility preservation prior to chemo-radiation. The fertility preservation did not delay the anticipated start of her chemo-radiation treatment.\n\nThe patient had no significant medical or gynecological history. On physical exam, the patient was a healthy-appearing woman. She had left lower extremity weakness and instability. Transvaginal ultrasound demonstrated a normal-appearing uterus and ovaries bilaterally. A dominant follicle was noted on her right ovary; therefore, it was decided to administer HCG 10,000 IU at the time of her presentation to trigger ovulation, thus enabling the initiation of gonadotropins two weeks later. The patient had a high antral follicle count (6 on right, 7 on left).\n\nThe patient received low dose gonadotropins: 1 ampule of Human Menopausal Gonadotropin (Menopur®, Ferring Pharmaceuticals, Parsippany, NJ, USA), 75–187.5 IU of FSH (Gonal F®, EMD Serono, Rockland, MA, USA) for 10 days and cetrorelix acetate (Ganirelex®, GnRH antagonist, EMD Serono, Rockland, MA, USA) for the last 6 days. Final oocyte maturation was triggered with Lupron Luprolide Acetate (Lupron®, GnRH agonist, SANDOZ Pharmaceuticals, Princeton, NJ, USA) 40u. Twelve oocytes were retrieved transvaginally under ultrasound guidance. Eight embryos developed and were vitrified in liquid nitrogen (6 on day 3 and 2 on day 5 post-retrieval).\n\nThe patient returned to our Center one year later after she was cleared by her neuro-oncologist following the completion of chemotherapy and radiation. The patient had 6 weeks of radiation therapy with Temozolomide (Temodar®, Merck&Co, Inc., Whitehouse Station, NJ, USA) followed by 6 months of maintenance dose. Her last dose of chemotherapy was one month prior to returning to the office. The patient had maintained regular cycles post chemotherapy. The patient underwent a frozen-thaw natural cycle embryo transfer of a single day-3 embryo with vaginal progesterone (Crinone®, Actavis, Parsippany, NJ, USA) luteal phase support. The patient remained on Keppra® 500 TID (levetiracetam, UCB Pharmacueticals, Brussels, Belgium) and Lactulose throughout the pregnancy. A viable singleton pregnancy was seen on ultrasound 1 month later. The patient delivered a healthy female baby weighing 7lbs 5 oz. at term.\n\nThe patient returned two years later desirous of another pregnancy. Her neurological status had been stable, was tumor free and was cleared by her oncologist to conceive again. This time the patient was treated with Estrace® (estradiol, Warner Chilcott, Rockaway, NJ, USA) 6 mg a day and underwent a frozen-thaw cycle with a single day-5 blastocyst transferred. The patient conceived with a viable singleton pregnancy and delivered a healthy male at term weighing 6lbs.\n\nThroughout the patient’s treatment regimen for fertility preservation and frozen embryo transfers, no adverse or unanticipated events were encountered.\n\nDiscussion and conclusions\nWomen diagnosed with gliomas during child-bearing years may undergo fertility preservation prior to receiving chemotherapy and radiation to harvest oocytes and freeze them or freeze embryos if they have a partner, since their postoperative treatment, especially chemotherapy, is potentially gonadotoxic and may render them sterile. Studies have shown that the risk of ovarian failure as a result of chemotherapy varies based on both the drugs used as well as the patient’s age [10, 11]. Temozolomide (Temodar®, Merck&Co, Inc., Whitehouse Station, NJ, USA) is an alkylating agent, and while the effects of other alkylating agents used for chemotherapy on fertility have been studied, little is published about the gonadotoxicity of temozolomide in females. A handful of small studies have shown that fertility potential is affected in males [12, 13], with one case resulting in fathering a healthy child after treatment with temozolomide [13]. A study from France followed fertility outcomes in two groups of glioma survivors who had received temozolomide categorized based on whether the patient pursued fertility preservation [14]. They observed one spontaneous pregnancy in a woman who did not undergo fertility preservation and three pregnancies – one delivery, one spontaneous miscarriage, and one ongoing pregnancy – in women that underwent fertility preservation (four out of 24 women followed for one to five years). In the absence of more data, we recommend to assume high gonadotoxicity level of temozolomide, and pursuing fertility preservation in such patients following clearance by the neuro-oncologist.\n\nA remaining concern for oncologists and oncologic surgeons is whether fertility preservation delays critical treatment. In cases when the patient receives adjuvant therapy, such as the one presented here, there is typically a sufficient interval between surgery and planned adjuvant therapy (chemotherapy and/or radiation) to allow for a short window of opportunity to freeze eggs or embryos without affecting the cancer treatment timeline at all. In addition, if neoadjuvant therapy is recommended in other cases, recent advances in reproductive technologies allows for fertility preservation to be initiated any time during the menstrual cycle (“random start”). This allows patient to start an ovulation induction cycle on the day she presents to the oncofertility specialist, and it is expected that the cycle will be no more than 2 weeks. Thus, fertility preservation should not delay or alter treatment regimens for cancer patients.\n\nThe literature is scarce regarding the possible interactions between gliomas and pregnancy. Changes of the biological behavior of some tumor subtypes may occur during pregnancy, such as an accelerated tumor growth and/or malignant transformation. Several reports have discussed interactions between pregnancy and the growth of gliomas. One study analyzed velocity of diametric expansion (VDE) of WHO grade II gliomas in 11 pregnant women and demonstrated an increase in VDE during pregnancy [4]. Multiple case series have demonstrated cases where woman with WHO grade II gliomas developed de-differentiation of the tumor during pregnancy which became apparent either clinically, radiologically or confirmed histologically by post-delivery surgeries [5–7]. A recent case report revealed a malignant transformation from diffuse astrocytoma (WHO grade II) to glioblastoma (WHO grade IV) in a post-partum patient 1 month following the patient’s delivery [8].\n\nThe mechanism by which tumor growth is enhanced during pregnancy stems from the idea that the large amount of hormones and growth factors excreted during pregnancy simultaneously increase tumor growth. Placental growth factor for example, is an angiogenic element necessary for both fetal development and the growth of gliomas [9]. Due to the relative paucity of cases reported, the majority of cases focus on gliomas diagnosed during pregnancy. There are no guidelines for the management of gliomas diagnosed either during or prior to pregnancy. If a woman with a treated glioma desires a pregnancy it is advised to perform very close neurological follow-up with repeat MRI’s in addition to obstetrical monitoring.\n\nThe use of antiepileptic drugs (AEDs) during the course of pregnancy may be teratogenic and increase the risk of congenital malformations. Levetiracetam (Keppra®) is considered a safe medication for use during pregnancy. The North American AED pregnancy registry published data collected from pregnant women taking Levetiracetam monotheraphy from 1997 to 2011. The relative risk of major malformations was not increased in comparison to women with epilepsy who did not take AEDs while pregnant [15].\n\nTo our knowledge this is the first report of successful pregnancies following fertility preservation for AA. This case illustrates the realistic possibility of oocyte or embryo cryo-preservation prior to chemotherapy and radiation with subsequent embryo transfers. A recent article published in Neuro-Oncology [16], describes a study reviewing primary brain tumor patients age 18–45, referred for fertility preservation. Seventy-three percent accepted referral to a sperm bank (87% men) or a reproductive endocrinologist (56% women). The study concludes that there is significant interest in fertility preservation among these patients, particularly if they had no children [16]. Patients should be informed at the time of tumor diagnosis about the option of preserving their fertility. Proper referral to a reproductive endocrinologist as well as a mental health professional is recommended to help make informed decisions [17].\n\nIt is incumbent upon physicians to engage in discussion of the ethical perspectives of fertility preservation in patients with brain tumors. For childless women, the option of post-treatment pregnancy opens a window of hope that may elevate their mood, helping them cope with a potentially fatal diagnosis and difficult treatment. However, the possibility that pregnancy may negatively affect prognosis remains a major concern.\n\nAbbreviations\nAAAnaplastic Astrocytoma\n\nAEDAntiepileptic Drug\n\nFETFrozen Embryo Transfer\n\nIDHIsocitrate Dehydrogenase\n\nIVFIn Vitro Fertilization\n\nVDEVelocity of Diametric Expansion\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors’ contributions\nAP and SLB reviewed the entire case and was a major contributor in writing the manuscript. AH was the primary physician on the case and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nResearch reported in the study was performed in accordance with the Declaration of Helsinki and was exempt by the Northwell Health Institutional Review Board under Policy and Procedure Section 25.0.\n\nConsent for publication\nDocumented written consent from the patient was obtained to report the details of the case.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Burger PC, Green SB. Patient age, histologic features, and length of survival in patients with glioblastoma multiforme. Cancer [Internet]. 1987 [cited 2017 Feb 14];59:1617–25. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3030531\n2. Smoll NR, Hamilton B. Incidence and relative survival of anaplastic astrocytomas. Neuro Oncol. [Internet]. 2014 [cited 2017 Feb 14];16:1400–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24723565\n3. Reuss DE, Mamatjan Y, Schrimpf D, Capper D, Hovestadt V, Kratz A, et al. IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO. Acta Neuropathol. [Internet]. 2015 [cited 2017 Feb 14];129:867–73. Available from: http://link.springer.com/10.1007/s00401-015-1438-8\n4. Pallud J, Mandonnet E, Deroulers C, Fontaine D, Badoual M, Capelle L, et al. Pregnancy increases the growth rates of World Health Organization grade II gliomas. Ann Neurol. [Internet]. 2010 [cited 2017 Feb 14];67:398–404. Available from: http://doi.wiley.com/10.1002/ana.21888\n5. Lynch JC, Gouvêa F, Emmerich JC, Kokinovrachos G, Pereira C, Welling L, et al. Management strategy for brain tumour diagnosed during pregnancy. Br J Neurosurg. [Internet]. 2011 [cited 2017 Feb 14];25:225–30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20825287\n6. Pallud J, Duffau H, Razak RA, Barbarino-Monnier P, Capelle L, Fontaine D, et al. Influence of pregnancy in the behavior of diffuse gliomas: clinical cases of a French glioma study group. J Neurol. [Internet]. 2009 [cited 2017 Feb 14];256:2014–20. Available from: http://link.springer.com/10.1007/s00415-009-5232-1\n7. Daras M, Cone C, Peters KB. Tumor progression and transformation of low-grade glial tumors associated with pregnancy. J Neurooncol. [Internet]. 2014 [cited 2017 Feb 14];116:113–7. Available from: http://link.springer.com/10.1007/s11060-013-1261-9\n8. Hanada T, Rahayu TU, Yamahata H, Hirano H, Yoshioka T, Arita K. Rapid malignant transformation of low-grade astrocytoma in a pregnant woman. J Obstet Gynaecol Res. [Internet]. 2016 [cited 2017 Feb 14];42:1385–9. Available from: http://doi.wiley.com/10.1111/jog.13072\n9. Yust-Katz S, de Groot JF, Liu D, Wu J, Yuan Y, Anderson MD, et al. Pregnancy and glial brain tumors. Neuro Oncol. [Internet]. 2014 [cited 2017 Feb 14];16:1289–94. Available from: https://academic.oup.com/neuro-oncology/article-lookup/doi/10.1093/neuonc/nou019\n10. Meirow D Lewin A Or R Rachmilewitz E Slavin S Schenker J Ovarian failure post-chemotherapy in young cancer patients - risk assessment indicate the need for intervention Am Soc Reprod Med Annu Meet Cincinatti 1997 68 S218 \n11. Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update [Internet]. 2001 [cited 2017 Feb 14];7:535–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11727861\n12. Strowd RE, Blackwood R, Brown M, Harmon M, Lovato J, Yalcinkaya T, et al. Impact of temozolomide on gonadal function in patients with primary malignant brain tumors. J Oncol Pharm Pract. [Internet]. 2013 [cited 2017 Feb 14];19:321–7. Available from: http://journals.sagepub.com/doi/10.1177/1078155212469243\n13. Palmieri C, Brock C, Newlands ES. Maintenance of fertility following treatment with temozolomide for a high grade astrocytoma. J Neurooncol. [Internet]. 2005 [cited 2017 Feb 14];73:185. Available from: http://link.springer.com/10.1007/s11060-004-3577-y\n14. Sitbon Sitruk L, Sanson M, Prades M, Lefebvre G, Schubert B, Poirot C. [Unknown gonadotoxicity chemotherapy and preservation of fertility: example of Temozolomide]. Gynecol Obstet Fertil. [Internet]. 2010 [cited 2017 Feb 14];38:660–2. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21030284\n15. Hernandez-Diaz S, Smith CR, Shen A, Mittendorf R, Hauser WA, Yerby M, et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology [Internet]. 2012 [cited 2017 Feb 14];78:1692–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22551726\n16. Stone JB, Kelvin JF, DeAngelis LM. Fertility preservation in primary brain tumor patients. Neuro-Oncology Pract [Internet]. 2017 [cited 2017 Feb 14];npw005. Available from: https://academic.oup.com/nop/article-lookup/doi/10.1093/nop/npw005\n17. Goossens J, Delbaere I, Van Lancker A, Beeckman D, Verhaeghe S, Van Hecke A. Cancer patients’ and professional caregivers’ needs, preferences and factors associated with receiving and providing fertility-related information: a mixed-methods systematic review. Int J Nurs Stud [Internet]. 2014 [cited 2017 Feb 14];51:300–19. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0020748913001971\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "18(1)",
"journal": "BMC cancer",
"keywords": "Anaplastic astrocytoma; Brain cancer; Fertility preservation; Glioma",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000328:Adult; D001254:Astrocytoma; D001932:Brain Neoplasms; D059186:Chemoradiotherapy, Adjuvant; D003399:Craniotomy; D015925:Cryopreservation; D004624:Embryo Transfer; D005260:Female; D059247:Fertility Preservation; D006801:Humans; D007231:Infant, Newborn; D050498:Live Birth; D008297:Male; D009865:Oocytes; D010296:Parietal Lobe; D011247:Pregnancy",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "544",
"pmc": null,
"pmid": "29739361",
"pubdate": "2018-05-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29479452;19763385;23870448;27356501;24078174;24723565;23292971;3030531;11727861;21030284;15981111;20825287;25962792;20373352",
"title": "Two successful pregnancies following fertility preservation in a patient with anaplastic astrocytoma: a case report.",
"title_normalized": "two successful pregnancies following fertility preservation in a patient with anaplastic astrocytoma a case report"
} | [
{
"companynumb": "US-TEVA-2018-US-905543",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LACTULOSE"
},
"drugadditional": null,
... |
{
"abstract": "A 50-year-old man who was being treated for both pneumonia and type 2 diabetes mellitus complained of abdominal distention on the 16th hospital day. Liver enzyme elevation without symptoms was detected on the 17th hospital day. Based on a Roussel Uclaf Causality Assessment Method score of 10 and a Japan Digestive Disease Week score of 9, we diagnosed the patient as having drug-induced liver injury (DILI). Simultaneous assays of the levels of cytokines revealed that the elevation of the levels of interleukin (IL)-1β, IL-10, IL-12, IL-13 and tumor necrosis factor-α preceded the elevation of the serum liver enzymes. This case suggests that some cytokines or related molecules are potentially useful as early-phase biomarkers for DILI.",
"affiliations": "Department of Gastroenterology, Kazuno Kosei Hospital, Kazuno, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan.",
"authors": "Kakisaka|Keisuke|K|;Takikawa|Yasuhiro|Y|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1111/hepr.12253",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6346",
"issue": "44(10)",
"journal": "Hepatology research : the official journal of the Japan Society of Hepatology",
"keywords": "Bio-Plex; interleukin-1β; monocytic chemotactic protein-1; tumor necrosis factor-α",
"medline_ta": "Hepatol Res",
"mesh_terms": null,
"nlm_unique_id": "9711801",
"other_id": null,
"pages": "E284-9",
"pmc": null,
"pmid": "24119001",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Elevation of serum cytokines preceding elevation of liver enzymes in a case of drug-induced liver injury.",
"title_normalized": "elevation of serum cytokines preceding elevation of liver enzymes in a case of drug induced liver injury"
} | [
{
"companynumb": "PHHY2017JP159796",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": "1",
"dru... |
{
"abstract": "OBJECTIVE\nTo report the rare incidence of retinal pigment epithelial detachment (RPED) followed by topical travoprost therapy and its subsequent reattachment after cessation of the drug.\n\n\nMETHODS\nA 60-year-old male presented with gradual loss of vision in both eyes and distorted images in right eye. He gave a history of visiting an ophthalmologist a week ago for a routine eye examination. His previous reports revealed best-corrected visual acuity (BCVA) of 6/6, N6 in both eyes with raised intraocular pressures. A diagnosis of primary open-angle glaucoma was made and prescribed topical travoprost 0.004% eye drops. This patient's subsequent visit with diagnosis and treatment is mentioned in this case report.\n\n\nRESULTS\nOn examination, his BCVA was found to be 6/36, N12 and 6/6, N6 in right and left eyes, respectively. Optical coherence tomography (OCT) macular scan revealed RPED involving fovea in the right eye and inferotemporal to fovea in the left eye. Patient was advised to discontinue topical travoprost and started brinzolamide 1% eye drops. Ten-day follow-up visit revealed partially resolved RPED by OCT with 6/9 and 6/6 visual acuity in the right and left eyes, respectively. After 1 month, reversal of RPED was noted in OCT with 6/6 vision in both eyes.\n\n\nCONCLUSIONS\nHence, clinicians should be aware of this rare incidence of RPED followed by travoprost therapy. First case of RPED following travoprost therapy and complete reattachment upon withdrawal is reported here in this case report.",
"affiliations": "Ahalia School of Optometry, Ahalia Foundation Eye Hospital, Kozhipara Post, Palakkad, Kerala, India. kalikivayi@yahoo.com.;Ahalia Foundation Eye Hospital, Kozhipara Post, Palakkad, Kerala, India.;Ahalia Foundation Eye Hospital, Kozhipara Post, Palakkad, Kerala, India.;Ahalia Foundation Eye Hospital, Kozhipara Post, Palakkad, Kerala, India.;Ahalia Foundation Eye Hospital, Kozhipara Post, Palakkad, Kerala, India.;Ahalia Foundation Eye Hospital, Kozhipara Post, Palakkad, Kerala, India.",
"authors": "Kalikivayi|Venkataramana|V|;Joseph|Jerry|J|;Mathews|Blessy Thankom|BT|;Maheswari|Rajkumar|R|;Vadakara|Satyajit Mulanjur|SM|;Jacob|Sajeev Cherian|SC|",
"chemical_list": "D000959:Antihypertensive Agents; D000069557:Travoprost",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10792-017-0711-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5701",
"issue": "38(5)",
"journal": "International ophthalmology",
"keywords": "Intraocular pressure; Prostaglandin analogues; Retinal pigment epithelial detachment; Travoprost",
"medline_ta": "Int Ophthalmol",
"mesh_terms": "D000287:Administration, Topical; D000959:Antihypertensive Agents; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D005901:Glaucoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D012163:Retinal Detachment; D055213:Retinal Pigment Epithelium; D041623:Tomography, Optical Coherence; D000069557:Travoprost; D014792:Visual Acuity; D028761:Withholding Treatment",
"nlm_unique_id": "7904294",
"other_id": null,
"pages": "2227-2231",
"pmc": null,
"pmid": "29569087",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19038628;22106918;1582791;15834085;23410821;10896355;3209082;18537988;2408659;24932106;18988179;17472800",
"title": "Reversal of retinal pigment epithelial detachment after cessation of topical travoprost therapy.",
"title_normalized": "reversal of retinal pigment epithelial detachment after cessation of topical travoprost therapy"
} | [
{
"companynumb": "IN-MYLANLABS-2018M1077243",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRAVOPROST"
},
"drugadditional": "1",
... |
{
"abstract": "Hepatitis C-induced mixed cryoglobulinemia leading to rapidly progressive gangrene, necessitating amputations, is a rare presentation. We describe a case of a 55-year-old man with untreated chronic hepatitis C virus (HCV) presenting with arthralgia and palpable purpura, which rapidly progressed to life-threatening gangrene of all extremities requiring amputations in the setting of mixed cryoglobulinemia. Treatment for HCV was initiated which led to the arrest of gangrene progression and the patient's survival. Patients with HCV-induced cryoglobulinemia should be closely monitored and started on early therapy with direct-acting antiviral therapy to prevent progression of vasculitis to gangrene. Universal screening for HCV can aid in early diagnosis and treatment to prevent devastating consequences.",
"affiliations": "Department of Internal Medicine, University of California San Francisco-Fresno, Fresno, CA, USA.;Department of Gastroenterology & Hepatology, University of California San Francisco-Fresno, Fresno, CA, USA.;Department of Internal Medicine, University of California San Francisco-Fresno, Fresno, CA, USA.;Department of Internal Medicine, University of California San Francisco-Fresno, Fresno, CA, USA.;Department of Rheumatology, University of California San Francisco-Fresno, Fresno, CA, USA.;Department of Gastroenterology & Hepatology, University of California San Francisco-Fresno, Fresno, CA, USA.",
"authors": "Khalid|Sameeha|S|https://orcid.org/0000-0001-9643-3473;Alhankawi|Dhuha|D|;Kaur|Kamalmeet|K|;Ali|Ali|A|;Kazaryan|Anna|A|;Roytman|Marina|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/8244432",
