article dict | reports listlengths 1 3.97k |
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{
"abstract": "Rituximab, a chimeric monoclonal antibody, produces response rates of up to 73% in patients with previously untreated indolent non-Hodgkin's lymphoma (NHL), and has high activity when combined with chemotherapy. The purpose of this phase II study was to determine the efficacy and safety of rituximab plus cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) chemotherapy in patients with indolent NHL. In all, 42 patients (median age 67 years) with previously untreated follicular, marginal zone or small lymphocytic/lymphoplasmacytic NHL received six infusions of rituximab (375 mg/m(2)) in combination with six cycles of CNOP. The overall response rate was 90% comprising 30 complete (71%) and eight partial (19%) responses. Although patients with marginal zone lymphoma or International Prognostic Index (IPI) score 3 had lower complete response rates, no significant difference in overall response rate was observed between the histological groups (P=0.24) or between patients stratified according to IPI score (P>0.05). Median overall survival, time-to-progression and response duration had not been reached after a median 19.5-month follow-up. In all, 31 patients (74%) are currently free from progression and 38 (90%) remain alive. Treatment was well tolerated. One patient (2%) experienced grade 3/4 infusion-related toxicity; 13 (31%) grade 3/4 leukopenia and 18 (43%) grade 3/4 neutropenia. Infection was observed in nine patients: eight (19%) grade 1/2 and one (2.4%) grade 3. This study demonstrates that combining rituximab with CNOP achieves high remission rates without significant additional toxicity in patients with previously untreated indolent NHL. Further follow-up will determine response duration and survival.",
"affiliations": "Second Department of Internal Medicine-Propaedeutic, Athens University, Evangelismos Hospital, Athens, Greece. economopoulosth@ath.forthnet.gr",
"authors": "Economopoulos|Theofanis|T|;Fountzilas|George|G|;Pavlidis|Nicholas|N|;Kalantzis|Dimitris|D|;Papageorgiou|Efstathios|E|;Christodoulou|Christos|C|;Hamilos|George|G|;Nicolaides|Costas|C|;Dimopoulos|Meletios|M|",
"chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D014750:Vincristine; D003520:Cyclophosphamide; D011239:Prednisolone; D008942:Mitoxantrone",
"country": "England",
"delete": false,
"doi": "10.1038/sj.thj.6200229",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1466-4860",
"issue": "4(2)",
"journal": "The hematology journal : the official journal of the European Haematology Association",
"keywords": null,
"medline_ta": "Hematol J",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone; D011239:Prednisolone; D012074:Remission Induction; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "100965523",
"other_id": null,
"pages": "110-5",
"pmc": null,
"pmid": "12750729",
"pubdate": "2003",
"publication_types": "D016430:Clinical Trial; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Rituximab in combination with CNOP chemotherapy in patients with previously untreated indolent non-Hodgkin's lymphoma.",
"title_normalized": "rituximab in combination with cnop chemotherapy in patients with previously untreated indolent non hodgkin s lymphoma"
} | [
{
"companynumb": "GR-ROCHE-1846079",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nA small number of reports have described subarachnoid hemorrhage resulting from a ruptured aneurysm embedded within a prolactinoma. To the best of our knowledge, no reports have described an embedded carotid cavernous fistula. We report a patient with carotid cavernous fistula secondary to a ruptured internal carotid artery aneurysm embedded within a prolactinoma.\n\n\nMETHODS\nA 61-year-old woman was referred to our hospital with sudden headache, vomiting, and dizziness. Magnetic resonance imaging demonstrated a small acute subdural hematoma, recurrent prolactinoma, and left cavernous carotid aneurysm. Conservative therapy was initiated. Her serum prolactin level at hospitalization was 11,300 μg/L; therefore, we initiated cabergoline therapy. Twenty days after cabergoline administration, she suddenly presented with left conjunctival injection and pulsatile tinnitus. Angiography showed a left direct carotid cavernous fistula with a connection between the cavernous internal carotid artery and the cavernous sinus via the aneurysm and venous congestion. To prevent hemorrhagic stroke, we scheduled staged surgery. First, we urgently performed embolization of the cavernous sinus and fistula. One month later, to prevent aneurysm rerupture, we performed a radical operation with superficial temporal artery-middle cerebral artery double anastomosis with proximal occlusion of the left internal carotid artery at the cervical portion. The patient was discharged 2 weeks after surgery without neurological deficits. Follow-up angiography revealed complete occlusion of the aneurysm 2 months postoperatively.\n\n\nCONCLUSIONS\nAn aneurysm embedded within a prolactinoma should be closely observed when cabergoline administration is started.",
"affiliations": "Department of Neurosurgery, Kita-harima Medical Center, Ono, Hyogo, Japan. Electronic address: nakkfm@gmail.com.;Department of Neurosurgery, Kita-harima Medical Center, Ono, Hyogo, Japan; Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.;Department of Neurosurgery, Kita-harima Medical Center, Ono, Hyogo, Japan.;Department of Neurosurgery, Kita-harima Medical Center, Ono, Hyogo, Japan.;Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.;Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.",
"authors": "Nakahara|Masahiro|M|;Uozumi|Yoichi|Y|;Chiba|Yoshiyuki|Y|;Miyake|Shigeru|S|;Fujita|Atsushi|A|;Kohmura|Eiji|E|",
"chemical_list": "D000077465:Cabergoline",
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2018.11.071",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "122()",
"journal": "World neurosurgery",
"keywords": "Acute subdural hematoma; Carotid cavernous fistula; Cavernous carotid aneurysm; Direct surgery; Endovascular treatment; Prolactinoma",
"medline_ta": "World Neurosurg",
"mesh_terms": "D017542:Aneurysm, Ruptured; D000077465:Cabergoline; D002343:Carotid Artery, Internal; D002533:Cerebral Angiography; D004621:Embolization, Therapeutic; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D008875:Middle Aged; D015175:Prolactinoma; D016896:Treatment Outcome",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "495-499",
"pmc": null,
"pmid": "30465960",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Direct Carotid Cavernous Fistula Due to Rupture of a Cavernous Carotid Aneurysm Embedded Within a Prolactinoma After Cabergoline Administration.",
"title_normalized": "direct carotid cavernous fistula due to rupture of a cavernous carotid aneurysm embedded within a prolactinoma after cabergoline administration"
} | [
{
"companynumb": "JP-IMPAX LABORATORIES, LLC-2018-IPXL-04393",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CABERGOLINE"
},
"drugadditio... |
{
"abstract": "Calcineurin inhibitor (CNI) combined with mycophenolate mofetil (MMF) and steroid is mainly used as immunosuppressive therapy after the living-donor liver transplantation (LDLT). However, the nephrotoxicity caused by CNI remains a critical problem for patients with chronic renal failure, especially on early postoperative period. A 62-year-old woman with decompensated liver cirrhosis secondary to hepatitis B (Child-Pugh C, MELD score 11 points) and chronic renal failure due to diabetic nephropathy (Cr 1.56 mg/dl, GFR 27 ml/min/1.73 m2) experienced LDLT. During the reconstruction of hepatic vein, the supra-and infra-hepatic vena cava was totally clamped. The estimated right lobe liver graft volume was 540 g, representing 51.3% of the standard liver volume of the recipient. Because of the perioperative renal dysfunction due to diabetic nephropathy and the total clamping the vena cava which induced the congestion kidney, MMF (1500 mg/day) and steroid (250 mg/day converted into predonisolone) were mainly introduced as an immunosuppressive therapy after LDLT. The low-dose CNI, tacrolimus also induced the nephrotoxicity and was given for only a short time. Finally, according to the postoperative renal function, the low-dose CNI, cyclosporin (50 mg/day) was able to be added to the introduced immunosuppressive therapy. After having left the hospital, MMF (1500 mg/day), steroid (20 mg/day converted into predonisolone) and cyclosporin (75 mg/day) continued to be given as the immunosuppressive therapy and neither acute graft rejection nor drug-induced renal dysfunction was occurred. This is a case report of introducing with mainly MMF and steroid as an immunosuppressive therapy after LDLT for a patient with perioperative renal dysfunction.",
"affiliations": null,
"authors": "Kuramitsu|Shotaro|S|;Iguchi|Tomohiro|T|;Ninomiya|Mizuki|M|;Yamashita|Yo-ichi|Y|;Harimoto|Norifumi|N|;Ikegami|Toru|T|;Uchiyama|Hideaki|H|;Yoshizumi|Tomoharu|T|;Soejima|Yuji|Y|;Shirabe|Ken|K|;Kawanaka|Hirofumi|H|;Ikeda|Tetsuo|T|;Furuta|Toshiya|T|;Tamada|Ryuichiro|R|;Maehara|Yoshihiko|Y|",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011239:Prednisolone; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-254X",
"issue": "105(3)",
"journal": "Fukuoka igaku zasshi = Hukuoka acta medica",
"keywords": null,
"medline_ta": "Fukuoka Igaku Zasshi",
"mesh_terms": "D016572:Cyclosporine; D003928:Diabetic Nephropathies; D005260:Female; D006509:Hepatitis B; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D008103:Liver Cirrhosis; D016031:Liver Transplantation; D019520:Living Donors; D008875:Middle Aged; D009173:Mycophenolic Acid; D011239:Prednisolone; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "9423321",
"other_id": null,
"pages": "79-83",
"pmc": null,
"pmid": "25000660",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case report of introducing MMF and steroids as an immunosuppressive therapy after living-donor liver transplantation for a patient with the diabetic nephropathy.",
"title_normalized": "case report of introducing mmf and steroids as an immunosuppressive therapy after living donor liver transplantation for a patient with the diabetic nephropathy"
} | [
{
"companynumb": "JP-WATSON-2014-20294",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"... |
{
"abstract": "Lenvatinib is approved as a standard systemic therapy for unresectable hepatocellular carcinoma (HCC) patients; however, experience with lenvatinib in clinical practice is insufficient. We present the case of a patient with advanced HCC whose prothrombin time - international normalized ratio (PT-INR) was elevated after cotreatment with lenvatinib and warfarin potassium. The patient was a 26-year-old man with congenital abnormalities who had to take warfarin potassium because he had a mechanical heart valve. He was diagnosed with unresectable HCC at 24 years old and was treated by transcatheter arterial chemoembolization and transcatheter arterial infusion. After some interventional radiology treatments, lenvatinib was started. After 4 days of treatment with lenvatinib and warfarin potassium, his PT-INR increased to 4.13, and the treatment had to be stopped. No changes were observed in other Child-Pugh score factors. The elevation in the PT-INR after cotreatment with lenvatinib and warfarin potassium was thought to be caused by pharmacological effects of concurrent use or pharmacological sensitivity to warfarin potassium in this patient with liver dysfunction. The PT-INR must be monitored when lenvatinib is given to advanced HCC patients taking warfarin potassium.",
"affiliations": "Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.",
"authors": "Sasaki|Yoichi|Y|;Sakamori|Ryotaro|R|https://orcid.org/0000-0002-1580-607X;Yamada|Ryoko|R|;Shigekawa|Minoru|M|;Tahata|Yuki|Y|;Makino|Yuki|Y|;Nakabori|Tasuku|T|;Kodama|Takahiro|T|;Hikita|Hayato|H|https://orcid.org/0000-0003-2488-7315;Tatsumi|Tomohide|T|;Takehara|Tetsuo|T|https://orcid.org/0000-0001-5036-3457",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1111/hepr.13379",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6346",
"issue": "49(11)",
"journal": "Hepatology research : the official journal of the Japan Society of Hepatology",
"keywords": "hepatocellular carcinoma; lenvatinib; prothrombin time; warfarin potassium",
"medline_ta": "Hepatol Res",
"mesh_terms": null,
"nlm_unique_id": "9711801",
"other_id": null,
"pages": "1357-1361",
"pmc": null,
"pmid": "31119866",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cotreatment with lenvatinib and warfarin potassium caused prothrombin time prolongation.",
"title_normalized": "cotreatment with lenvatinib and warfarin potassium caused prothrombin time prolongation"
} | [
{
"companynumb": "JP-TEVA-2020-JP-1171169",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LENVATINIB"
},
"drugadditional": null,
... |
{
"abstract": "The present study is a review of a cardiometabolic clinic for consumers taking clozapine. This clinic was recently established and co-located with the clozapine clinic at a regional hospital in New South Wales, Australia, to enhance engagement and improve the physical health outcomes of consumers taking antipsychotic medication. A descriptive analysis of clients' (n = 73) information collected during routine care for the first 6 months of the clinic's operation, from January 2016 to July 2016, was conducted. First-visit data were analysed to establish a client profile, consisting of weight, height, blood pressure, pulse, a range of blood measurements, smoking status, alcohol consumption, and eating and exercise habits. Data collected for clients who had three or more visits with the general practitioner (n = 40) were analysed separately for outcomes. Two case studies are used to depict the service received and client profile. At the first appointment, the majority of clients had metabolic syndrome that was mostly left untreated; many of these clients were commenced on metformin. The outcomes are positive, and show that the majority of clients lost weight (82.5%) and had a reduction in body mass index (84.6%); nearly half (44.4%) had a reduction in waist circumference. The majority of clients self-reported increased physical activity (72.5%, n = 29) and positive dietary changes (77.5%, n = 31) since their first appointment. The model trialled by the cardiometabolic clinic integrated a specialist mental health and primary care service, and demonstrates success in engaging clients with severe mental illness in physical health care. Co-location is conceptualized as critical for positive patient outcomes and high levels of engagement.",
"affiliations": "Central Coast Local Health District, Central Coast Mental Health, Gosford, New South Wales, Australia.;Central Coast Local Health District, Central Coast Mental Health, Gosford, New South Wales, Australia.;Central Coast Local Health District, Central Coast Mental Health, Gosford, New South Wales, Australia.;Central Coast Local Health District, Central Coast Mental Health, Gosford, New South Wales, Australia.",
"authors": "Coates|Dominiek|D|;Woodford|Patricia|P|;Higgins|Oliver|O|;Grover|Deborah|D|",
"chemical_list": "D011619:Psychotropic Drugs; D003024:Clozapine",
"country": "Australia",
"delete": false,
"doi": "10.1111/inm.12321",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1445-8330",
"issue": "27(1)",
"journal": "International journal of mental health nursing",
"keywords": "antipsychotic medication; clozapine; metabolic syndrome",
"medline_ta": "Int J Ment Health Nurs",
"mesh_terms": "D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases; D003024:Clozapine; D005260:Female; D058005:General Practitioners; D006304:Health Status; D006801:Humans; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D009517:New South Wales; D015397:Program Evaluation; D011619:Psychotropic Drugs; D040242:Risk Reduction Behavior; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101140527",
"other_id": null,
"pages": "303-310",
"pmc": null,
"pmid": "28233407",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of a general practitioner-led cardiometabolic clinic: Physical health profile and treatment outcomes for clients on clozapine.",
"title_normalized": "evaluation of a general practitioner led cardiometabolic clinic physical health profile and treatment outcomes for clients on clozapine"
} | [
{
"companynumb": "AU-MYLANLABS-2018M1067301",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": "3",
... |
{
"abstract": "A 63-year-old man with rheumatoid arthritis presented with pain and swelling of his right buttock. Imaging and tissue biopsy revealed a diffuse large B-cell, non-Hodgkin's lymphoma. The disease-modifying drugs he was taking, cyclosporin and methotrexate, were stopped, and the lymphoma resolved spontaneously without the use of chemotherapy.",
"affiliations": "Department of Rheumatology, Royal North Shore Hospital, St Leonards, NSW, Australia.",
"authors": "Lim|Irwin G S|IG|;Bertouch|James V|JV|",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine; D008727:Methotrexate",
"country": "Australia",
"delete": false,
"doi": "10.5694/j.1326-5377.2002.tb04919.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-729X",
"issue": "177(9)",
"journal": "The Medical journal of Australia",
"keywords": null,
"medline_ta": "Med J Aust",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D002081:Buttocks; D016572:Cyclosporine; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents; D016393:Lymphoma, B-Cell; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D019042:Muscle Neoplasms; D018482:Muscle, Skeletal; D012075:Remission, Spontaneous",
"nlm_unique_id": "0400714",
"other_id": null,
"pages": "500-1",
"pmc": null,
"pmid": "12405893",
"pubdate": "2002-11-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Remission of lymphoma after drug withdrawal in rheumatoid arthritis.",
"title_normalized": "remission of lymphoma after drug withdrawal in rheumatoid arthritis"
} | [
{
"companynumb": "AU-CONCORDIA PHARMACEUTICALS INC.-GSH201802-000585",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"d... |
{
"abstract": "OBJECTIVE\nTumor necrosis factor a is one of the principal cytokines involved in the pathogenesis of acute graft-versus-host-disease (GVHD). Infliximab is an antibody to this cytokine.\n\n\nMETHODS\nWe performed a retrospective analysis to evaluate the activity of infliximab in 32 patients with severe steroid-refractory acute GVHD. The patients received a median of 3 weekly courses of infliximab. The main organs involved in the patients were skin (n=2) liver (n=1), bowel (n=19), liver and bowel at the same stage (n=10).\n\n\nRESULTS\nNineteen out 32 patients (59%) responded to infliximab with 6 (19%) complete and 13 (40%) partial responses. Age younger than 35 years, intestinal involvement and a longer time between hematopoietic stem cell transplantation and infliximab administration were factors predicting a favorable response. Infective episodes developed in 23/32 (72%) patients. All the 13 unresponsive patients died of GVHD shortly after infliximab. Thirteen of 19 responsive patients were alive at a median follow-up of 449 days (range 155-842) after infliximab, with no signs of chronic GVHD (n=5), limited (n=5) or extensive involvement (n=3). Six patients who responded subsequently died, one of chronic lung GVHD, the others of vascular complications or infections (2 fungal diseases).\n\n\nCONCLUSIONS\nWe conclude that infliximab is active in the treatment of severe steroid-refractory acute GVHD, particularly when the intestine is involved. Infections commonly followed its administration. The clinical activity of infliximab and the possibility that it increases the risk of infections are worth investigating in prospective trials.",
"affiliations": "Division of Haematology, Dept. of Clinical and Morphological Research, University of Udine, Italy. francesca.patriarca@med.uniud.it <francesca.patriarca@med.uniud.it>",