"fulltext": "\n==== Front\nCase Reports Hepatol\nCase Reports Hepatol\nCRIHEP\nCase Reports in Hepatology\n2090-6587\n2090-6595\nHindawi\n\n10.1155/2021/8244432\nCase Report\nA Devastating Case of Hepatitis C-Induced Mixed Cryoglobulinemia\nhttps://orcid.org/0000-0001-9643-3473\nKhalid Sameeha sameeha.khalid@ucsf.edu\n1\nAlhankawi Dhuha 2\nKaur Kamalmeet 1\nAli Ali 1\nKazaryan Anna 3\nRoytman Marina 2\n1Department of Internal Medicine, University of California San Francisco-Fresno, Fresno, CA, USA\n2Department of Gastroenterology & Hepatology, University of California San Francisco-Fresno, Fresno, CA, USA\n3Department of Rheumatology, University of California San Francisco-Fresno, Fresno, CA, USA\nAcademic Editor: Mauro Vigano\n\n2021\n8 10 2021\n2021 82444329 8 2021\n24 9 2021\nCopyright © 2021 Sameeha Khalid et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nHepatitis C-induced mixed cryoglobulinemia leading to rapidly progressive gangrene, necessitating amputations, is a rare presentation. We describe a case of a 55-year-old man with untreated chronic hepatitis C virus (HCV) presenting with arthralgia and palpable purpura, which rapidly progressed to life-threatening gangrene of all extremities requiring amputations in the setting of mixed cryoglobulinemia. Treatment for HCV was initiated which led to the arrest of gangrene progression and the patient's survival. Patients with HCV-induced cryoglobulinemia should be closely monitored and started on early therapy with direct-acting antiviral therapy to prevent progression of vasculitis to gangrene. Universal screening for HCV can aid in early diagnosis and treatment to prevent devastating consequences.\n==== Body\npmc1. Introduction\n\nMixed cryoglobulinemia is a rare condition, with a prevalence of 1 : 100,000 in the United States. The most common cause is chronic hepatitis C virus (HCV); however, a number of other etiologies including other infections, autoimmune diseases, and lymphoproliferative disorders are known to precipitate mixed cryoglobulinemia [1]. Meltzer coined the clinical triad of mixed cryoglobulinemia as palpable purpura, arthralgia, and weakness in 1966; however, it is unlikely for patients to present with all three, and palpable purpura is the most common presentation [2].\n\nChronic HCV infection is known to be the underlying disorder in a majority (80–90%) of cases of mixed cryoglobulinemia; however, only 5–10% of HCV patients are estimated to have symptomatic disease [2, 3]. In many cases, the extrahepatic manifestations of HCV can occur in patients without features of overt liver disease. The role played by HCV in the development of this disease is thought to stem from chronic stimulation of the immune system causing B-cell hyperactivation and selective expansion of cryoglobulin-producing B-cell clones which express rheumatoid factor (RF) and proliferate in the liver, serum, and lymph nodes [4, 5]. Circulating cryoglobulins precipitate at low temperatures below 37 degrees Celsius and deposit in small and medium vessels, leading to complement activation and inflammation and subsequently causing systemic vasculitis and damage to various end organs [4]. It is the circulation of these large cryoproteins that leads to increased blood viscosity causing hypoperfusion and subsequently gangrenes [2].\n\nThere is a wide spectrum of manifestations associated with cryoglobulinemia which can range from mild (>50%) to moderate or severe (35%) and even life-threatening conditions (<15%) [6]. Life-threatening cryoglobulinemia vasculitis can be diagnosed if any of the following are present: renal involvement, gastrointestinal involvement, lung involvement, CNS involvement, heart involvement, widespread vasculitis (multiorgan involvement), hyperviscosity syndrome, or liver failure in HCV-related mixed cryoglobulinemia [3]. Such life-threatening features carry a mortality rate between 20% and 80% and in almost two-thirds of cases may be the initial clinical manifestation of cryoglobulinemia [6]. HCV-induced mixed cryoglobulinemia leading to rapidly progressive gangrene of all four extremities, necessitating amputations, is a rare presentation of cryoglobulinemia that we present here.\n\n2. Case Report\n\nA 55-year-old man with treatment-naive HCV infection (genotype 1a) presented to the emergency room with bilateral hand pain and diffuse purpuric rash. He described associated arthralgias, purpuric lesions, weakness, and numbness. Physical examination showed palpable purpura and extensive gangrene affecting bilateral upper and lower extremities (Figures 1 and 2). Laboratory investigation revealed positive rheumatoid factor (>1,200 IU/mL), hypocomplementemia (C4 <8.0 mg/dL), HCV RNA 2,390,000 IU/mL, and positive cryoglobulins. Skin biopsy of the leg showed mixed, predominantly acute, infiltrate with scattered small to mid-sized vessels with features of fibrin thrombi with or without associated vasculitis. The patient was diagnosed with mixed cryoglobulinemia complicated by severe cutaneous vasculitis with ischemic limbs.\n\nPlasmapheresis was initiated; however, gangrene continued to progressively worsen despite it (Figures 3 and 4). He was transitioned to immunosuppressive therapy with high-dose pulse steroids followed by prednisone 60 mg daily for four weeks in combination with rituximab without improvement. Given progressive gangrene despite multiple surgical debridements, inpatient treatment with sofosbuvir/velpatasvir was started for treatment of chronic HCV infection. After initiation of HCV treatment, the viral load went from 2,390,000 IU to <15 IU after four weeks and there was no further spread of gangrene. The necrotic limbs were unsalvageable, requiring serial limb amputations including bilateral above the knee amputations, right metacarpophalangeal disarticulation of fingers, right interphalangeal disarticulation of the thumb, and left wrist disarticulation. He was discharged to a skilled nursing facility. On follow-up with Hepatology, the patient achieved sustained virologic response week 12 (SVR-12) and has not had further recurrence of manifestations associated with mixed cryoglobulinemia.\n\n3. Discussion\n\nThere is a wide spectrum of manifestations associated with cryoglobulinemia with severe and life-threatening presentations being relatively rare (<15% of cases) [6]. Most patients with such severe presentations do not survive. One case study by Manuel Ramos-Casals, MD, of 29 patient cases demonstrated a 66% mortality in patients presenting with severe, life-threatening cryoglobulinemia vasculitis [7]. It remains unclear why some patients manifest a severe form of cryoglobulinemia vasculitis, and information regarding clinical presentation and prognosis of these patients is limited. Our patient with HCV-related mixed cryoglobulinemia presented with severe cutaneous vasculitis progressing to gangrene of all extremities with the catastrophic result of unsalvageable limbs. Upon literature review, this is one of the most aggressive cases of mixed cryoglobulinemia vasculitis reported thus far that resulted in the patient's survival. There have been no other cases reported that have resulted in multiple limb amputations secondary to this extent of cryoglobulinemia. As such, this case serves to increase clinician awareness of the severe gangrene that may rapidly develop in mixed cryoglobulinemia. These cases require early recognition and aggressive treatment to prevent progression to the extent of limb amputation and even death.\n\nThe mainstays of treatment of HCV-induced mixed cryoglobulinemia include the eradication of HCV infection, deletion of underlying B-cell clonal expansions, and depletion of cryoproteins [1, 8]. Multiple studies agree that regardless of the severity of mixed cryoglobulinemia, an attempt to eradicate HCV should be pursued whenever possible and as soon as possible as suppression of viral replication may limit or halt the immunopathogenic process triggered by HCV [9, 10]. In the presence of life-threatening manifestations of mixed cryoglobulinemia, it is vital to begin rapid treatment with immunosuppressive therapy concomitantly with direct-acting antiviral (DAA) therapy. A prospective study showed that DAA therapy is highly effective and safe for patients with HCV-induced mixed cryoglobulinemia with an overall 100% clinical response rate for vasculitis [11].\n\nThis case notably highlights the necessity of universal screening for HCV and portrays the devastating effects that delayed screening and therefore delayed treatment may have. Universal screening is imperative for the early detection, treatment, and prevention of the intrahepatic and extrahepatic consequences of HCV, such as mixed cryoglobulinemia.\n\nData Availability\n\nNo data were used to support this study.\n\nConsent\n\nInformed patient consent was obtained for publication of the case details as well as images.\n\nDisclosure\n\nThe abstract was presented earlier at the ACG Annual Scientific Meeting on October 23–28, 2020. The abstract was published in The American Journal of Gastroenterology: October 2020—Volume 115—Issue—p S1325.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nAuthors' Contributions\n\nSameeha Khalid, Kamalmeet Kaur, and Ali Ali were involved in direct patient care, conception of the work, drafting the work, and revising it. Dhuha Alhankawi, Anna Kazaryan, and Marina Roytman carried out direct patient care and revised the work critically for important intellectual content.\n\nFigure 1 Patient's hand on initial presentation.\n\nFigure 2 Patient's foot on initial presentation.\n\nFigure 3 Progression of gangrene 10 days after initial presentation.\n\nFigure 4 Bilateral gangrenous lower extremities 10 days after initial presentation.\n==== Refs\n1 Lauletta G. Russi S. Conteduca V. Sansonno L. Hepatitis C virus infection and mixed cryoglobulinemia Clinical and Developmental Immunology 2012 2012 11 502156 10.1155/2012/502156 2-s2.0-84864950157\n2 Charles E. D. Dustin L. B. Hepatitis C virus-induced cryoglobulinemia Kidney International 2009 76 8 818 824 10.1038/ki.2009.247 2-s2.0-70349658771 19606079\n3 Rosenthal E. Cacoub P. Extrahepatic manifestations in chronic hepatitis C virus carriers Lupus 2015 24 4-5 469 482 10.1177/0961203314556140 2-s2.0-84925684776 25801890\n4 Mebust D. Mixed cryoglobulinemia: an unusual presentation of hepatitis C The Permanente Journal 2013 17 3 e112 e113 10.7812/TPP/12-071 24355899\n5 Dammacco F. Sansonno D. Therapy for hepatitis C virus-related cryoglobulinemic vasculitis New England Journal of Medicine 2013 369 11 1035 1045 10.1056/NEJMra1208642 2-s2.0-84883709468\n6 Retamozo S. Díaz-Lagares C. Bosch X. Life-threatening cryoglobulinemic patients with hepatitis C Medicine 2013 92 5 273 284 10.1097/MD.0b013e3182a5cf71 2-s2.0-84887997688 23974248\n7 Ramos-Casals M. Robles A. Brito-Zerón P. Life-threatening cryoglobulinemia: clinical and immunological characterization of 29 cases Seminars in Arthritis and Rheumatism 2006 36 3 189 196 10.1016/j.semarthrit.2006.08.005 2-s2.0-33751174965 16996578\n8 Schamberg N. J. Lake-Bakaar G. V. Hepatitis C virus-related mixed cryoglobulinemia: pathogenesis, clinica manifestations, and new therapies Gastroenterology and Hepatology 2007 3 9 695 703 21960882\n9 Sise M. E. Bloom A. K. Wisocky J. Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents Hepatology 2016 63 2 408 417 10.1002/hep.28297 2-s2.0-84956783742 26474537\n10 Pietrogrande M. De Vita S. Zignego A. L. Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients Autoimmunity Reviews 2011 10 8 444 454 10.1016/j.autrev.2011.01.008 2-s2.0-79957655345 21303705\n11 Gragnani L. Visentini M. Fognani E. Prospective study of guideline-tailored therapy with direct-acting antivirals for hepatitis C virus-associated mixed cryoglobulinemia Hepatology 2016 64 5 1473 1482 10.1002/hep.28753 2-s2.0-84983655975 27483451\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6595",
"issue": "2021()",
"journal": "Case reports in hepatology",
"keywords": null,
"medline_ta": "Case Reports Hepatol",
"mesh_terms": null,
"nlm_unique_id": "101622103",
"other_id": null,
"pages": "8244432",
"pmc": null,
"pmid": "34659845",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "21960882;23974248;27483451;19606079;24355899;26474537;25801890;16996578;21303705;22844322;24024840",
"title": "A Devastating Case of Hepatitis C-Induced Mixed Cryoglobulinemia.",
"title_normalized": "a devastating case of hepatitis c induced mixed cryoglobulinemia"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP031670",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugaddition... |
{
"abstract": "OBJECTIVE\nA case of daptomycin-associated acute eosinophilic pneumonia (AEP) with positive rechallenge is reported.\n\n\nCONCLUSIONS\nAEP associated with daptomycin is reported in the literature, and the product labeling contains a warning and precaution statement. Criteria for diagnosing daptomycin-induced AEP varies and generally includes bronchoalveolar lavage (BAL) eosinophils ≥ 25%. We report a case of a 70-year-old woman with cough, shortness of breath, and altered mental status who presented ~ 9 days after starting therapy with daptomycin to treat methicillin-resistant <italic>Staphylococcus aureus</italic> (MRSA) osteomyelitis. Daptomycin was utilized because of a presumed vancomycin allergy. Aspiration pneumonia was suspected and IV ampicillin and sulbactam was initiated. Clinical status improved initially but ~ 1 week later, her respiratory status declined. During work-up, peripheral eosinophils were abnormal at 11.6%, so daptomycin therapy was discontinued. BAL revealed 5% eosinophils with negative infectious work-up. Respiratory status rapidly improved after discontinuation of daptomycin. Linezolid therapy was initiated. Due to an uncertain association with daptomycin and concerns associated with long-term linezolid therapy, the patient agreed to rechallenge with daptomycin. Within 24 hours, respiratory symptoms returned and daptomycin was permanently discontinued. The patient rapidly recovered without the need for systemic corticosteroid treatment.\n\n\nCONCLUSIONS\nOur case supports a broadened definition of pulmonary eosinophilia associated with daptomycin administration. It is important for clinicians to consider daptomycin as an etiology of pneumonia with abnormal eosinophils when other causes have been excluded. Clinicians could also consider peripheral eosinophilia as a possible indication of AEP when BAL is not available or cannot be obtained.
.",
"affiliations": null,
"authors": "Nickerson|Melanie|M|;Bhargava|Ashish|A|;Kale-Pradhan|Pramodini B|PB|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017576:Daptomycin",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP202952",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "55(6)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D017576:Daptomycin; D005260:Female; D006801:Humans; D011657:Pulmonary Eosinophilia",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "521-524",
"pmc": null,
"pmid": "28406091",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Daptomycin-associated eosinophilic pneumonia with rechallenge: a case report
.",
"title_normalized": "daptomycin associated eosinophilic pneumonia with rechallenge a case report"
} | [
{
"companynumb": "US-AXELLIA-001076",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizatio... |
{
"abstract": "BACKGROUND\nThe brown recluse spider (BRS) (Loxosceles reclusa) envenomation can lead to multiple complications, including hemolysis. We present a case of refractory hemolysis after a BRS bite treated with therapeutic plasma exchange (TPE).\n\n\nMETHODS\nA 17-year-old female presented with fever, fatigue, and dyspnea. She was diagnosed with sepsis and received intravenous (IV) fluids, inotropic support, and antibiotics. On hospital day 1 she was noted to have skin lesion consistent with a BRS bite and developed hemolysis. Systemic loxoscelism with hemolysis was then suspected and methylprednisolone IV was initiated. She was discharged with a stable HGB on hospital day 3 on oral prednisolone. She was re-admitted 24 h later, with signs of worsening hemolysis. Methylprednisolone was restarted and she was transfused 4 units of packed red blood cells. TPE was initiated due to the refractory hemolysis. Shortly after the TPE session, her clinical and laboratory status improved. She required no further transfusions and was discharged on a steroid taper.\n\n\nCONCLUSIONS\nTPE is an extra-corporeal method to remove substances from the blood by separating plasma from cellular blood components and replacing it with physiologic fluids. TPE has been used for snake envenomation but there are no reports detailing its use for BRS envenomations. Improvement was associated with TPE initiation and may have been due to removal of complement components activated by the spider venom. This report suggests that TPE could be a possible treatment modality for systemic loxoscelism with refractory hemolysis due to BRS envenomation. Further investigation is warranted.",
"affiliations": "Department of Pediatrics, Pediatric Resident, PGY 3, School of Medicine, University of Kansas, 3901 Rainbow Boulevard, MS 4004, Kansas City, KS, 66160, USA, Mabraham3@kumc.edu.",
"authors": "Abraham|Manjusha|M|;Tilzer|Lowell|L|;Hoehn|K Sarah|KS|;Thornton|Stephen L|SL|",
"chemical_list": "D013111:Spider Venoms; C055161:loxosceles venom; D010727:Phosphoric Diester Hydrolases",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-015-0485-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "11(3)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": null,
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000293:Adolescent; D000818:Animals; D063287:Brown Recluse Spider; D005260:Female; D006461:Hemolysis; D006801:Humans; D010727:Phosphoric Diester Hydrolases; D010951:Plasma Exchange; D001098:Spider Bites; D013111:Spider Venoms; D016896:Treatment Outcome",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "364-7",
"pmc": null,
"pmid": "26002217",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25163809;24631373;24086749;22305333;22502777;12144196;431064;14478302;15663070;17963462;16390557;15716564;10428252;16619226",
"title": "Therapeutic Plasma Exchange for Refractory Hemolysis After Brown Recluse Spider (Loxosceles reclusa) Envenomation.",
"title_normalized": "therapeutic plasma exchange for refractory hemolysis after brown recluse spider loxosceles reclusa envenomation"
} | [
{
"companynumb": "US-CONCORDIA PHARMACEUTICALS INC.-GSH201701-000094",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"dr... |
{
"abstract": "The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients.\n\n\n\nAdult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months.\n\n\n\nA total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide.\n\n\n\nThe results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.",
"affiliations": "Hematology and Cellular Therapy Department, Saint-Antoine Hospital, Pierre & Marie Curie University, Paris, France. Electronic address: mohamad.mohty@inserm.fr.;Hematology and Medical Oncology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, Athens, Greece.;Servicio de Hematologia, Hospital Universitario de Salamanca, Centro de Investigación del Cáncer, Instituto de Biología Molecular y Cellular del Cáncer (Universitario de Salamanca-Consejo Superior de Investigaciones Científicas), Salamanca, Spain.;Seràgnoli Institute of Hematology, University of Bologna, Bologna, Italy.;Department of Doctoral Studies, Riga Stradiņš University, Riga, Latvia.;Department of Hematology, Ankara University, Ankara, Turkey.;Hematology and Cell Therapy, Etablissement Hospitalier Universitaire, Oran, Algeria.;Department Hemato-Oncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland.;Hematology and Medical Oncology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, Athens, Greece.;University Clinic of Hematology, Medical Faculty, Skopje, Macedonia.;Hematologia, Complejo Hospitalario de Jaén, Jaén, Spain.;Institute of Hematology, Catholic University, Rome, Italy.;Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, University of Pavia, Pavia, Italy.;State Budget Healthcare Institution of Moscow, City Outpatient Clinic, 68 of Healthcare Department of Moscow, Branch 3, Moscow, Russia.;North Estonia Medical Centre Foundation, Tallinn, Estonia.;Université de Bretagne Occidentale, Brest, France.;Multiples Myelom, Asklepios Klinik Altona, Hamburg, Germany.;Institute of Blood Pathology and Transfusion Medicine, Lviv, Ukraine.;Hematology, Oncology, and Transfusion Medicine Center, Vilnius University Hospital, Santariskiu Klinikos, Vilnius, Lithuania.;Universitätsklinik Innsbruck Innere Medizin V, and Oncotyrol - Center for Personalized Cancer Medicine, Innsbruck, Austria.;Department of Medical Oncology and Hematology, University Health Network, Toronto, ON, Canada.;Department of Internal Medicine, University of the Free State, Bloemfontein, South Africa.;Internal Medicine, Clinical Hospital Centre Zagreb, Zagreb, Croatia.;Szegedi Tudomanyegyetem, II. Belgyógyászati Klinika, Szeged, Hungary.;Hematology, Meir Medical Center, Kfar Saba, Israel.;Regionshospitalet i Holstebro, Medicinsk Afdeling, Holstebro, Denmark.;Division of Internal Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia.;Janssen-Cilag, Neuss, Germany.;Janssen-Cilag, Issy-les-Moulineaux, France.;Janssen Research and Development, Beerse, Belgium.;Janssen-Cilag, Issy-les-Moulineaux, France.;Myeloma Unit, Division of Hematology, Città della Salute e della Scienza, University of Torino, Turin, Italy.",
"authors": "Mohty|Mohamad|M|;Terpos|Evangelos|E|;Mateos|Maria-Victoria|MV|;Cavo|Michele|M|;Lejniece|Sandra|S|;Beksac|Meral|M|;Bekadja|Mohamed Amine|MA|;Legiec|Wojciech|W|;Dimopoulos|Meletios|M|;Stankovic|Svetlana|S|;Durán|Maria Soledad|MS|;De Stefano|Valerio|V|;Corso|Alessandro|A|;Kochkareva|Yulia|Y|;Laane|Edward|E|;Berthou|Christian|C|;Salwender|Hans|H|;Masliak|Zvenyslava|Z|;Pečeliūnas|Valdas|V|;Willenbacher|Wolfgang|W|;Silva|João|J|;Louw|Vernon|V|;Nemet|Damir|D|;Borbényi|Zita|Z|;Abadi|Uri|U|;Pedersen|Robert Schou|RS|;Černelč|Peter|P|;Potamianou|Anna|A|;Couturier|Catherine|C|;Feys|Caroline|C|;Thoret-Bauchet|Florence|F|;Boccadoro|Mario|M|;|||",
"chemical_list": "D001897:Boronic Acids; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2018.06.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "18(10)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Bortezomib; Global; Observational study; Routine practice; Stem cell transplantation",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D003907:Dexamethasone; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009364:Neoplasm Recurrence, Local; D010818:Practice Patterns, Physicians'; D011446:Prospective Studies; D016879:Salvage Therapy; D015996:Survival Rate; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "e401-e419",
"pmc": null,
"pmid": "30030033",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Multiple Myeloma Treatment in Real-world Clinical Practice: Results of a Prospective, Multinational, Noninterventional Study.",
"title_normalized": "multiple myeloma treatment in real world clinical practice results of a prospective multinational noninterventional study"
} | [
{
"companynumb": "FR-JNJFOC-20181209544",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAmiodarone is an important antiarrhythmic drug used in paediatric practice, mainly in children with complex congenital cardiac diseases and/or severe arrhythmias. One of the side effects of amiodarone therapy is thyroid dysfunction, which is observed in about 20% of patients. The thyroid dysfunction may present with various forms: from subclinical changes in hormone levels to amiodaroneinduced thyrotoxicosis (AIT) and amiodarone-induced hypothyroidism (AIH).\n\n\nMETHODS\nWe reported six patients in the age range from two weeks to 14 years, with complex congenital cardiac diseases and severe arrhythmias, who developed amiodarone-induced thyroid dysfunctions: thyrotoxicosis or hypothyroidism or both together. The clinical signs and symptoms of all thyroid dysfunctions were atypical, most patients presented with an aggravation of heart insufficiency. Our patients with thyrotoxicosis were treated with combined therapy including thionamides and corticosteroids due to the presentation of mixed-identified type of AIT.\n\n\nRESULTS\nCurrently, five patients (one patient's status is unknown) are in biochemical and clinical euthyreosis; however, in one of them it was impossible to discharge amiodarone treatment. Three of them are still treated with levothyroxine, and two do not need thyroid treatment.\n\n\nCONCLUSIONS\nAmiodarone-induced thyroid dysfunction is usually atypical; therefore, monitoring of thyroid status before, during, and after amiodarone is demanded. AIH could significantly influence the development of the child, while AIT could significantly deteriorate the clinical status of children with complex cardiac diseases. Early and proper diagnose of AIT and AIH allows the introduction of immediate and appropriate treatment considering the cardiac condition of the young patient.",
"affiliations": "Department of Paediatric and Adolescent Endocrinology, Paediatric Institute, Medical College, Jagiellonian University in Cracow, Cracow, Poland.;Department of Paediatric and Adolescent Endocrinology, Paediatric Institute, Medical College, Jagiellonian University in Cracow, Cracow, Poland. anna.wedrychowicz@uj.edu.pl.;Department of Paediatric and Adolescent Endocrinology, Paediatric Institute, Medical College, Jagiellonian University in Cracow, Cracow, Poland.;Department of Paediatric and Adolescent Endocrinology, Paediatric Institute, Medical College, Jagiellonian University in Cracow, Cracow, Poland.;Department of Paediatric and Adolescent Endocrinology, Paediatric Institute, Medical College, Jagiellonian University in Cracow, Cracow, Poland.;Department of Paediatric Cardiology, Paediatric Institute, Medical College, Jagiellonian University in Cracow, Cracow, Poland.;Department of Paediatric Cardiology, Paediatric Institute, Medical College, Jagiellonian University in Cracow, Cracow, Poland.;Department of Paediatric and Adolescent Endocrinology, Paediatric Institute, Medical College, Jagiellonian University in Cracow, Cracow, Poland.",