"authors": "Patriarca|Francesca|F|;Sperotto|Alessandra|A|;Damiani|Daniela|D|;Morreale|Giuseppe|G|;Bonifazi|Francesca|F|;Olivieri|Attilio|A|;Ciceri|Fabio|F|;Milone|Giuseppe|G|;Cesaro|Simone|S|;Bandini|Giuseppe|G|;Dini|Giorgio|G|;Corradini|Paolo|P|;Fanin|Renato|R|",
"chemical_list": "D000911:Antibodies, Monoclonal; D013256:Steroids; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6078",
"issue": "89(11)",
"journal": "Haematologica",
"keywords": null,
"medline_ta": "Haematologica",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013256:Steroids; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0417435",
"other_id": null,
"pages": "1352-9",
"pmc": null,
"pmid": "15531458",
"pubdate": "2004-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Infliximab treatment for steroid-refractory acute graft-versus-host disease.",
"title_normalized": "infliximab treatment for steroid refractory acute graft versus host disease"
} | [
{
"companynumb": "IT-JNJFOC-20170912054",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "Here we describe a wide complex tachycardia after bupropion overdose that was responsive to sodium bicarbonate. This rhythm was likely secondary to bupropion-induced sodium channel blockade and corrected QT interval (QTc) prolongation. It is critical for the emergency medicine physician to recognize that a wide complex rhythm in a patient with bupropion overdose may be secondary to sodium channel toxicity and prolonged QTc as this rhythm may be responsive to sodium bicarbonate. Identifying this rhythm as purely ventricular tachycardia can lead to the administration of medications such as amiodarone that may further prolong QTc and contribute to sodium channel blockade, exacerbating bupropion-induced cardiotoxicity.",
"affiliations": "Emergency Medicine, UCLA Medical Center, Los Angeles, CA. Electronic address: vfranco@mednet.ucla.edu.",
"authors": "Franco|Vanessa|V|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "33(10)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000328:Adult; D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion; D062787:Drug Overdose; D004562:Electrocardiography; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D013610:Tachycardia",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1540.e3-5",
"pmc": null,
"pmid": "26311156",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Wide complex tachycardia after bupropion overdose.",
"title_normalized": "wide complex tachycardia after bupropion overdose"
} | [
{
"companynumb": "US-PAR PHARMACEUTICAL COMPANIES-2015SCPR014384",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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{
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"activesubstance": {
"activesubstancename": "BUPROPION HYDROCHLORIDE"
},
... |
{
"abstract": "Although hepatotoxicity induced by immune checkpoint inhibitors (ICPIs) can cause severe clinical complications, the risk factors associated with hepatotoxicity have rarely been investigated. The purpose of this study was to determine the potential risk factors for the incidence of hepatotoxicity and for time to ICPI-induced hepatotoxicity. Patients who received ICPIs (atezolizumab, nivolumab, pembrolizumab, and ipilimumab) were included in this retrospective 2-center study. Collected data included sex, age, body weight, body surface area, Eastern Cooperative Oncology Group performance status, underlying disease, liver metastasis, programmed cell death ligand-1 expression, interval from previous chemotherapy, and concomitant drug use. Among the 194 patients, patients who experienced hepatotoxicity after ICPI administration was 64.4% (n=125) in all grade and 10.8% (n=21) in grade III or higher. Multivariate analysis showed that patients aged 30-50 and 50-70 years had increased risks of hepatotoxicity by 4.9-fold (95% confidence interval, 1.3-18.0) and 2.7-fold (95% confidence interval, 1.3-5.5), respectively, compared with those older than 70 years. The use of acetaminophen increased the occurrence of hepatotoxicity by 2.1 times; the attributable risk was 53.2%. Male patients and patients younger than 65 years had around 1.5-fold increased hazard of time to reach hepatotoxicity. Patients treated with 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors had a 4.7-fold higher risk of grade III-IV hepatotoxicity compared with those without HMG-CoA reductase inhibitors; the attributable risk was 78.8%. In conclusion, close monitoring of liver function is recommended, especially in male patients, patients younger than 65 years old, and when there is concomitant use of hepatotoxic drugs including acetaminophen and HMG-CoA reductase inhibitors.",
"affiliations": "College of Pharmacy, Gyeongsang National University.;College of Pharmacy, Chungbuk National University, Osong.;College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Graduate School of Clinical Biohealth, Ewha Womans University.;Department of Pathology, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Gyeongsangnam-do Province.;Department of Pharmacy, Gangnam Severance Hospital, Seoul.;College of Pharmacy, Sunchon National University, Suncheon, Jeollanam-do Province, Republic of Korea.;College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Graduate School of Clinical Biohealth, Ewha Womans University.",
"authors": "Cho|Young Ah|YA|;Han|Ji Min|JM|;Kang|Sun Young|SY|;Kim|Dong Chul|DC|;Youn|Young Ju|YJ|;Choi|Kyung Hee|KH|;Gwak|Hye Sun|HS|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1097/CJI.0000000000000347",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-9557",
"issue": "44(1)",
"journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)",
"keywords": null,
"medline_ta": "J Immunother",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D056486:Chemical and Drug Induced Liver Injury; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012189:Retrospective Studies; D012307:Risk Factors; D012737:Sex Factors",
"nlm_unique_id": "9706083",
"other_id": null,
"pages": "16-21",
"pmc": null,
"pmid": "33290362",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Analysis of Risk Factors for Hepatotoxicity Induced by Immune Checkpoint Inhibitors.",
"title_normalized": "analysis of risk factors for hepatotoxicity induced by immune checkpoint inhibitors"
} | [
{
"companynumb": "KR-JNJFOC-20210208987",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "Coinfection with hepatitis B virus (HBV) is not uncommon in human immunodeficiency virus (HIV)-infected individuals and patients with HIV-HBV coinfection are at high risk for progression of liver disease. Current guidelines regarding the treatment of HIV infection recommend that patients who are coinfected with HIV and HBV receive highly active antiretroviral therapy (HAART) with activity against hepatitis B. While HIV-HBV coinfected patients often experience liver enzyme elevations after starting antiretroviral therapy, acute liver failure (ALF) is rare and typically occurs with older antiretroviral agents with known potential for hepatotoxicity. We describe two cases of fatal ALF in the setting of HIV-HBV coinfection after initiation of HAART. These cases occurred despite treatment with antiretrovirals that have activity against HBV and highlight the challenges in distinguishing drug hepatotoxicity and HBV immune reconstitution inflammatory syndrome. HIV-HBV coinfected patients should be monitored closely when initiating HAART, even when treatment includes agents that have activity against HBV.",
"affiliations": "Emory University School of Medicine, Grady Health System Infectious Diseases Program, 341 Ponce de Leon Avenue, Atlanta, Georgia, GA 30308, USA. aande2@emory.edu",
"authors": "Anderson|Albert M|AM|;Mosunjac|Marina B|MB|;Palmore|Melody P|MP|;Osborn|Melissa K|MK|;Muir|Andrew J|AJ|",
"chemical_list": "D000998:Antiviral Agents",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v16.i32.4107",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "16(32)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D015897:Comorbidity; D017809:Fatal Outcome; D006678:HIV; D015658:HIV Infections; D006509:Hepatitis B; D006515:Hepatitis B virus; D006801:Humans; D008099:Liver; D017114:Liver Failure, Acute; D008297:Male",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "4107-11",
"pmc": null,
"pmid": "20731028",
"pubdate": "2010-08-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10094979;11830344;16771623;19052126;12800071;6105519;12626885;11153671;19417577;15802978;11137479;19640227;12493258;18453854;19372929;19372904;18171303;19373004;12089658;18090405;18004087;15841455;19826970;11998781;11997718;20032006",
"title": "Development of fatal acute liver failure in HIV-HBV coinfected patients.",
"title_normalized": "development of fatal acute liver failure in hiv hbv coinfected patients"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-15339815",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RITONAVIR"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nCoronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 was first identified in Wuhan, China. All ages are susceptible to SARS-CoV-2 infection. Few studies had reported milder course in children however, severe course of illness has been reported. We aimed to describe the clinical features of COVID-19 in pediatric patients including diagnostic findings and therapeutic interventions in sever disease manifestation.\n\n\nMETHODS\nWe retrospectively reviewed 742 patients with SARS-CoV-2 proven infection at King Abdullah Specialist Children's Hospital, from April 2020 and July 2020. Inpatients, outpatient, including those with sever manifestation treated at the Intensive Care Unit (ICU) were included. We collected data including demographic data, comorbidities, symptoms, imaging data, laboratory findings, treatments and clinical outcomes of patients with COVID-19.\n\n\nRESULTS\nAmong of 742 patients, 71 (9.6%) were hospitalized. The median age of patients was 75 months old and 53.6 were male. A total of 461 (62.1%) had close contact with confirmed cases, 45 (6.1%) had no contact history, and 236 (31.8%) with unknown exposure risk. The most common symptoms at the onset of illness were fever (32.5%), respiratory symptoms (21%) and gastrointestinal symptoms (10.3%). Among the entire cohort, 7 patients were admitted to PICU with COVID-19 related symptoms, five patients diagnosed with MIS-C, one patient with Kawasaki, and one patient with pneumonia. All patients received supportive therapy, no antiviral treatment had been used however, in MIS-C patients IVIG had been given to all patients, five patients received Anakinra; and one patient received tocilizumab.\n\n\nCONCLUSIONS\nIn this study, children infected with SARS-CoV-2 are less likely to develop symptomatic or serious diseases. Among symptomatic children, the most common clinical features were fever and respiratory symptoms followed by gastrointestinal manifestations. The majority of infected children have reported contact with an infected individual. MIS-C associated with COVID-19 is a severe presentation of SARS-CoV-2 infection and of a major concern as an overlapping features with other diseases could happen, making the diagnosis challenging.",
"affiliations": "King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh, Saudi Arabia; Department of Pediatrics, King Abdullah Specialist Children's Hospital, Riyadh, Saudi Arabia. Electronic address: harbimus@ngha.med.sa.;King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh, Saudi Arabia; Department of Pediatrics, King Abdullah Specialist Children's Hospital, Riyadh, Saudi Arabia.;King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh, Saudi Arabia; Department of Pediatrics, King Abdullah Specialist Children's Hospital, Riyadh, Saudi Arabia.;King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh, Saudi Arabia; Department of Pediatrics, King Abdullah Specialist Children's Hospital, Riyadh, Saudi Arabia.;King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh, Saudi Arabia; Department of Pediatrics, King Abdullah Specialist Children's Hospital, Riyadh, Saudi Arabia.;Department of Pediatrics, King Abdullah Specialist Children's Hospital, Riyadh, Saudi Arabia.;Department of Pediatrics, King Abdullah Specialist Children's Hospital, Riyadh, Saudi Arabia.;Department of Pediatrics, King Abdullah Specialist Children's Hospital, Riyadh, Saudi Arabia.;King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh, Saudi Arabia; Department of Pediatrics, King Abdullah Specialist Children's Hospital, Riyadh, Saudi Arabia.;King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; Department of Pathology Medicine, KAMC, MNGHA, Riyadh, Saudi Arabia.",
"authors": "Alharbi|Musaed|M|;Kazzaz|Yasser M|YM|;Hameed|Tahir|T|;Alqanatish|Jubran|J|;Alkhalaf|Hamad|H|;Alsadoon|Alaa|A|;Alayed|Maria|M|;Hussien|Shahad Abu|SA|;Shaalan|Mohammed Al|MA|;Al Johani|Sameera M|SM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jiph.2020.12.034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-0341",
"issue": "14(4)",
"journal": "Journal of infection and public health",
"keywords": "Coronavirus disease 2019; Novel coronavirus; SARS-CoV-2; Severe acute respiratory syndrome coronavirus-2, epidemiological characteristics, children, COVID-19, Saudi Arabia",
"medline_ta": "J Infect Public Health",
"mesh_terms": "D000086382:COVID-19; D002648:Child; D002675:Child, Preschool; D002681:China; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D012189:Retrospective Studies; D012529:Saudi Arabia; D018746:Systemic Inflammatory Response Syndrome; D062606:Tertiary Care Centers",
"nlm_unique_id": "101487384",
"other_id": null,
"pages": "446-453",
"pmc": null,
"pmid": "33765595",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "SARS-CoV-2 infection in children, clinical characteristics, diagnostic findings and therapeutic interventions at a tertiary care center in Riyadh, Saudi Arabia.",
"title_normalized": "sars cov 2 infection in children clinical characteristics diagnostic findings and therapeutic interventions at a tertiary care center in riyadh saudi arabia"
} | [
{
"companynumb": "SA-BEH-2021130227",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ANAKINRA"
},
"drugadditional": null,
"drug... |
{
"abstract": "Severe Strongyloides stercoralis, such as hyperinfection syndrome, carries a high mortality risk. Even with appropriate treatment, patients may experience infectious complications and failure of therapy. Currently, there are no Food and Drug Administration-approved parenteral therapies available for treatment in patients who develop gastrointestinal complications from hyperinfection, including small bowel obstruction. A veterinary form of ivermectin is available as a subcutaneous injection, although current literature in humans is limited. We report on the successful treatment of two surviving immunocompromised patients with S. stercoralis hyperinfection syndrome after prompt recognition and initiation of veterinary subcutaneous ivermectin therapy.",
"affiliations": "Department of Pharmacy, Tampa General Hospital, Tampa, Florida, USA.;Department of Pharmacy, Tampa General Hospital, Tampa, Florida, USA.;Division of Pulmonary and Critical Care Medicine, University of South Florida, Tampa, Florida, USA.;Division of Pulmonary and Critical Care Medicine, University of South Florida, Tampa, Florida, USA.;Division of Infectious Diseases and International Medicine, Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida, US.;Division of Infectious Diseases and International Medicine, Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida, US.;Division of Pulmonary and Critical Care Medicine, University of South Florida, Tampa, Florida, USA.",
"authors": "Zeitler|Kristen|K|;Jariwala|Ripal|R|;Restrepo-Jaramillo|Ricardo|R|;Kapadia|Shyam|S|;Casanas|Beata|B|;Alrabaa|Sally|S|;Sriaroon|Chakrapol|C|",
"chemical_list": "D015507:Drugs, Investigational; D005938:Glucocorticoids; D007559:Ivermectin; D003907:Dexamethasone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-223138",
"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepcasereportsbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2017-22313810.1136/bcr-2017-223138Novel Treatment (New Drug/Intervention; Established Drug/Procedure in New Situation)152215061330Case ReportSuccessful use of subcutaneous ivermectin for the treatment of Strongyloides stercoralis hyperinfection in the setting of small bowel obstruction and paralytic ileus in the immunocompromised population Zeitler Kristen 1Jariwala Ripal 1Restrepo-Jaramillo Ricardo 2Kapadia Shyam 2Casanas Beata 3Alrabaa Sally 3Sriaroon Chakrapol 2\n1 \nDepartment of Pharmacy, Tampa General Hospital, Tampa, Florida, USA\n\n2 \nDivision of Pulmonary and Critical Care Medicine, University of South Florida, Tampa, Florida, USA\n\n3 \nDivision of Infectious Diseases and International Medicine, Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida, US\nCorrespondence to Dr Chakrapol Sriaroon, csriaro@health.usf.edu2018 4 6 2018 4 6 2018 2018 bcr20172231381 5 2018 © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.2018This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Severe Strongyloides stercoralis, such as hyperinfection syndrome, carries a high mortality risk. Even with appropriate treatment, patients may experience infectious complications and failure of therapy. Currently, there are no Food and Drug Administration–approved parenteral therapies available for treatment in patients who develop gastrointestinal complications from hyperinfection, including small bowel obstruction. A veterinary form of ivermectin is available as a subcutaneous injection, although current literature in humans is limited. We report on the successful treatment of two surviving immunocompromised patients with S. stercoralis hyperinfection syndrome after prompt recognition and initiation of veterinary subcutaneous ivermectin therapy.\n\ntropical medicine (infectious disease)infectious diseasesspecial-featureunlocked\n==== Body\nBackground\nStrongyloidiasis is an infection caused by Strongyloides species, a parasite common in tropical, subtropical and warm temperate climates.1–3 Strongyloidiasis has been identified in the USA, predominantly in the southeastern region, as well as in travellers and immigrants from South America or sub-Saharan Africa.4 This organism can migrate through the skin and mucosa into the intestinal tract and travel to other organs, frequently affecting the skin, lungs and gastrointestinal (GI) tract.2 5 Hyperinfection can result in disruption of mucosa, ulcerations and ileus.1 In these situations, the organism can travel through the systemic circulation to the lungs causing bronchospasm, diffuse alveolar haemorrhage or respiratory failure.6 Hyperinfection can also be precipitated in the setting of an immunocompromised host. In particular, glucocorticoid use and human T-lymphotropic virus type 1 infection (HTLV-I) have been identified in promoting hyperinfection.7 Glucocorticoids may blunt the eosinophil response while HTLV-I can impair the function of the T-cell lymphocytes.7\n\n\nThe Centers for Disease Control and Prevention (CDC) recognises ivermectin as the first-line agent for the treatment of strongyloidiasis as well as Strongyloides hyperinfection. In the USA, ivermectin is available in oral and parenteral formulations, but the Food and Drug Administration (FDA) has approved only the oral formulation for human use.8 The CDC recognises the use of veterinary subcutaneous ivermectin may be a therapeutic option when oral and/or rectal administration of the drug is not possible9; however, this use requires an investigational new drug (IND) exemption from the FDA.\n\nWe present individual cases of two immunocompromised patients diagnosed with Strongyloides hyperinfection syndrome who developed GI complications, including small bowel obstruction and ileus, during the course of their hospital stay. Both patients were critically ill in the intensive care unit (ICU), and it was unclear if enteral absorption of oral ivermectin was optimal. Thus, therapy with veterinary subcutaneous ivermectin was pursued for each patient. This case series adds to the body of literature regarding the use of veterinary subcutaneous ivermectin in human for the treatment of Strongyloides hyperinfection as well as the importance of early recognition and diagnosis of this infection.\n\nCase presentation\nCase 1\nOur first patient was a 42-year-old Cuban-American man, who relocated to Florida when he was 6 years old. His medical history was significant for asthma and deep vein thrombosis. He presented with diffuse abdominal pain, anorexia, vomiting, diarrhoea and dizziness for approximately 1 week. He was taking oral dexamethasone 6 mg by mouth daily for treatment of asthma. His physical examination was remarkable for diffuse abdominal tenderness and an erythematous, maculopapular rash with occasional pustules over the anterior abdomen. Laboratory values on admission are shown in table 1. Abdominal CT scan demonstrated bowel wall thickening and inflammatory stranding involving the caecum, ascending colon and transverse colon concerning for colitis. Concentrated examination of the stool with iodine staining demonstrated many Strongyloides parasitic larvae (figure 1). He was diagnosed with hyperinfection syndrome and started on albendazole. Colonic biopsy revealed active colitis with focal architectural changes and focal granulomas associated with Strongyloides. On admission day 5, he developed acute hypoxic respiratory failure and was intubated. A bronchoscopy with bronchoalveolar lavage (BAL) was performed, which revealed diffuse friable mucosa. Additionally, Strongyloides stercoralis was isolated in the wet preparation in parasitic larvae form and a send-out Strongyloides IgG serum antibody test was found to be positive. The patient was switched to oral ivermectin 200 µg/kg/day (13 mg) via nasogastric tube; however, due to paralytic ileus, ivermectin was changed to rectal suspension retention enema (tablets crushed and suspended in 30 cc Ora-Plus; Perrigo, Minneapolis, Minnesota, USA) administered daily as a bridge while awaiting emergency IND approval (IND no. 128369) from the FDA in addition to expedited institutional review board approval at our institution for the use of subcutaneous ivermectin (1%, 50 cc). The patient was extubated on admission day 10 but remained nothing by mouth due to paralytic ileus. On admission day 11, he was transitioned from rectal retention enema to subcutaneous ivermectin 200 µg/kg/day given in two divided syringes, one to each arm, every 48 hours.\n\nFigure 1 Stool demonstrating Strongyloides stercoralis in ova and parasite specimen.\n\nTable 1 Laboratory and clinical details of both cases\n\nLaboratory value (units)\tCase 1\tCase 2\t\nWhite blood cell count (×109 /L)\t14.7\t24.6\t\nEosinophils (%)\t0.5\t0.9\t\nSodium (mEq/L)\t126\t129\t\nPotassium (mmol/L)\t3.4\t4.1\t\nAlbumin (g/dL)\t2.6\t2.7\t\nTotal bilirubin (mg/dL)\t0.9\t4.4\t\nProcalcitonin (ng/mL)\tNA\t<0.05\t\nDuration of subcutaneous ivermectin therapy (days)\t6\t26\t\nTotal duration of admission (days)\t17\t104\t\nOutcome\tAlive; discharged\tAlive; discharged\t\nNA, not applicable.\n\nCase 2\nOur second patient was a 33-year-old Ethiopian woman living in Florida with a medical history of HIV infection. She emigrated from Ethiopia when she was 18 years old. Three months prior to admission, the patient had a CD4 count >500 cells/mm3 and she was compliant with her antiretroviral therapy. She presented with nausea, vomiting and epigastric pain. Her physical examination was benign except for abdominal tenderness. Laboratory values from admission are shown in table 1. Right upper quadrant ultrasound was significant for a slightly dilated common bile duct; a subsequent hepatobiliary iminodiacetic acid scan was normal. The patient underwent an oesophagogastroduodenoscopy, which revealed diffuse, severe gastric inflammation with oedema and friable mucosa in the second portion of the duodenum. On admission day 4, she developed acute hypoxic respiratory failure from presumed acute respiratory distress syndrome. She was transferred to the ICU and was intubated. A bronchoscopy showed progressively bloodier aliquots consistent with diffuse alveolar haemorrhage. BAL cytology revealed numerous S. stercoralis in both parasitic larvae and adult forms (figure 2). Subsequent CT of chest and abdomen imaging showed diffuse ground-glass opacities bilaterally, small bowel obstruction, colitis and urinary bladder wall thickening with emphysematous cystitis. A concentrated stool examination with iodine staining demonstrated S. stercoralis in adult forms. Additionally, a duodenal biopsy noted abundant Strongyloides in parasitic larvae and adult form. She was diagnosed with Strongyloides hyperinfection. Ivermectin therapy was initiated orally at 200 µg/kg/day (12 mg). Unfortunately, the patient developed a small bowel obstruction and due to concern for malabsorption, FDA approval and an emergency IND application (IND no. 131494) were submitted for subcutaneous dosing. On receiving approval, the patient was transitioned to subcutaneous ivermectin (1%, 50 cc), obtained from a local veterinary hospital, at the same dose of 200 µg/kg/day given in two divided syringes, one to each arm, every 48 hours. Stool and sputum samples were sent every few days to document clearance of infection.\n\nFigure 2 Bronchoalveolar lavage washings with Strongyloides stercoralis.\n\nTreatment\nSee above.\n\nOutcome and follow-up\nCase 1\nStool and sputum were sent for Strongyloides every 3 to 4 days, and by admission day 13, S. stercoralis was no longer detected on sputum gram stain, although it was still present in the stool at discharge. The patient received three doses of subcutaneous ivermectin and was restarted on oral ivermectin by admission day 17. At the time of discharge, he had received 12 days of ivermectin and was sent home with an additional 2-week course of oral therapy.\n\nCase 2\nShe continued on subcutaneous therapy for 26 days before transitioning to oral ivermectin, as directed by the medical team due to her slow response to therapy. Due to depressed mental status and concern for further disease dissemination, a lumbar puncture was performed to rule out central nervous system involvement; this work-up was negative. Additionally, HTLV-I/II antibodies were ordered; tests were non-reactive. By day 39 of ivermectin therapy, larvae were no longer seen in her stool or sputum cultures and she was deemed to have completed therapy. She continued to have a prolonged hospital course and was eventually discharged home.\n\nDiscussion\nIn this case series, we highlight the successful use of non-oral ivermectin for the treatment of S. stercoralis hyperinfection syndrome in two immunocompromised patients. In the available literature, at least 22 cases of subcutaneous ivermectin use have been reported, with 11 patients surviving treatment.10 In an immunocompromised patient from an endemic area, a strong clinical suspicion for strongyloidiasis is warranted, as symptoms may be vague and delays in diagnosis can negatively impact a patient’s outcome. Strongyloidiasis has been commonly encountered in patients living in tropical and subtropical climates. A 2010 publication identified 347 strongyloidiasis-related deaths in the USA; of note, over 50% of cases occurred in patients born in the southeastern region.11 Thus, it is important for healthcare professionals in this area of the USA to be vigilant for this infection when evaluating patients presenting with respiratory and/or GI symptoms consistent with strongyloidiasis. Consistently, high mortality (up to 90%) has been documented due to the underdetection of this infection along with its wide range of clinical presentations.12 However, the CDC provides guidance to healthcare professionals in Strongyloides screening and identifies the following individuals at risk: initiating or currently receiving corticosteroids or other immunosuppression medication, history of HTLV-I infection, those who are being evaluated or have a history of organ transplantation, persistent peripheral or unexplained eosinophilia, and recent or remote travel history to endemic areas.12 In our two patients, they each met at least one screening criteria outlined by CDC as well as residence in the southeastern region of the USA. Our cases reinforce the need for early screening in at-risk individuals as well as promoting awareness of this infection and its risk factors to healthcare professionals practising in the southeastern USA.\n\nCases of severe S. stercoralis infection have been seen more frequently in patients receiving immunosuppressive therapies as well as those with HTLV infection.7 13 14 Although once thought to be an AIDS-defining illness, few cases of strongyloidiasis in this patient population have been detected in clinical practice.7 15 A retrospective study of HIV-positive immigrants at two Italian hospitals between January 2000 and August 2009 noted that 11% (15/138) of patients indeed had Strongyloides infection, as evidenced by positive laboratory testing with either an indirect immunofluorescent antibody test and/or direct parasitological tests with or without stool culture for S. stercoralis; however, no cases could be classified as hyperinfection syndrome.16 Croker and colleagues identified 12.5% of patients in their study population in the USA with HIV who died from strongyloidiasis; similar to the previous study, none of these patients were diagnosed with hyperinfection syndrome.11 A recent publication by Geri and colleagues reviewed 133 patients with Strongyloides hyperinfection syndrome, noting 10.7% of this population had HIV infection; however, this was not found to be predictive of ICU mortality or shock.17 Although not commonly encountered in the HIV population, high clinical suspicion is warranted in the appropriate context due to the high mortality associated with Strongyloides hyperinfection syndrome.\n\nIvermectin’s mechanism of action focuses on its binding to glutamate chloride ion channels, resulting in hyperpolarisation of the cell leading to death of the parasite.8 Ivermectin has high oral bioavailability and is highly protein bound (93%); therefore, free serum drug levels can be increased in individuals with hypoalbuminemia.8 18 Neurotoxicity is a major concern and the altered pharmacokinetics in critically ill patients can affect serum levels of ivermectin.18 Veterinary subcutaneous ivermectin, the product used for our two patients, is a sterile solution containing glycerol formal and propylene glycol.19 These compounds are used as drug vehicles for this product due to ivermectin’s insolubility in water.20 Additionally, this non-aqueous drug formulation has been shown to have activity against internal parasites, including Strongyloides spp., and external parasites.20 Use of subcutaneous ivermectin was preferred in order to ensure adequate systemic absorption and distribution to all infected areas in the body21 22; however, we did not use therapeutic drug monitoring for either of our patients due to limited access to levels. There is no standardised therapeutic range recognised with the use of subcutaneous ivermectin. Barrett and colleagues published a summary of previous case reports on subcutaneous ivermectin, including any use of ivermectin serum levels.10 Values varied significantly across the publications from 2.7 to 35.4 ng/mL. The weight-based dose was the same in each case; however, the frequency of administration differed. Additionally, patient outcomes did not appear to correlate with serum ivermectin concentrations. Some in vitro data suggest 2.4 ng/mL of ivermectin is needed to paralyse 50% of other Strongyloides spp.23 24; however, the dose of 200 µg/kg/day, which was used in both of our cases, has resulted in high parasitic eradication.25 Clinical use and pharmacokinetic studies of subcutaneous ivermectin have primarily been in animals. Unfortunately, there is little pharmacokinetic data in humans at present and further studies are needed for dose optimisation and potential licensure for human use.\n\nImpaired immunity likely played a role in promoting hyperinfection in both of our cases. Geri and colleagues noted 83.5% of their patients with Strongyloides hyperinfection syndrome on corticosteroids at a median dose of 40 mg per day, highlighting the significant role of this drug therapy on infection risk.17 Our first case involved a patient who had been receiving chronic corticosteroids, which may have led to a blunted eosinophil response. Eosinophils are known to combat parasitic infections, yet were not detected by laboratory tests in either patient. From previous cases, it has been noted that eosinophil counts are lower in individuals with severe strongyloidiasis compared with individuals who are asymptomatic.4 The degree of immunosuppression appeared to be significant in our first case and may have accelerated the patient’s hyperinfection. Our second case involved an HIV patient with a CD4 count above 500 cells/mm3. Testing for HTLV during admission was noted to be non-reactive. Interestingly, hyperinfection is not commonly seen in the HIV population but can occur in individuals who are undergoing immune reconstitution inflammatory syndrome in endemic areas.26 The exact mechanism is unclear, but it has been noted that HIV can decrease Th-1 lymphocytes. As the immune system reconstitutes, the increase of Th-1 lymphocytes may promote autoinfection.26 Our patient was from an endemic area for Strongyloides spp. and also exhibited GI symptoms during her hospitalisation. It is likely she had chronic strongyloidiasis that evolved into hyperinfection. In the setting of depressed immunity and residence in an endemic area, these patients were at risk for development of strongyloidiasis, including hyperinfection.\n\nLearning points\nThe use of veterinary subcutaneous ivermectin in the treatment of Strongyloides hyperinfection offers an option to patients with unreliable gastrointestinal absorption in order to achieve adequate drug serum levels.\n\nResidence in endemic areas and impaired immunity can predispose patients to infection with Strongyloides spp.\n\nPrompt recognition and diagnosis of infection along with timely initiation of appropriate treatment is paramount in the management of Strongyloides hyperinfection syndrome.\n\nContributors: KZ: contributed to planning of manuscript, conception and design for writing, acquisition of data, interpretation of data, writing of manuscript and editing/approval of final version. RJ: contributed to planning of manuscript, conception and design for writing, acquisition of data, interpretation of data, writing of manuscript and editing/approval of final version. RR-J: contributed to planning of manuscript, conception and design for writing, acquisition of data, interpretation of data, writing of manuscript and editing/approval of final version. SK: contributed to planning of manuscript, conception and design for writing, acquisition of data, interpretation of data, writing of manuscript and editing/approval of final version. SA: contributed to planning of manuscript, conception and design for writing, acquisition of data, interpretation of data, writing of manuscript and editing /approval of final version. BC: contributed to planning of manuscript, conception and design for writing, acquisition of data, interpretation of data, writing of manuscript and editing/approval of final version. CS: contributed to planning of manuscript, conception and design for writing, acquisition of data, interpretation of data, writing of manuscript and editing/approval of final version.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 \nSiddiqui AA , Berk SL \nDiagnosis of Strongyloides stercoralis infection . Clin Infect Dis \n2001 ;33 :1040 –7 . 10.1086/322707 \n11528578 \n2 \nKassalik M , Mönkemüller K \n\nStrongyloides stercoralis hyperinfection syndrome and disseminated disease . Gastroenterol Hepatol \n2011 ;7 :766 –8 .\n3 \nCenters for Disease Control and Prevention . Epidemiology & risk factors. https://www.cdc.gov/parasites/strongyloides/epi.html (accessed 8 Feb 2017 ).\n4 \nIriemenam NC , Sanyaolu AO , Oyibo WA , et al \nStrongyloides stercoralis and the immune response . Parasitol Int \n2010 ;59 :9 –14 . 10.1016/j.parint.2009.10.009 \n19892034 \n5 \nCenters for Disease Control and Prevention . Strongyloidiasis . https://www.cdc.gov/dpdx/strongyloidiasis/index.html (accessed 18 Feb 2017 ).\n6 \nVadlamudi RS , Chi DS , Krishnaswamy G \nIntestinal strongyloidiasis and hyperinfection syndrome . Clin Mol Allergy \n2006 ;4 :8 \n10.1186/1476-7961-4-8 \n16734908 \n7 \nKeiser PB , Nutman TB \nStrongyloides stercoralis in the immunocompromised population . Clin Microbiol Rev \n2004 ;17 :208 –17 . 10.1128/CMR.17.1.208-217.2004 \n14726461 \n8 \nStromectol [package insert] . Whitehouse Station . NJ : Merck & Co, Inc , 2010 .\n9 \nMarty FM , Lowry CM , Rodriguez M , et al \nTreatment of human disseminated strongyloidiasis with a parenteral veterinary formulation of ivermectin . Clin Infect Dis \n2005 ;41 :e5 –8 . 10.1086/430827 \n15937753 \n10 \nBarrett J , Broderick C , Soulsby H , et al \nSubcutaneous ivermectin use in the treatment of severe Strongyloides stercoralis infection: two case reports and a discussion of the literature . J Antimicrob Chemother \n2016 ;71 :220 –5 . 10.1093/jac/dkv315 \n26462990 \n11 \nCroker C , Reporter R , Redelings M , et al \nAm J Trop Med Hyg \n2010 ;83 :422 –6 .20682893 \n12 \nCenters for Disease Control and Prevention . Resources for Health Professionals . https://www.cdc.gov/parasites/strongyloides/health_professionals/index.html (accessed 8 Feb 2017 ).\n13 \nMejia R , Nutman TB \nScreening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by Strongyloides stercoralis\n . Curr Opin Infect Dis \n2012 ;25 :458 –63 . 10.1097/QCO.0b013e3283551dbd \n22691685 \n14 \nYee A , Boylen CT , Noguchi T , et al \nFatal Strongyloides stercoralis infection in a patient receiving corticosteroids . West J Med \n1987 ;146 :363 –4 .3577128 \n15 \nLucas SB \nMissing infections in AIDS . Trans R Soc Trop Med Hyg \n1990 ;84 (Suppl 1 ):34 –8 . 10.1016/0035-9203(90)90453-L \n\n16 \nMascarello M , Gobbi F , Angheben A , et al \nPrevalence of Strongyloides stercoralis infection among HIV-positive immigrants attending two Italian hospitals, from 2000 to 2009 . Ann Trop Med Parasitol \n2011 ;105 :617 –23 . 10.1179/2047773211Y.0000000006 \n22325821 \n17 \nGeri G , Rabbat A , Mayaux J , et al \n\nStrongyloides stercoralis hyperinfection syndrome: a case series and a review of the literature . Infection \n2015 ;43 :691 –8 . 10.1007/s15010-015-0799-1 \n26008854 \n18 \nMoura EB , Maia MO , Ghazi M , et al \nSalvage treatment of disseminated strongyloidiasis in an immunocompromised patient: therapy success with subcutaneous ivermectin . Braz J Infect Dis \n2012 ;16 :479 –81 . 10.1016/j.bjid.2012.08.008 \n22975175 \n19 \nIVOMEC . Package insert . Duluth, GA : Merial Limited , 2010 .\n20 \nWilliams MJ \nU.S. Patent No. 4, 853, 372 . Rahway, NJ : U.S , 1989 .\n21 \nBogoch II , Khan K , Abrams H , et al \nFailure of ivermectin per rectum to achieve clinically meaningful serum levels in two cases of Strongyloides hyperinfection . Am J Trop Med Hyg \n2015 ;93 :94 –6 . 10.4269/ajtmh.15-0077 \n25918215 \n22 \nFusco DN , Downs JA , Satlin MJ , et al \nNon-oral treatment with ivermectin for disseminated strongyloidiasis . Am J Trop Med Hyg \n2010 ;83 :879 –83 . 10.4269/ajtmh.2010.10-0258 \n20889884 \n23 \nLeung V , Al-Rawahi GN , Grant J , et al \nCase report: failure of subcutaneous ivermectin in treating Strongyloides hyperinfection . Am J Trop Med Hyg \n2008 ;79 :853 –5 .19052292 \n24 \nGrein JD , Mathisen GE , Donovan S , et al \nSerum ivermectin levels after enteral and subcutaneous administration for Strongyloides hyperinfection: a case report . Scand J Infect Dis \n2010 ;42 :234 –6 . 10.3109/00365540903443165 \n20085425 \n25 \nTurner SA , Maclean JD , Fleckenstein L , et al \nParenteral administration of ivermectin in a patient with disseminated strongyloidiasis . Am J Trop Med Hyg \n2005 ;73 :911 –4 .16282302 \n26 \nWeatherhead JE , Mejia R \nImmune Response to Infection with Strongyloides stercoralis in Patients with Infection and Hyperinfection . Curr Trop Med Rep \n2014 ;1 :229 –33 . 10.1007/s40475-014-0032-9\n\n",