"authors": "Furtak|Aleksandra|A|0000-0001-6527-940X;Wędrychowicz|Anna|A|0000-0003-0864-6810;Kalicka-Kasperczyk|Anna|A|;Januś|Dominika|D|;Wójcik|Małgorzata|M|;Kordon|Zbigniew|Z|0000-0002-2363-3818;Rudziński|Andrzej|A|;Starzyk|Jerzy B|JB|0000-0002-4086-6525",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000638:Amiodarone",
"country": "Poland",
"delete": false,
"doi": "10.5603/EP.a2019.0030",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0423-104X",
"issue": "70(5)",
"journal": "Endokrynologia Polska",
"keywords": "amiodarone; congenital heart disease; hypothyroidism; thyrotoxicosis",
"medline_ta": "Endokrynol Pol",
"mesh_terms": "D000293:Adolescent; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007037:Hypothyroidism; D007223:Infant; D013960:Thyroid Function Tests; D013961:Thyroid Gland; D013971:Thyrotoxicosis",
"nlm_unique_id": "0370674",
"other_id": null,
"pages": "392-400",
"pmc": null,
"pmid": "31274186",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Amiodarone-induced thyroid dysfunction in the developmental period: prenatally, in childhood, and adolescence - case reports and a review of the literature.",
"title_normalized": "amiodarone induced thyroid dysfunction in the developmental period prenatally in childhood and adolescence case reports and a review of the literature"
} | [
{
"companynumb": "PL-PFIZER INC-2019332188",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMIODARONE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Catatonia is a rare manifestation of benzodiazepine withdrawal in elderly patients who have used it for a long time. We present a case of lorazepam withdrawal catatonia and highlight issues in diagnosis and management.",
"affiliations": "Psychiatric Rehabilitation Services, NIMHANS, Bangalore, India. Electronic address: drt.sivakumar@yahoo.co.in.",
"authors": "Sivakumar|Thanapal|T|;Yadav|Anil|A|;Sood|Mamta|M|;Khandelwal|Sudhir K|SK|",
"chemical_list": "D008140:Lorazepam",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-2018",
"issue": "6(6)",
"journal": "Asian journal of psychiatry",
"keywords": "Benzodiazepine; Catatonia; Elderly; Medical comorbidity",
"medline_ta": "Asian J Psychiatr",
"mesh_terms": "D002389:Catatonia; D006801:Humans; D008140:Lorazepam; D008297:Male; D008875:Middle Aged; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "101517820",
"other_id": null,
"pages": "620-1",
"pmc": null,
"pmid": "24309887",
"pubdate": "2013-12",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Lorazepam withdrawal catatonia: a case report.",
"title_normalized": "lorazepam withdrawal catatonia a case report"
} | [
{
"companynumb": "IN-BAUSCH-BL-2018-033232",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LOSARTAN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe aim of this study was to evaluate the efficacy and toxicities of second-line chemotherapy regimens with docetaxel and gemcitabine (GD), or paclitaxel and gemcitabine (GP) for advanced or metastatic urothelial carcinoma (UC) that did not respond to first-line platinum-based chemotherapy.\n\n\nMETHODS\nFrom 2002 to 2017, 78 patients with metastatic UCs that progressed after platinum-based chemotherapy were treated with either GD (n = 41) or GP (n = 37). We compared these two different regimens by analyzing their efficacy and toxicities in a retrospective manner.\n\n\nRESULTS\nOf the 78 patients enrolled in this study, it was possible to determine treatment efficacy in 70; the proportion of patients with objective response and disease control were 8.6 (9/70) and 54.3% (38/70), respectively. The median progression-free survival and overall survival in the total population (GP and GD) were 3.5 (95% CI 0.6-53.3) and 9.6 months (95% CI 1.2-53.3), respectively. There was no significant difference between the two regimens (GD or GP) regarding survival outcomes. Treatment-related adverse events were mostly manageable, but one patient died as a result of febrile neutropenia. The presence of liver metastasis and anemia (Hb < 10.0 g/dl) was prognostic factors for worse survival.\n\n\nCONCLUSIONS\nCombination chemotherapy with either GP or GD was a favorable and well-tolerated second-line treatment regimen for patients with advanced or metastatic UC following the failure of a platinum-based regimen. Further study using a large prospective cohort is needed to identify patients who will benefit from second-line combination therapy.",
"affiliations": "Department of Urology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno, Osaka, 545-8585, Japan.;Department of Urology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno, Osaka, 545-8585, Japan. kato.minoru@med.osaka-cu.ac.jp.;Department of Urology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno, Osaka, 545-8585, Japan.;Department of Urology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno, Osaka, 545-8585, Japan.;Department of Urology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno, Osaka, 545-8585, Japan.;Department of Urology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno, Osaka, 545-8585, Japan.;Department of Urology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno, Osaka, 545-8585, Japan.;Department of Urology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno, Osaka, 545-8585, Japan.",
"authors": "Takeyama|Yuji|Y|;Kato|Minoru|M|;Nishihara|Chikako|C|;Yamasaki|Takeshi|T|;Iguchi|Taro|T|;Tamada|Satoshi|S|;Kuratsukuri|Katsuyuki|K|;Nakatani|Tatsuya|T|",
"chemical_list": "D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C056507:gemcitabine; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10147-018-1288-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-9625",
"issue": "23(5)",
"journal": "International journal of clinical oncology",
"keywords": "Bladder cancer; Chemotherapy; Docetaxel; Paclitaxel",
"medline_ta": "Int J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D043823:Taxoids; D014571:Urologic Neoplasms",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "944-950",
"pmc": null,
"pmid": "29785621",
"pubdate": "2018-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "23419284;14584068;20231682;23206856;20682548;16034041;15718315;15464919;12767086;27284445;9164195;16409425;11753976;27272172;11408496;28916371;25425701;26454620;23749066;29556919;9215826;26487582;11001674;28212060;24156324;2189954;26264159;19211575",
"title": "Comparison of efficacy and toxicity of second-line combination chemotherapy regimens in patients with advanced urothelial carcinoma.",
"title_normalized": "comparison of efficacy and toxicity of second line combination chemotherapy regimens in patients with advanced urothelial carcinoma"
} | [
{
"companynumb": "JP-HQ SPECIALTY-JP-2018INT000216",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,... |
{
"abstract": "Radiotherapy has played a pivotal role in palliation of symptoms in progressive incurable stages of malignancies. Ionizing radiation has been employed to decrease cancer induced bone pain, control bleeding and mass effects from inoperable tumor with significant success. The advent of new systemic anti-neoplastic drugs has broadened options available for management of cancers in palliative intent. The outcome of systemic anti-neoplastic therapy in the role of palliation has received variable acceptance while radiotherapy has generally remained the workhorse for palliation.\n\n\n\nA young female with a diagnosis of left-sided breast cancer who had received adjuvant anthracycline based chemotherapy, but not whole breast radiotherapy, following lumpectomy had an axillary lymphnode recurrence three years later. Though the recurrence was salvaged with a radical mastectomy and followed up with a combination of taxane and platin-based chemotherapy, there was a recurrence of axillary lymph nodes during the course. Following six cycles of combination chemotherapy, the mass progressed to form a large ulcer with pain and discharge. The recurrent malignancy was diagnosed to be triple negative subtype upon microscopic and immunohistochemical study.\n\n\n\nThe ulcerated mass not only responded to palliative radiotherapy by complete healing of the ulcer, but it also led to improvement in overall performance score and quality of life as measured objectively.\n\n\n\nIn triple negative subtype of breast cancer [TNBC], axillary lymphnodal recurrence is not uncommon after loco-regional surgery and peri‑operative chemptherapy; particularly when adjuvant radiotherapy is omitted. Chemotherapy refractory axillary lymphnodal recurrence showing good response to palliative radiotherapy signifies the differing molecular signatures within TNBC subtype.\n\n\n\nRadiotherapy is an effective modality for loco-regional palliation of recurrent breast cancer, particularly TNBC subtype. It holds potency even when the disease is chemotherapy refractory and can improve subjective as well as objective quality of life parameters significantly.",
"affiliations": "Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India 751019.;Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India 751019. Electronic address: sovan.sarangdhar@gmail.com.;Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India 751019.;Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India 751019.;Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India 751019.;Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India 751019.",
"authors": "Majumdar|Saroj Kumar Das|SKD|;Dhar|Sovan Sarang|SS|;Pattanaik|Ashutosh|A|;Kanungo|Satyabrata|S|;Mahapatra|Bikash Ranjan|BR|;Parida|Dillip Kumar|DK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jmir.2021.05.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-7982",
"issue": "52(3)",
"journal": "Journal of medical imaging and radiation sciences",
"keywords": "Radiotherapy response; Recurrent malignant axillary lymphadenopathy; Triple negative breast cancer",
"medline_ta": "J Med Imaging Radiat Sci",
"mesh_terms": "D005260:Female; D006801:Humans; D000072281:Lymphadenopathy; D008408:Mastectomy; D015412:Mastectomy, Segmental; D009364:Neoplasm Recurrence, Local; D011788:Quality of Life",
"nlm_unique_id": "101469694",
"other_id": null,
"pages": "478-482",
"pmc": null,
"pmid": "34294511",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "An unusual response of recurrent breast cancer axillary lymphadenopathy to palliative radiotherapy: A case report.",
"title_normalized": "an unusual response of recurrent breast cancer axillary lymphadenopathy to palliative radiotherapy a case report"
} | [
{
"companynumb": "IN-MYLANLABS-2022M1015493",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "4",
... |
{
"abstract": "In patients with gamma-hydroxybutyrate (GHB) use disorder (GUD), withdrawal can have a fulminant course with rapid progression of severe, potentially life-threatening complications. Case: We present a 45-year old man with severe GHB withdrawal, resistant to conventional treatment with pharmaceutical GHB, high doses of benzodiazepines and baclofen. GHB withdrawal finally responded to thiopental-induced coma therapy, with burst suppression pattern on electroencephalography (EEG). The patient fully recovered, without withdrawal or residual neuropsychiatric symptoms. Discussion: To our knowledge, this is the first case report in which barbiturates were used to induce a coma to treat severe, treatment resistant GHB withdrawal. This case suggests barbiturate coma therapy might be considered in severe GHB withdrawal which does not respond to conventional treatment.",
"affiliations": "Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.;Department Intensive Care, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.",
"authors": "Vos|Cornelis F|CF|;Pop-Purceleanu|Monica|M|;van den Berg|Maarten J W|MJW|;Schellekens|Arnt F A|AFA|",
"chemical_list": "D001569:Benzodiazepines; D012978:Sodium Oxybate; D013874:Thiopental",
"country": "United States",
"delete": false,
"doi": "10.1080/08897077.2020.1827124",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0889-7077",
"issue": "42(1)",
"journal": "Substance abuse",
"keywords": null,
"medline_ta": "Subst Abus",
"mesh_terms": "D001569:Benzodiazepines; D003128:Coma; D006801:Humans; D008297:Male; D008875:Middle Aged; D012978:Sodium Oxybate; D013375:Substance Withdrawal Syndrome; D013874:Thiopental",
"nlm_unique_id": "8808537",
"other_id": null,
"pages": "33-38",
"pmc": null,
"pmid": "33044905",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of severe, treatment resistant GHB withdrawal through thiopental-coma.",
"title_normalized": "successful treatment of severe treatment resistant ghb withdrawal through thiopental coma"
} | [
{
"companynumb": "NL-LUPIN PHARMACEUTICALS INC.-2021-24979",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLONIDINE"
},
"drugadditional"... |
{
"abstract": "Recurrent high-grade gliomas in adults remain a deadly cancer with median survival of less than 1 year. In the absence of effective agents, immunotherapy with checkpoint inhibitors has been adopted as a potentially beneficial next step for recurrences with hypermutated or mismatch repair-mutated phenotypes. The rationale for their use, however, is based on case reports and studies with other types of cancer.\nWe reviewed 4 cases of hypermutated or mismatch repair-mutated recurrent high-grade gliomas treated with checkpoint inhibitors.\nAll cases had recurrent high-grade glioma that harbored either a hypermutated phenotype and/or a mismatch repair mutation. Treatment with checkpoint inhibitor therapy resulted in no significant response.\nIn our experience, hypermutated or mismatch repair-mutated high-grade gliomas in adults do not respond to checkpoint inhibitors alone. This lack of efficacy is in agreement with underwhelming results of clinical trials examining checkpoint inhibitors in high-grade gliomas. The case reports of responders have been in pediatric patients with glioma and are likely a different subtype altogether.",
"affiliations": "University of Virginia School of Medicine, Division of Neuro-Oncology, Department of Neurology, University of Virginia, Charlottesville.;University of Virginia School of Medicine, Division of Neuro-Oncology, Department of Neurology, University of Virginia, Charlottesville.;University of Virginia School of Medicine, Division of Neuro-Oncology, Department of Neurology, University of Virginia, Charlottesville.;University of Virginia School of Medicine, Division of Neuro-Oncology, Department of Neurology, University of Virginia, Charlottesville.",
"authors": "Ahmad|Haroon|H|;Fadul|Camilo E|CE|;Schiff|David|D|;Purow|Benjamin|B|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/nop/npz016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2054-2577",
"issue": "6(6)",
"journal": "Neuro-oncology practice",
"keywords": "glioblastoma; glioma; hypermutation; immunotherapy; mismatch-repair",
"medline_ta": "Neurooncol Pract",
"mesh_terms": null,
"nlm_unique_id": "101640528",
"other_id": null,
"pages": "424-427",
"pmc": null,
"pmid": "31832212",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports",
"references": "22464345;26545842;26450194;29452419;25740784;25691825;16618716;28371827;17404084;27001570;27197178;26028255;27270107;30171077;26940869;19584161;27683556;20516446;24336570",
"title": "Checkpoint inhibitor failure in hypermutated and mismatch repair-mutated recurrent high-grade gliomas.",
"title_normalized": "checkpoint inhibitor failure in hypermutated and mismatch repair mutated recurrent high grade gliomas"
} | [
{
"companynumb": "US-ACCORD-175144",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Electrical disturbances following blunt cardiac injuries are rare but can be caused by electrical or structural damage to the heart. We present the case of a patient who had conduction abnormalities following blunt traumatic injury that were incidentally detected on telemetry.\nA 64-year-old female with no history of cardiac disease was brought to the emergency department after a motor vehicle collision that resulted in chest wall bruising. The patient was found to have L-spine fractures and was admitted for observation. During her hospitalization, the patient had multiple episodes of heart block. A temporary pacemaker was inserted because of the recurrent episodes, and a dual-chamber permanent pacemaker was placed on day 4 of her hospitalization.\nHeart block as a consequence of blunt cardiac injury is rare; however, it needs to be recognized as early as possible. Permanent pacemaker placement is usually indicated for patients with prolonged or recurrent episodes.",
"affiliations": "Department of Internal Medicine, MedStar Washington Hospital Center, Washington, DC.;Department of Cardiology, University of Miami/JFK Medical Center, Atlantis, FL.;Cardiovascular Department, Creighton University, Omaha, NE.;Interventional Cardiology, Heartland Cardiology/Wesley Medical Center, University of Kansas, Wichita, KS.;Department of Interventional Cardiology, Detroit Heart Hospital, Wayne State University, Detroit Medical Center, Detroit, MI.",
"authors": "Soud|Mohamad|M|;Alrifai|Abdulah|A|;Kabach|Amjad|A|;Fanari|Zaher|Z|;Alraies|M Chadi|MC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.31486/toj.17.0116",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-5012",
"issue": "18(3)",
"journal": "The Ochsner journal",
"keywords": "Arrhythmias; heart block; trauma",
"medline_ta": "Ochsner J",
"mesh_terms": null,
"nlm_unique_id": "101125795",
"other_id": null,
"pages": "277-279",
"pmc": null,
"pmid": "30275796",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "23801827;9632447;13573559;20220186;28583850",
"title": "Trauma-Induced Conduction Disturbances.",
"title_normalized": "trauma induced conduction disturbances"
} | [
{
"companynumb": "US-ASTELLAS-2019US005443",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nPrevious studies have documented increased risk of pneumonia with antipsychotic use in the elderly; however, differential risk across individual atypical antipsychotics remains unaddressed. This study examines the effect of individual atypical antipsychotics on risk of pneumonia in elderly patients.\n\n\nMETHODS\nThis retrospective cohort study was conducted using a large claims database. The study population included new users of atypical antipsychotics (≥65 years). The multiple propensity-score adjusted survival model was used to examine risk of pneumonia within a 1-year follow-up period.\n\n\nRESULTS\nA total of 92 234 patients newly prescribed atypical antipsychotic medication were identified. Of these, 41 780 (45.30%) were quetiapine users, 31 048 (33.66%) risperidone users, 11 375 (12.33%) olanzapine users, 6790 (7.36%) aripiprazole users, and 1241 (1.35%) ziprasidone users. Within the 1-year follow-up period, 12 411 (13.46%) patients taking atypical antipsychotics had a diagnosis of pneumonia. The multiple propensity-score-adjusted survival model revealed increased risk of pneumonia with the use of risperidone (hazard ratios (HR) 1.14, 95%CI 1.10-1.18) and olanzapine (HR 1.10, 95%CI 1.04-1.16) compared with the use of quetiapine.\n\n\nCONCLUSIONS\nThis large population-based study suggests that use of risperidone and olanzapine increases risk of pneumonia compared with use of quetiapine in elderly patients. This study provides new information on the comparative risk of pneumonia associated with different atypical antipsychotics in the elderly to support optimal treatment decisions.",
"affiliations": "Quintiles, Inc., Cambridge, MA, USA.;Inovalon, Inc., Bowie, MD, USA.;Inovalon, Inc., Bowie, MD, USA.;Inovalon, Inc., Bowie, MD, USA.",
"authors": "Mehta|Sandhya|S|;Pulungan|Zulkarnain|Z|;Jones|Barton T|BT|;Teigland|Christie|C|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1002/pds.3882",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-8569",
"issue": "24(12)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": "atypical antipsychotics; comparative; elderly; multiple propensity scores; pharmacoepidemiology; pneumonia; risk; safety; second generation",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D015331:Cohort Studies; D005260:Female; D006299:Health Services for the Aged; D006801:Humans; D007345:Insurance Claim Review; D008297:Male; D011014:Pneumonia; D015995:Prevalence; D012189:Retrospective Studies; D018570:Risk Assessment; D016019:Survival Analysis; D014481:United States",
"nlm_unique_id": "9208369",
"other_id": null,
"pages": "1271-80",
"pmc": null,
"pmid": "26445931",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Comparative safety of atypical antipsychotics and the risk of pneumonia in the elderly.",
"title_normalized": "comparative safety of atypical antipsychotics and the risk of pneumonia in the elderly"
} | [
{
"companynumb": "US-JNJFOC-20160116653",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "The capacity of respiratory viruses to undergo evolution within the respiratory tract raises the possibility of evolution under the selective pressure of the host environment or drug treatment. Long-term infections in immunocompromised hosts are potential drivers of viral evolution and development of infectious variants. We showed that intrahost evolution in chronic human parainfluenza virus 3 (HPIV3) infection in immunocompromised individuals elicited mutations that favored viral entry and persistence, suggesting that similar processes may operate across enveloped respiratory viruses. We profiled longitudinal HPIV3 infections from 2 immunocompromised individuals that persisted for 278 and 98 days. Mutations accrued in the HPIV3 attachment protein hemagglutinin-neuraminidase (HN), including the first in vivo mutation in HN's receptor binding site responsible for activating the viral fusion process. Fixation of this mutation was associated with exposure to a drug that cleaves host-cell sialic acid moieties. Longitudinal adaptation of HN was associated with features that promote viral entry and persistence in cells, including greater avidity for sialic acid and more active fusion activity in vitro, but not with antibody escape. Long-term infection thus led to mutations promoting viral persistence, suggesting that host-directed therapeutics may support the evolution of viruses that alter their biophysical characteristics to persist in the face of these agents in vivo.",
"affiliations": "Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.;Department of Pediatrics and.;Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.;Department of Pediatrics and.;Department of Pediatrics and.;Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.;Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.;Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.;Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA.;Department of Pediatrics and.;Department of Pediatrics and.;Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA.;Center for Experimental Medicine, Queen's University, Belfast, Northern Ireland, United Kingdom.;Department of Pediatrics and.;Department of Pediatrics and.",
"authors": "Greninger|Alexander L|AL|;Rybkina|Ksenia|K|;Lin|Michelle J|MJ|;Drew-Bear|Jennifer|J|;Marcink|Tara C|TC|;Shean|Ryan C|RC|;Makhsous|Negar|N|;Boeckh|Michael|M|;Harder|Olivia|O|;Bovier|Francesca|F|;Burstein|Shana R|SR|;Niewiesk|Stefan|S|;Rima|Bert K|BK|;Porotto|Matteo|M|;Moscona|Anne|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-9738",
"issue": "131(23)",
"journal": "The Journal of clinical investigation",
"keywords": "Influenza; Virology",
"medline_ta": "J Clin Invest",
"mesh_terms": null,
"nlm_unique_id": "7802877",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34609969",
"pubdate": "2021-12-01",
"publication_types": "D016428:Journal Article",
"references": "25210187;16007245;32047132;18568847;31064833;34048692;28551476;19781656;20533871;2161938;30245734;14625580;26980833;6256653;7996144;30742688;15893837;6389770;30487282;22669629;22993149;22246027;20719945;26185620;19203106;14730265;16414997;17229690;21396476;17567695;23820396;22438532;24599766;12610140;12477836;19159905;8411349;25670774;28319790;27795347;23228170;8525632;26524513;19942616;18596815;22723641;33569576;9323433;21859271;20399493;29970463;19386708;2995550;22590688;24103895;24149514;15681439;11070006;33176080;8965678;26582658;32544442;11462020",
"title": "Human parainfluenza virus evolution during lung infection of immunocompromised individuals promotes viral persistence.",