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"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "infectious diseases; tropical medicine (infectious disease)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000818:Animals; D001249:Asthma; D016638:Critical Illness; D003907:Dexamethasone; D015507:Drugs, Investigational; D005260:Female; D005938:Glucocorticoids; D015658:HIV Infections; D006801:Humans; D016867:Immunocompromised Host; D007279:Injections, Subcutaneous; D007411:Intestinal Diseases, Parasitic; D007415:Intestinal Obstruction; D007418:Intestinal Pseudo-Obstruction; D007559:Ivermectin; D008297:Male; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis",
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"pmid": "29866667",
"pubdate": "2018-06-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "3577128;22325821;14726461;20085425;11528578;16734908;2201111;16282302;26008854;20682893;22691685;19892034;26462990;19052292;22975175;15937753;22298975;20889884;25918215",
"title": "Successful use of subcutaneous ivermectin for the treatment of Strongyloides stercoralis hyperinfection in the setting of small bowel obstruction and paralytic ileus in the immunocompromised population.",
"title_normalized": "successful use of subcutaneous ivermectin for the treatment of strongyloides stercoralis hyperinfection in the setting of small bowel obstruction and paralytic ileus in the immunocompromised population"
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"abstract": "Foetal ductus arteriosus (DA) constriction can be found in complex foetal heart malformations, but rarely as an isolated defect. Although many cases of DA constriction are usually related to Non-steroidal Anti-Inflammatory Drugs (NSAIDs) maternal intake, other causes remain without an established aetiology and are referred to as idiopathic. Recently, a wide range of risks factors or substances (polyphenol-rich foods intake, naphazoline, fluoxetine, caffeine and pesticides) showed a definitive effect upon the pathway of inflammation, causing DA constriction. We report a case of a premature DA constriction in a woman whose possible risk factor was identified in her maternal occupational exposure to solvents and a comprehensive literature review of 176 cases of NSAID-unrelated DA constriction. A 30-year-old Asian woman was referred to our institution at 33 gestational weeks and 0 days because of suspicion of premature DA constriction. The woman had no history of medication intake, including NSAIDs, alcohol, tobacco or polyphenol-rich-food consumption during pregnancy. A detailed foetal echocardiography revealed a normal cardiac anatomy with hypertrophic, hypokinetic and a dilated right ventricle due to right pressure overload, holosystolic tricuspid regurgitation, and, at the level of the DA, high systolic and diastolic velocities, indicating premature ductal restriction. The right outflow showed dilatation of the pulmonary artery with narrow DA. An urgent caesarean section was performed at 33 gestational weeks and 4 days due to worsening of DA PI and signs of right pressure overload, despite the interruption of exposure to solvents. We assume a relationship exists between premature DA constriction and a maternal occupational exposure to solvents. This hypothesis is reinforced by the presence of associated foetal malformations in in two of the patient's children. Further research is needed to confirm the role of exposure to solvents and toxic chemicals in the pathogenesis of DA constriction, also with experimental animal models.KEY MESSAGESMany cases of DA constriction are usually related to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) maternal intake.A wide range of risks factors or substances (polyphenol-rich foods intake, naphazoline, fluoxetine, caffeine and pesticides) can cause foetal DA constriction.Further investigation are needed to confirm the role of maternal exposure to solvents in the pathogenesis of DA constriction.",
"affiliations": "Woman's Health Sciences Department, Gynecologic Section, Polytechnic University of Marche, Ancona, Italy.;Woman's Health Sciences Department, Gynecologic Section, Polytechnic University of Marche, Ancona, Italy.;Woman's Health Sciences Department, Gynecologic Section, Polytechnic University of Marche, Ancona, Italy.;Woman's Health Sciences Department, Gynecologic Section, Polytechnic University of Marche, Ancona, Italy.;Woman's Health Sciences Department, Gynecologic Section, Polytechnic University of Marche, Ancona, Italy.;Department of Paediatric and Congenital Cardiac Surgery and Cardiology, Ospedali Riuniti, Ancona, Italy.;Department of Paediatric and Congenital Cardiac Surgery and Cardiology, Ospedali Riuniti, Ancona, Italy.;Woman's Health Sciences Department, Gynecologic Section, Polytechnic University of Marche, Ancona, Italy.",
"authors": "Battistoni|Giovanna|G|;Montironi|Ramona|R|;Di Giuseppe|Jacopo|J|;Giannella|Luca|L|;Delli Carpini|Giovanni|G|;Baldinelli|Alessandra|A|;Pozzi|Marco|M|;Ciavattini|Andrea|A|0000-0003-0074-5996",
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"doi": "10.1080/07853890.2021.1921253",
"fulltext": "\n==== Front\nAnn Med\nAnn Med\nAnnals of Medicine\n0785-3890\n1365-2060\nTaylor & Francis\n\n34096417\n10.1080/07853890.2021.1921253\n1921253\nVersion of Record\nReview Article\nPregnancy, Childbirth & Women’s Health\nFoetal ductus arteriosus constriction unrelated to non-steroidal anti-Inflammatory drugs: a case report and literature review\nG. Battistoni et al.\nBattistoni Giovanna a\nMontironi Ramona a\nDi Giuseppe Jacopo a\nGiannella Luca a\nDelli Carpini Giovanni a\nBaldinelli Alessandra b\nPozzi Marco b\nhttps://orcid.org/0000-0003-0074-5996\nCiavattini Andrea a\na Woman’s Health Sciences Department, Gynecologic Section, Polytechnic University of Marche, Ancona, Italy\nb Department of Paediatric and Congenital Cardiac Surgery and Cardiology, Ospedali Riuniti, Ancona, Italy\nCONTACT Andrea Ciavattini ciavattini.a@libero.itWoman’s Health Sciences Department, Gynecologic Section, Polytechnic University of Marche, Ancona, Italy\n7 6 2021\n2021\n53 1 860873\n© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group\n2021\nThe Author(s)\nhttps://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nFoetal ductus arteriosus (DA) constriction can be found in complex foetal heart malformations, but rarely as an isolated defect. Although many cases of DA constriction are usually related to Non-steroidal Anti-Inflammatory Drugs (NSAIDs) maternal intake, other causes remain without an established aetiology and are referred to as idiopathic. Recently, a wide range of risks factors or substances (polyphenol-rich foods intake, naphazoline, fluoxetine, caffeine and pesticides) showed a definitive effect upon the pathway of inflammation, causing DA constriction. We report a case of a premature DA constriction in a woman whose possible risk factor was identified in her maternal occupational exposure to solvents and a comprehensive literature review of 176 cases of NSAID-unrelated DA constriction. A 30-year-old Asian woman was referred to our institution at 33 gestational weeks and 0 days because of suspicion of premature DA constriction. The woman had no history of medication intake, including NSAIDs, alcohol, tobacco or polyphenol-rich-food consumption during pregnancy. A detailed foetal echocardiography revealed a normal cardiac anatomy with hypertrophic, hypokinetic and a dilated right ventricle due to right pressure overload, holosystolic tricuspid regurgitation, and, at the level of the DA, high systolic and diastolic velocities, indicating premature ductal restriction. The right outflow showed dilatation of the pulmonary artery with narrow DA. An urgent caesarean section was performed at 33 gestational weeks and 4 days due to worsening of DA PI and signs of right pressure overload, despite the interruption of exposure to solvents. We assume a relationship exists between premature DA constriction and a maternal occupational exposure to solvents. This hypothesis is reinforced by the presence of associated foetal malformations in in two of the patient’s children. Further research is needed to confirm the role of exposure to solvents and toxic chemicals in the pathogenesis of DA constriction, also with experimental animal models.KEY MESSAGES\n\nMany cases of DA constriction are usually related to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) maternal intake.\n\nA wide range of risks factors or substances (polyphenol-rich foods intake, naphazoline, fluoxetine, caffeine and pesticides) can cause foetal DA constriction.\n\nFurther investigation are needed to confirm the role of maternal exposure to solvents in the pathogenesis of DA constriction.\n\nKeywords\n\nDuctus arteriosus constriction\nNSAID\nfoetal\nsolvents\nmaternal exposure\n==== Body\nIntroduction\n\nThe ductus arteriosus (DA) is an essential component of foetal circulation. Connecting the pulmonary artery to the descending aorta, it allows 80–85% of the right ventricle output to reach the systemic circulation, bypassing the high resistance fluid-filled lungs [1–4]. This communication between the pulmonary and systemic circulations establishes the parallel circulation in the foetus and equalizes pressure in the right and left ventricle. The patency of DA is maintained during gestation by locally produced and circulating prostaglandins, especially Prostaglandin E2 (PGE2), nitric oxide and low foetal oxygen saturation [5].\n\nWith advancing gestation, the DA becomes more sensitive to constricting factors, because it is subject to a progressive vascular remodelling to prepare itself to postnatal closure [6]. This histological maturation process starts at the second trimester and consists of the thickening of muscular layer [7].\n\nPremature intra-uterine DA constriction could be diagnosed in complex congenital heart malformations, including Tetralogy of Fallot and truncus arteriosus. As an isolated defect, it is usually secondary to the use of medication like NSAIDs, isoxsuprine, fluoxetine and some foods rich in polyphenol like herbal teas, dark chocolate, orange juice, red/purple grapes, berries and coffee [8–12].\n\nThe mechanism of NSAID action is inhibition of prostaglandin production by direct constriction of the enzyme cyclooxygenase (COX). Production of prostaglandins is dependent on two enzymes which act in different states, cyclo-oxygenase-1 (COX-1), expressed endogenously, and cyclo-oxygenase-2 (COX-2), locally induced during the inflammatory processes [13]. Both animal and human studies have demonstrated constriction of the ductus after administration of prostaglandin synthetase inhibitors. This effect was not shown to depend on foetal serum concentration of the drug [14,15]. In recent years, also the antiinflammatory and antioxidant effects of foods rich in polyphenol have been demonstrated [16]; these effects are secondary to inhibition of the metabolic route of prostaglandins, especially of COX-2, preventing the transformation of arachidonic acid into prostaglandin [9].\n\nOther possible risk factors could be the exposure to solvents or chemicals, but more case confirmations are required [17–18]. Idiopathic premature ductal constriction is considered a rare event.\n\nWe describe the case of a premature DA constriction in a woman whose possible risk factor was identified in her maternal occupational exposure to solvents. Moreover, we report, for the first time, a literature review on all cases of DA constriction unrelated to NSAID or congenital heart defects, to investigate the role of others risk factors.\n\nCase presentation\n\nA 30-year-old Asian woman was referred to our institution at 33 gestational weeks and 0 days because of a suspicion of premature DA constriction on a routine third trimester ultrasound. The patient signed a standard written informed consent form for the use of data, pictures, and videos used for teaching and research purposes. This was the third pregnancy. The first newborn was affected by a lip and palate cleft, while the second one was healthy. The current pregnancy had no complications. The woman had no history of medication intake, including NSAIDs, alcohol, tobacco or polyphenol-rich-food consumption during pregnancy. In particular, in order to quantify the polyphenol ingestion, a food frequency questionnaire for consumption of polyphenol-rich foods in pregnant women was performed [19–20]. The total dietary amount of flavonoids was calculated from the USDA Database for the Flavonoid Content of Selected Foods [21], considering the 27 items with higher concentrations of polyphenols higher than 30 mg/100 g of food (green and black tea, mate tea, grape derivatives, dark chocolate, orange juice, fruit teas, olive oil, soy beans, berries, tomato, apples, spinach, and others) as reported by Zielinsky et al. [22]. On the other hand, her occupational exposure to solvents and toxic chemicals, as a hairdresser, (especially cosmetic products) resulted from the maternal and paternal history. A detailed foetal echocardiography revealed a normal cardiac anatomy with hypertrophic, hypokinetic and dilated right ventricle due to right pressure overload. The effects of premature DA constriction (mild pericardial effusion and a dilated and poorly functioning right ventricle) can be seen in Figure 1. The colour and pulsed Doppler interrogation showed holosystolic tricuspid regurgitation (130 cm/s) (Figure 1(B)) with jet that reached the roof of the atrium and at the level of the DA showed high systolic (200 cm/s) and diastolic (80 cm/s) velocities with a reduction in the pulsatility index (PI) (0.8), indicating premature ductal restriction. The right outflow showed dilatation of the pulmonary artery with narrow DA (Figure 2(B)). After the administration of corticosteroids, an urgent caesarean section was performed at 33 gestational weeks and 4 days due to worsening of DA PI and signs of right pressure overload, despite the interruption of exposure to solvents. A 2250 g-male neonate born with Apgar score of 5 and 9 at 1 and 5 min respectively. Post-natal echocardiography revealed an anatomically normal heart with progressive improvement of hypertrophy and right ventricular dilatation.\n\nFigure 1. (A) Four chamber view at 33 gestational weeks: hypertrophic and dilated right ventricle, with mild pericardial effusion. (B) Tricuspid valve regurgitation peak velocity (130 cm/s).\n\nFigure 2. Two-dimensional echocardiography, showing ductus arteriosus constriction (arrow). (A) Right outflow tract. (B) Ductal arch view. (C) three-vessel view.\n\nThe newborn was treated immediately after birth with PGE infusion with the aim of reducing the pressure overload of the right ventricle and pulmonary hypertension. This use of prostaglandins is off-label, but free from major side effects. Due to poor response to PGE treatment, it was stopped after 18 h, and therapy with inotropic agents (dopamine) and nitric oxide was initiated to reduce the pulmonary pressure. Closure of DA took place 30 h after birth. Collaterally, congenital cataract was found. Normal human karyotype was found in the newborn.\n\nMethods: comprehensive review of the literature\n\nThe electronic medical database Medline/PubMed was used for research, combining the following terms: foetal ductus arteriosus constriction (472 articles). Titles and abstracts of these articles were screened for relevance by authors to determine which articles were to undergo full-text review (human cases of prenatal DA constriction/closure no NSAIDs or CHD induced). Animal cases of prenatal ductus arteriosus constriction, cases of NSAID related DA constriction, or related to heart defects were excluded (Figure 3). Articles identified at this stage as potentially relevant moved into full text review (Figure 3). The bibliographies of included studies were reviewed to identify additional publications not found through the database search.\n\nFigure 3. Search strategy flowchart.\n\nResults\n\nTo date, 176 cases of NSAID-unrelated (and congenital hearth defects- unrelated, CHD) premature DA constriction have been reported in the English language literature (from 1946 to 2020).\n\nIncluding the present report, there are 177 cases of NSAID-unrelated (and not related to hearth disease) [4,8,23–54] (Table 1).\n\nTable 1. Prenatal restriction/closure of DA: human cases in literature no NSAIDs or CHD induced (1946–2020).\n\nAuthors (Y)\tSample size\tN\tStudy design\tMA (y)\tCausative agent (Substance exposure/idiopathic)\tDominant echo findings\tGA at diagnosis (W)\tTreatment\tDelivery\tGA at birth (w)\tPostnatal presentation\tPostnatal treatment and course\t\nBattistoni et al. (the present report)\t1\t1\tCase report\t30\tSolvents and toxic chemicals\tRV dilatation, PA dilatation, narrowed DA, ↓ PI on DA, TR, pericardial effusion.\t33\tCS after corticosteroids\tImmediate CS after corticosteroids\t34\tProgressive improvement of hypertrophy and right ventricular dilatation\tUneventful. Congenital cataract was found\t\nEnzesberger et al. 2012 [23]\t3\t2\tCase series\t29\tIdiopathic\tTR, RA dilatation, constricted DA, ↑ PSV,PDV and ↓ PI on DA\t33\tDaily FU\tCS (maternal request)\t38\tA, Normal-sized heart\tDischarged d 4\t\n3\t \t29\tIdiopathic\tRV dilatation, ↑ PSV,PDV and ↓ PI on DA, negative a wave DV\t34\tDaily FU\tCS (breech- ↓RH function\t35\tA, Hypertrophic RV\tDischarged d 16\t\n4\t \t26\tIdiopathic\tCardiomegaly, RH hypertrophy, TR, ↑ PSV,PDV and ↓ PI on DA, negative a wave DV\t36\tCS\tCS (non-reassuring stress test)\t36\tA, RV hypertrophy, TR\tDischarged d 5\t\nGenovese et al.2015 [4]\t1\t5\tCase report\t38\tParacetamol\tRV hypertrophy, ↑ PSV,PDV and ↓ PI on DA, tortuous S-shaped DA\t34\tCS after corticosteroids\tElective CS\t35\tRDS, Marked RV hypertrophy with impaired function, little and tortuous DA\tOxygen by nasal cannula Discharged d 15\t\nLopes et al 2015 [8]\t16\t6\tRetrospective analysis\t16–43\tIdiopathic\tRV dilatation, severe TR, ↑ PSV,PDV and ↓ PI on DA\t29\tFU\tND\tND\tA\tUneventful\t\n7\t \t16–43\tIdiopathic\t↑ PSV,PDV and ↓ PI on DA\t34\tFU\tND\tND\tA\tUneventful\t\n8\t \t16–43\tIdiopathic\tRV dilatation, mild TR↑ PSV,PDV and ↓ PI on DA\t32\tFU\tND\t37\tA\tUneventful\t\n9\t \t16–43\tIdiopathic\tRV dilatation and akinetic, severe TR, pericardial effusion, ↑ PSV,PDV and ↓ PI on DA\t37\tImmediate delivery\tND\tND\tSevere PH, severe RV dysfunction\tNormal heart 3m\t\n10\t \t16–43\tIdiopathic\tRV dilatation, mild TR, ↑ PSV,PDV and ↓ PI on DA\t34\tFU\tND\tND\tA\tUneventful\t\n11\t \t16–43\tIdiopathic\tRV dilatation, severe TR, ↑ PSV,PDV and ↓ PI on DA\t36\tFU\tND\tND\tA\tUneventful\t\n12\t \t16–43\tIdiopathic\tRV dilatation, mild TR, ↑ PSV,PDV and ↓ PI on DA\t35\tFU\tND\tND\tA\tUneventful\t\n13\t \t16–43\tIdiopathic\tRV dilatation, mild TR, ↑ PSV,PDV and ↓ PI on DA\t28\tFU\tND\tND\tA\tUneventful\t\n14\t \t16–43\tNaphazoline (abusive use of nasal drops)\tMild TR, ↑ PSV,PDV and ↓ PI on DA\t38\tFU\tND\tND\tA\tUneventful\t\n15\t \t16–43\tAsthma attack after pest control (unknown pesticide) with bronchodilators\tRV dilatation, severe TR, ↑ PSV,PDV and ↓ PI on DA\t33\tFU\tCS for persistent DA constriction\t37\tPH\tNormal heart 15 d\t\n16\t \t16–43\tIsoxsuprine-B2 agonist\tRV dilatation, moderate TR, ↑ PSV,PDV and ↓ PI on DA\t34\tFU\tND\tND\tA\tUneventful\t\n17\t \t16–43\tCaffeine (abusive ingestion of cola soft drink, 3–4 l/d)\tRV dilatation, moderate TR, ↑ PSV,PDV and ↓ PI on DA\t31\tFU\tND\tND\tA\tUneventful\t\n18\t \t16–43\tFluoxetine 60 mg/d (since beginning of pregnancy)\t↑ PSV,PDV and ↓ PI on DA,\t28\tFU\tND\tND\tA\tUneventful\t\n19\t \t16–43\tCaffeine (abusive ingestion of cola soft drink)\t↑ PSV,PDV and ↓ PI on DA\t33\tFU\tND\tND\tA\tUneventful\t\n20\t \t16–43\tOxymetazoline+ Naphazoline (abusive use of nasal drops)\tRV dilatation, mild TR, ↑ PSV,PDV and ↓ PI on DA C\t34\tFU\tND\tND\tA\tUneventful\t\n21\t \t16–43\tCaffeine (abusive ingestion of cola soft drink)\tRV dilatation, ↑ PSV,PDV and ↓ PI on DA\t30\tFU\tND\tND\tA\tUneventful\t\nTrevett et al. 2004 [24]\t1\t22\tCase report\t34\tIdiopathic\tModerate RV hypertrophy, mild TR, ↑ PSV and ↓ PI on DA, tortuous S-shaped DA\t33\tWeekly FU\tInduction for GDM, VD\t38\tA, hypertrophic RV\tDischarged d 3\t\nRakha S. 2017 [10]\t1\t23\tCase report\t23\tOrange intake (up to 2 kg/d)\tRH dilatation, ↑ PSV,PDV and ↓ PI on DA, narrowed DA\t31\tStop orange intake + FU\tSpontaneous VD\t39\tA, Normal heart\tUneventful\t\nOkada et al 2018 [25]\t1\t24\tCase report\t27\tIdiopathic\tLV and RA dilatation, severe TR, hypertrophic RV, narrowed DA, no blood flow on DA\t37\tCS\tEmergency CS (sinusoidal pattern on CTG)\t37\tSevere dyspnoea, dilated cardiomyopathy\tRespiratory support (intubation), Inotropes and diuretic administration.\t\nDischarged d 47.\t\nResolution of cardiomyopathy 6 m\t\nShima et al.2010 [26]\t1\t25\tCase report\t27\tIdiopathic\tRA dilatation, severe TR, hypertrophic RV, narrowed DA, pericardial effusion\t38\tCS\tEmergency CS\t38\tTachypnea,RA dilatation, massive TR, hypertrophic RV, mild pericardial effusion,\tOxygen\t\nDischarged d 7\t\nNormal heart 3 m\t\nVian et al. 2018 [27]\t35\t26–60\tCase-control\tND\tIdiopathic\t↑ PSV,PDV and ↓ PI on DA, narrowed DA,TR\t≥28\tPolyphenol-rich food restriction\tND\tND\tA, Normal-sized heart\tUneventful\t\nYaman et al. 1999 [28]\t1\t61\tCase report\tND\tIdiopathic\tRV hypertrophy , PA retrograde flow, ↑ PSV,PDV and ↓ PI on DA\t39\tND\tND\t39\tPH\tND\t\nAzancot-Benisty et al. 1995 [29]\t1\t62\tCase report\t38\tBetamethasone (four courses )\tRV hypertrophy, ↑ PSV,PDV and ↓ PI on DA, TR, mild pericardial effusion, narrowed DA\t27\tStop steroids\tCS for placenta Previa\t38\tA, normal-sized heart\tUneventful\t\nWei S. et al 2011 [30]\t1\t63\tCase report\t28\tIdiopathic\tNo flow through DA, no narrowing of DA, RH dilatation, RV hypertrophy, severe TR, negative a wave on DV\t38\tCS\tEmergency CS\t38\tA, mild TR, moderate PH, cardiomegaly, RV hypertrophy, closed DA\tUneventful\t\nDischarged d 3\t\nNormal heart d 14\t\nInatomi et al. 2017 [31]\t1\t64\tCase report\t38\tIdiopathic\tCardiomegaly, dilatation of pulmonary trunk, ↑ PSV,PDV and ↓ PI on DA, moderate TR, narrowed DA\t36\tCS\tEmergency CS (progression to hydrops)\t36\tdyspnoea, PH, severe TR with rupture of the anterior papillary muscle, RV hypertrophy\tOxygen, CPAP, cardiotonic drugs, NO (until d 7)\t\nSridharan et al. 2009 [32]\t2\t65\tCase report\t34\tCamomile tea\t↑ PSV,PDV and ↓ PI on DA, narrowed DA\t20\tStop tea\tND\tND\tND\tND\t\n66\t \t32\tCamomile tea\tRV dilatation and poorly contractile, moderate TR and PR, ↑ PSV,PDV and ↓ PI on DA, narrowed DA\t35\tCS\tImmediate CS\t35\tA, DA closed, dilatated RV, mild TR, PR\tUneventful\t\nHayes 2016 [33]\t1\t67\tCase report\t33\tBio-Oil® (x2/d from II trim)\tRA dilatation, hypertrophic and poorly contractile RV, moderate TR, pericardial effusion,↑ PSV,PDV and ↓ PI on DA, narrowed DA, negative a wave on DV\t37\tCS\tImmediate CS\t37\tDyspnoea, cardiomegaly, PH, RV systolic dysfunction, TR\tOxygen\t\nDischarged d 6.\t\nNormal heart 6 m\t\nSrinivasan et al 2018 [34]\t4\t68–71\tCase series\t20–34\tALGS/WS\tRV hypertrophy and dilatation, ↑ PSV,PDV and ↓ PI on DA, TR, narrowed DA\t21–36\tFollow up\tInduction/CS (non-reassuring CTG)\t32–36\tDyspnoea, PH, RV hypertrophy, ↑ flow velocities on peripheral PA\tOxygen up to 6 m\t\nNormal heart 6 m, bur PPS persisted.\t\nSchierz et al. 2018 [35]\t1\t72\tCase report\tND\tParacetamol (3g/d four 4 d in the III trimester), polyphenol rich-foods\tND\t38\tCS\tEmergency CS\t38\tRDS, closed DA, severe cardiomyopathy, RV dysfunction, functional PA stenosis\tOxygen up to 6 d.\t\nCardiomyopathy regression at 2 m.\t\nHofstadler et al. 1995 [36]\t4\t73\tCase report\tND\tIdiopathic\tRV hypertrophy and dysfunction, TR, PR\t37\tInduction\tCS\t37\tDyspnoea, PH, closed DA, RV hypertrophy and dilatation\tOxygen for 46h.\t\nDischarged d 9.\t\nNormal heart at 7 w.\t\n74\tND\tIdiopathic\tRV hypertrophy and dysfunction, TR, abnormal umbilical vein pulsations, PA regurgitation\t37\tInduction of labour\tVD\t37\tDyspnoea, closed DA, RV hypertrophy and dilatation. Hyperechoic RV endocardium and papillary muscle.\tOxygen for 36h\t\nAntibiotics (sepsis).\t\nDischarged d 9.\t\n75\tND\t6-days course antibiotics and phenyldimethylpyrazolam, glucocorticoids and ß-blocker\tClosed DA, RV hypertrophy and dysfunction, ascites, TR, abnormal umbilical vein pulsations, PA regurgitation\t38\tCS\tEmergency CS\t38\tDyspnoea, PH, closed DA, RV hypertrophy and dilatation ,TR\tOxygen for 14h.\t\nDischarged d 6.\t\nAt 3 m uncomplete regression of RV hypertrophy, but baby is clinically well.\t\n76\tND\tBethametasone single course\tRV hypertrophy and dysfunction, TR, PA regurgitation\t \t \t \t34\tInduction of labour\tVD\t35\tClosed DA, RV Hypertrophy and dilatation, mild TR\tDischarged d 8.\t\nAt 5w uncomplete regression of RV hypertrophy, but baby asymptomatic.\t \t \t \t\nSoslow et al. 2008 [37]\t1\t77\tCase report\tND\tBethametasone single course\tResctricted DA.\t31\tWeekly FU\tEmergency CS (worsening of RV function)\t32\tClosed DA, RV hypertrophy and dilatation, mild TR\tNormal RV function, with mild residual RV hypertrophy at 3 w\t \t \t \t\nRV hypertrophy and dysfunction, TR.\t \t \t \t\nAbdominal meconium pseudocyst.\t \t \t \t\nChoi et al. 2013 [38]\t1\t78\tCase report\t22\tIdiopathic\tRV hypertrophy, RA dilatation, tortuous S-shaped DA, no flow on DA, mild TR\t33\tInduction\tVD\t34\tDyspnoea, closed DA, RV hypertrophy, mild TR\tOxygen with mechanical ventilator.\t \t \t \t\nDischarged d 12\t \t \t \t\nNormal heart 7 m.\t \t \t \t\nZielinsky et al. 2012 [39]\t51\t79–129\tCase-control\t28 ± 6.5\tPolyphenol rich-foods\t↑ PSV,PDV and ↓ PI on DA, turbulent flow on DA, TR, RV hypertrophy\t32 ± 3\tPolyphenol-rich food restriction and FU after 3w\tSpontaneous delivery\tND\tA, normal sized heart\tUneventful\t \t \t \t\nMielke et al. 1995 [40]\t1\t130\tCase report\t28\tIdiopathic\t↑ PSV,PDV and ↓ PI on DA, S-shaped DA, severe TR, RA and RV dilatation, transient PR\t32\tFU\tCS (↑ tricuspid valve insufficiency)\t36\tClosed DA, RV hypertrophy and dilatation, mild TR\tProgressive normal heart in the following d.\t \t \t \t\nIshida et al. 2011 [41]\t1\t131\tCase report\t29\tIdiopathic\t↑ PSV,PDV and ↓ PI on DA, mild TR, RH dilatation, PR, hydrops\t32\tCS\tEmergency CS\t32\tclosed DA, dyspnoea, RV hypertrophy and dilatation, mild TR\tOxygen Endotracheal intubation, Catecholamine, Discharged d 31. Normal heart 2 m.\t \t \t \t\nMielke et al. 1996 [42]\t1\t132\tCase report\t34\tIdiopathic\t↑ PSV and ↓ PI on DA, narrowed DA, RA dilatation, foetal atrial flutter\t31\tWeekly FU, digoxin + verapamil to obtain cardioversion\tSpontaneous\t39\tRV hypertrophy. RA dilatation\tNormal heart 3 m\t \t \t \t\nGewillig et al. 2017 [43]\t19\t133\tCase series\tND\tIdiopathic\t↑ PSV and PDV, ↓ PI on DA, narrowed DA, severe RV dilatation and hypertrophy\t27\tFU\tSpontaneous\t40\tA, severe RV hypertrophy\tResolved\t \t \t \t\n134\t \tND\tIdiopathic\t↑ PSV and PDV, ↓ PI on DA, narrowed DA, severe RV dilatation\t26\tFU, Induction (↑ RH dysfunction)\tVD\t36\tCyanosis,, severe RV dilatation and hypertrophy\tCPAP\t \t \t \t\n135\t \tND\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, narrowed DA, severe RV hypertrophy\t28\tFU, Induction (progression RH dysfunction)\tVD\t38\tA, severe RV hypertrophy, critical Pulmonary stenosis\tPulmonary atresia angioplasty, stent DA\t \t \t \t\n136\t \tND\tParacetamol\t↑ PSV, and PDV, ↓ PI on DA, narrowed DA, Pulmonary atresia dilatation\t24\tFU\tSpontaneous VD\t40\tA, Pulmonary stenosis\tPulmonary atresia angioplasty\t \t \t \t\n137\t \tND\tParacetamol\t↑ PSV, and PDV, ↓ PI on DA, narrowed DA, severe TR, severe RV dilatation, pericardial effusion\t25\tFU, Induction (progression RH dysfunction)\tVD\t37\tCyanosis, PH, severe TR, moderate RV dilatation, severe RH dilatation\tIPPV, NO, Inotropes, Tricuspid valve repair at 3 w\t \t \t \t\n138\t \tND\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, narrowed DA, severe TR, severe RH dilatation\t37\tFU\tCS\t39\tCyanosis, SVT, mild TR, severe RV hypertrophy, RA dilatation\tOxygen, Ablation 2 m\t \t \t \t\n139\t \tND\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, narrowed DA, severe RV hypertrophy\t32\tFU\tSpontaneous VD\t40\tA, moderate RV hypertrophy\tResolved\t \t \t \t\n140\t \tND\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, no flow DA, severe RV hypertrophy\t34\tFU\tVD\t40\tCyanosis, sever PH, severe TR, severe RV hypertrophy, RVOTO\tIPPV, NO, inotropes, death 3 m after attempted palliative surgery of RVOTO\t \t \t \t\n141\t \tND\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, no flow DA, severe TR, moderate RV dilatation\t27\tFU, Induction (↑RH dysfunction with hydrops)\tVD\t29\tCyanosis, PH, severe RV hypertrophy, cardiomyopathy\tIPPV, NO, inotropes, mitral valve ring a 4 y\t \t \t \t\n142\t \tND\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, no flow DA, severe TR, moderate RH dilatation, severe RV hypertrophy\t34\tFU, Induction for progression RH dysfunction\tVD\t35\tCyanosis, PH, severe TR, moderate RH dilatation, severe RV hypertrophy, functional PuV atresia\tIPPV, NO, inotropes, death on day 1 due to high pulmonary vascular resistance\t \t \t \t\n143\t \tND\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, no flow DA, Moderate RV hypertrophy\t33\tFU, Induction (↑RH dysfunction)\tVD\t34\tCyanosis, mild TR, severe RV hypertrophy\tCPAP, resolved\t \t \t \t\n144\t \tND\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, no flow DA, Moderate RV hypertrophy ad dilatation, mild TR, microcystic lungs\t20\tFU\tSpontaneous VD\t39\tCyanosis, Air trapping, mild RV dilatation, severe RV hypertrophy, aneurismal dilatation PA trunk and branches\tIPPV, inotropes, death at 3 for respiratory failure\t \t \t \t\n145\t \tND\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, no flow DA, mild TR, Moderate RH dilatation, moderate RV hypertrophy, PS, PR\t28\tFU, Induction (↑RH dysfunction)\tVD\t37\tCyanosis, mild TR, Moderate RA dilatation, severe RV hypertrophy, PS/PR\tCPAP, PuV replacement 2y and 8 y\t \t \t \t\n146\t \tND\tParacetamol\t↑ PSV, and PDV, ↓ PI on DA, no flow DA, mild RV dilatation, PuV thickened\t21\tFU\tCS\t39\tCyanosis, Moderate RV dilatation, Agenesis PuV\tOxygen, PuV replacement 7 days\t \t \t \t\n147\t \tND\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, no flow DA, Severe RV hypertrophy, Pericardial effusion, RV hypocontractilty\t38\tImmediate CS\tCS\t38\tCyanosis, severe RV hypertrophy\tOxygen, resolved\t \t \t \t\n148\t \tND\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, no flow DA, severe RV hypertrophy, severe TR, mild RA dilatation\t33\tFU\tSpontaneous VD\t39\tA, severe RV hypetrophy\tResolved\t \t \t \t\n149\t \tND\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, no flow DA, severe TR, mild RH dilatation, Pericardial effusion\t39\tInduction\tVD\t39\tA\tResolved\t \t \t \t\n150\t \tND\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, no flow DA, severe RV dilatation, mild RV hypertrophy\t39\tFU\tSpontaneous VD\t40\tA, severe RV hypertrophy, mild TR\tResolved\t \t \t \t\n151\t \tND\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, no flow DA, mild RV dilatation, mild TR, severe RV hypertrophy\t36\tFU\tSpontaneous VD\t36\tCyanosis, mild RV hypertrophy\tCPAP, resolved\t \t \t \t\nBabaoğlou et al. 2013 [44]\t1\t152\tCase report\t29\tIdiopathic\t↑ PSV, and PDV, ↓ PI on DA, narrowed DA, RH dilatation, RV Hypertrophy, mild TR, hydrops\t33\tCS\tCS\t33\tDyspnoea, closed DA, mild TR, mild RV hypertrophy\tOxygen. Discharged d 8. Normal heart d 8.\t \t \t \t\nBecker et al. 1977 [45]\t2\t153\tCase report\tND\tIdiopathic\tND\tND\tNone\tSpontaneous VD\t39\tCyanosis, asphyxia, hydrops, RH dilatation, markedly Narrowed DA\tDeath after delivery\t \t \t \t\n154\t \tND\tIdiopathic\tND\tND\tNone\tSpontaneous VD\t40\tAsphyxia, hydrops, RA dilatation, markedly Narrowed DA\tDeath 1 h after delivery\t \t \t \t\nLeal et al. 1997 [46]\t3\t155\tCase series\t28–38\tIdiopathic\tNo flow on DA, RV dilatation, mild TR, mild PuV insufficiency\t32\tND\tCS\tND\tA, absent DA flow, RV dilatation\tUneventful, Normal-sized heart on follow up\t \t \t \t\n156\t \t28–38\tIdiopathic\tNo flow on DA, RV dilatation, mild TR, mild PuV insufficiency\t41\tND\tCS\tND\tA ,absent DA flow, RV dilatation\tUneventful, Normal-sized heart on follow up\t \t \t \t\n157\t \t28–38\tIdiopathic\tNo flow on DA, RV dilatation, mild TR, mild PuV insufficiency\t40\tND\tCS\tND\tA, absent DA flow, RV dilatation\tUneventful, Normal-sized heart on follow up\t \t \t \t\nTalemal et al. 2016 [47]\t1\t158\tCase report\t31\tDexamethasone (1w) for suspected myocardial inflammation in anti-SSA-exposed foetus\t↑ PSV, and PDV, ↓ PI on DA, narrowed DA, mild RH dilatation, mild TR, hyperechoic Mitral valve\t28\tFollow up\tSpontaneous VD\t38\tRDS, RH dilatation, RV dysfunction, no myocardial inflammation\tEndotracheal intubation for 24h, normal heart at 2w.\t \t \t \t\nEidem et al 2000 [48]\t1\t159\tCase report\t35\tIdiopathic\tnarrowed DA\t23\tFU\tInducted VD for IUGR\t38\tA, constricted DA\tUneventful\t \t \t \t\nCorti et al. 2020 [49]\t1\t160\tCase report\t35\tSertraline (25mg/d) Lorazepam (10drops/d) Paracetamol (2–4 g/d first trimester and 1–2 g occasionally in the third trimester)\tNo flow on DA, severe RH dilatation, TR, PuV insufficiency, decreased function of RV, Negative a-wave on DV,\t \t \t \t33\tCS after single course of corticosteroids\tCS\t33\tDyspnoea, PH, No DA, RV hypertrophy and dilatation, mild PuV insufficiency\tOxygen by nasal cannula\t\nNormal heart 1 m.\t \t \t \t\nKim et al. 2003 [50]\t1\t161\tCase report\t35\tIdiopathic\t↑ PSV, and PDV on DA, narrowed and S-shaped kinking DA, RH dilatation, RV Hypertrophy, mild TR, mild pericardial effusion\t26\tFU\tCS (foetal distress)\t31\tDyspnoea, PH, Tortuous DA, RV hypertrophy, mild TR, mild pericardial effusion\tOxygen with mechanical ventilator (1 w).\t \t \t \t\nDischarged 5 w.\t \t \t \t\nNormal heart 4 m.\t \t \t \t\nEllis et al. 2013 [51]\t1\t162\tCase report\tND\tLithium (throughout pregnancy)\tRH dilatation\t18\tFU\tPreterm delivery\tND\tClosed DA\tND\t \t \t \t\nBecquet et al. 2018 [52]\t1\t163\tCase series\t27\tParacetamol (for 7 d after 34 w)\t↑ PSV, PDV and ↓ PI on DA, narrowed DA, RV dilatation, mild TR\t37\tInduction\tVD\t37\tA, mild TR, mild RV hypertrophy and hypocontractility, totally closed DA\tUneventful.\t \t \t \t\nProgressive normal heart.\t \t \t \t\nDischarged d 5.\t \t \t \t\nChugh et al.2020 [53]\t1\t164\tCase series\t31\tIdiopathic\t↑ PSV, PDV and ↓ PI on DA, narrowed and S-shaped DA, mild TR\t32\tFU\tCS (worsening RV dysfunction)\t38\tDyspnoea, severe RV dilatation and hypertrophy, severe TR. Closed DA.\tMechanic ventilation for 2d.\t \t \t \t\nDischarged d 10.\t \t \t \t\nNormal heart at 1 m.\t \t \t \t\nLuchese et al. 2003 [54]\t13\t165\tRetrospective analysis\t19\tIdiopathic\t↑ PSV, PDV and ↓ PI on DA, RH dilatation, hypertrophic RV, mild PR\t33\tFU\tND\tND\tPH\tND\t \t \t \t\n \t166\t \t32\tIdiopathic\t↑ PSV, PDV and ↓ PI on DA, dilatated/hypocontractile RV, mild TR\t27\tFU\tND\tND\tPH\tND\t \t \t \t\n167\t \t17\tIdiopathic\t↑ PSV, PDV and ↓ PI on DA, dilatated RH and PA, mild TR\t37\tFU\tND\tND\tA\tUneventful\t \t \t \t\n168\t \t35\tIdiopathic\tNo flow on DA, dilatated RH and PA, severe TR and PR, hypertrophic RV\t36\tFU\tND\tND\tND\tUneventful\t \t \t \t\n169\t \t21\tIdiopathic\t↑ PSV and ↓ PI on DA, mild RV dilatation, mild TR\t34\tFU\tND\tND\tND\tUneventful\t \t \t \t\n170\t \t32\tIdiopathic\t↑ PSV, PDV and ↓ PI on DA, mild PR\t31\tFU\tND\tND\tA\tUneventful\t \t \t \t\n171\t \t36\tIdiopathic\t↑ PSV, PDV and ↓ PI on DA, dilatated RH, mild PR\t34\tFU\tND\tND\tA\tUneventful\t \t \t \t\n172\t \t25\tIdiopathic\t↑ PSV, PDV and ↓ PI on DA, dilatated/hypocontractile RH\t32\tFU\tND\tND\tA\tUneventful\t \t \t \t\n173\t \t41\tIdiopathic\t↑ PSV, PDV and ↓ PI on DA, mild TR, dilatated RV, severe hydrops\t28\tFU\tND\tND\tNeonate death\tNeonate death\t \t \t \t\n174\t \t17\tIdiopathic\t↑ PSV, PDV and ↓ PI on DA\t38\tFU\tND\tND\tA\tUneventful\t \t \t \t\n175\t \t20\tIdiopathic\t↑ PSV, PDV and ↓ PI on DA, mild TR\t32\tFU\tND\tND\tA\tUneventful\t \t \t \t\n176\t \t28\tIdiopathic\t↑ PSV, PDV and ↓ PI on DA, dilatated RH, hypertrophic RV, mild PR\t33\tFU\tND\tND\tA\tUneventful\t \t \t \t\n177\t \t39\tIdiopathic\t↑ PSV, PDV and ↓ PI on DA\t33\tFU\tND\tND\tA\tUneventful\t \t \t \t\nGA: gestational age; W: weeks; Y: years; D: days; M: months; H: hours; FU: follow up; N: case number; MA: maternal age; RV: right ventricle; RA: right atrium; RH: right heart; PA: pulmonary artery; PuV: pulmonary valve; LF: left ventricle; PI: pulsatility index; DV: ductus venosus; PSV: peak systolic velocity; PDV: peak diastolic velocity; TR: tricuspid regurgitation; PR: pulmonary regurgitation; PS: pulmonary stenosis; RVOTO: right ventricle outflow tract obstruction; ND: no data available; CS: caesarean section; VD: vaginal delivery; PH: pulmonary hypertension; A: asymptomatic; CPAP: continuous positive airway pressure; IPPV: intermittent positive pressure ventilation; NO: nitrous oxide; NICU: neonatal intensive care unit; RDS: respiratory distress syndrome; SVT: supraventricular tachycardia; GDM: gestational diabetes; CTG: cardiotocography; ALGS: Alagille syndrome; WS: Williams syndrome; PPS: peripheral pulmonary stenosis.\n\nFigure 4 report the distribution of etiopathogenesis of human cases in literature no NSAIDs or CHD induced; of the 177 cases found 96 were idiopathic (54.2%), 58 were related to polyphenol rich-food, 5 to paracetamol, 4 were related to genetic arteriopathy (Alagille and Williams Syndrome), 4 cases were related to sympatomimetics drugs, 4 to corticosteroids, 4 to miscellaneous causes, 1 to SSRI consumption and 1 case to lithium consumption. In the literature, many cases are considered as idiopathic, but no one reported about maternal employment. However, it would be important to investigate whether there is a common pathogenetic mechanism form in many cases, such as occupational exposure to solvents or intake of paracetamol (acetaminophen), a drug considered safe in pregnancy. In particular, a repeated dose intake, especially in the third trimester of pregnancy, can have a vasoconstrictive effect [55].\n\nFigure 4. Distribution of etiopathogenesis of human cases in literature no NSAIDs or CHD induced.\n\nDiscussion\n\nPatient history was accurately reviewed to identify a possible causative agent. The woman had no chronic illness and was not a smoker. The foetus’s heart had no congenital defects. We asked about medications (especially NSAIDs) and polyphenol-rich foods intake. The mother denied the consumption of any kind of medicine, herbal tea, grapes or other polyphenol-rich food during pregnancy. A dietary intervention for maternal restriction of polyphenol-rich foods or suspension of NSAIDs consumption in the third trimester of pregnancy is accompanied by increase in plasma levels of PGE2 and reversal of foetal ductal constriction [10,27,39,56,57].