"title_normalized": "human parainfluenza virus evolution during lung infection of immunocompromised individuals promotes viral persistence"
} | [
{
"companynumb": "US-APOTEX-2022AP003063",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "This clinical trial assessed the efficacy and toxicity of panitumumab combined with oxaliplatin and capecitabine as first-line treatment in KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. Patients with exon 2 KRAS wild-type mCRC received panitumumab 9 mg/Kg, oxaliplatin 130 mg/m2, and capecitabine 2000 mg/m2 repeated every 3 weeks. The primary endpoint was objective response rate (ORR, minimum 42 responses). We retrospectively assessed mutations in genes implicated in CRC with massively parallel sequencing; ERBB2 and EGFR amplification with fluorescence in situ hybridization, and tumor-infiltrating lymphocyte density. Among 78 patients enrolled, 45 (57.7%) completed 6 cycles. Most common grade 3-4 toxicities were skin rash (19.2%), diarrhea (18%), and neuropathy (6.4%). Among 5 (6.4%) potentially treatment-related deaths, 2 (2.6%) were characterized toxic. Objective response occurred in 43 (55.1%) of the patients (complete 6.4% and partial response 48.7%; stable 17.9% and progressive disease 7.7%), while 3.8% were non-evaluable and 15% discontinued their treatment early. Additional mutations in KRAS/NRAS/BRAF were found in 11/62 assessable (18%) tumors. After 51 months median follow-up, median progression-free (PFS) was 8.1 and overall survival 20.2 months, independently of KRAS/NRAS/BRAF or PI3K-pathway mutation status. Patients with TP53 mutations (n = 34; 55%), as well as those with left colon primary tumors (n = 66; 85%), had significantly better PFS, also confirmed in multivariate analysis. Although the clinical trial met its primary endpoint, according to the current standards, the efficacy and tolerability of the drug combination are considered insufficient. Extended genotyping yielded interesting results regarding the significance of TP53 mutations.ClinicalTrials.gov identifier: NCT01215539, Registration date: Sep 29, 2010.",
"affiliations": "Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, 11527, Athens, Greece. georgexoinis@gmail.com.;Department of Pathology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.;Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.;Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece.;Department of Medical Oncology, Faculty of Medicine, School of Health Sciences, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.;Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.;Department of Radiology, Aretaieio Hospital, National and Kapodistrian University of Athens, Athens, Greece.;Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.;Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.;Department of Pathology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.;Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.;Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.;Department of Pathology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.;Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.;Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece.;Department of Surgery, School of Health Sciences, General Oncologic Hospital of Kifisia, National and Kapodistrian University of Athens, Athens, Greece.;Oncology Department, General Hospital of Chania, Crete, Greece.;Department of Surgery, St. Luke's Hospital, Thessaloniki, Greece.;Oncology Unit GPP, Sotiria General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.;Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece.;Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, 11527, Athens, Greece.;Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.",
"authors": "Papaxoinis|George|G|http://orcid.org/0000-0001-6900-784X;Kotoula|Vassiliki|V|;Giannoulatou|Eleni|E|;Koliou|Georgia-Angeliki|GA|;Karavasilis|Vasilios|V|;Lakis|Sotirios|S|;Koureas|Andreas|A|;Bobos|Mattheos|M|;Chalaralambous|Elpida|E|;Daskalaki|Emily|E|;Chatzopoulos|Kyriakos|K|;Tsironis|George|G|;Pazarli|Elisavet|E|;Chrisafi|Sofia|S|;Samantas|Epaminontas|E|;Kaklamanos|Ioannis G|IG|;Varthalitis|Ioannis|I|;Konstantara|Athina|A|;Syrigos|Konstantinos N|KN|;Pentheroudakis|George|G|;Pectasides|Dimitrios|D|;Fountzilas|George|G|",
"chemical_list": "D000911:Antibodies, Monoclonal; D009944:Organoplatinum Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; D000069287:Capecitabine; D000077544:Panitumumab",
"country": "United States",
"delete": false,
"doi": "10.1007/s12032-018-1160-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1357-0560",
"issue": "35(7)",
"journal": "Medical oncology (Northwood, London, England)",
"keywords": "Metastatic colorectal cancer; Next generation sequencing; Panitumumab; TP53; Tumor sidedness",
"medline_ta": "Med Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D015179:Colorectal Neoplasms; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077544:Panitumumab; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53",
"nlm_unique_id": "9435512",
"other_id": null,
"pages": "101",
"pmc": null,
"pmid": "29855806",
"pubdate": "2018-05-31",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": "21300933;19367287;22270724;27672422;25605843;22508783;28275039;24225001;27121213;23348520;27907852;21228335;16172461;27302369;25877892;25088940;22810696;25713148;19888477;17060456;18349029;24500602;12602909;22665543;21738013;27819229;20619739;21641636;20921465;27856123;23321777;27507128;29298682;25851630;27630318;25574081;24687833;24018975;24942275",
"title": "Phase II study of panitumumab combined with capecitabine and oxaliplatin as first-line treatment in metastatic colorectal cancer patients: clinical results including extended tumor genotyping.",
"title_normalized": "phase ii study of panitumumab combined with capecitabine and oxaliplatin as first line treatment in metastatic colorectal cancer patients clinical results including extended tumor genotyping"
} | [
{
"companynumb": "GR-PFIZER INC-2018234207",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PANITUMUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Forty patients with refractory and/or relapsing acute leukaemia were treated with AMSA (90-120 mg/sq m/day) for 5 days combined with high dose cytosine-arabinoside (HDARAC) (3 g/sq m/12 hours) during the first 2 days. Complete remission was obtained in 46% of the 26 cases of acute myelogenous leukaemia, and the complete remission rate was fair (44%) in the 20 patients refractory to conventional induction treatments. The results were less satisfactory in the few patients with other cytological types: there were 2 complete remissions in 10 patients with acute lymphoblastic leukaemia and none in 4 patients with blast crisis of chronic myelocytic leukaemia. Haematological toxicity was severe, and 6 patients died during the aplastic phase. No cardiac toxicity associated with AMSA was observed, nor did the ocular, cutaneous or cerebellar side-effects described after longer courses of HDARAC develop. Complete remissions were relatively short, and 11 of 14 remitters relapsed after 2 to 11 months (median 4 months). However, 3 remitters underwent allogenic bone marrow transplantation with 2 surviving. Another patient has a prolonged fourth complete remission with AMSA + HDARAC maintenance treatment. It is concluded that the AMSA-HDARAC combination seems to be one of the best salvage induction regimens in acute myelogenous leukaemia.",
"affiliations": null,
"authors": "Zittoun|R|R|;Rio|B|B|;Marie|J P|JP|;Blanc|C M|CM|",
"chemical_list": "D000609:Aminoacridines; D000677:Amsacrine; D003561:Cytarabine",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0755-4982",
"issue": "14(26)",
"journal": "Presse medicale (Paris, France : 1983)",
"keywords": null,
"medline_ta": "Presse Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000609:Aminoacridines; D000677:Amsacrine; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D003561:Cytarabine; D005260:Female; D006801:Humans; D007945:Leukemia, Lymphoid; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8302490",
"other_id": null,
"pages": "1417-20",
"pmc": null,
"pmid": "3161047",
"pubdate": "1985-06-29",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Combination of AMSA-high dose cytosine arabinoside in acute leukemia.",
"title_normalized": "combination of amsa high dose cytosine arabinoside in acute leukemia"
} | [
{
"companynumb": "FR-PFIZER INC-2017000092",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMSACRINE"
},
"drugadditional": null,
... |
{
"abstract": "Cytomegalovirus (CMV) retinitis is exceptionally rare outside the clinical context of acquired immunodeficiency syndrome and organ allografting. In a population where seropositivity for past CMV infection exceeded 90 %, CMV retinitis was observed in five of 138 patients (3.6 %) receiving fludarabine-containing regimens together with rituximab, which was significantly more frequent than in 141 patients receiving fludarabine-containing regimens alone, where no case was observed (P = 0.029). Treatment of CMV retinitis comprised both intravitreal and systemic ganciclovir/foscarnet. Upon recovery, secondary retinal atrophy occurred in all patients, leading to blindness in 86 % of affected eyes. CMV retinitis is an important complication in patients receiving concomitant rituximab and fludarabine-containing regimens.",
"affiliations": "Department of Medicine, Queen Mary Hospital, Professorial Block, Pokfulam Road, Hong Kong, China.",
"authors": "Chan|Thomas S Y|TS|;Cheung|Carol Y M|CY|;Yeung|Ian Y L|IY|;Hwang|Yu-Yan|YY|;Gill|Harinder|H|;Wong|Ian Y|IY|;Kwong|Yok-Lam|YL|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D014740:Vidarabine; C024352:fludarabine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-014-2296-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "94(6)",
"journal": "Annals of hematology",
"keywords": null,
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D017726:Cytomegalovirus Retinitis; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D014740:Vidarabine",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1043-7",
"pmc": null,
"pmid": "25572171",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cytomegalovirus retinitis complicating combination therapy with rituximab and fludarabine.",
"title_normalized": "cytomegalovirus retinitis complicating combination therapy with rituximab and fludarabine"
} | [
{
"companynumb": "PHHY2015CN101379",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPIRUBICIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "There are several reports to demonstrate that rifampicin, a major anti-tuberculosis agent, is associated with some adverse renal effects, with a few cases of rifampicin-induced minimal change disease (MCD). In the present case, a 68-year-old female presented with nausea, vomiting, foamy urine, general weakness and edema. She had been taking rifampicin for 4 weeks due to pleural tuberculosis. The patient had no proteinuria before the anti-tuberculosis agents were started, but urine tests upon admission showed heavy proteinuria with a 24-h urinary protein of 9.2 g/day, and serum creatinine, albumin, and total cholesterol levels were 1.36 mg/dL, 2.40 g/dL, and 283 mg/dL, respectively. MCD was diagnosed, and the patient achieved complete remission after cessation of rifampicin without undergoing steroid therapy.",
"affiliations": "Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. ohjmd@yuhs.ac.",
"authors": "Park|Dong Hyuk|DH|;Lee|Sul A|SA|;Jeong|Hyeon Joo|HJ|;Yoo|Tae-Hyun|TH|;Kang|Shin-Wook|SW|;Oh|Hyung Jung|HJ|",
"chemical_list": "D000904:Antibiotics, Antitubercular; D012293:Rifampin",
"country": "Korea (South)",
"delete": false,
"doi": "10.3349/ymj.2015.56.2.582",
"fulltext": "\n==== Front\nYonsei Med JYonsei Med. JYMJYonsei Medical Journal0513-57961976-2437Yonsei University College of Medicine 10.3349/ymj.2015.56.2.582Case ReportNephrology & UrologyRifampicin-Induced Minimal Change Disease Is Improved after Cessation of Rifampicin without Steroid Therapy Park Dong Hyuk 1Lee Sul A 1Jeong Hyeon Joo 2Yoo Tae-Hyun 1Kang Shin-Wook 1Oh Hyung Jung 11 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.2 Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.\nCorresponding author: Dr. Hyung Jung Oh, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea. Tel: 82-2-2228-1939, Fax: 82-2-393-6884, ohjmd@yuhs.ac01 3 2015 09 2 2015 56 2 582 585 25 2 2014 08 4 2014 10 4 2014 © Copyright: Yonsei University College of Medicine 20152015This 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.There are several reports to demonstrate that rifampicin, a major anti-tuberculosis agent, is associated with some adverse renal effects, with a few cases of rifampicin-induced minimal change disease (MCD). In the present case, a 68-year-old female presented with nausea, vomiting, foamy urine, general weakness and edema. She had been taking rifampicin for 4 weeks due to pleural tuberculosis. The patient had no proteinuria before the anti-tuberculosis agents were started, but urine tests upon admission showed heavy proteinuria with a 24-h urinary protein of 9.2 g/day, and serum creatinine, albumin, and total cholesterol levels were 1.36 mg/dL, 2.40 g/dL, and 283 mg/dL, respectively. MCD was diagnosed, and the patient achieved complete remission after cessation of rifampicin without undergoing steroid therapy.\n\nMinimal change diseaserifampicinsteroid\n==== Body\nINTRODUCTION\nRifampicin is one of the standard drugs used to treat tuberculosis, however, has been reported to induce some adverse renal effects.1,2,3,4,5,6,7,8,9,10 The most frequent form of nephrotoxicity is a syndrome consisting of acute renal failure with pathological findings of tubular necrosis, while other forms of nephrotoxicity include interstitial nephritis with or without mild glomerular lesions, rapidly progressive glomerulonephritis and light chain proteinuria.2 Rifampicin-associated nephrotic syndrome has been published, including cases of rifampicin-induced minimal change disease (MCD).4,7,9 Generally, MCD is treated with glucocorticoids,11,12 and rifampicin-induced MCD was treated with a steroid in a previous case.9 Herein, however, we report a patient with MCD after rifampicin treatment, which was improved after rifampicin cessation without steroid therapy.\n\nCASE REPORT\nA 68-year-old female was admitted to the hospital because of a 5-day history of left pleuritic chest pain. She had no other relevant medical history except for a ten-year history of hypertension. On admission, her blood pressure was 146/70 mm Hg and her body temperature was 36.9℃. Physical examination was unremarkable, and urinalysis did not reveal any abnormal findings. Laboratory findings were as follows: hemoglobin 11.7 g/dL, hematocrit 32.7%, blood urea nitrogen (BUN) 6.9 mg/dL, serum creatinine 0.74 mg/dL, sodium 130 mEq/L, potassium 3.9 mEq/L, total protein 5.6 g/dL, albumin 3.9 g/dL, and total cholesterol 167 mg/dL. According to chest X-ray, a pleural effusion was present in the left lower lobe. The pleural fluid (PF) was exudative, and PF analysis showed a pH of 7.4, total protein of 5800 mg/dL, albumin of 3200 mg/dL, lactate dehydrogenase of 679 IU/L, and glucose of 92 mg/dL. In addition, the white blood cell (WBC) count was 3879/mm3 with 99% mononuclear cells, and adenosine deaminase (ADA) was shown to be 104.0 IU/L in the PF. Pleural biopsy and pleural cytology were negative for malignancy. Based on the exudative characteristics and the high ADA level in the PF, pleural tuberculosis was suspected and anti-tuberculosis treatment was started. Treatment comprised rifampicin 600 mg/day, isoniazid 300 mg/day, ethambutol hydrochloride 1200 mg/day, and pyrazinamide 1500 mg/day.\n\nDuring the 4-week anti-tuberculosis therapy regimen, the patient developed nausea, vomiting, general weakness, and edema. Urinalysis revealed 4+proteinuria with a few transitional epithelial cells, some coarse granular casts, and many mucous threads. According to a 24-h urine collection, protein and albumin values were 9.2 and 6.2 g/day, respectively. Laboratory findings were as follows: hemoglobin 12.1 g/dL, WBC 5490/mm3, BUN 33.2 mg/dL, serum creatinine 1.36 mg/dL, creatinine clearance 39 mL/min, total protein 5.6 g/dL, albumin 2.4 g/dL, serum aspartate aminotransferase 282 IU/L, alanine aminotransferase 282 IU/L, normal total bilirubin, and a total cholesterol of 283 mg/dL. Antinuclear antibody and P-anti-neutrophil cytoplasmic antibody (ANCA) and C-ANCA were all negative with normal serum complement levels.\n\nAccording to a renal biopsy, MCD was present with focal thinning of the glomerular basement membrane (Fig. 1A). Non-sclerotic glomeruli were normocellular without mesangial expansion, and the tubules showed minimal atrophy and mild focal tubular injury. Additionally, the interstitium was widened by minimal fibrosis, and no depositions of immunoglobulins or complement components were observed in the glomeruli. Electron microscopy showed the podocyte foot processes to be diffusely effaced (Fig. 1B).\n\nDue to toxic hepatitis, rifampicin and isoniazid were discontinued, but ethambutol hydrochloride and pyrazinamide were maintained. Moxifloxacin was added after 1 week, and isoniazid was added after 2 weeks. The pleural tuberculosis was well controlled with isoniazid, ethambutol hydrochloride, and moxifloxacin thereafter.\n\nWhen her diagnosis was confirmed to be MCD, we determined to use steroid therapy at first. However, she was afraid of adverse effects of steroid treatment and asked us to observe closely. Moreover, we found out that heavy proteinuria was developed after using anti-tuberculosis agents. In addition, hepatitis also occurred after anti-tuberculosis agents started, and then we had to stop rifampicin and isoniazid agents. Fortunately, she improved spontaneously without steroid use only after quitting rifampicin. Therefore, we observed and followed up continuously. Her nausea, vomiting, and general edema improved and her body weight recovered from 68 kg to 63 kg at 3 weeks after rifampicin discontinuation, and a random urine protein-to-creatinine ratio was 0.14 at 8 weeks (Fig. 2). Furthermore, her serum albumin and cholesterol levels were shown to be 3.9 g/dL and 180 mg/dL, respectively, 8 weeks after stopping rifampicin.\n\nDISCUSSION\nRifampicin is a commonly used anti-tuberculosis agent, and it has been associated with several nephrotoxicities.1,2,3,4,5,6,7,8,9,10 Although there are a few case reports of nephrotic syndrome in patients using rifampicin, rifampicin-induced MCD reaching complete remission without steroid therapy has not yet been reported.4,7,9 Thus, we described herein a case of MCD that developed after rifampicin treatment that resolved after cessation of rifampicin without steroid therapy.\n\nFrom a clinical perspective, apparently idiopathic MCD in some cases, compared with secondary MCD, may in fact represent a lesion arising secondary to an extraglomerular disease process. In many instances, the association between the extraglomerular disease process and MCD is quite obvious; on the other hand, however, the clinical findings of the underlying extraglomerular disease process can be quite subtle. According to Glassock13 secondary MCD evokes the characteristic changes in permselectivity and morphology, and the morphology is similar to idiopathic MCD.13 It is possible that similar or identical pathogenetic mechanisms are operative and a distinct etiologic link has been suggested to exist between the extraglomerular disease process and the occurrence of MCD.13 The linkage would strongly be indicated if the cure of extraglomerular disease leads to the eradication of MCD and if the recurrence of extraglomerular disorder is associated with relapse.13 We thoroughly examined her medical histories including medication uses. She had no other relevant medical history except for a ten-year history of hypertension, and she was not taking any other medications except for daily 10 mg of amlodipine. We found out that heavy proteinuria developed after using anti-tuberculosis agents. Fortunately, her proteinuria was improved after discontinuation of rifampicin and isoniazid. In addition, we added isoniazid except for rifampicin, but MCD did not recur. Taken together, the use of rifampicin seems to have resulted in developing MCD mostly in this case.\n\nAlthough there are no definite mechanisms offered for rifampicin-induced MCD, a hypersensitivity mechanism has been suggested in many drug-induced MCD cases. For example, drug exposure can result in the release of permselectivity promoting factors from activated inflammatory or immune cells, causing MCD.13 Another possible mechanism of MCD is via direct toxin effects on glomerular epithelial cells, resulting in abnormal permeability and effacement of the foot processes.13 Neugarten, et al.7 reported the first case of rifampicin-induced nephrotic syndrome, and described the patient as having acute interstitial nephritis with heavy proteinuria and effacement of the glomerular epithelial cells. They suggested that cell-mediated and humoral immune responses to the rifampicin treatment could develop,7 and Tada, et al.9 suggested that endothelial injury resulting from rifampicin-induced hemolysis and thrombocytopenia seems to play a role in the development of nephrotic syndrome.9 In our case, there was no electron-dense glomerular deposits or immune complex glomerulonephritis to suggest a humoral immune mechanism.7 Additionally, there was no hemolysis or thrombocytopenia. Thus, we surmised that, rifampicin-induced MCD in this case, might have originated from direct toxin effects.\n\nIn many cases, withdrawal of the offending drugs can lead to a full recovery, and glucocorticoids may hasten the return of renal function and ameliorate proteinuria.13 In one rifampicin-induced MCD case, the MCD was improved after oral administration of prednisolone and the cessation of rifampicin.9 We simply terminated the rifampicin instead of initiating steroid therapy, and the patient recovered from heavy proteinuria, edema and hypoalbuminemia thereafter.\n\nAlthough additional studies are required, simply discontinuing rifampicin may improve the rifampicin-induced MCD without the need for steroid therapy.\n\nThe authors have no financial conflicts of interest.\n\nFig. 1 (A) Light microscopy shows minor abnormalities of the glomeruli. The tubules show minimal atrophy and mild focal tubular injury. The interstitium is widened by minimal fibrosis. Non-sclerotic glomeruli are normocellular without mesangial expansion (H&E staining). (B) Electron microscopy shows diffusely effaced foot processes. The glomerular basement membranes are relatively even, but focal thinning of the lamina densa is noted. The mesangium is not expanded and is free of electron-dense deposits (H&E staining).\n\nFig. 2 Clinical course. After discontinuation of rifampicin, the UPCr was recovered. UPCr, random urine protein-to-creatinine ratio.\n==== Refs\n1 Covic A Goldsmith DJ Segall L Stoicescu C Lungu S Volovat C Rifampicin-induced acute renal failure: a series of 60 patients Nephrol Dial Transplant 1998 13 924 929 9568851 \n2 De Vriese AS Robbrecht DL Vanholder RC Vogelaers DP Lameire NH Rifampicin-associated acute renal failure: pathophysiologic, immunologic, and clinical features Am J Kidney Dis 1998 31 108 115 9428460 \n3 Gabow PA Lacher JW Neff TA Tubulointerstitial and glomerular nephritis associated with rifampin. Report of a case JAMA 1976 235 2517 2518 946666 \n4 Kohno K Mizuta Y Yoshida T Watanabe H Nishida H Fukami K Minimal change nephrotic syndrome associated with rifampicin treatment Nephrol Dial Transplant 2000 15 1056 1059 10862648 \n5 Murray AN Cassidy MJ Templecamp C Rapidly progressive glomerulonephritis associated with rifampicin therapy for pulmonary tuberculosis Nephron 1987 46 373 376 3658067 \n6 Muthukumar T Jayakumar M Fernando EM Muthusethupathi MA Acute renal failure due to rifampicin: a study of 25 patients Am J Kidney Dis 2002 40 690 696 12324902 \n7 Neugarten J Gallo GR Baldwin DS Rifampin-induced nephrotic syndrome and acute interstitial nephritis Am J Nephrol 1983 3 38 42 6837651 \n8 Rekha VV Santha T Jawahar MS Rifampicin-induced renal toxicity during retreatment of patients with pulmonary tuberculosis J Assoc Physicians India 2005 53 811 813 16334628 \n9 Tada T Ohara A Nagai Y Otani M Ger YC Kawamura S A case report of nephrotic syndrome associated with rifampicin therapy Nihon Jinzo Gakkai Shi 1995 37 145 150 7752507 \n10 Yoshioka K Satake N Kasamatsu Y Nakamura Y Shikata N Rapidly progressive glomerulonephritis due to rifampicin therapy Nephron 2002 90 116 118 11744817 \n11 Black DA Rose G Brewer DB Controlled trial of prednisone in adult patients with the nephrotic syndrome Br Med J 1970 3 421 426 4916790 \n12 Waldman M Crew RJ Valeri A Busch J Stokes B Markowitz G Adult minimal-change disease: clinical characteristics, treatment, and outcomes Clin J Am Soc Nephrol 2007 2 445 453 17699450 \n13 Glassock RJ Secondary minimal change disease Nephrol Dial Transplant 2003 18 Suppl 6 vi52 vi58 12953043\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0513-5796",