\n\nIn the absence of the most common aetiologies, the occupational exposure to solvents or an idiopathic premature constriction of DA was suggested. The occupation of both parents as hairdressers, which involved the daily use of organic solvents, could be suspected. Widely discussed in the literature is the association between maternal occupational exposure to solvents (as in hairdressing and cosmetology) and an increased risk of adverse obstetrics outcomes, such as spontaneous abortion, preterm birth, small for gestational age (SGA), low birth weight (LBW) and congenital malformations (especially cleft lip and palate, urinary malformations, hypospadias and eye diseases) [17,18,58–62]. Our case could underline this association. The mother did not stop working before and during pregnancy and the foetus had not only the premature DA constriction but also congenital cataract, without any other risk factors. In addition, the first child was affected by lip and palate cleft. Hairdressers are predominantly women, and many of them are of childbearing age. Hairdressers work in a complex environment where they are in daily contact with various chemical substances which can be found in hair care product used for washing, dyeing, bleaching, spraying and perming. Their main routes of exposure are dermal and respiratory. Several solvents have been shown to be teratogenic for animals. In mice, for example, toluene and xylene (petroleum solvents) have been associated with the occurrence of cleft palate [18], and ethylene glycol monomethyl ether has been associated with the occurrence of neural tube defects [62], while in zebrafish, p-phenylenediamine, often included in hair dye, it can cause cardiovascular defects [63]. Also aromatic amines and aldehydes could have a role in COX2 inhibition that determine congenital heart defects [64]. In humans, malformations and cytogenetic effects have been observed among the offspring of women exposed to glycol ethers during pregnancy [65]. Some studies [66–69], but not others [70], report an excess risk of spontaneous abortion among women occupationally exposed to solvents. A small prospective cohort [71], and a meta-analysis [72], performed by the same research group both report associations between maternal occupational exposure to solvents and major malformations. Two occupational cohort studies of women working in laboratories suggest similar results [73–74]. Various case-control studies have shown relations between maternal occupational exposure to solvents and some subtypes of malformations, mostly oral clefts [75–77]. Some significant associations have also been reported between maternal exposure to solvents and cardiac malformations [75,78], visual impairment [17] and neural tube defects [75,79].\n\nConclusion\n\nPremature constriction of DA is a rare event and in most cases is secondary to maternal intake of NSAIDs or foods rich in polyphenols. For the first time, the present review reported all cases of DA constriction not related to NSAIDs intake or to CHD.\n\nThe gynaecologist must take into account that there are not only forms of DA constriction secondary to the intake of NSAIDs. We assume a relationship between premature DA constriction and a maternal occupational exposure to solvents. This association between a maternal occupational exposure to solvents and an increased risk of adverse obstetrics outcomes has been widely discussed in the literature. In our case report and in the previous newborns this hypothesis is reinforced by the presence of other associated foetal malformations. It is therefore important to carry out through an occupational history and inform the patient about the potential risks associated with the exposure to solvents and toxic chemicals. Further investigation is needed to confirm their role in the pathogenesis of DA constriction, as in experimental animal models, such as those already performed in pregnant rats and sheep with polyphenols. A randomized clinical trial is needed to analyse the role of solvents in inducing this condition would be desirable, respecting the ethical aspects of the research.\n\nDisclosure statement\n\nNo potential conflict of interest was reported by the author(s).\n==== Refs\nReferences\n\n1 Mott JC. Patent ductus arteriosus: experimental aspects. Arch Dis Child. 1980; 55 (2 ):99–105.6769398\n2 Brezinka C. Fetal ductus arteriosus-how far may it bend? Ultrasound Obstet Gynecol. 1995;6 (1 ):6–7.8528805\n3 Gewillig M, Brown SC, De Catte L, et al. 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"fulltext_license": "CC BY",
"issn_linking": "0785-3890",
"issue": "53(1)",
"journal": "Annals of medicine",
"keywords": "Ductus arteriosus constriction; NSAID; foetal; maternal exposure; solvents",
"medline_ta": "Ann Med",
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"title": "Foetal ductus arteriosus constriction unrelated to non-steroidal anti-Inflammatory drugs: a case report and literature review.",
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"abstract": "OBJECTIVE\nStiff person syndrome (SPS) is commonly associated with antibodies directed against 65-kDa glutamic acid decarboxylase (GAD65). Therapeutic Plasma Exchange (TPE) has been used as an adjunct therapy in patients who do not respond well to conventional treatment, which includes immunosuppression therapies, anti-anxiety medications, muscle relaxants, anticonvulsants, and pain relievers.\n\n\nMETHODS\nWe retrospectively analyzed the clinical data and outcomes of ten patients with the clinical diagnosis of anti-GAD65 positive SPS in which TPE was employed to improve symptoms refractory to conventional treatment during an eight-year period.\n\n\nRESULTS\nTPE was initiated as complementary therapy in patients with worsening of symptoms characteristic of SPS. Six patients underwent chronic treatment with TPE following an initial course, of which the frequency of TPE was guided by the clinical response. Two patients only had transient improvements with further disease progression. Four patients developed a relapse of symptoms when the interval between procedures was increased. One of the four patients dependent on TPE had worsening of symptoms following complete cessation of TPE due to lack of insurance coverage. Four patients underwent only an acute hospitalized course of treatment with TPE; one demonstrated complete resolution of symptoms; one had a partial response; and two experienced no improvement.\n\n\nCONCLUSIONS\nOur study supports previous reports that TPE may be beneficial for the management of patients with anti-GAD65 positive SPS, both for acute exacerbations and long-term maintenance, either as an adjunct therapy, or in lieu of treatment with disease modifying agents.",
"affiliations": "Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9072, USA. Electronic address: Albahra@Gmail.com.;Department of Pathology, Division of Transfusion Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.;Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9072, USA.;Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9072, USA.;Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9072, USA.;Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9072, USA.",
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"abstract": "Disseminated peritoneal leiomyomatosis is a rare condition manifesting as hormone-sensitive soft tissue nodules lining the peritoneal cavity. Given the extensiveness of this disease, surgical management is challenging, making hormonal suppression the primary treatment.\n\n\n\nA 23-year-old woman presenting with abdominal pain was found to have innumerable abdominopelvic nodules on imaging. Biopsy of these lesions was consistent with disseminated peritoneal leiomyomatosis. Treatment using leuprolide acetate led to satisfactory results but was discontinued owing to vasomotor symptoms. Treatment was changed to cyclic ulipristal acetate, a selective progesterone receptor modulator. Over the past 2 years, the patient has completed five 3-month courses of ulipristal acetate with excellent symptomatic and radiologic response.\n\n\n\nThe use of ulipristal acetate may be an effective, novel therapeutic option for the management of disseminated peritoneal leiomyomatosis.",
"affiliations": "Department of Obstetrics and Gynecology, London Health Sciences Centre, Western University, London, and the Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.",
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"abstract": "Takotsubo syndrome (TS) is an acute cardiac disease entity with a clinical presentation resembling that of an acute coronary syndrome. Numerous physical stress factors including pheochromocytoma, epinephrine, and norepinephrine administration, and even physiological exercise have been reported to induce TS. Takotsubo syndrome induced by medications causing elevation of plasma norepinephrine as serotonin-norepinephrine reuptake inhibitor or selective norepinephrine reuptake inhibitor (atomoxetine) has been reported.\nWe report on the case of a 49-year-old woman who was on atomoxetine treatment for attention deficit hyperactivity disorder, developed TS in association with sexual intercourse.\nThe TS pattern in this patient was the type of mid-apical ballooning with apical tip-sparing at presentation. Two days later, TS evolved to mid-ventricular pattern. Takotsubo syndrome resolved completely 1 month after the index presentation.",
"affiliations": "Heart and Vascular Theme, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden.;Heart and Vascular Theme, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden.",
"authors": "Athanassopoulos|Petros|P|0000-0002-9495-9233;Y-Hassan|Shams|S|0000-0001-5228-9035",
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"fulltext": "\n==== Front\nEur Heart J Case RepEur Heart J Case RepehjcrEuropean Heart Journal: Case Reports2514-2119Oxford University Press 10.1093/ehjcr/ytz151ytz151Case ReportsA case report: ‘happy heart’ syndrome in a patient treated with atomoxetine for attention deficit hyperactivity disorder http://orcid.org/0000-0002-9495-9233Athanassopoulos Petros http://orcid.org/0000-0001-5228-9035Y-Hassan Shams Liga Riccardo Handling EditorGarg Pankaj EditorMusella Francesca EditorMukherjee Rahul EditorThomson Ross Editor\nHeart and Vascular Theme, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden Corresponding author. Tel: +46858580000, Email: petros.athanasopoulos@sll.se12 2019 30 9 2019 30 9 2019 3 4 1 5 21 3 2019 3 4 2019 26 7 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.2019 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nTakotsubo syndrome (TS) is an acute cardiac disease entity with a clinical presentation resembling that of an acute coronary syndrome. Numerous physical stress factors including pheochromocytoma, epinephrine, and norepinephrine administration, and even physiological exercise have been reported to induce TS. Takotsubo syndrome induced by medications causing elevation of plasma norepinephrine as serotonin-norepinephrine reuptake inhibitor or selective norepinephrine reuptake inhibitor (atomoxetine) has been reported.\n\nCase summary\nWe report on the case of a 49-year-old woman who was on atomoxetine treatment for attention deficit hyperactivity disorder, developed TS in association with sexual intercourse.\n\nDiscussion\nThe TS pattern in this patient was the type of mid-apical ballooning with apical tip-sparing at presentation. Two days later, TS evolved to mid-ventricular pattern. Takotsubo syndrome resolved completely 1 month after the index presentation.\n\nCase reportAtomoxetineTakotsubo syndromeHappy Heart\n==== Body\nLearning points\n\nA woman treated with a selective norepinephrine reuptake inhibitor (atomoxetine) developed Takotsubo syndrome (TS) during sexual intercourse.\n\nInitial left ventricular mid-apical ballooning pattern with apical tip-sparing evolved to mid-ventricular TS, which recovered completely 1 month after index presentation.\n\n\n\n\n\n\n\nIntroduction\nTakotsubo syndrome (TS) is an acute cardiac disease entity with a clinical presentation resembling that of an acute coronary syndrome.1–3 The disease is characterized by a transient left ventricular wall motion abnormality with regional distribution resulting in a conspicuous ballooning of the left ventricle during systole.4 It affects predominantly women and is often preceded by emotional or physical stress.1,3,4 Countless physical stress factors including pheochromocytoma,5 epinephrine,6 and norepinephrine7 administration, and even physiological exercise have been reported as a trigger factor for TS.1,3 Takotsubo syndrome induced by exogenously administered norepinephrine or medications causing elevation of plasma norepinephrine as serotonin-norepinephrine reuptake inhibitor or selective norepinephrine reuptake inhibitor (S-NRI) (atomoxetine) has been reported.7 To our knowledge, only two cases of atomoxetine-triggered TS have been described.7 Herein, we report on the case of a 49-year-old woman who was on atomoxetine treatment for attention deficit hyperactivity disorder (ADHD) and developed TS in association with sexual intercourse.\n\nTimeline\nSymptoms\tClinical examination\tLaboratory findings\tInitial treatment\tClinical investigation\tFinal treatment\tFollow-up and outcome\t\nDay 1\t\t\t\tDay 2–3\t\t1 month\t\nChest pain, dyspnoea, and dizziness in association with sexual intercourse in a woman treated with atomoxetine for attention deficit hyperactivity disorder\t\nBlood pressure 120/94 mmHg\n\nElectrocardiogram with no remarkable changes\n\n\n\t\nTroponin 710 ng/L\n\nEchocardiography showed mid-apical ballooning with apical tip-sparing, good basal contraction, and markedly depressed left ventricular ejection fraction (30–35%)\n\n\n\tAtomoxetine discontinued and treatment with acetylsalicylic acid, beta-blocker, and angiotensin-converting enzyme inhibitor was initiated\t\nInvasive coronary angiography revealed normal coronary arteries\n\nNew echocardiography showed findings typical for mid-ventricular takotsubo syndrome\n\n\n\tAcetylsalicylic acid, beta-blocker, and angiotensin-converting enzyme inhibitor\t\nPatient clinically recovered\n\nCardiac magnetic resonance imaging showed complete resolution of the left ventricular wall motion abnormality; there was no late gadolinium enhancement\n\n\n\t\nCase presentation\nA 49-year-old woman presented with acute chest pain. The past history was not remarkable apart from being treated with thyroxine 125 µg o.d. for hypothyroidism, pregabalin 150 mg b.i.d. for chronic neurogenic back pain, and atomoxetine 60 and 18 mg daily for ADHD. In association with sexual intercourse, she developed acute chest pain associated with mild dyspnoea and some dizziness. The chest pain disappeared after sublingual nitroglycerine on admission to the hospital. The patient developed transient hypotension and bradycardia after nitroglycerine, which stabilized after atropine injection. The electrocardiogram (Figure 1) revealed no remarkable changes. Laboratory results showed modest elevation of troponin T (maximum 710 ng/L), C-reactive protein <5 mg/L, and normal cholesterol levels. Echocardiography 1 day after admission revealed a-/hypokinesia in the mid-apical regions with good contraction of the apical tip segment (apical tip-sparing) and the basal segments with marked reduction of left ventricular ejection fraction, 30–35% (Supplementary material online, Video S1, echocardiography). Atomoxetine was discontinued and treatment with acetylsalicylic acid, beta blocker, and angiotensin-converting enzyme inhibitor was initiated. Invasive coronary angiography 1 day after admission showed normal coronary arteries (Figure 2A and B; Supplementary material online, Video S2, left coronary artery). A new echocardiography 3 days after admission showed a-/hypokinesia in the middle segments of the left ventricle circumferentially, with good contractions in both the basal and apical segments resulting in a pattern consistent with mid-ventricular TS (Supplementary material online, Video S3, contrast echocardiography). Left ventricular systolic function recovered completely within 1 month from admission as demonstrated by cardiac magnetic resonance imaging, which did not show late gadolinium enhancement (Supplementary material online, Video S4, cardiac magnetic resonance imaging).\n\n\nFigure 1 The 12 leads electrocardiogram shows sinus rhythm. No remarkable changes are seen.\n\nFigure 2 Left coronary artery in (A) and right coronary artery in (B) showed no signs of obstructive coronary artery disease.\n\nDiscussion\nWe present a case of a woman treated with atomoxetine for ADHD who developed TS following sexual intercourse (‘happy heart’ syndrome). The TS had a mid-apical pattern with apical tip-sparing (Supplementary material online, Video S1, echocardiography), which evolved to typical mid-ventricular TS pattern 2 days later (Supplementary material online, Video S3, contrast echocardiography). Of 1750 TS patients, Ghadri et al.8 identified a total of 485 TS patients with a definite emotional trigger factor. Of these, 20 TS patients (4.1%) presented with pleasant preceding events. The mid-ventricular TS pattern was more prevalent among the ‘happy hearts’ than among the ‘broken hearts’. Our patient had also mainly mid-ventricular involvement.\n\nAtomoxetine, a S-NRI used for the treatment of ADHD,9 has been reported to trigger TS.7 To our knowledge, two cases of documented atomoxetine-triggered TS have been reported (Table 1). Both cases10,11 developed apical TS pattern after increasing the dose of atomoxetine. In our case, atomoxetine dose was not increased before the index presentation, but further physical stress could have triggered TS.\n\n\nTable 1 Clinical features on admission, in-hospital complications and outcome in the three known patients with atomoxetine-induced TS\n\nAuthors\tYear\tAge, years\tGender\tS-NRI, trigger factor\tReasons for S-NRI administration\tPresenting symptoms, manifestations\tTS localization/time (where available)\tComplications\tRecovery/time\t\nYamaguchi et al.\t2014\t11\tMale\tAtomoxetine\tDose increased for ADHD\tLoss of consciousness, bradycardia\tApical\tLong QT time (829 ms), need of pacemaker 4 days later\tYes/2 weeks\t\nNaguy et al.\t2016\t26\tFemale\tAtomoxetine\tDose increased to 40 mg b.i.d. for ADHD; the patient continued fluoxetine treatment\tChest pain and dyspnoea\tApical\tNo\tYes/5 weeks\t\nCurrent case\t2019\t49\tFemale\tAtomoxetine, sexual intercourse\tADHD\tChest pain, dyspnoea and dizziness\tMid-apical (apical tip sparing), Day 1; mid-ventricular, Day 3\tNo\tYes/4 weeks\t\nADHD, attention-deficit hyperactivity disorder; S-NRI, selective norepinephrine reuptake inhibitor; TS, takotsubo syndrome.\n\nConclusion\nA case of ‘happy heart’ syndrome triggered by a lovely physical activity in a woman who was treated with atomoxetine for ADHD is described. The TS pattern was of mid-apical ballooning with apical tip-sparing at presentation, which evolved to mid-ventricular pattern 2 days later and recovered completely 1 month after admission.\n\nLead author biography\nDr Petros Athanassopoulos BSc, MD, PhD, is a Consultant Cardiologist at the Karolinska University Hospital in Stockholm, Sweden. Dr Athanassopoulos has an international clinical- and research-background in Vascular Medicine, Heart Failure (HF) and Heart Transplantation. He received his PhD on ‘Chemokine-receptor mediated dendritic-cell and T-cell recirculation in heart failure and transplantation’ from Erasmus University Rotterdam, The Netherlands. He took up his current consultant post in 2014. He has a special interest in the pathophysiology of different HF phenotypes and is currently involved in research into the development of HF device therapies.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\n\nConsent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.\n\n\nConflict of interest: none declared.\n\nSupplementary Material\nytz151_Supplementary_Data Click here for additional data file.\n==== Refs\nReferences\n1 \nGhadri JR , Wittstein IS , Prasad A , Sharkey S , Dote K , Akashi YJ , Cammann VL , Crea F , Galiuto L , Desmet W , Yoshida T , Manfredini R , Eitel I , Kosuge M , Nef HM , Deshmukh A , Lerman A , Bossone E , Citro R , Ueyama T , Corrado D , Kurisu S , Ruschitzka F , Winchester D , Lyon AR , Omerovic E , Bax JJ , Meimoun P , Tarantini G , Rihal C , Y.-Hassan S , Migliore F , Horowitz JD , Shimokawa H , Lüscher TF , Templin C. \nInternational Expert Consensus Document on Takotsubo Syndrome (Part I): clinical characteristics, diagnostic criteria, and pathophysiology . Eur Heart J 2018 ;39 :2032 –2046 .29850871 \n2 \nY-Hassan S , Tornvall P. \nEpidemiology, pathogenesis, and management of takotsubo syndrome . Clin Auton Res 2018 ;28 :53 –65 .28917022 \n3 \nGhadri JR , Wittstein IS , Prasad A , Sharkey S , Dote K , Akashi YJ , Cammann VL , Crea F , Galiuto L , Desmet W , Yoshida T , Manfredini R , Eitel I , Kosuge M , Nef HM , Deshmukh A , Lerman A , Bossone E , Citro R , Ueyama T , Corrado D , Kurisu S , Ruschitzka F , Winchester D , Lyon AR , Omerovic E , Bax JJ , Meimoun P , Tarantini G , Rihal C , Y.-Hassan S , Migliore F , Horowitz JD , Shimokawa H , Lüscher TF , Templin C. \nInternational Expert Consensus Document on Takotsubo Syndrome (Part II): diagnostic workup, outcome, and management . Eur Heart J 2018 ;39 :2047 –2062 .29850820 \n4 \nY-Hassan S , De Palma R. \nContemporary review on the pathogenesis of takotsubo syndrome: the heart shedding tears: Norepinephrine churn and foam at the cardiac sympathetic nerve terminals . Int J Cardiol 2017 ;228 :528 –536 .27875730 \n5 \nY-Hassan S. \nClinical features and outcome of pheochromocytoma-induced takotsubo syndrome: analysis of 80 published cases . Am J Cardiol 2016 ;117 :1836 –1844 .27103159 \n6 \nY-Hassan S. \nClinical features and outcome of epinephrine-induced takotsubo syndrome: analysis of 33 published cases . Cardiovasc Revasc Med 2016 ;17 :450 –455 .27499059 \n7 \nY-Hassan S. \nSerotonin norepinephrine re-uptake inhibitor (SNRI)-, selective norepinephrine reuptake inhibitor (S-NRI)-, and exogenously administered norepinephrine-induced takotsubo syndrome: Analysis of published cases . Int J Cardiol 2017 ;231 :228 –233 .28073659 \n8 \nGhadri JR , Sarcon A , Diekmann J , Bataiosu DR , Cammann VL , Jurisic S , Napp LC , Jaguszewski M , Scherff F , Brugger P , Jäncke L , Seifert B , Bax JJ , Ruschitzka F , Lüscher TF , Templin C. \nHappy heart syndrome: role of positive emotional stress in takotsubo syndrome . Eur Heart J 2016 ;37 :2823 –2829 .26935270 \n9 \nGarnock-Jones KP , Keating GM. \nAtomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents . Paediatr Drugs 2009 ;11 :203 –226 .19445548 \n10 \nYamaguchi H , Nagumo K , Nakashima T , Kinugawa Y , Kumaki S. \nLife-threatening QT prolongation in a boy with attention-deficit/hyperactivity disorder on atomoxetine . Eur J Pediatr 2014 ;173 :1631 –1634 .24233333 \n11 \nNaguy A , Al-Mutairi H , Al-Tajali A. \nAtomoxetine-related Takotsubo Cardiomyopathy . J Psychiatr Pract 2016 ;22 :232 –233 .27123802\n\n",
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"keywords": "Atomoxetine; Case report; Happy Heart; Takotsubo syndrome",
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"title": "A case report: 'happy heart' syndrome in a patient treated with atomoxetine for attention deficit hyperactivity disorder.",
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"abstract": "Several chemotherapy molecules, monoclonal antibodies and tyrosine kinase inhibitors, have been linked to Takotsubo cardiomyopathy (TC).\n\n\n\nIn this article, we describe the case of a 45-year-old woman who developed TC after receiving an intra-arterial and intra-venous polychemotherapy for locally advanced epidermoid carcinoma of the anal canal. This is the first described case of TC associated with intra-arterial chemotherapy.\n\n\n\nA review of the literature points to 5-fluorouracil as the most common molecule associated with TC and highlights the potential risk associated with rechallenging patient with the same drug.",
"affiliations": "Department of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland.;Department of Internal Medical Specialties, Division of Cardiology, Geneva University Hospitals, Geneva, Switzerland.;Department of Internal Medical Specialties, Division of Oncology, Geneva University Hospitals, rue Gabrielle Perret-Gentil 4, 1211, Geneva 14, Switzerland.;Department of Internal Medical Specialties, Division of Oncology, Geneva University Hospitals, rue Gabrielle Perret-Gentil 4, 1211, Geneva 14, Switzerland. Thibaud.Kossler@hcuge.ch.",
"authors": "Coen|Matteo|M|;Rigamonti|Fabio|F|;Roth|Arnaud|A|;Koessler|Thibaud|T|0000-0001-9196-9076",
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"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 338410.1186/s12885-017-3384-4Case ReportChemotherapy-induced Takotsubo cardiomyopathy, a case report and review of the literature Coen Matteo Matteo.Coen@hcuge.ch 1Rigamonti Fabio Fabio.Rigamonti@hcuge.ch 2Roth Arnaud Arnaud.Roth@hcuge.ch 3http://orcid.org/0000-0001-9196-9076Koessler Thibaud Thibaud.Kossler@hcuge.ch 31 0000 0001 0721 9812grid.150338.cDepartment of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland 2 0000 0001 0721 9812grid.150338.cDepartment of Internal Medical Specialties, Division of Cardiology, Geneva University Hospitals, Geneva, Switzerland 3 0000 0001 0721 9812grid.150338.cDepartment of Internal Medical Specialties, Division of Oncology, Geneva University Hospitals, rue Gabrielle Perret-Gentil 4, 1211 Geneva 14, Switzerland 2 6 2017 2 6 2017 2017 17 39428 6 2016 24 5 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nSeveral chemotherapy molecules, monoclonal antibodies and tyrosine kinase inhibitors, have been linked to Takotsubo cardiomyopathy (TC).\n\nCase presentation\nIn this article, we describe the case of a 45-year-old woman who developed TC after receiving an intra-arterial and intra-venous polychemotherapy for locally advanced epidermoid carcinoma of the anal canal. This is the first described case of TC associated with intra-arterial chemotherapy.\n\nConclusions\nA review of the literature points to 5-fluorouracil as the most common molecule associated with TC and highlights the potential risk associated with rechallenging patient with the same drug.\n\nKeywords\nTakotsubo cardiomyopathyChemotherapyIntra-arterial chemotherapyRechallengeCase reportissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nFor oncologists challenging questions remain after TC diagnosis: is the chemotherapy responsible for the TC? Most importantly, how should we treat the patient next? This last question is especially difficult in a curative setting like our case.\n\nWe describe a case of nonfatal chemotherapy induced TC in a woman diagnosed with locally advanced epidermoid carcinoma of the anal canal. The TC developed after intra-arterial chemotherapy with cisplatin, 5-fluorouracil, methotrexate, mitomycin, and intra-venous bleomycin. Intra-arterial chemotherapy is very effective at closing anal cancer-related fistulas before the initiation of standard chemoradiation; this strategy has the advantage of increasing the concentration of chemotherapeutics locally. The intra-arterial chemotherapy regimen consisted of cisplatin (8.5 mg/m2), 5-fluorouracil (275 mg/m2), methotrexate (27.5 mg/m2), mitomycin (1.2 mg/m2), four intra-arterial infusions per day for two days, and a single intravenous dose of bleomycin (10 mg) on the first day [1].\n\nThis is the first report of TC occurring after intra-arterial infusion chemotherapy. TC is a rare and unpredictable event in oncology which needs to be recognized by oncologists as fatal cases of TC are reported when patients are rechallenged with the same molecule.\n\nCase presentation\nA 45-year-old woman was admitted to the Oncology Unit to receive an induction intra-arterial chemotherapy for a locally advanced epidermoid carcinoma of the anal canal (T4NxMx), before the initiation of standard radio-chemotherapy with 5-fluorouracil and mitomycin C [1, 2]. The day after her chemotherapy, she developed nausea and vomiting accompanied by a poorly defined thoracic pain symptoms. Vital signs and physical examination were unremarkable. Symptoms were controlled by ondansetron. Later on the same day, she developed two episodes of oppressive retrosternal pain radiating to the right shoulder. At this time, the ECG (Fig. 1a) demonstrated 1.5 to 2 mm ST-segment elevation in leads V4 and V5; cardiac troponin T levels were elevated to 349 ng/l (normal values <14 ng/l). Shortly after, the patient developed hypotension (systolic blood pressure: 70 mmHg, Mean Arterial Pressure: 57 mmHg) and lost consciousness. Hypotension was refractory to aggressive fluid resuscitation (cardiogenic shock). The patient was admitted to the Intensive Care Unit (ICU) for aminergic support. Emergency coronary angiography showed no evidence of coronary artery disease or spasm. Transthoracic echocardiogram (TTE) revealed a reduced left ventricular ejection fraction (LVEF) of 30%, with apical and midventricular akinesis and preserved right ventricular function. Within 48 h, evolution was favorable, ECG normalized (Fig. 1b) and the patient was discharged from the ICU to the general ward. Low-dose metoprolol and lisinopril was initiated. The rest of the hospital course was uneventful and the patient was discharged home 13 days after chemotherapy.Fig. 1 ECG during (a) and after haemodynamic instability (b). ECG interpretation (during the hemodynamic instability, a): Sinus rhythm with 78 bpm, PR of 200 ms, QRS of 100 ms and QT of 360 ms; interventricular conduction delay and signs of early repolarization in V4-V6 as well as II, III et aVF; presence of a negative T wave in V1 concordant with the QRS axe; precordial transition in V4. The ECG after haemodynamic instability (b) was performed 24 h after the first one (a)\n\n\n\n\nTTE, performed 2 weeks after discharge showed normal LV function with LVEF of 60-65%. The diagnosis of TC was retained, according to the Mayo Clinic diagnostic criteria: 1. left ventricular mid segments akinesis with apical ballooning, 2. absence of angiographically evidence coronary disease or plaque rupture, 3. new ECG abnormalities with elevation in cardiac troponins; 4. absence of pheochromocytoma and myocarditis. [3, 4]. The patient was totally asymptomatic and both beta-blockers and ACE inhibitors were stopped. No other trigger except chemotherapy was found. She was not rechallenged with intra-arterial chemotherapy. A month after being discharged, she started chemoradiotherapy. She was given mitomycin only, due to the possible involvement of 5-fluorouracil, and to avoid any risk she was hospitalized to receive her chemotherapy and kept under close cardiac monitoring. The chemo-radiation was uneventful.\n\nDue to the poly-chemotherapy used we are unable to identify for sure the agent responsible. 5-fluorouracil and cisplatin have well-known cardiotoxic effects. Although less common, cardiotoxicity has been reported to occur also with methotrexate, mitomycin and bleomycin [5]. Because 5-fluorouracil is the most commonly incriminated molecule we can only conjecture that it is the culprit in our case. Of note, our patient did not appear to be in psychological distress, making the psychological trigger less likely.\n\nDiscussion & Conclusions\nTC (stress cardiomyopathy, apical ballooning syndrome, broken heart syndrome) is a form of reversible cardiomyopathy first described by Sato and colleagues in 1990 [6]. TC mimics myocardial infarction (chest pain, ECG abnormalities, cardiac troponin elevation) and is characterized by an acute and reversible dysfunction of the left ventricle (left ventricular mid segments akinesis with apical ballooning) in the absence of angiographically evidence coronary disease or plaque rupture [7].\n\nTC occurs most commonly in postmenopausal women (5.2/100000 women versus 0.6/100000 men), in a community setting or in a healthcare-related setting [8, 9]. Two percent of patients referred to the hospital for an acute coronary syndrome are diagnosed with TC [10]. Stress, either psychological (“primary form” of TC, up to ≈27% of the cases) or physical (“secondary form” of TC) is a common trigger of TC, however, for many cases no trigger is found. Hypertension, hyperlipidemia, diabetes mellitus, smoking and family history of cardiovascular disease are known TC risk factors, but their implication in the pathogenesis of TC is unclear [11].\n\nTC has a low mortality rate (1-3%) and most have completely recovered in a few weeks; a ≈ 10% recurrence is reported [8, 12]. Notably, a high-risk TC characterized by unfavorable clinical outcomes both in the short and in the long term has recently been described [11].\n\nTC pathogenesis is unclear; different paths have been suggested such as: increased sympathetic activity, coronary spasm, microvascular dysfunction, acute coronary syndrome with reperfusion injury, myocardial microinfarction, impaired myocardial fatty acid metabolism, oestrogen deficiency [13]. The most credited hypothesis is stress-induced release of cathecolamines, resulting in microvascular dysfunction and/or direct myocardial toxicity finally leading to myocardial stunning. Reduced estrogen levels in menopausal women may render the heart more vulnerable to catecholaminergic stress, thus explaining the higher frequency of TC in this population [14].\n\nSeveral reports have described the occurrence of TC during cancer treatment either by chemotherapy, tyrosine kinase inhibitors or monoclonal antibodies (Table 1). The occurrence of TC during oncologic treatments is commonly attributed to direct cardiotoxicity of the treatment (mostly via free radicals-induced cardiac myocyte damage and death) [15]. Other hypotheses such as a paraneoplastic phenomenon or a cancer-related stress (either psychological or physical, i.e. related to treatment or diagnostic procedures) have been described [16].Table 1 Oncology drugs associated with stress cardiomyopathy\n\nOncology drug(s)\tReferences\t\n5-Fluorouracil\tCheriparambil KM, et al. Angiology. 2000 [23]\nDalzell JR, et al. Anticancer Drugs. 2009 [24]\nGianni M, et al. Blood Coagul Fibrinolysis. 2009 [35]\nKobayashi N, et al. J Nippon Med Sch. 2009 [21]\nStewart T, et al. Intern Med J. 2010 [22]\nBasselin C, et al. Pharmacotherapy. 2011 [25]\nRadhakrishnan V, et al. J Pediatr Hematol Oncol. 2011 [19]\nGrunwald MR, et al. J Clin Oncol. 2012 [26]\nOzturk MA, et al. Blood Coagul Fibrinolysis. 2013 [17]\nKnott K, et al. Int J Cardiol. 2014 [20]\t\nCapecitabine\tQasem, et al. Am J Ther. 2014 [27]\nY-Hassan S, et al. Cardiovasc Revasc Med. 2013 [28]\t\nCytarabine\tMadias JE. Oncol Res Treat. 2015 [40]\nBaumann S, et al. Oncol Res Treat. 2014 [37]\t\nCisplatin, docetaxel\tToyooka S, et al. Gen Thorac Cardiovasc Surg. 2012 [38]\t\nCytarabine, daunorubicin\tGoel S, et al.World J Clin Cases. 2014 [33]\t\nPaclitaxel, hydroxyurea, 5-Fluorouracil, concurrent radiation\tSchweizer MT, et al. J Clin Oncol. 2011 [41]\t\nAxitinib\tOvadia D, et al. J Clin Oncol. 2015 [30]\t\nSunitinib\tNumico G, et al. J Clin Oncol. 2012 [39]\t\nBevacizumab\tFranco TH, et al. Ther Clin Risk Manag 2008 [31]\t\nRituximab\tSmith SA, et al. Heart Fail Clin. 2013 [15]\nNg KH, et al. BMJ Case Rep. 2015 [32]\t\nTrastuzumab\tBurgy M, et al. Anticancer Res. 2014 [42]\nKhanji M, et al. Clin Oncol (R Coll Radiol) 2013 [43]\t\nCetuximab, irinotecan\tKim L, et al. J Invasive Cardiol. 2008 [29]\t\nCombretastatin\tBhakta S, et al. Clin Cardiol. 2009 [18]\t\n\n\n\nSince 2000, 27 cases of cancer therapy-related TC have been reported in the literature, 19 attributed to chemotherapy (Table 1), 6 to monoclonal antibody and 2 to tyrosine kinase inhibitor therapies (Table 1). Amongst these 27 cases, 11 (40.7%) had 5-fluorouracil as part of the regiment, 8 were poly-chemotherapies. 5-fluorouracil is the most common drug associated to TC probably due to the ubiquitous use of this drug in oncology. Ozturk et al., have proposed a possible pathogenic mechanisms of TC due to 5-FU involving the formation of circulating microthrombi due to a 5FU-mediated kallikrein-thrombin generation finally leading to ventricular dysfunction [17].\n\nOf the 27 TC, 14 (52%) were male and 13 (48%) female. The median age was 60.0 years and the mean age 53.6 (standard deviation of ±23.7 years). Cardiovascular risk factors were reported in 11 patients (40.7%): including smoking (3/11; 27.2%), hypertension (5/11; 45.4%), dyslipidemia (3/11; 27.2%) and diabetes (2/11; 18.1%). TC tends to occur early after therapy administration. Of 26 TC cases, 4 (15.4%) occurred during treatment administration, and 14 (61.5%) within the first 6 days (hours: mean 45.3, median 38.0, standard deviation ±40.7) [17–34]. A later occurrence, (between 2 to 6 weeks) has been observed in 5 cases (15.4%) [31, 35–38]. One case occurred 4 years after tyrosine kinase inhibitor administration [39].\n\nIn 12 cases, it is not known whether rechallenge with the incriminated molecule was attempted. In 15 cases, 12 patients were deliberately changed to another regime, 3 patients were rechallenged with the same regimen. In 2 cases, patients suffered a cardiac arrest during or soon after infusion of 5-fluorouracil and platinum agent; despite prompts cardiopulmonary resuscitation the patient described by Radhakrishnan et al. died [19, 25]. In one case (an 85-year-old woman with diffuse large B cell lymphoma), the rechallenge with R-CHOP under close cardiac surveillance and using incrementally increasing doses of doxorubicin was successful [34].\n\nIn conclusion, TC is a rare and unpredictable event among oncologic patients. Nevertheless, patients under significant stress (physical or psychological) like the oncologic once and those with cardiovascular risk factors complaining of cardiac symptoms in particular within the first 6 days of their oncologic treatment should be carefully examined for signs of TC. The most frequent agent linked to TC is 5-fluorouracil. Rechallenging should be avoided.\n\nAbbreviations\nECGElectrocardiogram\n\nICUIntensive care unit\n\nLVLeft ventricular\n\nLVEFLeft ventricular ejection fraction\n\nR-CHOPRituximab, cyclophosphamide, doxorubicin, vincristine, prednisone\n\nTCTakotsubo cardiomyopathy\n\nTTETransthoracic echocardiogram\n\nAcknowledgements\nThe authors would like to thank Dr. Mary Flannery for her critical reading and suggestions.\n\nFunding\nAuthors have had no funding for this research.\n\nAvailability of data and materials\nPatient’s data are filed at the university hospital of Geneva. Transthoracic echocardiogram video during Takotsubo cardiomyopathy and after recovery are available on request. The coronarography video is available on request.\n\nAuthors’ contributions\nMC: collected patient data, drafted the manuscript. FR: Carried the transthoracic echocardiogram and the coronarography. AR: collected patient data, drafted the manuscript. TK: collected patient data, drafted the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nThe authors have obtained written informed consent from the patient for publication of this case report.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Kridel R, Cochet S, Roche B, Bressoud A, Gervaz P, Betz M, et al. Successful closure of anal cancer-related fistulas with upfront intra-arterial chemotherapy: a report of 8 cases. Dis Colon Rectum. 2011;54(5):566–9.\n2. Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB 3rd, Thomas CR Jr, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA. 2008;299(16):1914–21.\n3. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, Wright RS, Rihal CS. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Intern Med. 2004; 7;141(11):858-865. Review.\n4. Prasad A Lerman A Rihal CS Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction Am Heart J 2008 155 3 408 417 10.1016/j.ahj.2007.11.008 18294473 \n5. Floyd JD, Nguyen DT, Lobins RL, Bashir Q, Doll DC, Perry MC. Cardiotoxicity of cancer therapy. J Clin Oncol. 2005; 20;23(30):7685-7696.\n6. Sato H Tateishi H Uchida T Kodama K Haze K Hon M Takotsubo-type cardiomyopathy due to multivessel spasm Clinical aspect of myocardial injury: from ischemia to heart failure 1990 Tokyo, Japan Kagakuhyouronsha 56 64 \n7. Yoshikawa T. Takotsubo cardiomyopathy, a new concept of cardiomyopathy: clinical features and pathophysiology. Int J Cardiol. 2015,1;182:297-303.\n8. Gopalakrishnan M, Hassan A, Villines D, Nasr S, Chandrasekaran M, Klein LW. Predictors of short- and long-term outcomes of Takotsubo cardiomyopathy. Am J Cardiol. 