"issue": "56(2)",
"journal": "Yonsei medical journal",
"keywords": "Minimal change disease; rifampicin; steroid",
"medline_ta": "Yonsei Med J",
"mesh_terms": "D000368:Aged; D000904:Antibiotics, Antitubercular; D004487:Edema; D005260:Female; D006801:Humans; D007677:Kidney Function Tests; D007678:Kidney Glomerulus; D009325:Nausea; D009402:Nephrosis, Lipoid; D011507:Proteinuria; D012074:Remission Induction; D012293:Rifampin; D016896:Treatment Outcome; D014396:Tuberculosis, Pleural",
"nlm_unique_id": "0414003",
"other_id": null,
"pages": "582-5",
"pmc": null,
"pmid": "25684013",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article",
"references": "10862648;11744817;12324902;12953043;4916790;946666;17699450;3658067;7752507;9428460;9568851;16334628;6837651",
"title": "Rifampicin-induced minimal change disease is improved after cessation of rifampicin without steroid therapy.",
"title_normalized": "rifampicin induced minimal change disease is improved after cessation of rifampicin without steroid therapy"
} | [
{
"companynumb": "PHHY2015KR027551",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "OBJECTIVE\nThe frequency with which patients coming to an emergency room with hypertensive emergency received excessive or inadequate blood-pressure reduction was studied.\n\n\nMETHODS\nA retrospective chart review was conducted for all patients who were treated for hypertensive emergency at a 696-bed university teaching hospital between November 2003 and April 2004. Patients who received a continuous i.v. infusion of an antihypertensive agent for >30 minutes in the emergency department or the intensive care unit were included in the study. The primary outcomes measured were number of patients treated appropriately, number of patients treated excessively (reduction in mean arterial pressure [MAP] beyond 25% at the end of the two-hour acute-phase treatment window), and number of treatment failures within the two-hour window.\n\n\nRESULTS\nA total of 427 patients with hypertensive emergency were identified, of whom 47 met the study criteria. Fifteen patients (32%) were appropriately treated, 27 (57%) were excessively treated, and 5 (11%) had treatment failures during the two-hour acute-phase treatment period. Only 6 patients (13%) had been appropriately treated at six hours. Patients who were given nicardipine had a greater risk of an excessive MAP reduction at two hours than all other patients. One or more treatment-related adverse events occurred in 44 patients (94%).\n\n\nCONCLUSIONS\nExcessive reduction of MAP was common among patients who came to an emergency department with hypertensive emergency.",
"affiliations": "Methodist University Hospital, 1265 Union Avenue, Memphis, TN 38104, USA.",
"authors": "Brooks|Tyson W A|TW|;Finch|Christopher K|CK|;Lobo|Bob L|BL|;Deaton|Paul R|PR|;Varner|C Ferrell|CF|",
"chemical_list": "D000959:Antihypertensive Agents",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp070105",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "64(24)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents; D001794:Blood Pressure; D004632:Emergency Medical Services; D005260:Female; D006801:Humans; D006973:Hypertension; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013997:Time Factors",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "2579-82",
"pmc": null,
"pmid": "18056947",
"pubdate": "2007-12-15",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Blood pressure management in acute hypertensive emergency.",
"title_normalized": "blood pressure management in acute hypertensive emergency"
} | [
{
"companynumb": "US-PFIZER INC-2020027063",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SODIUM NITROPRUSSIDE"
},
"drugadditional": "3"... |
{
"abstract": "BACKGROUND\nOral anticoagulants and painkillers, some with an additional effect on the coagulation system, are widely used and are therefore prone to abuse and (intentional) overdose. We report the case of a patient with a massive mixed anticoagulant intoxication.\nThe patient had ingested 1960 mg rivaroxaban, 31.5 mg phenprocoumon, 1425 mg diclofenac, and 21,000 mg metamizole in suicidal intention.\nMassive mixed anticoagulant overdose.\n\n\nMETHODS\nThe patient was closely monitored. The phenprocoumon overdose was treated by the administration of vitamin K and PCC.\n\n\nRESULTS\nDespite the massive inhibition of the coagulation system, the patient did not experience bleeding apart from a slight gross hematuria.\n\n\nCONCLUSIONS\nDespite the ingestion of a massive amount of rivaroxaban, the plasma levels were not as high as feared, due to the ceiling effect of rivaroxaban absorption. Elimination occurred according to the half-life of rivaroxaban and was not unduly prolonged by the ingested quantity.",
"affiliations": "Transfusion Medicine and Hemostaseology Department Department of Internal Medicine 4 Department of Forensic Medicine, University Hospital Erlangen, Erlangen, Germany.",
"authors": "Pfeiffer|Hella|H|;Herbst|Larissa|L|;Schwarze|Bernd|B|;Eckstein|Reinhold|R|;Weisbach|Volker|V|",
"chemical_list": "D000925:Anticoagulants; D016861:Cyclooxygenase Inhibitors; D065427:Factor Xa Inhibitors; D004008:Diclofenac; D000069552:Rivaroxaban; D010644:Phenprocoumon",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000005343",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2785891910.1097/MD.0000000000005343053433900Research ArticleClinical Case ReportMassive intoxication with rivaroxaban, phenprocoumon, and diclofenac A case reportPfeiffer Hella MDa∗Herbst Larissa MDbSchwarze Bernd PhDcEckstein Reinhold aWeisbach Volker aZhou. Wen a Transfusion Medicine and Hemostaseology Departmentb Department of Internal Medicine 4c Department of Forensic Medicine, University Hospital Erlangen, Erlangen, Germany.∗ Correspondence: Hella Pfeiffer, Transfusion Medicine and Hemostaseology Department, University Hospital Erlangen, Krankenhausstr. 12, D-91054 Erlangen, Germany (e-mail: hella.pfeiffer@uk-erlangen.de).11 2016 04 11 2016 95 44 e534314 7 2016 10 10 2016 11 10 2016 Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nOral anticoagulants and painkillers, some with an additional effect on the coagulation system, are widely used and are therefore prone to abuse and (intentional) overdose. We report the case of a patient with a massive mixed anticoagulant intoxication.\n\nPatient concerns:\nThe patient had ingested 1960 mg rivaroxaban, 31.5 mg phenprocoumon, 1425 mg diclofenac, and 21,000 mg metamizole in suicidal intention.\n\nDiagnoses:\nMassive mixed anticoagulant overdose.\n\nInterventions:\nThe patient was closely monitored. The phenprocoumon overdose was treated by the administration of vitamin K and PCC.\n\nOutcomes:\nDespite the massive inhibition of the coagulation system, the patient did not experience bleeding apart from a slight gross hematuria.\n\nLessons:\nDespite the ingestion of a massive amount of rivaroxaban, the plasma levels were not as high as feared, due to the ceiling effect of rivaroxaban absorption. Elimination occurred according to the half-life of rivaroxaban and was not unduly prolonged by the ingested quantity.\n\nKeywords\nanticoagulant intoxicationcase reportoverdosephenprocoumonrivaroxabanOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nA 23-year-old male patient presented himself after the suicidal ingestion of a mix of 4 different drugs (rivaroxaban, phenprocoumon, diclofenac, and metamizole), 3 of which have a known effect on the coagulation system.\n\nLiterature research revealed 3 case reports with an intentional, massive rivaroxaban overdose (1400, 1800, and 1960 mg),[1–3] with 1 patient having additionally administered enoxaparin.[1] Additionally, 1 case of surreptitious rivaroxaban intake was found.[4]\n\nWe present, to our knowledge, the first case with a massive combination overdose of rivaroxaban, phenprocoumon, and diclofenac, and also metamizole.\n\n2 Case report\n2.1 History\nThe patient had experienced an extensive deep vein thrombosis of the right upper leg 5 months previously (Table 1). Research revealed an aplasia of the inferior vena cava with extensive collaterals, a relevant risk factor for venous thrombosis.[5] A lifelong anticoagulation was advised. Treatment with rivaroxaban (20 mg daily) was started, but after a re-thrombosis of the right upper leg 2 months after the initial thrombosis (confirmed daily rivaroxaban intake and without further recognizable risk factors), the patient was switched to phenprocoumon with an international normalized ratio (INR) target of 3.0 to 3.5. No further relevant endogenous risk factors for venous thrombophilia were detected. One week before the suicide attempt, the hemoglobin level had been 12.6 g/dL, the hematocrit 38.3%, and the platelet count 329.000/μL.\n\nTable 1 Timeline of previous patient history, adapted according to.[6]\n\nHe had a history of depression, but had not been on antidepressants during the past 5 years.\n\n2.2 Presenting condition\nA 23-year-old male (74 kg, nonsmoker) presented himself at the emergency room of an external clinic approximately 12 hours after the intentional, suicidal ingestion of 1960 mg rivaroxaban (Xarelto, Bayer Pharma AG, Germany), 31.5 mg phenprocoumon, 1425 mg diclofenac, and 21,000 mg metamizole (ingestion occurred around 7 p.m.). He reported 1 episode of vomiting during the night (no blood or pills were observed, time since ingestion unknown).\n\nUpon admission, no bleeding was observed. The physical examination and the electrocardiogram showed no abnormalities. The laboratory results showed a prothrombin time (PT) higher than 34 seconds (no further specification of this result was available at that time), INR was not measurable, activated partial thromboplastin time (aPTT) was 128 seconds. The blood count was normal (hemoglobin 13.3 g/dL, hematocrit 41%, platelet count 349.000/μL). Electrolytes, liver, and kidney function were normal [calculated glomerular filtration rate 110 mL/min (modification of diet in renal disease-formula), lactate dehydrogenase (LDH) 177 U/L, alanine aminotransferase (ALT) 10 U/L]. He received 20 mg of intravenous vitamin K, 2000 IU of prothrombin complex concentrate (PCC), 50 g oral charcoal, 40 mg pantoprazole, and 1 L of intravenous electrolyte solution (Jonosteril, Fresenius, Germany).\n\n2.3 Initial therapy\nThe patient was transferred to an intensive care unit in our hospital 18 hours after ingestion. The rivaroxaban level at that time was 1211 ng/mL, measured through anti Xa-inhibition (test: STA-Liquid Anti-Xa, Diagnostica Stago S.A.S., Asnières sur Seine Cedex, France. Calibrator: Multi Hep calibrator, Diagnostica Stago S.A.S., Asnières sur Seine Cedex, France). The PT was longer than 34 seconds, the INR was larger than 6, and the aPTT was 47.2 seconds (laboratory-defined reference range for the aPTT is 23.4–34.8 seconds and <16.1 seconds for the PT) [controls: STA-Quali-Clot I (Lot 113071) with 13.8 seconds (11.5–16.0 seconds) for the PT and 32.5 seconds (27.0–38.0 seconds) for the aPTT]. The blood count showed hemoglobin of 11.5 g/dL, hematocrit of 35.2%, and platelets of 316,000/μL). Analysis of the platelet function (using PFA-200 (Siemens, Germany) and Multiplate (Roche Diagnostics, Switzerland)) revealed a pronounced diclofenac-induced platelet dysfunction, but no apparent additional congenital platelet disorder.[7]\n\nThe patient was closely monitored, and, within 3 hours of admission in our clinic, received 3000 IU PCC pre-emptively, 60 mg vitamin K intravenously, a total of 32 g cholestyramine during his inpatient stay, and 40 mg pantoprazole once daily. Platelet concentrates were not transfused. PCC and vitamin K were given to counteract the massive phenprocoumon overdose. Because of the rivaroxaban overdose, an effective anticoagulation was ensured despite the temporary interruption of the phenprocoumon effect.\n\nApart from a slight gross hematuria upon admission, the patient never showed signs of bleeding. He was always completely oriented and never unconscious. The rivaroxaban levels (through anti-Xa inhibition) were measured every couple of hours until they were no longer detectable (Table 2). Requiring long-term anticoagulation because of his patient history, he was started on unfractionated heparin IV the moment the routine coagulation parameters (INR and aPTT) were normalized, which happened 30 hours after ingestion (approximately 18 hours after admission).\n\nTable 2 Coagulation parameters.\n\n2.4 Follow-up and outcome\nThree days after ingestion, the patient was transferred to our psychiatric clinic for further treatment. The PT upon transfer was 17.8 seconds, the INR was 1.38, the aPTT 60.9 seconds (heparin IV), and the rivaroxaban level was lower than 25 ng/mL. Hemoglobin was 13.3 g/dL and the hematocrit 41%. The patient was transferred to the psychiatry unit on unfractionated heparin. Later, he was started on oral anticoagulation with phenprocoumon (as previously done) and trained to do self-management. The lowest observed hemoglobin was 11.5 g/dL.\n\nAfter stabilization and transfer to the psychiatric clinic, the exact plasma concentrations of rivaroxaban and phenprocoumon were evaluated by liquid chromatography tandem mass spectrometry (Fig. 1). The rivaroxaban level 12 hours after ingestion, determined by spectrometry, was extremely high (4.4 μg/mL). Eighteen hours post ingestion, the levels were still high, with a marked discrepancy between our anti-Xa measurement (1211 ng/mL) and the spectrometry measurement (2.3 μg/mL). The reason for this remains unclear, as literature research revealed a good correlation between these 2 methods with only slight differences.[8] Rivaroxaban levels dropped as expected by their half-life and the patients unimpaired renal function, whereas phenprocoumon levels did not differ significantly over the course of these 3 days. Fifty-nine hours post ingestion, rivaroxaban had been almost cleared (both measurements).\n\nFigure 1 Exact plasma levels of rivaroxaban and phenprocoumon, evaluated by liquid chromatography tandem mass spectrometry. The routine anticoagulation phenprocoumon level is between 1 and 3 μg/mL. For rivaroxaban, no such references exist in our laboratory.\n\nNo renal and/or liver dysfunction, as a late effect especially of intoxication with diclofenac and metamizole, was observed during the following weeks. Since this is a case report, neither institutional review board approval nor patient consent was sought.\n\n3 Medication background information\nRivaroxaban is an oral, direct, and selective factor Xa inhibitor.[9] The plasma levels and therefore the maximum anticoagulant effects of rivaroxaban are reached within 2 to 4 hours, with a half-life of 5 to 9 hours, which may be prolonged in older patients or in cases of insufficient renal function (11–13 hours).[10,11] About one-third is eliminated unchanged via the kidneys.[12] After 16 hours, the expected anticoagulant effect is low and only a minimal effect is noticeable after more than 24 hours.[11] An apparent ‘ceiling effect’ after (about 50 mg) was observed after the ingestion of higher doses with a limitation to the maximum potential anti-Xa inhibitory effect.[10]\n\nMonitoring through determination of anti-Xa activity, using special calibrators, is a precise way to ascertain the quantitative anticoagulant effect, but this is seldom routinely available.[13,14] The gold standard is measurement by liquid chromatography tandem mass spectrometry.[14] PT and aPTT are affected without any linearity, depending on the reagents used, but normal PT and aPTT seem to exclude relevant rivaroxaban plasma levels.[9,15,16]\n\nIn case of acute rivaroxaban overdose, the major concern is bleeding. Since no specific antidote is available,[17] close monitoring and supportive measures are of utmost importance. Gastrointestinal decontamination using activated charcoal may be useful only if applied shortly after ingestion.[11] In our case, it is not clear whether the administration of charcoal 12 hours after ingestion was helpful. Rivaroxaban is not dialyzable due to its high plasma protein binding.[17]\n\nTreatment of bleeding complications include mechanical methods, radiological interventions, and surgery.[11] Since a specific antidote is not available, administration of PCC seems to be the best option in cases of severe bleeding (same dosage as for vitamin K antagonist-induced bleeding, ie, 25–50 IU per kg bodyweight).[11,18] Fresh frozen plasma (FFP) or recombinant factor VIIa might also be used, although their prothrombotic potential might be higher than that of PCC.[18]\n\nPhenprocoumon is a vitamin K antagonist with a high protein binding (> 95%), which prevents its elimination via dialysis.[9,15] Although peak concentrations are reached about 90 minutes after intake, the half-life is 5.5 days with an accordingly slow onset and end of efficient anticoagulation.[15] Because of its inhibition of the synthesis of vitamin K-dependent coagulation factors (factors II, VII, IX, and X, and also proteins C and S), onset of coagulation is slow, whereas multiple interactions with food, other drugs, and genetic variability are observed.[9,15,19] The therapeutic index is relatively small, but the anticoagulation effect can be easily monitored by the INR, which is readily available in most clinics.[9,15] Vitamin K is the preferred antidote, but requires a certain amount of time to become effective.[9,15] For a fast termination of the phenprocoumon effect, PCC or FFP can be administered, but a rebound effect is to be expected.[9,15] Whereas supratherapeutic levels of vitamin K antagonists are a common side effect in patients requiring oral anticoagulation, massive overdoses are relatively rare.[19]\n\nDiclofenac is a reversible cyclooxygenase inhibitor with a half-life of 1 to 2 hours, an antinoceptive and a marked antiphlogistic effect.[20,21] Common side effects include gastrointestinal, cardiac, and vascular adverse events, and also a reversible inhibition of the platelet function (in accordance to the plasma half-life) and renal adverse effects.[20] Most cases of overdose show a benign outcome, with only rare serious adverse events.[22] Treatment is strictly supportive, although the administration of oral charcoal is advised.[22] Diclofenac cannot be eliminated by dialysis.[22]\n\nMetamizole (also known as dipyrone) is a reversible cyclooxygenase inhibitor, has a half-life of approximately 2 to 4 hours, and the maximum peak level is reached after about 1 to 1.5 hours.[20,23,24] No clinically relevant inhibition of platelet function has been observed.[20] Common side effects include gastrointestinal, cardiovascular, renal, or hypertensive adverse events, whereas agranulocytosis is a rare but serious side effect.[20,23]\n\n4 Discussion\nLiterature research revealed 3 case reports with an intentional, massive rivaroxaban overdose (1400, 1800, and 1960 mg),[1–3] with 1 patient having additionally administered enoxaparin.[1] Additionally, 1 case of surreptitious rivaroxaban intake was found.[4] We present, to our knowledge, the first case with a massive combination overdose of rivaroxaban, phenprocoumon, and diclofenac, and also metamizole, resulting in a massive inhibition of the secondary, and also the primary coagulation system. Despite this, the patient never showed signs of significant bleeding, thereby underlining the importance of stable blood vessels.\n\nDue to the ceiling effect of rivaroxaban absorption, the rivaroxaban plasma levels were comparably low considering the massive ingestion. Elimination occurred according to the known half-life of rivaroxaban. The phenprocoumon overdose was well-treated by the fast and ample administration of vitamin K and PCC.\n\nIn all 3 previous case reports with a massive rivaroxaban overdose, patients were middle-aged, clinically stable, and fully conscious upon admission.[1–3] Two patients received PCC pre-emptively—in 1 case with additional active charcoal and in the other case with tranexamic acid.[2,3] No bleeding episodes were recorded.[1–3] Elimination of rivaroxaban and therefore normalization of blood coagulation (and its parameters) was observed 22 to 48 hours after ingestion.[1–3] In the case of surreptitious rivaroxaban intake, the patient presented with menorrhagia, epistaxis, and easy bruising, but no serious bleeding was observed and no treatment was necessary.[4] All 4 case reports postulated that a pre-emptive administration of coagulation factors might not be necessary, but dependent on clinical findings, and likely did not improve the clinical outcome.[1–4]\n\nIn this patient, the risk of bleeding complications was estimated to be very high. Because of the confusing coagulation situation, with a massive inhibition of the primary, and also the secondary coagulation system, the patient was given PCC and vitamin K to counteract at least some of the phenprocoumon effect. This therapy was likely not effective in counteracting the rivaroxaban overdose, thereby ensuring an effective anticoagulation despite the massive procoagulatory therapy. In the future, with more experience concerning mixed anticoagulation overdoses, a different therapy approach or a reduced procoagulatory treatment might be possible.\n\nAbbreviations: ALT = alanine aminotransferase, aPTT = activated partial thromboplastin time, INR = international normalized ratio, LDH = lactate dehydrogenase, PCC = prothrombin complex concentrate, PT = prothrombin time.\n\nThe authors declare that they have no conflicts of interest relevant to the manuscript.\n==== Refs\nReferences\n1 Bandali F Thomas Z Gozzo Y \n1205. Conservative management of massive rivaroxaban and enoxaparin overdose . Crit Care Med \n2014 ; 42 :A1642 .\n2 Lehmann T Hofer KE Baumann M \nMassive human rivaroxaban overdose . Thromb Haemost \n2014 ; 112 :834 –836 .25055741 \n3 Linkins LA Moffat K \nMonitoring the anticoagulant effect after a massive rivaroxaban overdose . J Thromb Haemost \n2014 ; 12 :1570 –1571 .25040104 \n4 Katragadda L Murphy MC Harris NS \nSteps to diagnosis of a case of surreptitious intake of one of the newer direct oral anticoagulants: a case report and literature review . Blood Coagul Fibrinolysis \n2015 ; 26 :574 –576 .25692524 \n5 Sagban TA Scharf RE Wagenhäuser MU \nElevated risk of thrombophilia in agenesis of the vena cava as a factor for deep vein thrombosis . Orphanet J Rare Dis \n2015 ; 10 :3 .25604085 \n6 Gagnier JJ Kienle G Altman DG \nThe care guidelines: consensus-based clinical case reporting guideline development . Glob Adv Health Med \n2013 ; 2 :38 –43 .\n7 Gresele P \nthe Subcommittee on Platelet Physiology of the International Society on Thrombosis and Hemostasis. Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH . J Thromb Haemost \n2015 ; 13 :314 –322 .25403439 \n8 Douxfils J Tamigniau A Chatelain B \nComparison of calibrated chromogenic anti-Xa assay and PT tests with LC-MS/MS for the therapeutic monitoring of patients treated with rivaroxaban . Thromb Haemost \n2013 ; 110 :723 –731 .23846172 \n9 Mega JL Simon T \nPharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments . Lancet \n2015 ; 386 :281 –291 .25777662 \n10 Kubitza D Becka M Roth A \nDose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects . Curr Med Res Opin \n2008 ; 24 :2757 –2765 .18715524 \n11 Haas S Bode C Norrving B \nPractical guidance for using rivaroxaban in patients with atrial brillation: balancing benefit and risk . Vasc Health Risk Manag \n2014 ; 10 :101 –114 .24648742 \n12 Kubitza D Becka M Mueck W \nEffects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor . Br J Clin Pharmacol \n2010 ; 70 :703 –712 .21039764 \n13 Samama MM Contant G Spiro TE \nLaboratory assessment of rivaroxaban: a review . Thromb J \n2013 ; 11 :11 .23822763 \n14 Rathbun S Tafur A Grant R \nComparison of methods to determine rivaroxaban anti-factor Xa activity . Thromb Res \n2015 ; 135 :394 –397 .25476589 \n15 Salem JE Sabouret P Funck-Brentano C \nPharmacology and mechanisms of action of new oral anticoagulants . Fundam Clin Pharmacol \n2015 ; 29 :10 –20 .25196680 \n16 Stevenson JW Minns AB Smollin C \nAn observational case series of dabigatran and rivaroxaban exposures reported to a poison control system . Am J Emerg Med \n2014 ; 32 :1077 –1084 .24908445 \n17 Bayer Pharma AG. Xarelto (Rivaroxaban). Summary of product information [German]. 2014. Available at: http://www.fachinfo.de/suche/fi/013452. Accessed June 8, 2015 .\n18 Turpie AGG Kreutz R Llau J \nManagement consensus guidance for the use of rivaroxaban, an oral, direct factor Xa inhibitor . Thromb Haemost \n2012 ; 108 :876 –886 .23014816 \n19 Levine M Pizon AF Padilla-Jones A \nWarfarin overdose: a 25-year experience . J Med Toxicol \n2014 ; 10 :156 –164 .24488527 \n20 Jage J Laufenberg-Feldmann R Heid F \nDrugs for postoperative analgesia: routine and new aspects. Part 1: non-opioids . Anaesthesist \n2008 ; 57 :382 –390 .18351305 \n21 Patrignani P Patrono C \nCyclooxygenase inhibitors: from pharmacology to clinical read-outs . Biochim Biophys Acta \n2015 ; 1851 :422 –432 .25263946 \n22 Smolinske SC Hall AH Vandenberg SA \nToxic effects of nonsteroidal anti-inflammatory drugs in overdose. An overview of recent evidence on clinical effects and dose-response relationships . Drug Saf \n1990 ; 5 :252 –274 .2198051 \n23 Edwards J Meseguer F Faura C \nSingle dose dipyrone for acute postoperative pain . Cochrane Database Syst Rev \n2010 ; CD003227 .20824835 \n24 Volz M Kellner HM \nKinetics and metabolism of pyrazolones (propyphenazone, aminopyrine and dipyrone) . Br J Clin Pharmacol \n1980 ; 10 \n(suppl 2) :299S –308S .7002187\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "95(44)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000925:Anticoagulants; D016861:Cyclooxygenase Inhibitors; D004008:Diclofenac; D065427:Factor Xa Inhibitors; D006801:Humans; D008297:Male; D010644:Phenprocoumon; D000069552:Rivaroxaban; D055815:Young Adult",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e5343",
"pmc": null,
"pmid": "27858919",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18351305;25403439;20824835;25692524;25476589;23822763;23014816;25196680;25055741;24416692;2198051;24488527;21039764;25777662;18715524;23846172;7002187;25040104;25604085;25263946;24648742;24908445",
"title": "Massive intoxication with rivaroxaban, phenprocoumon, and diclofenac: A case report.",
"title_normalized": "massive intoxication with rivaroxaban phenprocoumon and diclofenac a case report"
} | [
{
"companynumb": "PHHY2016DE149875",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND\nStandard treatment of idiopathic intracranial hypertension (IIH) involves reduction of intracranial pressure (ICP) to normal range, often via a ventriculoperitoneal shunt (VPS). We describe a case of a middle-aged man who presented with symptoms consistent with IIH. After ICP was normalized with a VPS, the patient had neurologic deterioration into a coma. He completely recovered after a month when his ICP was allowed to increase and remain above the normal range.\n\n\nMETHODS\nA 50-year-old man presented with daily headaches, visual loss (right > left), and increased lumbar opening pressure consistent with IIH. A VPS was inserted using a Strata II valve with a pressure setting of 1.5, lowering ICP into the normal range. The patient initially had a normal postoperative course, but then became comatose and developed imaging signs consistent with intracranial hypotension. A Codman Certas valve was placed at a setting of 7 and a distal slit-cut peritoneal catheter was used (as opposed to standard open output). This custom system drained at pressure >26 mm Hg based on intraoperative manometry. The patient tolerated this well and is currently planned for a gradual reduction in ICP with valve setting adjustments as an outpatient.\n\n\nCONCLUSIONS\nIn patients with chronic IIH, reduction to normal ICP may unexpectedly lead to encephalopathic changes. Personalized shunts may facilitate reduction of ICP to still elevated but tolerable levels in these patients.",
"affiliations": "Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA. Electronic address: ayahanda@wustl.edu.;Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA.;Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA.;Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA.;Department ofNeurology, Washington University School of Medicine, St. Louis, Missouri, USA.;Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA.",
"authors": "Yahanda|Alexander T|AT|;Shah|Amar S|AS|;Hacker|Carl|C|;Akbari|Syed Hassan|SH|;Keyrouz|Salah|S|;Osbun|Joshua|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2020.01.142",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "136()",
"journal": "World neurosurgery",
"keywords": "Custom shunt; Idiopathic intracranial hypertension; Pseudotumor cerebri; Ventriculoperitoneal shunt",
"medline_ta": "World Neurosurg",
"mesh_terms": "D057785:Catheters; D004867:Equipment Design; D006801:Humans; D019585:Intracranial Hypotension; D007427:Intracranial Pressure; D008279:Magnetic Resonance Imaging; D008297:Male; D008365:Manometry; D008875:Middle Aged; D009765:Obesity; D011183:Postoperative Complications; D011559:Pseudotumor Cerebri; D016896:Treatment Outcome; D017287:Ventriculoperitoneal Shunt",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "318-322",
"pmc": null,
"pmid": "31996337",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Custom Shunt System for Increased Baseline Intracranial Pressure in a Patient with Idiopathic Intracranial Hypertension.",
"title_normalized": "custom shunt system for increased baseline intracranial pressure in a patient with idiopathic intracranial hypertension"
} | [
{
"companynumb": "US-TEVA-2020-US-1222420",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAZOLAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Extramedullary blast crisis (EBC) in chronic myeloid leukemia (CML) is a rare phenomenon and represents infiltration of leukemic blasts in areas other than bone marrow. Lymph node is the most common site of involvement by EBC. We herein present a case of CML who suffered from two discrete episodes of EBC at atypical locations (scalp and paravertebral) within an interval duration of nine months. A-38-year-old female was diagnosed as a case of CML with extramedullary blast crisis in scalp at presentation. She received treatment with imatinib 600 mg once daily through Novartis Oncology Access Program (NOA). She achieved hematological remission. However nine months later she was readmitted with spinal shock due to cord compression secondary to paraspinal chloroma. She was started on tablet Nilotinib in view of failure to 1st line therapy. Her compressive myelopathy was treated with pulses of high dose dexamethasone. However soon she died due to pneumonia.",
"affiliations": "Department of Clinical Hematology, Internal Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India.;Department of Clinical Hematology, Internal Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India.;Department of Histopathology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.;Department of Clinical Hematology, Internal Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India.;Department of Histopathology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.;Department of Hematopathology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.;Department of Clinical Hematology, Internal Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India.",
"authors": "Sahu|Kamal Kant|KK|;Malhotra|Pankaj|P|;Uthamalingam|Preithy|P|;Prakash|Gaurav|G|;Bal|Amanjit|A|;Varma|Neelam|N|;Varma|Subhash Chandar|SC|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s12288-014-0471-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0971-4502",
"issue": "32(Suppl 1)",
"journal": "Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion",
"keywords": null,
"medline_ta": "Indian J Hematol Blood Transfus",
"mesh_terms": null,
"nlm_unique_id": "9425818",
"other_id": null,
"pages": "89-95",
"pmc": null,
"pmid": "27408365",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports",
"references": "17454789;16758687;2097454;23486000;2756456;10221523;23171293;2012070;18417213;21618900;2004308;9827981;11108312;12574966;24180494;2358205;7597876;24371785;15075103;22653972;12924504;11684281;15995975;11939268;17315214;9009247;15389905;18343792;2065281;10594858;3931208;11877262;8398844;10704692;7803300;23417967;12196931;15914360;12585040;10936425;12203863;22444689;16615875;10428738;23018220;16706941;16019565;17078470;11590459;16084356",
"title": "Chronic Myeloid Leukemia with Extramedullary Blast Crisis: Two Unusual Sites with Review of Literature.",
"title_normalized": "chronic myeloid leukemia with extramedullary blast crisis two unusual sites with review of literature"
} | [
{
"companynumb": "PHHY2016IN099402",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadditional": null,
"drugad... |
{
"abstract": "BACKGROUND\nWilson's disease is a rare, autosomal recessive inherited disorder characterized by impaired liver metabolism of copper leading to decreased biliary excretion and incorporation of ceruloplasmin levels mainly in the liver and brain. Untreated Wilson's disease has been shown to cause subfertility and even in cases where pregnancy occurs, it often results in spontaneous miscarriage.\n\n\nMETHODS\nWe present four cases of successful pregnancy outcomes in three patients diagnosed with Wilson's disease along with the literature review. All the patients were managed with zinc sulphate without any postnatal complications.\n\n\nCONCLUSIONS\nPatients with Wilson's disease receiving regular treatment who remain asymptomatic are usually able to conceive and achieve successful outcomes. However, these pregnancies should be considered high risk and merit regular surveillance.",
"affiliations": "Medical Student, Medical College, The Aga Khan University Hospital, Stadium Road, P,O, Box 3500, Karachi 74800, Pakistan. alianwar90@hotmail.com.",
"authors": "Malik|Ayesha|A|;Khawaja|Ali|A|;Sheikh|Lumaan|L|",
"chemical_list": "D019287:Zinc Sulfate; D003300:Copper; D002570:Ceruloplasmin",
"country": "England",
"delete": false,
"doi": "10.1186/1756-0500-6-421",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central 1756-0500-6-4212413960210.1186/1756-0500-6-421Case ReportWilson’s disease in pregnancy: case series and review of literature Malik Ayesha 1ayesha.malik@aku.eduKhawaja Ali 2alianwar90@hotmail.comSheikh Lumaan 1lumaan.sheikh@aku.edu1 Department of Obstetrics and Gynecology, The Aga Khan University Hospital, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan2 Medical Student, Medical College, The Aga Khan University Hospital, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan2013 18 10 2013 6 421 421 28 11 2012 15 10 2013 Copyright © 2013 Malik et al.; licensee BioMed Central Ltd.2013Malik et al.; licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nWilson’s disease is a rare, autosomal recessive inherited disorder characterized by impaired liver metabolism of copper leading to decreased biliary excretion and incorporation of ceruloplasmin levels mainly in the liver and brain. Untreated Wilson’s disease has been shown to cause subfertility and even in cases where pregnancy occurs, it often results in spontaneous miscarriage.\n\nCase presentations\nWe present four cases of successful pregnancy outcomes in three patients diagnosed with Wilson’s disease along with the literature review. All the patients were managed with zinc sulphate without any postnatal complications.\n\nConclusion\nPatients with Wilson’s disease receiving regular treatment who remain asymptomatic are usually able to conceive and achieve successful outcomes. However, these pregnancies should be considered high risk and merit regular surveillance.\n\nCopper metabolismInfertilityPregnancyWilson’s diseaseZinc sulphate\n==== Body\nBackground\nWilson’s disease is a rare autosomal recessive disorder with a prevalence of 1:50,000-1:100,000 live births [1]. Mutation of ATP 7B on chromosome 13q14 leads to impaired biliary excretion and ceruloplasmin incorporation causing copper accumulation mainly in the liver and brain [2]. This accumulation results in liver cirrhosis and nervous system manifestations such as movement disorders and ataxia [3].\n\nUntreated Wilson’s disease usually causes subfertility and in cases where pregnancy does occur, it often results in spontaneous miscarriage [4]. However, therapeutic evolution in the past decades has resulted in multiple successful pregnancy outcomes in patients with Wilson’s disease [3-8]. Penicillamine, zinc salts, trientine and tetrathiomolybdate have been shown to be highly efficacious in treating this disorder [1].\n\nWe report four cases of successful pregnancy outcomes in three women with Wilson’s disease (all treated with zinc) together with the literature review regarding the impact of Wilson’s disease on fetomaternal outcomes.\n\nCase presentations\nCase 1\nA 30 year old lady presented to our antenatal clinic during the first trimester of her pregnancy. She was diagnosed with Wilson’s disease at the age of twenty two while being investigated for involuntary generalized shaking of the body. Her laboratory investigations revealed increased level of copper in the urine and low serum ceruloplasmin. She was prescribed Zinc Sulphate 50 mg twice daily subsequently. Her brother and a sister were also diagnosed to have Wilson’s disease. She had previously conceived on clomiphene after two years of subfertility but underwent two first trimester miscarriages and a stillbirth at 30 weeks of pregnancy due to preeclampsia and placental abruption.\n\nDuring her initial presentation, the patient complained of headache and tremors for which the neurology team was consulted. The dose of zinc sulphate was increased to 50 mg thrice a day after which the neurological symptoms subsided gradually. Ophthalmologic examination revealed Kayser-Fleischer rings. Serum copper and ceruloplasmin levels were then obtained which were 76.5 μg/dL (118–302 μg/dL) and 0.03 g/L (0.25-0.63 g/L), respectively. Maternal echocardiogram was performed which was within normal limits while ultrasound of the upper abdomen revealed inflammatory changes in the liver with echogenicity of the parenchyma. An anomaly scan was performed at 20 weeks of gestation which did not reveal any congenital anomaly while a growth scan performed at 35 weeks of gestation showed a live fetus weighing 2.5 kg and having adequate amniotic fluid index. Renal and liver function tests remained within normal limits throughout the pregnancy. Serum copper level was again obtained at 30 weeks of gestation which was 30.72 μg/dL.\n\nThe patient underwent spontaneous labour at 37 weeks of gestation. Intra-partum course of events was unremarkable and a healthy baby boy weighing 3 kg with a good Apgar score was delivered vaginally.\n\nCase 2\nA 33 year old lady with a prior history of a missed miscarriage, presented to our antenatal clinic at six weeks of gestation. She was diagnosed to have Wilson’s disease four years ago while undergoing evaluation for muscle weakness. The urinary copper level was high while serum copper and cerulopasmin levels were found to be below normal limits and she was started on zinc sulphate three times a day.\n\nThe patient had conceived spontaneously and was asymptomatic at the time of presentation. Zinc sulphate was continued at 30 mg thrice a day throughout her pregnancy. As a part of her baseline workup, an ultrasound upper abdomen was performed which showed portal hypertension. Serum copper level was 33 μg/dL while serum ceruloplasmin was 0.05 g/L. The blood pressure during her first antenatal visit was within normal limits. However, it was found to be raised (150/100 mmHg) at 18 weeks of gestation due to which methyldopa 500 mg three times a day was started subsequently. Blood pressure on her following visits remained between 130/80 mmHg and 140/90 mmHg. Anomaly scan performed at 22 weeks of gestation did not reveal any congenital anomaly. At 24 weeks of gestation, 50 grams glucose challenge test was performed for screening of gestational diabetes mellitus which was found to be deranged; one hour value of 177 mg/dl (normal value = 140 mg/dl). Oral glucose tolerance test was therefore performed which also revealed raised blood glucose levels confirming the diagnosis of gestational diabetes mellitus. Her sugars, however, remained well controlled through dietary measures throughout the antenatal period. A growth scan was performed at 34 weeks of gestation which showed a live fetus with an estimated fetal weight of 2.1 kg with normal amniotic fluid index. Serum copper and ceruloplasmin levels performed during this time period were 70.86 μg/dL and 0.07 g/L, respectively. During her 38th week of pregnancy, she developed preeclampsia with a blood pressure of 140/95 mmHg and proteinuria of 0.3 mg/dl. Therefore, induction of labour was offered. The bishop score prior to the induction was four and cervical ripening was performed through an intra-cervical foley’s catheter followed by an intra-vaginal prostaglandin E2. Syntocinon was later started at a cervical dilatation of 3 cm. However, an emergency caesarean section had to be performed due to non-progress of labour. An alive baby boy weighing 3.3 kg with a good Apgar score was delivered successfully. Her blood pressure normalized during the postpartum period. One year later, the patient had another spontaneous pregnancy which terminated in a missed miscarriage at 7 weeks of gestation.\n\nCase 3\nA 21 year old primigravida, presented to our antenatal clinic for her booking appointment. She was diagnosed to have Wilson’s disease at the age of eighteen years when she started having symptoms of depression. The laboratory workup revealed an elevated level of copper in the urine (250 μg/day; normal value <60 μg/day) and low serum ceruloplasmin level (0.1 g/l; normal range 0.25-0.63 g/l). Her father was also diagnosed to have Wilson’s disease. She had been using zinc sulphate 60 mg three times a day and relaxipam 2 mg daily since the time of diagnosis and continued it throughout her pregnancy.\n\nThe patient did not have any symptoms of Wilson’s disease at the time of presentation. All the antenatal laboratory tests were within normal limits. Urinary copper level was obtained at the tenth week of gestation which was 2.88 μg/day. Anomaly scan performed at 20 weeks revealed no gross congenital anomalies while the growth scan done at the 30th week of gestation showed satisfactory growth of the fetus. Maternal echocardiography performed at 24 weeks did not reveal any abnormality with an ejection fraction of 60%. Oral glucose tolerance test was obtained at the 24th week of gestation which ruled out gestational diabetes.\n\nAntenatal course was uneventful except for the two episodes of gastroenteritis at the 23rd and 36th week of gestation for which she was admitted and managed conservatively.\n\nAt 40 weeks of gestation, she was admitted electively for the induction of labor. Bishop score at the time of admission was six. The induction of labour was initiated with an intracervical foley’s catheter followed by an intravaginal prostaglandin E2. Amniotomy was subsequently performed followed by intravenous oxytocin once the contractions started. During her intrapartum monitoring, blood pressure was found to be escalating and due to a persistently raised diastolic pressure of 100 mmHg, an intravenous hydralazine was administered. Spot protein/creatinine ratio obtained during this time period was 0.33 mg/dl which was suggestive of preeclampsia. However, labour progressed satisfactorily and the patient delivered an alive baby boy weighing 3.4 kg with a good Apgar score via spontaneous vaginal delivery. In the post partum period, blood pressure remained within normal limits on 5 mg of amlodipine.\n\nCase 4\nThe same patient conceived spontaneously one year later. Her antenatal visits were regular and unremarkable. She was asymptomatic for Wilson’s disease throughout the pregnancy. Serum ceruloplasmin levels were checked at 24 and 36 weeks of gestation which were 0.73 and 0.75 g/L, respectively. Anomaly and Growth scans were unremarkable.\n\nAt 38 weeks of gestation, she presented with complains of abdominal heaviness, stiffness, vomiting and raised blood pressure of 140/100 mmHg. Urinalysis was negative for proteinuria while full blood count, liver function tests and uric acid were within normal limits. She was admitted and planned for induction of labor.\n\nIntrapartum period remained uneventful culminating in a spontaneous vaginal delivery of a healthy baby boy weighing 3.5 kg. Patient remained normotensive in the postpartum period and was discharged on the second postnatal day.\n\nIn all our patients, serum ceruloplasmin level was ascertained by nephlometric method while urinary and serum copper levels were determined by FASS (flame atomic absorption spectrometry) methodology.\n\nDiscussion\nAlthough there are a few case reports pertaining to successful pregnancy outcomes in women with Wilson’s disease [3-8], the present case series enforces the effectiveness of zinc sulphate in managing pregnancies in patients diagnosed with Wilson’s disease.\n\nLiver is the primary storage organ for copper after which it can be distributed in circulation to other tissues such as nervous system, eyes and kidneys. Accumulation of excessive copper due to decreased excretion can adversely affect these tissues leading to hepatic injury and cirrhosis, neurological symptoms such as dyskinesias and tremors, kayser-fleishcer ring around limbus and renal tubular damage [9]. Moreover, it can lead to menstrual irregularities due to hepatotoxicity and recurrent miscarriages due to copper deposition in the uterus in women in reproductive age group [1,4]. Women with Wilson’s disease may require infertility treatment but many patients conceive spontaneously. In our case series, one patient received clomephine citrate. However, women with severe liver disease leading to bleeding episodes from eosophageal varices or hepatic insufficiency are usually discouraged from getting pregnant [8].\n\nThe serum copper and ceruloplasmin levels have been observed to change as the pregnancy progresses. The levels may increase till 24 weeks followed by a modest decline probably due to fetal intake of copper [7]. There is approximately 12 mg of copper in a neonate and the fetus is thought to remove an average of 0.044 mg of copper per day from the maternal serum, due to which improvement in symptoms of Wilson’s disease have also been reported [7,10].\n\nUntreated, Wilson’s disease may lead to early pregnancy complications [4]. Two out of three of our patients had at least one miscarriage. The mechanism has been postulated to be similar to that of copper containing contraceptive devices which exert their contraceptive effect by causing deposition of copper in the endometrium giving rise to an excess of copper ions [11]. Such high concentrations of intrauterine copper may lead to miscarriages as seen in patients with Wilson’s disease.\n\nWilson’s disease, if not treated promptly, can lead to significant morbidity and can be potentially fatal. It is hence imperative that it is identified early and treated effectively. Safety of Pencillamine in managing Wilson’s disease during pregnancy has been reported by multiple studies [4-6,8]. Only one case report states an infant developing connective tissue disorder in a mother with a daily intake of 2 grams of pencillamine which is approximately twice the dose used for Wilson’s disease in pregnancy [12]. It has also been suggested to reduce the dose of pencillamine to 0.25 grams per day, one to six weeks prior to a caesarean section in order to prevent delayed wound healing [13-15]. Trientine is an oral chelating drug used as an alternate when patients develop a reaction to pencillamine. Its effectiveness has been proven and case reports regarding its use in pregnancy do not show any adverse fetomaternal outcomes [16,17].\n\nMore recently, zinc is increasingly being used as a therapeutic option in managing Wilson’s disease. Zinc interferes with the absorption of copper from the gastrointestinal tract; however, its long-term side-effects are still not well studied. Zinc performs its function by induction of intestinal cells metallothionein which has a high affinity for copper and prevents serosal transfer of copper into blood [18]. Brewer et al. reports use of Zinc Sulphate in 26 pregnancies out of which 24 had a normal infant, one infant had a congenital heart defect and one had microcephaly [10]. In our case series, all the patients were treated with zinc sulphate without occurrence of any congenital anomaly in the neonates.\n\nIn our case series, three out of four pregnancies were complicated with pregnancy induced hypertension/preeclampsia. This complication has been reported previously in patients with Wilson’s disease [1,19]. It may be hypothesized that these patients are at risk of developing pregnancy induced hypertension or preeclampsia. However, it is still unknown if this finding is related to the presence of the underlying disease or is related to the anti-copper therapy used during pregnancy. These patients might be at risk for other complications including placental abruption and thrombocytopenia and deranged coagulation [3,19,20]. However, such complications were not encountered in our patients.\n\nConclusions\nPatients with Wilson’s disease receiving regular treatment who remain asymptomatic are usually able to conceive with successful outcomes. Zinc Sulphate is an effective therapeutic option and can be safely used in managing patients with Wilson’s disease throughout the pregnancy. However, since there seems to be an association of Wilson’s disease with miscarriages and pregnancy induced hypertension/preeclampsia, these pregnancies should be considered high risk and merit regular surveillance.\n\nConsent\nWritten informed consent was obtained from the patients for publication of this Case Series. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nAM followed the patients regularly, collected the required data and contributed in manuscript writing. AK contributed towards data collection and manuscript writing. LS identified the patients and critically edited the manuscript. All authors read and approved the final manuscript.\n==== Refs\nMustafa MS Shamina AH Five successful deliveries following 9 consecutive spontaneous abortions in a patient with Wilson disease Aust N Z J Obstet Gynaecol 1998 6 312 314 9761160 \nDobyns WB Goldstein NP Gordon H Clinical Spectrum of Wilson’s disease (hepatolenticular degeneration) Mayo Clinic Proc 1979 6 35 \nFurman B Bashiri A Wiznitzer A Erez O Holcberg G Mazor M Wilson’s disease in pregnancy: five successful consecutive pregnancies of the same woman Eur J Obstet Gynecol Reprod Biol 2001 6 232 234 11384817 \nMorimoto I Ninomiya H Komatsu K Satho M Pregnancy and penicillamine treatment in a patient with Wilson’s disease Jpn J Med 1986 6 59 62 3712863 \nScheinberg IH Sternlieb I Pregnancy in penicilamine-treated patients with Wilson’s disease N Engl J Med 1975 6 1300 1186824 \nBerghella V Steele D Spector T Cambi F Johnson A Successful pregnancy in a neurologically impaired woman with Wilson’s disease Am J Obstet Gynecol 1997 6 712 714 9077636 \nShervin AL Beck IT Mckenna RD The course of Wilson’s disease (hepatolenticular degeneration) during pregnancy and after delivery Canad MAJ 1960 6 160 \nHerbert S Irmin S Pregnancy in Penicillamine treated patients with Wilson’s disease N Engl J Med 1975 6 1300 1302 \nScheinberg IH Sternlieb I Wilson’s disease 1984 Philadelphia: WB Saunders \nBrewer GJ Johnson VD Dick RD Fink JK Kluin KJ Treatment of Wilson’s disease with zinc, XVII: treatment during pregnancy Hepatology 2000 6 364 370 10655259 \nOster G Salgo MP The copper intrauterine device and its mode of action N Engl J Med 1968 6 352 359 \nMjolnerod OK Dommerud SA Rasmussen K Gjeruldsen ST Congenital connective-tissue defect probably due to D-penicillamine treatment in pregnancy Lancet 1971 6 673 675 4101615 \nGeever EF Youssef S Seifter E Levenson SM Penicillamine and wound healing in young guinea pigs J Surg Res 1967 6 160 166 6020593 \nWalshe JM Pregnancy in Wilson’s disease Q J Med 1977 6 73 83 866569 \nNimmi MF Bavetta LA Collagen defect induced by Penicillamine Science 1965 6 905 909 \nWalshe JM The management of pregnancy in Wilson’s disease treated with trientine Q J Med 1986 6 81 87 3704107 \nDupont P Irion O Beguin F Pregnancy in a patient with treated Wilson’s disease: a case report Am J Obstet Gynecol 1990 6 1527 1528 2240101 \nYuzbasiyan-Gurkan V Grider A Nostrant T Cousins RJ Brewer GJ The treatment of Wilson’s death with zinc; X. intestinal metallothionein induction J Lab Clin Med 1992 6 380 386 1517684 \nCzłonkowska A Gromadzka G Büttner J Chabik G Clinical features of hemolysis, elevated liver enzymes, and low platelet count syndrome in undiagnosed Wilson disease: report of two cases Arch Gynecol Obstet 2010 6 129 134 19381668 \nTheodoridis TD Zepiridis L Athanatos D Dinas K Tzevelekis F Bontis JN Placenta abruption in a woman with Wilson’s disease: a case report Cases J 2009 6 8699 19918395\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1756-0500",
"issue": "6()",
"journal": "BMC research notes",
"keywords": null,
"medline_ta": "BMC Res Notes",
"mesh_terms": "D000328:Adult; D058070:Asymptomatic Diseases; D001921:Brain; D002570:Ceruloplasmin; D003300:Copper; D005260:Female; D006527:Hepatolenticular Degeneration; D006801:Humans; D007247:Infertility, Female; D008099:Liver; D011247:Pregnancy; D012307:Risk Factors; D016896:Treatment Outcome; D019287:Zinc Sulfate",
"nlm_unique_id": "101462768",
"other_id": null,
"pages": "421",
"pmc": null,
"pmid": "24139602",
"pubdate": "2013-10-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14445906;10655259;1171364;3712863;3704107;759736;11384817;866569;2240101;19381668;6020593;1186824;1517684;9761160;19918395;9077636;4101615",
"title": "Wilson's disease in pregnancy: case series and review of literature.",
"title_normalized": "wilson s disease in pregnancy case series and review of literature"
} | [
{
"companynumb": "PHHY2014PK118648",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLDOPA"
},
"drugadditional": null,
"drug... |
{
"abstract": "Mesalazine formulations are essential for treating ulcerative colitis (UC), and intolerance to these formulations complicates the treatment of this condition. Some cases of mesalazine formulation intolerance are caused by the excipients rather than the active ingredient mesalazine. Therefore, mesalazine administration can be continued in such cases by changing the mesalazine formulation. This report describes a case of intolerance to mesalazine in which UC was effectively treated by switching mesalazine formulations. A drug-induced lymphocyte stimulation test suggested that allergy to the additive povidone was the cause of mesalazine formulation intolerance. This is the first case study to identify an additive that caused mesalazine formulation intolerance.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, -41-2 Aoto, Katsushika-ku, Tokyo, 105-8461, Japan. yoshinori.a1@gmail.com.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, -41-2 Aoto, Katsushika-ku, Tokyo, 105-8461, Japan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, -41-2 Aoto, Katsushika-ku, Tokyo, 105-8461, Japan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, -41-2 Aoto, Katsushika-ku, Tokyo, 105-8461, Japan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, -41-2 Aoto, Katsushika-ku, Tokyo, 105-8461, Japan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, -41-2 Aoto, Katsushika-ku, Tokyo, 105-8461, Japan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, -41-2 Aoto, Katsushika-ku, Tokyo, 105-8461, Japan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, -41-2 Aoto, Katsushika-ku, Tokyo, 105-8461, Japan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, -41-2 Aoto, Katsushika-ku, Tokyo, 105-8461, Japan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, -41-2 Aoto, Katsushika-ku, Tokyo, 105-8461, Japan.;Department of Endoscopy, The Jikei University Katsushika Medical Center, Tokyo, Japan.;Department of Endoscopy, The Jikei University Katsushika Medical Center, Tokyo, Japan.;Department of Endoscopy, The Jikei University Katsushika Medical Center, Tokyo, Japan.;Department of Endoscopy, The Jikei University Katsushika Medical Center, Tokyo, Japan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, -41-2 Aoto, Katsushika-ku, Tokyo, 105-8461, Japan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, -41-2 Aoto, Katsushika-ku, Tokyo, 105-8461, Japan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.",
"authors": "Arai|Yoshinori|Y|http://orcid.org/0000-0002-0726-3474;Ogawa|Maiko|M|;Yamane|Fumitsugu|F|;Sumiyoshi|Natsuki|N|;Arimoto|Rikako|R|;Ando|Yoshitaka|Y|;Endo|Daisuke|D|;Nakada|Tatsuya|T|;Sugawara|Ichiro|I|;Yokoyama|Hiroshi|H|;Shimoyama|Keiko|K|;Inomata|Hiroko|H|;Kawahara|Yosuke|Y|;Kato|Masayuki|M|;Arihiro|Seiji|S|;Hokari|Atsushi|A|;Saruta|Masayuki|M|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D005079:Excipients; D019804:Mesalamine",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-020-01216-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "13(6)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Drug-induced lymphocyte stimulation test; Excipient; Mesalazine formulation intolerance; Ulcerative colitis",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D003093:Colitis, Ulcerative; D005079:Excipients; D006801:Humans; D006967:Hypersensitivity; D019804:Mesalamine",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "1200-1204",
"pmc": null,
"pmid": "32880812",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mesalazine formulation intolerance due to suspected excipient allergy in the treatment of ulcerative colitis: a case report.",
"title_normalized": "mesalazine formulation intolerance due to suspected excipient allergy in the treatment of ulcerative colitis a case report"
} | [
{
"companynumb": "JP-MYLANLABS-2021M1057724",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": "1",
... |
{
"abstract": "We sought to investigate whether magnesium oxide bound to soy protein (MGP) increases serum magnesium concentrations with less diarrhea compared to commonly prescribed magnesium salts. Subjects were switched to MGP at a near-equivalent daily elemental magnesium dose. Mean serum magnesium levels were compared. If magnesium levels remained <1.7 mg/dL after switching to MGP, subjects were enrolled into Part 2 and received a one-time MGP dose adjustment. The MGP daily dose was increased by 266 mg. For both parts 1 and 2, subjects recorded the number and quality of their stools to assess gastrointestinal (GI) tolerability of MGP. Twelve pediatric kidney transplant recipients completed Part 1. Mean serum magnesium levels increased from 1.61 (SD 0.1) on standard MG to 1.69 (SD 0.1); t(11) = 2.6, P = .02 on MGP. Five subjects completed Part 2, and all achieved serum magnesium ≥1.7 mg/dL (mean 1.75 mg/dL, SD 0.06; t(4) = 2.7, P = .06). Subjects reported the same number of, but looser bowel movements with MGP; however, individuals did not perceive intolerable GI symptoms with MGP therapy and all chose to remain on MGP at the end of the study. At an equivalent mg/kg/d dose of elemental magnesium, serum magnesium levels on MGP were significantly higher.",
"affiliations": "Department of Pharmacy: Clinical and Administrative Sciences, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.;College of Pharmacy: Office of Instructional Science and Assessment, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.;Department of Nephrology, Phoenix Children's Hospital, Phoenix, AZ, USA.",
"authors": "Lewis|Teresa V|TV|0000-0002-5884-4439;Neely|Stephen|S|;Turman|Martin A|MA|",
"chemical_list": "D015415:Biomarkers; D030262:Soybean Proteins; D008277:Magnesium Oxide; D008274:Magnesium",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13170",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "22(4)",
"journal": "Pediatric transplantation",
"keywords": "calcineurin inhibitors; magnesium; magnesium deficiency",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016030:Kidney Transplantation; D008274:Magnesium; D008275:Magnesium Deficiency; D008277:Magnesium Oxide; D008297:Male; D011183:Postoperative Complications; D030262:Soybean Proteins; D016896:Treatment Outcome",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13170",
"pmc": null,
"pmid": "29582552",
"pubdate": "2018-06",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Efficacy and tolerability of magnesium plus protein for managing hypomagnesemia in pediatric kidney transplant patients.",
"title_normalized": "efficacy and tolerability of magnesium plus protein for managing hypomagnesemia in pediatric kidney transplant patients"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-04892",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "Bilateral quadriceps tendon rupture (BQTR) is a rare diagnosis only reported in about 100 cases in international literature, and is often associated with medical diseases, trauma or certain medications. We present a 64-year-old man with spontaneous BQTR, diagnosed and treated at our hospital. His risk factors were obesity (BMI = 30.95 kg/m2), statin use, and recreational tennis at time of injury. The diagnosis of BQTR is difficult and is often missed initially. There is also emerging thoughts that the use of statins may be a risk factor for BQTR. The evidence, however, is scarce.",
"affiliations": "Wilhelm Johannsens Vej 36, 6200 Aabenraa. lars.l.thomsen@gmail.com.",
"authors": "Thomsen|Lars Lykkeberg|LL|;Laursen|Jens Ole|JO|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin",
"country": "Denmark",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-5782",
"issue": "176(50)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007718:Knee Injuries; D008297:Male; D008875:Middle Aged; D009765:Obesity; D011859:Radiography; D012307:Risk Factors; D012421:Rupture; D019821:Simvastatin; D013708:Tendon Injuries; D013715:Tennis; D014463:Ultrasonography",
"nlm_unique_id": "0141730",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25498184",
"pubdate": "2014-12-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Spontaneous bilateral quadriceps tendon rupture in obese patient medicated with statin.",
"title_normalized": "spontaneous bilateral quadriceps tendon rupture in obese patient medicated with statin"
} | [
{
"companynumb": "DK-ACCORD-063948",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "Complex lymphatic anomalies (CLA) are a group of conditions that pose diagnostic and therapeutic challenges due to their rarity and overlapping clinical findings. This case series describes the complex pathology and novel combination therapies of three patients diagnosed with various types of CLA. A retrospective review of medical records was performed for three patients treated for CLA between 2011 and 2019. Diagnostics, imaging, treatment, and follow-up were reviewed in the electronic medical record and combined with the literature review within the analysis. One patient had involvement of her skull base and ear canals, diagnosed after ear canal abnormalities were detected on computed tomography following meningitis. The second patient had involvement of her posterior ribs and T7-T12 vertebral bodies, with thoracic instability requiring a back brace. The third patient had involvement of his left lower extremity and hemipelvis, necessitating a left above the knee amputation. Case 1 progressed on sirolimus and pamidronate but responded to zoledronic acid (ZA). She developed flares of coagulopathy and cellulitis that required reinforcement with vincristine and steroid pulses. Similarly, case 2 progressed on sirolimus and ZA alone, but achieved stable disease with added vincristine. Upon further disease progression, stabilization was obtained by the reinforcement of ZA. Case 3 required a combination of surgery as well as medical management with sirolimus and pamidronate. All three patients now have stable disease. This case series depicts a multidisciplinary and multiagent approach to the management of CLA with severe bony involvement using sirolimus, bisphosphonates, vincristine, and steroids.",
"affiliations": "Departments of Hematology/Oncology, Pathology, Radiology, University of North Texas Health Science Center, Fort Worth, Texas, USA.;Departments of Hematology/Oncology, Pathology, Radiology, University of North Texas Health Science Center, Fort Worth, Texas, USA.;Departments of Hematology/Oncology, Pathology, Radiology, University of North Texas Health Science Center, Fort Worth, Texas, USA.;Cook Children's Medical Center, Fort Worth, Texas, USA.;Cook Children's Medical Center, Fort Worth, Texas, USA.;Cook Children's Medical Center, Fort Worth, Texas, USA.;Cook Children's Medical Center, Fort Worth, Texas, USA.;Cook Children's Medical Center, Fort Worth, Texas, USA.",
"authors": "Anthony|Megan D|MD|;Swilling|Aubrey|A|;Jiwani|Zahra M|ZM|;Heym|Kenneth|K|;Margraf|Linda R|LR|;Fierke|Shelby|S|;Akers|Lauren J|LJ|;Ray|Anish|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/lrb.2021.0011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1539-6851",
"issue": null,
"journal": "Lymphatic research and biology",
"keywords": "Gorham–Stout disease; bisphosphonate; complex lymphatic anomaly; kaposiform lymphangiomatosis; lymphatic malformation",
"medline_ta": "Lymphat Res Biol",
"mesh_terms": null,
"nlm_unique_id": "101163587",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34435889",
"pubdate": "2021-08-25",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Multidisciplinary Multiagent Treatment of Complex Lymphatic Anomalies with Severe Bone Disease: A Single-Site Experience.",
"title_normalized": "multidisciplinary multiagent treatment of complex lymphatic anomalies with severe bone disease a single site experience"
} | [
{
"companynumb": "US-drreddys-LIT/USA/22/0150842",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "In this study, we describe three patients who each had an electroclinical overlap of two different epileptic encephalopathies (EE), with onset in a certain age period. Patient 1 had electroclinical features compatible with continuous spikes and waves during slow sleep (CSWSS) syndrome that changed into Lennox-Gastaut syndrome (LGS) (symptomatic, cause porencephalic cyst) at the age of 8.5 years. Patient 2 had LGS which evolved into CSWSS at the age of 6 years (symptomatic, cause polymicrogyria). The third patient had cryptogenic CSWSS syndrome at age the age of 7 years which evolved into LGS at the age of 7.5 years. All three patients could be considered to have two EE: CSWSS syndrome and LGS or to have had overlapping features of these epileptic syndromes.",
"affiliations": "Neurology Department, Hospital de Pediatría Prof. Dr. Juan P Garrahan, Buenos Aires, Argentina. rhcaraballo@arnet.com.ar",
"authors": "Caraballo|Roberto Horacio|RH|;Soraru|Alejandra|A|;Cersósimo|Ricardo Oscar|RO|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.eplepsyres.2012.03.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-1211",
"issue": "101(1-2)",
"journal": "Epilepsy research",
"keywords": null,
"medline_ta": "Epilepsy Res",
"mesh_terms": "D000374:Aggression; D001927:Brain Diseases; D020863:Central Nervous System Cysts; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D004569:Electroencephalography; D004827:Epilepsy; D019305:Epilepsy, Rolandic; D004830:Epilepsy, Tonic-Clonic; D020233:Gait Disorders, Neurologic; D006801:Humans; D006948:Hyperkinesis; D008607:Intellectual Disability; D007859:Learning Disabilities; D065768:Lennox Gastaut Syndrome; D008297:Male; D054220:Malformations of Cortical Development; D009069:Movement Disorders; D012640:Seizures; D012890:Sleep; D012893:Sleep Wake Disorders; D013036:Spasms, Infantile",
"nlm_unique_id": "8703089",
"other_id": null,
"pages": "185-90",
"pmc": null,
"pmid": "22483538",
"pubdate": "2012-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Electroclinical overlap of two types of epileptic encephalopathy occurring in the same children in a certain age period?",
"title_normalized": "electroclinical overlap of two types of epileptic encephalopathy occurring in the same children in a certain age period"
} | [
{
"companynumb": "AR-APOTEX-2017AP020481",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nNo study has assessed predictors of physician choice between the succinylcholine (Succ) and rocuronium (Roc) for rapid sequence intubation (RSI) during the initial resuscitation of trauma patients in the emergency department (ED).\n\n\nMETHODS\nWe retrospectively evaluated of the use of Succ and Roc for adult trauma patients undergoing RSI at a Level 1 trauma center. The primary outcome was to identify factors affecting physician choice of paralytic agent for RSI analyzed by cluster analysis using pre-intubation vital signs and early mortality. The secondary outcome was to identify factors influencing physician choice of paralytic agent using a logistic regression model reported as adjusted odds ratios (aOR).\n\n\nRESULTS\nThe analysis included 215 patients, including 148 receiving Succ and 67 receiving Roc. The two groups were similar in regard to age, provider level of training, mean GCS (10 vs. 10) and median ISS (27 vs. 27). Cluster analysis using peri-intubation patient vital signs and early mortality indicates that patients with predominantly abnormal vital signs and early mortality were more likely to receive Roc (74%) than those without abnormal vital signs prior to intubation or early mortality (24%). Hypoxemia prior to RSI (aOR 12.3 [2.5-60.9]) and the use of video laryngoscopy (VL) (aOR 5.5 [1.2-24.6]) were associated with the choice to use Roc.\n\n\nCONCLUSIONS\nRoc was more frequently chosen for paralysis in the patient cluster with predominantly abnormal peri-intubation vital signs and higher rate of early ED mortality. The use of Roc was associated with hypoxemia prior to RSI and VL.",
"affiliations": "Lincoln Medical and Mental Health Center, Department of Emergency Medicine, Weill Cornell Medicine of Cornell University, Bronx, NY, United States. Electronic address: westj3@nychhc.org.;Lincoln Medical and Mental Health Center, Department of Emergency Medicine, Weill Cornell Medicine of Cornell University, Bronx, NY, United States.;Lincoln Medical and Mental Health Center, Department of Emergency Medicine, Weill Cornell Medicine of Cornell University, Bronx, NY, United States.;Lincoln Medical and Mental Health Center, Department of Emergency Medicine, Weill Cornell Medicine of Cornell University, Bronx, NY, United States.;Lincoln Medical and Mental Health Center, Department of Emergency Medicine, Weill Cornell Medicine of Cornell University, Bronx, NY, United States.",
"authors": "West|Jason R|JR|;Lott|Catherine|C|;Donner|Lee|L|;Kanter|Marc|M|;Caputo|Nicholas D|ND|",
"chemical_list": "D009467:Neuromuscular Depolarizing Agents; D013390:Succinylcholine; D000077123:Rocuronium",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2017.11.038",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "36(7)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000328:Adult; D002755:Choice Behavior; D000066491:Clinical Decision-Making; D016000:Cluster Analysis; D004638:Emergency Treatment; D006801:Humans; D000860:Hypoxia; D007442:Intubation, Intratracheal; D009467:Neuromuscular Depolarizing Agents; D010820:Physicians; D010818:Practice Patterns, Physicians'; D012189:Retrospective Studies; D000077123:Rocuronium; D013390:Succinylcholine; D013610:Tachycardia; D014193:Trauma Centers; D014947:Wounds and Injuries",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1151-1154",
"pmc": null,
"pmid": "29162438",
"pubdate": "2018-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Peri-intubation factors affecting emergency physician choice of paralytic agent for rapid sequence intubation of trauma patients.",
"title_normalized": "peri intubation factors affecting emergency physician choice of paralytic agent for rapid sequence intubation of trauma patients"
} | [
{
"companynumb": "US-009507513-1712USA004340",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ROCURONIUM BROMIDE"
},
"drugadditional": "3"... |
{
"abstract": "BACKGROUND\nBenign gynecologic tumor, such as uterine adenomyosis, has been suggested to develop hypercoagulability. Although some cases of cerebral infarction associated with adenomyosis have been reported, the mechanism of hypercoagulation initiated by adenomyosis is still not clear, and the therapeutic strategy is uncertain.\n\n\nMETHODS\nA 44-year-old woman was presented to our department with headache, left hand weakness, and gait disturbance during her menstrual phase. She had a history of adenomyosis and infertility treatment for 18 years and heavy menstrual bleeding. Magnetic resonance imaging on admission showed multiple hyperintense lesions in cortical and subcortical areas in the cerebrum and cerebellum on diffusion-weighted imaging. Transesophageal echocardiography showed neither embolic sources nor existence of foramen ovale. Her laboratory data revealed anemia, a high D-dimer level, and elevated levels of a mucinous tumor marker. She had adenomyosis and no malignancy was detected. Anticoagulation therapy with intravenous heparin followed by rivaroxaban did not prevent recurrence of cerebral infarction. We discontinued rivaroxaban, and started warfarin therapy with pseudomenopause treatment, which prevented recurrence for 6 months. Five months after her last pseudomenopause treatment, multiple cerebral infarctions occurred. Total hysterectomy was performed, which prevented recurrence of the multiple cerebral infarctions for 2 years without anticoagulation therapy.\n\n\nCONCLUSIONS\nOur findings reveal for the first time that anticoagulation therapy, including novel oral anticoagulants, had no preventive effect against cerebral infarctions associated with adenomyosis in a middle-aged woman. Although pseudomenopause treatment temporarily prevented recurrence, resection of the adenomyosis might be the most effective therapy in these cases.",
"affiliations": "Department of Neurology, Faculty of Medicine, Oita University, Yufu-city, Oita, 879-5593, Japan. yasuhiroaso@oita-u.ac.jp.;Department of Neurology, Faculty of Medicine, Oita University, Yufu-city, Oita, 879-5593, Japan.;Department of Neurology, Faculty of Medicine, Oita University, Yufu-city, Oita, 879-5593, Japan.;Department of Neurology, Faculty of Medicine, Oita University, Yufu-city, Oita, 879-5593, Japan.;Department of Neurology, Faculty of Medicine, Oita University, Yufu-city, Oita, 879-5593, Japan.",
"authors": "Aso|Yasuhiro|Y|http://orcid.org/0000-0003-1284-4190;Chikazawa|Ryo|R|;Kimura|Yuki|Y|;Kimura|Noriyuki|N|;Matsubara|Etsuro|E|",
"chemical_list": "D000925:Anticoagulants; D000069552:Rivaroxaban",
"country": "England",
"delete": false,
"doi": "10.1186/s12883-018-1117-1",
"fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 111710.1186/s12883-018-1117-1Case Report“Recurrent multiple cerebral infarctions related to the progression of adenomyosis: a case report” http://orcid.org/0000-0003-1284-4190Aso Yasuhiro yasuhiroaso@oita-u.ac.jp Chikazawa Ryo ryo-san@oita-u.ac.jp Kimura Yuki yuki-n@oita-u.ac.jp Kimura Noriyuki noriyuki@oita-u.ac.jp Matsubara Etsuro etsuro@oita-u.ac.jp 0000 0001 0665 3553grid.412334.3Department of Neurology, Faculty of Medicine, Oita University, Yufu-city, Oita 879-5593 Japan 21 8 2018 21 8 2018 2018 18 11931 8 2017 6 8 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nBenign gynecologic tumor, such as uterine adenomyosis, has been suggested to develop hypercoagulability. Although some cases of cerebral infarction associated with adenomyosis have been reported, the mechanism of hypercoagulation initiated by adenomyosis is still not clear, and the therapeutic strategy is uncertain.\n\nCase presentation\nA 44-year-old woman was presented to our department with headache, left hand weakness, and gait disturbance during her menstrual phase. She had a history of adenomyosis and infertility treatment for 18 years and heavy menstrual bleeding. Magnetic resonance imaging on admission showed multiple hyperintense lesions in cortical and subcortical areas in the cerebrum and cerebellum on diffusion-weighted imaging. Transesophageal echocardiography showed neither embolic sources nor existence of foramen ovale. Her laboratory data revealed anemia, a high D-dimer level, and elevated levels of a mucinous tumor marker. She had adenomyosis and no malignancy was detected. Anticoagulation therapy with intravenous heparin followed by rivaroxaban did not prevent recurrence of cerebral infarction. We discontinued rivaroxaban, and started warfarin therapy with pseudomenopause treatment, which prevented recurrence for 6 months. Five months after her last pseudomenopause treatment, multiple cerebral infarctions occurred. Total hysterectomy was performed, which prevented recurrence of the multiple cerebral infarctions for 2 years without anticoagulation therapy.\n\nConclusions\nOur findings reveal for the first time that anticoagulation therapy, including novel oral anticoagulants, had no preventive effect against cerebral infarctions associated with adenomyosis in a middle-aged woman. Although pseudomenopause treatment temporarily prevented recurrence, resection of the adenomyosis might be the most effective therapy in these cases.\n\nKeywords\nMultiple cerebral infarctionsAdenomyosisHypercoagulagulabilityAnticoagulation therapyissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nUterine adenomyosis is a benign gynecologic condition, defined as the presence of ectopic endometrial glands and stroma surrounded by hyperplastic smooth muscle within the myometrium. Approximately 20% of women attending a general gynecologic clinic were revealed to have adenomyosis [1]. Although common symptoms are menorrhagia, dysmenorrhea, and heavy menstrual bleeding, one-third of women are asymptomatic [2].\n\nSome patients with adenomyosis develop multiple cerebral infarctions (CIs) [3–5] (Table 1). Almost all patients are middle-aged, with severe anemia and elevated serum carbohydrate antigen 125 (CA125). These patients are initially administered conventional anticoagulant therapy, which is often combined with gonadotropin-releasing hormone (GnRH) therapy, and in some cases the adenomyosis is subsequently resected.Table 1 Patient characteristics and therapy for CI associated with adenomyosis\n\nCase\tAge (y.o.)\tD-dimer (μg/ml)\tFDP (μg/ml)\tCA125 (U/ml)\themoglobin (g/dl)\ttreatment for CI\ttreatment for adenomyosis\trecurrence of CI\treference\t\ninitial treatment\tsubsequent treatment\t\n1\t45\t1.1\t–\t159\t8.4\thepalin\tantipletelet therapy\tGnRH agonist\t–\tYamashiro K et al. 2012\t\n2\t44\t–\t5.9\t–\t7\thepalin\twarfalin\tGnRH agonist\t–\t\n3\t50\t0.57\t–\t42.6\t6.9\taspirin\t–\tGnRH agonist\t–\t\n4\t42\t6.0\t–\t1750\t8.6\tantiplatelet therapy\twarfalin\tGnRH agonist\t+\t\n5\t59\t7.0\t–\t334.8\t–\tantithrombotic therapy\t–\t–\t–\tHijikata N et al. 2016\t\n\n\nHere, we report the case of a middle-aged woman with adenomyosis who developed multiple CIs in her menstrual phase. Although she received edaravone and anticoagulation treatment with rivaroxaban, the recurrence of multiple CIs was not prevented. Pseudomenopause therapy with a GnRH agonist normalized her hypercoagulation state, but multiple CIs occurred after therapy was discontinued. Finally, a hysterectomy was performed, which successfully prevented CI recurrence. We propose that treatment of CIs due to adenomyosis with anticoagulant therapy is not effective, and briefly discuss the underlying etiology and therapeutic strategy.\n\nCase presentation\nA 44-year-old woman experienced sudden onset of difficulty using her left hand and walking during her menstrual phase. She had a history of adenomyosis and infertility treatment for 18 years, and heavy menstrual bleeding. She complained of headache, abdominal pain, nausea, and had a fever (37.7 °C) at presentation. She is not obese (BMI of 21.5 kg/m2), had no history of taking steroids or contraceptives. Neurologic examination revealed left spatial neglect, left facial hypoalgesia, mild paresis in her left arm, and right pyramidal signs. Brain magnetic resonance imaging (MRI) revealed bilaterally multiple infarctions in the cerebrum and cerebellum, including cortical and subcortical lesions (Fig. 1a). MR angiography presented severe stenosis in the M2, M3, >and M4 portions of right middle cerebral artery (Fig. 1b). Contrast computed tomography revealed a splenic infarction (Fig. 1c). Blood examination revealed normocytic anemia (hemoglobin 10.3 g/dl, mean corpuscular volume 90.5 μm3), thrombocytopenia (112,000 /μl), and low-grade elevation of C-reactive protein (2.9 mg/dl). The serum levels of D-dimer (17.0 μg/ml, normal < 0.5 μg/ml), CA125 (2115 U/ml, normal < 35.0 U/ml), and carbohydrate antigen 19–9 (CA19–9) (1824 U/ml, normal < 37.0 U/ml) were increased. Results of a hypercoagulable panel, including protein C and S, antithrombin Ш level, lupus anticoagulant, and anticardiolipin antibody titers, were within normal limits. Pelvic MRI revealed giant adenomyosis (Fig. 1d), but no malignancy was detected. Fluorine-18–2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography revealed FDG accumulation in the adenomyosis, but no malignancy was detected by cervical cytology. The result of continuous electrocardiography monitoring, transesophageal echocardiography with agitated saline injection, carotid ultrasonography, upper gastrointestinal endoscopy, and colonoscopy were normal.Fig. 1 Diffusion-weighted magnetic resonance imaging (MRI) scan of the brain reveals multiple infarctions in the cerebellum and cerebrum (a). The M2, M3, and M4 portions of the right middle cerebral artery were not well visualized by MR angiography (b). Contrast computed tomography revealed splenic infarction (c). Giant adenomyosis was revealed by a T2-weighted MRI scan of the pelvis (d)\n\n\n\nShe was treated with edaravone (60 mg/day) and anticoagulated with heparin for 2 weeks. Subsequently, she was treated with rivaroxaban (15 mg/day). Her serum levels of D-dimer, CA125, and CA19–9 improved (2.7 μg/ml, 911 U/ml, and 501 U/ml, respectively), and the treatment was continued.\n\nAt day 31, a day after her menstrual phase started, she complained of numbness in her left lower limb. Brain MRI revealed a new CI in the right cerebrum (Fig. 2a). The serum levels of D-dimer, CA125, CA19–9 were 2.4 μg/ml, 561 U/ml, 417 U/ml, respectively. We discontinued the rivaroxaban treatment, and started anticoagulant therapy with warfarin. Afterwards, her menstrual bleeding increased, the anemia progressed, and the serum level of D-dimer increased (14.1 μg/ml). She started to receive pseudomenopause treatment with a GnRH agonist for the adenomyosis. Ten days after initiating the GnRH agonist treatment, her serum D-dimer level improved (2.30 μg/ml). She continued the warfarin and GnRH agonist once a month for 6 months, and showed no recurrence of CIs during that time. The serum levels of CA125, CA19–9 improved after 3 months of initiating the therapy (117 U/ml, 224 U/ml, respectively).Fig. 2 Diffusion-weighted MRI revealed CIs in the right cerebrum (a). Multiple cortical and subcortical CIs in the left occipital lobe and right parietal lobe (b)\n\n\n\nShe presented with transient weakness of her right lower limb and visited our clinic 5 months after her last GnRH agonist therapy, when her irregular menstrual bleeding had continued for a month. Brain MRI revealed new multiple cortical and subcortical infarctions in the left occipital lobe and right parietal lobe (Fig. 2b). Her serum D-dimer, FDP, CA125, and CA19–9 levels were elevated (22.0 μg/ml, 56.5 μg/ml, 1291.6 U/ml, and 803.2 U/ml, respectively). Anticoagulant therapy with warfarin was well controlled (PT-INR 2.5), and her electrocardiographic findings were normal. We concluded that total hysterectomy would be the most effective therapy for preventing CI recurrence. She underwent total hysterectomy and bilateral salpingo-oophorectomy, which was effective in not only preventing CI recurrence, but also for normalizing the serum D-dimer, FDP, CA125, and CA19–9 levels for the last 2 years.\n\nDiscussion and conclusions\nHere we report a 44-year-old woman who developed multiple CIs after her menstrual phase, when the serum D-dimer, CA125, and CA19–9 levels were markedly elevated. Neither warfarin nor novel oral anticoagulants (NOAC) prevented CI recurrence. Although GnRH agonist therapy improved the levels of the three markers and prevented CI recurrence, the CIs recurred after the therapy was discontinued. Hysterectomy finally normalized the serum levels of the markers, and prevented CI recurrence. To our knowledge, this is the first report of an attempt to use NOAC to prevent recurrence of CI associated with adenomyosis. The clinical course of this case suggests that anticoagulation therapy is not sufficient to prevent blood hypercoagulation associated with adenomyosis, and thus resection may be the most effective therapy to normalize hypercoagulation and prevent the recurrence of thrombotic events.\n\nAlthough reports of CI associated with adenomyosis are rare, some similar cases were reported. Yamashiro et al. [3] reported four cases of CI associated with adenomyosis in middle-aged women. Two of the women developed CIs in their menstrual phase. All of them presented with severe anemia (hemoglobin levels 6.9–8.6 g/dl). The D-dimer levels were elevated in two cases (1.1 μg/ml and 6.0 μg/ml), and CA125 was elevated in three cases (159 U/ml, 42.6 U/ml, and 1750 U/ml). All four cases were treated with antiplatelet medicine or an anticoagulant with a GnRH agonist. One case experienced recurrent multiple CIs after discontinuation of the therapy, when the levels of D-dimer and CA125 again increased (4.1 μg/ml and 907 U/ml, respectively). Subsequently, she was treated with anticoagulant therapy and a GnRH agonist, and the D-dimer and CA125 levels normalized. These authors suggested that hypercoagulability in association with an elevated CA125 level, menstruation-related coagulopathy, or increased tissue factor (TF) expression level is a potential risk factor for developing CI. Hijikata et al. [5] reported 59-year-old woman with a 10-year history of hormone replacement therapy for menopausal symptoms who developed multiple CIs. Her laboratory tests revealed elevated CA125 (334.8 U/ml) and D-dimer (7.0 μg/ml) levels. Anticoagulant therapy with unfractionated heparin was started and the hormone therapy was discontinued. Although antithrombotic therapy was discontinued on day 7 because of withdrawal bleeding, the D-dimer and CA125 levels normalized. The authors concluded that both elevated CA125 levels and hormone replacement therapy are risk factors for hypercoagulability [5].\n\nThe mechanism of hypercoagulation initiated by adenomyosis remains uncertain. Several clinical studies reported an association of elevated serum CA125 and CA19–9 levels, and hypercoagulability [3–9]. CA125 is a typical mucin molecule [10], widely utilized for the diagnosis of epithelial ovarian cancer [11]. CA19–9 is a mucin-like high-molecular-weight glycoprotein utilized for the diagnosis of malignancies of the stomach, colon, and pancreas [12], and was recently reported to be associated with thrombosis in pancreatic adenocarcinoma [9]. These cancer-related-mucin molecules are suggested to play an important role in the hypercoagulative state in Trousseau’s syndrome [13]. In our case, the levels of CA125 and CA19–9 were considerably high. We suppose that the high levels of these markers induced the recurrence of multiple cerebral infarctions in our case. A recent experimental study revealed that carcinoma mucin promotes thrombosis through adhesion-dependent, bidirectional signaling in neutrophils and platelets [14]. This mechanism may explain why the hypercoagulation in our case was not prevented by warfarin or NOAC.\n\nIn Trousseau’s syndrome, induction of TF and its activity is postulated to promote hypercoagulability in patients with cancer [15, 16]. Expression of TF is also significantly higher in adenomyotic lesions [17], and it renders microparticles procoagulant. Increased release of TF-exposing microparticles is suggested to contribute to the development of thrombotic complications [18]. This pathology might play an important role in multiple thromboses induced by adenomyosis.\n\nAnemia is also a suspected cardiovascular factor [19, 20]. Anemia is considered a hyperkinetic state, and it disturbs endothelial adhesion molecule genes, which may lead to thrombus formation. In addition, anemia causes blood flow augmentation and turbulence, which may result in the migration of a thrombus, thus producing artery-to-artery embolism.\n\nIn conclusion, our findings suggest that middle-aged women with adenomyosis are at high risk for CI when the serum D-dimer, CA125, and CA19–9 levels are elevated. In those patients, anticoagulant therapy including NOAC therapy could not prevent CI. Adenomyosis resection may be the most effective therapy for preventing CI in these cases.\n\nAbbreviations\nCA125carbohydrate antigen 125\n\nCA19–9carbohydrate antigen 19–9\n\nCIcerebral infarction\n\nFDGFluorine-18–2-fluoro-2-deoxy-d-glucose\n\nGnRHgonadotropin-releasing hormone\n\nMRImagnetic resonance imaging\n\nNOACnovel oral anticoagulants\n\nTFtissue factor\n\nThe authors would like to acknowledge the following: Prof. Teruyuki Hirano at Kyorin University School of Medicine, Japan. The staff of Obstetrics and Gynecology, Oita University Faculty of Medicine, Japan.\n\nAvailability of data and materials\nAll data related to this case report are contained within the manuscript.\n\nAuthors’ contributions\nYA, RC and YK examined and managed the patient; YA drafted the manuscript and created the figs; NK helped and revised the manuscript; EM revised the final approval of the version to be published. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Naftalin J Hoo W Pateman K How common is adenomyosis? A prospective study of prevalence using transvaginal ultrasound in a gynaecology clinic Hum Reprod 2012 27 3432 3439 10.1093/humrep/des332 23001775 \n2. Azziz R Adenomyosis: current perspectives Obstet Gynecol Clin N Am 1989 16 221 235 \n3. Yamashiro K Tanaka R Nishioka K Cerebral infarcts associated with adenomyosis among middle-aged women J Stroke Cerebrovasc Dis 2005 21 910 \n4. Yamashiro K Furuya T Noda K Cerebral infarction developing in a patient without cancer with a markedly elevated level of mucinous tumor marker J Stroke Cerebrovasc Dis 2012 21 619 21277226 \n5. Hijikata N Sakamoto Y Nito C Multiple cerebral infarctions in a patient with adenomyosis on hormone replacement therapy: a case report J Stroke Cerebrovasc Dis 2016 25 e183 e184 10.1016/j.jstrokecerebrovasdis.2016.07.024 27520610 \n6. Nishioka K Tanaka R Tsutsumi S Cerebral dural sinus thrombosis associated with adenomyosis: a case report J Stroke Cerebrovasc Dis 2014 23 1985 1987 10.1016/j.jstrokecerebrovasdis.2014.01.027 24794947 \n7. Jovin TG Boosupalli V Zivkovic SA High titers of CA-125 may be associated with recurrent ischemic strokes in patients with cancer Neurology 2005 64 1944 1945 10.1212/01.WNL.0000163850.07976.63 15955949 \n8. Tas F Killic L Bilgin E Clinical and prognostic significance of coagulation assays in advanced epithelial ovarian cancer Int J Gynecol Cancer 2013 23 276 281 10.1097/IGC.0b013e31827b8796 23266651 \n9. Woei-A-Jin FJ Tesselaar ME Garcia Rodriguez P Tissue factor-bearing microparticles and CA19.9: two players in pancreatic cancer-associated thrombosis? Br J Cancer 2016 115 332 338 10.1038/bjc.2016.170 27404454 \n10. Bast RC Jr Feeney M Lazarus H Reactivity of a monoclonal antibody with human ovarian carcinoma J Clin Invest 1981 68 1331 1337 10.1172/JCI110380 7028788 \n11. Maggino T Gadducci A Serum markers as prognostic factors in epithelial ovarian cancer: an overview Eur J Gynaecol Oncol 2000 21 64 69 10726623 \n12. Lan MS Bast RC Jr Colnaghi MI Co-expression of human cancer-associated epitopes on mucin molecules Int J Cancer 1987 39 68 72 10.1002/ijc.2910390112 2432019 \n13. Varki A Trousseau's syndrome: multiple definitions and multiple mechanisms Blood 2007 110 1723 1729 10.1182/blood-2006-10-053736 17496204 \n14. Shao B Wahrenbrock MG Yao L Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of trousseau syndrome Blood 2011 118 4015 4023 10.1182/blood-2011-07-368514 21860019 \n15. Rickles FR Mechanisms of cancer-induced thrombosis in cancer Pathophysiol Haemost Thromb 2006 35 103 110 10.1159/000093551 16855354 \n16. Rak J Milsom C May L Klement P Tissue factor in cancer and angiogenesis: the molecular link between genetic tumor progression, tumor neovascularization, and cancer coagulopathy Semin Thromb Hemost 2006 32 54 70 10.1055/s-2006-933341 16479463 \n17. Li B Chen M Liu X Constitutive and tumor necrosis factor-α-induced activation of nuclear factor-κB in adenomyosis and its inhibition by andrographolide Fertil Steril 2013 100 568 577 10.1016/j.fertnstert.2013.04.028 23706331 \n18. Van Es N Bleker S Sturk A Clinical significance of tissue factor-exposing microparticles in arterial and venous thrombosis Semin Thromb Hemost 2015 41 718 727 10.1055/s-0035-1556047 26408926 \n19. Kaiafa G Savopoulos C Kanellos I Anemia and stroke: where do we stand? Acta Neurol Scand 2017 135 596 602 10.1111/ane.12657 27480069 \n20. Kannel WB Gordon T Wolf PA Hemoglobin and the risk of cerebral infarction: the Framingham study Stroke 1972 3 4 409 420 10.1161/01.STR.3.4.409 4261794\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2377",
"issue": "18(1)",
"journal": "BMC neurology",
"keywords": "Adenomyosis; Anticoagulation therapy; Hypercoagulagulability; Multiple cerebral infarctions",
"medline_ta": "BMC Neurol",
"mesh_terms": "D062788:Adenomyosis; D000328:Adult; D000925:Anticoagulants; D002544:Cerebral Infarction; D005260:Female; D006801:Humans; D007044:Hysterectomy; D000069552:Rivaroxaban",
"nlm_unique_id": "100968555",
"other_id": null,
"pages": "119",
"pmc": null,
"pmid": "30129425",
"pubdate": "2018-08-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26408926;23266651;15955949;22142777;27480069;21860019;17496204;23706331;16479463;27404454;16855354;2664619;21277226;23001775;27520610;7028788;4261794;10726623;2432019;24794947",
"title": "\"Recurrent multiple cerebral infarctions related to the progression of adenomyosis: a case report\".",
"title_normalized": "recurrent multiple cerebral infarctions related to the progression of adenomyosis a case report"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1066422",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": null,
... |
{
"abstract": "Ophthalmologists have a role in assessing immune-related adverse events (IRAE) in oncology patients on immunotherapy. We assessed the utility of a hospital-wide toxicity team in referring patients with new ocular symptoms for examination. We also identified new immunotherapy agents causing ocular side-effects.\nA cohort study of eight consecutive patients on immunotherapy, who developed ocular IRAE from November 1, 2017 to June 30, 2019. All were seen at the Ocular Immunology Division of the Wilmer Eye Institute and referred by the Johns Hopkins Toxicity Team.\nAll eight patients on had IRAEs; were treated with corticosteroid drops or observation with clinical resolution. Two new agents, epocadostat and daratumumab, were associated with the development of uveitis.\nOphthalmologists play an important role in a hospital-wide toxicity team and need to include IRAEs in their differential diagnosis. Given new drug development, ophthalmologists may be the first to identify IRAEs.",
"affiliations": "Ocular Immunology Division, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Ocular Immunology Division, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Ocular Immunology Division, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.",
"authors": "Parikh|Ruby A|RA|;Chaon|Benjamin C|BC|;Berkenstock|Meghan K|MK|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2020.1766082",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": null,
"journal": "Ocular immunology and inflammation",
"keywords": "Uveitis; drug toxicity; immunotherapy; multidisciplinary coordination of care; ocular adverse events",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": null,
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "32643982",
"pubdate": "2020-07-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ocular Complications of Checkpoint Inhibitors and Immunotherapeutic Agents: A Case Series.",
"title_normalized": "ocular complications of checkpoint inhibitors and immunotherapeutic agents a case series"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-126782",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.