2015, 15;116(10):1586-1590.\n9. Ghadri JR Ruschitzka F Lüscher TF Templin C Takotsubo cardiomyopathy: still much more to learn Heart 2014 100 22 1804 1812 10.1136/heartjnl-2013-304691 24711482 \n10. Sharkey SW Maron BJ Epidemiology and clinical profile of Takotsubo cardiomyopathy Circ J 2014 78 9 2119 2128 10.1253/circj.CJ-14-0770 25099475 \n11. Sharkey SW Pink VR Lesser JR Garberich RF Maron MS Maron BJ Clinical profile of patients with high-risk Tako-Tsubo Cardiomyopathy Am J Cardiol 2015 116 5 765 772 10.1016/j.amjcard.2015.05.054 26144453 \n12. Bybee KA, Prasad A. Stress-related cardiomyopathy syndromes. Circulation. 2008, 22;118(4):397-409.\n13. Komamura K, Fukui M, Iwasaku T, Hirotani S, Masuyama T. Takotsubo cardiomyopathy: Pathophysiology, diagnosis and treatment. World J Cardiol. 2014, 26;6(7):602-9.\n14. Boland TA Lee VH Bleck TP Stress-induced cardiomyopathy Crit Care Med 2015 43 3 686 693 10.1097/CCM.0000000000000851 25565459 \n15. Smith SA Auseon AJ Chemotherapy-induced takotsubo cardiomyopathy Heart Fail Clin 2013 9 2 233 242 10.1016/j.hfc.2012.12.009 23562124 \n16. Madias JE. Is Takotsubo syndrome in patients receiving chemotherapy drug-specific? World J Clin Cases. 2015, 16;3(2):204-205.\n17. Ozturk MA Ozveren O Cinar V Erdik B Oyan B Takotsubo syndrome: an underdiagnosed complication of 5-fluorouracil mimicking acute myocardial infarction Blood Coagul Fibrinolysis 2013 24 1 90 94 10.1097/MBC.0b013e3283597605 23249567 \n18. Bhakta S, Flick SM, Cooney MM, Greskovich JF, Gilkeson RC, Remick SC, et al. Myocardial stunning following combined modality combretastatin-based chemotherapy: two case reports and review of the literature. Clin Cardiol. 2009;32(12):E80–4.\n19. Radhakrishnan V Bakhshi S 5-fluorouracil-induced acute dilated cardiomyopathy in a pediatric patient J Pediatr Hematol Oncol 2011 33 4 323 10.1097/MPH.0b013e3181f46e65 21423045 \n20. Knott K, Starling N, Rasheed S, Foran J, Cafferkey C, Rosen S, Nicholson A, Baksi J, Lyon A. A case of Takotsubo syndrome following 5-fluorouracil chemotherapy. Int J Cardiol. 2014 15;177(2):e65-e67.\n21. Kobayashi N Hata N Yokoyama S Shinada T Shirakabe A Mizuno K A case of Takotsubo cardiomyopathy during 5-fluorouracil treatment for rectal adenocarcinoma J Nippon Med Sch 2009 76 1 27 33 10.1272/jnms.76.27 19305108 \n22. Stewart T Pavlakis N Ward M Cardiotoxicity with 5-fluorouracil and capecitabine: more than just vasospastic angina Intern Med J 2010 40 4 303 307 10.1111/j.1445-5994.2009.02144.x 20529041 \n23. Cheriparambil KM Vasireddy H Kuruvilla A Gambarin B Makan M Saul BI Acute reversible cardiomyopathy and thromboembolism after cisplatin and 5-fluorouracil chemotherapy--a case report Angiology 2000 51 10 873 878 10.1177/000331970005101011 11108333 \n24. Dalzell JR Samuel LM The spectrum of 5-fluorouracil cardiotoxicity Anti-Cancer Drugs 2009 20 1 79 80 10.1097/CAD.0b013e3283165f27 19353811 \n25. Basselin C, Fontanges T, Descotes J, Chevalier P, Bui-Xuan B, Feinard G, et al. 5-fluorouracil-induced Tako-Tsubo-like syndrome. Pharmacotherapy. 2011;31(2):226.\n26. Grunwald MR, Howie L, Diaz LA Jr. Takotsubo cardiomyopathy and fluorouracil: case report and review of the literature. J Clin Oncol. 2012, 10;30(2):e11–e14.\n27. Qasem A, Bin Abdulhak AA, Aly A, Moormeier J. Capecitabine-Induced Takotsubo Cardiomyopathy: A Case Report and Literature Review. Am J Ther. 2016;23(5):e1188–92.\n28. Y-Hassan S Tornvall P Törnerud M Henareh L Capecitabine caused cardiogenic shock through induction of global Takotsubo syndrome Cardiovasc Revasc med 2013 14 1 57 61 10.1016/j.carrev.2012.10.001 23218901 \n29. Kim L Karas M Wong SC Chemotherapy-induced takotsubo cardiomyopathy J Invasive Cardiol 2008 20 12 E338 E340 19057042 \n30. Ovadia D, Esquenazi Y, Bucay M, Bachier CR. Association between takotsubo cardiomyopathy and axitinib: case report and review of the literature. J Clin Oncol. 2015, 1; 33(1):e1-e3.\n31. Franco TH Khan A Joshi V Thomas B Takotsubo cardiomyopathy in two men receiving bevacizumab for metastatic cancer Ther Clin Risk Manag 2008 4 6 1367 1370 10.2147/TCRM.S3960 19337443 \n32. Ng KH Dearden C Gruber P Rituximab-induced Takotsubo syndrome: more cardiotoxic than it appears? BMJ Case Rep 2015 2 2015 \n33. Goel S, Sharma A, Garg A, Chandra A, Shetty V. Chemotherapy induced Takotsubo cardiomyopathy. World J Clin Cases. 2014, 16;2(10):565-568.\n34. Fernandez SF, Basra M, Canty JM Jr. Takotsubo Cardiomyopathy following initial chemotherapy presenting with syncope and Cardiogenic shock ? A case report and literature review. J Clinic Experiment Cardiol. 2:124.\n35. Gianni M Dentali F Lonn E 5 flourouracil-induced apical ballooning syndrome: a case report Blood Coagul Fibrinolysis 2009 20 4 306 308 10.1097/MBC.0b013e328329e431 19300240 \n36. Lim SH Wilson SM Hunter A Hill J Beale P Takotsubo cardiomyopathy and 5-fluorouracil: getting to the heart of the matter Case Rep Oncol Med 2013 2013 206765 24368954 \n37. Baumann S, Huseynov A, Goranova D, Faust M, Behnes M, Nolte F, et al. Takotsubo cardiomyopathy after systemic consolidation therapy with high-dose intravenous cytarabine in a patient with acute myeloid leukemia. Oncol res Treat. 2014;37(9):487–90.\n38. Toyooka S, Akagi S, Furukawa M, Nakamura K, Soh J, Yamane M, et al. Takotsubo cardiomyopathy associated with pulmonary resections after induction chemoradiotherapy for non-small cell lung cancer. Gen Thorac Cardiovasc Surg. 2012;60(9):599–602.\n39. Numico G, Sicuro M, Silvestris N, Mozzicafreddo A, Trogu A, Malossi A, Cristofano A, Thiebat B. Takotsubo syndrome in a patient treated with sunitinib for renal cancer. J Clin Oncol. 2012, 20;30(24):e218-e220.\n40. Madias JE Cytarabine, venous catheter removal, sepsis, diagnosis of malignancy, and takotsubo syndrome Oncol Res Treat 2015 38 3 125 10.1159/000380797 25792084 \n41. Schweizer MT, Mehta R, Salgia R, Villaflor VM. Takotsubo cardiomyopathy in a patient with squamous cell esophageal carcinoma. J Clin Oncol. 2011, 10;29(20):e598-e600.\n42. Burgy M, Brossat H, Barthelemy P, Imperiale A, Trinh A, Hazam CA, et al. First report of trastuzumab treatment after postoperative Takotsubo cardiomyopathy. Anticancer Res. 2014;34(7):3579–82.\n43. Khanji M Nolan S Gwynne S Pudney D Ionescu A Tako-Tsubo syndrome after trastuzumab - an unusual complication of chemotherapy for breast cancer Clin Oncol (R Coll Radiol) 2013 25 5 329 10.1016/j.clon.2012.12.007 23434354\n\n",
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"keywords": "Case report; Chemotherapy; Intra-arterial chemotherapy; Rechallenge; Takotsubo cardiomyopathy",
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"mesh_terms": "D001005:Anus Neoplasms; D002294:Carcinoma, Squamous Cell; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D054549:Takotsubo Cardiomyopathy",
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"title": "Chemotherapy-induced Takotsubo cardiomyopathy, a case report and review of the literature.",
"title_normalized": "chemotherapy induced takotsubo cardiomyopathy a case report and review of the literature"
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"abstract": "Many new serotonergic antidepressants have been introduced over the past decade. Although urinary incontinence is listed as one side effect of these drugs in their package inserts there is only one report in the literature. This concerns 2 male patients who experienced incontinence while taking venlafaxine. In the present paper the authors describe 2 female patients who developed incontinence secondary to the selective serotonin reuptake inhibitors paroxetine and sertraline, as well as a third who developed this side effect on venlafaxine. In 2 of the 3 cases the patients were also taking lithium carbonate and beta-blockers, both of which could have contributed to the incontinence. Animal studies suggest that incontinence secondary to serotonergic antidepressants could be mediated by the 5HT4 receptors found on the bladder. Further research is needed to delineate the frequency of this troubling side effect and how best to treat it.",
"affiliations": "Department of Psychiatry and Pharmacy, Ohio State University, Columbus 43210, USA.",
"authors": "Votolato|N A|NA|;Stern|S|S|;Caputo|R M|RM|",
"chemical_list": "D003511:Cyclohexanols; D017367:Serotonin Uptake Inhibitors; D017374:Paroxetine; D000069470:Venlafaxine Hydrochloride; D020280:Sertraline",
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"mesh_terms": "D000328:Adult; D001714:Bipolar Disorder; D003511:Cyclohexanols; D003866:Depressive Disorder; D005260:Female; D006801:Humans; D008875:Middle Aged; D017374:Paroxetine; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline; D014549:Urinary Incontinence; D000069470:Venlafaxine Hydrochloride",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Serotonergic antidepressants and urinary incontinence.",
"title_normalized": "serotonergic antidepressants and urinary incontinence"
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"abstract": "OBJECTIVE\nThe purpose of this study is to provide resistance data for Escherichia coli isolates causing urinary tract infections in emergency department (ED) patients not requiring admission and explore if differences between this subpopulation and the hospital antibiogram exist. Differences between community-acquired urinary tract infection (CA-UTI) and health care-associated (HA-UTI) subgroups were also investigated.\n\n\nMETHODS\nPatients with a positive urine culture treated and discharged from the ED of a 200-bed community hospital were reviewed. Patients with urinary isolates of more than 100000 colony-forming unit/mL and documented intention to treat were included. Patients who required admission, were pregnant, less than the age of 18 years, or who had a positive culture but without any evidence of intention to treat were excluded. Only the initial visit was included for patients who returned to the ED within 7 days.\n\n\nRESULTS\nOverall, 308 visits were screened, and 217 were included. Of these, 78.3% were CA-UTI, and 21.7% were HA-UTI. Females comprised 88.5% of all patients. E coli was the most common pathogen overall and in both subgroups. E coli resistance to levofloxacin was 13.5% overall, 9.2% for CA-UTI, and 38.5% for HA-UTI compared with 27% on the hospital antibiogram. E coli resistance to sulfamethoxazole/trimethoprim was 26.9% overall, 25.2% for CA-UTI, and 34.6% for HA-UTI vs 26% on the antibiogram.\n\n\nCONCLUSIONS\nE coli susceptibility for ED patients not requiring admission may not be accurately represented by hospital antibiograms that contain culture data from various patient types, sites of infection, or patients with varying illness severity. Separation of the ED population into CA-UTI and HA-UTI subgroups may be helpful when selecting empiric antibiotic therapy.",
"affiliations": "Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Athens, GA. Electronic address: vfleming@mail.rx.uga.edu.;St Francis Hospital, Columbus, GA.;Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Athens, GA.",
"authors": "Fleming|Virginia H|VH|;White|Bryan P|BP|;Southwood|Robin|R|",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D024881:Drug Resistance, Bacterial; D004636:Emergency Service, Hospital; D004927:Escherichia coli Infections; D005260:Female; D006764:Hospitals, Community; D006801:Humans; D064704:Levofloxacin; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D012189:Retrospective Studies; D012720:Severity of Illness Index; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014552:Urinary Tract Infections; D055815:Young Adult",
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"title": "Resistance of Escherichia coli urinary isolates in ED-treated patients from a community hospital.",
"title_normalized": "resistance of escherichia coli urinary isolates in ed treated patients from a community hospital"
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"abstract": "The association between immune checkpoint inhibitors (ICIs) and Stevens-Johnsons syndrome (SJS) /toxic epidermal necrolysis (TEN) is unclear. We assessed the risk of SJS and TEN related to ICIs, via a systematic analysis of SJS/TEN cases reported in clinical trials and the FDA Adverse Event Reporting System (FAERS).\nWe explored ICIs related SJS/TEN events in randomized control trials available in ClinicalTrials.gov and electronic databases (Pubmed, Embase, the Cochrane Central Register of Controlled Trials) up to 12 January 2021. Meta-analysis was performed by using Peto odds ratios (ORs) with 95% CIs. In a separate retrospective pharmacovigilance study of FAERs, cases of ICIs related SJS/TEN were extracted between the first quarter (Q1) of 2004 and Q4 of 2020. Disproportionality was analyzed using the proportional reports reporting odds ratio (ROR) and information components (IC). PROSPERO registration number: CRD42021232399.\nA total of 20 RCTs (11597 patients) were included. ICIs were associated with an increased risk of SJS/TEN (OR= 4.33, 95%CI:1.90-9.87). FAERS pharmacovigilance data identified 411 cases of SJS (n = 253) or TEN (n = 184) related to ICIs therapy. ICIs were significantly associated with SJS/TEN (n = 411; ROR=2.88, 95%CI:2.61-3.17; IC=1.49, 95%CI:1.35-1.65). The median onset time of SJS/TEN was 25.5 days (SJS:21.5 days; TEN:32 days) (n = 190), 97.5% of patients discontinued use of ICIs when suffering from SJS/TEN (n = 201). Of 305 cases that reported outcomes, 113 (37%) resulted in death (SJS:19.9%, TEN:61.6%).\nThese data suggest that ICIs were significantly associated with increased risk of SJS/TEN.",
"affiliations": "Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China.;Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China.;Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China.;Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China.;Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China.;Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China.;Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China.;Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China.;Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China.;Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China.",
"authors": "Zhu|Jianhong|J|;Chen|Guanghui|G|;He|Zhichao|Z|;Zheng|Yayuan|Y|;Gao|Siyuan|S|;Li|Jianfang|J|;Ling|Yin|Y|;Yu|Xiaoxia|X|;Qiu|Kaifeng|K|;Wu|Junyan|J|",
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"doi": "10.1016/j.eclinm.2021.100951",
"fulltext": "\n==== Front\nEClinicalMedicine\nEClinicalMedicine\nEClinicalMedicine\n2589-5370\nElsevier\n\nS2589-5370(21)00231-5\n10.1016/j.eclinm.2021.100951\n100951\nResearch Paper\nStevens-Johnson syndrome/toxic epidermal necrolysis in patients treated with immune checkpoint inhibitors: A safety analysis of clinical trials and FDA pharmacovigilance database\nZhu Jianhong ab1\nChen Guanghui ab1\nHe Zhichao ab1\nZheng Yayuan ab1\nGao Siyuan ab1\nLi Jianfang ab\nLing Yin ab\nYu Xiaoxia ab1\nQiu Kaifeng ab\nWu Junyan wujunyan@mail.sysu.edu.cn\nab⁎\na Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China\nb Department of pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510120, PR China\n⁎ Corresponding author. wujunyan@mail.sysu.edu.cn\n1 These authors contributed equally to this work.\n\n10 6 2021\n7 2021\n10 6 2021\n37 10095118 2 2021\n17 5 2021\n20 5 2021\n© 2021 The Author(s)\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nBackground\n\nThe association between immune checkpoint inhibitors (ICIs) and Stevens-Johnsons syndrome (SJS) /toxic epidermal necrolysis (TEN) is unclear. We assessed the risk of SJS and TEN related to ICIs, via a systematic analysis of SJS/TEN cases reported in clinical trials and the FDA Adverse Event Reporting System (FAERS).\n\nMethods\n\nWe explored ICIs related SJS/TEN events in randomized control trials available in ClinicalTrials.gov and electronic databases (Pubmed, Embase, the Cochrane Central Register of Controlled Trials) up to 12 January 2021. Meta-analysis was performed by using Peto odds ratios (ORs) with 95% CIs. In a separate retrospective pharmacovigilance study of FAERs, cases of ICIs related SJS/TEN were extracted between the first quarter (Q1) of 2004 and Q4 of 2020. Disproportionality was analyzed using the proportional reports reporting odds ratio (ROR) and information components (IC). PROSPERO registration number: CRD42021232399.\n\nFindings\n\nA total of 20 RCTs (11597 patients) were included. ICIs were associated with an increased risk of SJS/TEN (OR= 4.33, 95%CI:1.90–9.87). FAERS pharmacovigilance data identified 411 cases of SJS (n = 253) or TEN (n = 184) related to ICIs therapy. ICIs were significantly associated with SJS/TEN (n = 411; ROR=2.88, 95%CI:2.61–3.17; IC=1.49, 95%CI:1.35–1.65). The median onset time of SJS/TEN was 25.5 days (SJS:21.5 days; TEN:32 days) (n = 190), 97.5% of patients discontinued use of ICIs when suffering from SJS/TEN (n = 201). Of 305 cases that reported outcomes, 113 (37%) resulted in death (SJS:19.9%, TEN:61.6%).\n\nInterpretation\n\nThese data suggest that ICIs were significantly associated with increased risk of SJS/TEN.\n==== Body\nResearch in context\n\nEvidence before this study\n\nWe searched PubMed for articles published until February 1, 2021, with the terms (“immune checkpoint inhibitors” OR “PD1” OR “PD-L1” OR “nivolumab” OR “pembrolizumab” OR “cemiplimab” OR “atezolizumab” OR “avelumab” OR “durvalumab” OR “ipilimumab” OR “tremelimumab”) AND (“Stevens-Johnson syndrome” and “toxic epidermal necrolysis”). Our search retrieved no reports of meta-analyses or pharmacovigilance studies investigated the between immune checkpoint inhibitors and Stevens-Johnsons syndrome /toxic epidermal necrolysis.\n\nAdded value of this study\n\nTo the best of our knowledge, this study is the largest and most extensive analysis of Stevens-Johnsons syndrome/toxic epidermal necrolysis associated with immune checkpoint inhibitors collected data from both clinical trials and a worldwide pharmacovigilance database to date. Meta-analysis of 20 RCTs suggested that immune checkpoint inhibitors are associated with increased risk of Stevens-Johnsons syndrome/toxic epidermal necrolysis. FAERS pharmacovigilance data of 411 cases also indicated that immune checkpoint inhibitors were significantly associated with over-reporting frequencies of Stevens-Johnsons syndrome/toxic epidermal necrolysis. The median onset time of events was 25.5 days, with a mortality rate of 37%.\n\nImplications of all the available evidence\n\nBoth meta-analysis of RCT's and real-world FAERS pharmacovigilance data suggested that the immune checkpoint inhibitors may increase the risk of Stevens-Johnsons syndrome/toxic epidermal necrolysis. Further studies are needed to identify risk factors and optimal management of Stevens-Johnsons syndrome/toxic epidermal necrolysis-like reactions to immune checkpoint inhibitors.\n\nAlt-text: Unlabelled box\n\n1 Introduction\n\nImmune checkpoint inhibitors (ICIs), include agents target programmed death-1 receptor (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have radically transformed the therapeutic landscape for multiple cancer types [1]. Despite the survival benefits of ICIs therapy, these treatments can also lead to a variety of immune-related adverse events (irAEs), include cutaneous reactions, such as morbilliform, psoriasiform, lichenoid, eczematous, and rah are common in patients on these drugs [2,3].\n\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and life threatening skin adverse reactions, characterized by flaccid blister formation, rapidly progressive and extensive necrosis with epidermal detachment [4,5], SJS involves <10% body surface area and TEN >30% body surface area [4]. Therefore, knowing the incidence and risk of SJS/TEN associated with ICIs will help practitioners to make appropriate measures to limit their effects. SJS/TEN events related to ICIs are reported occasionally in small case series and case reports [6,7], but no definitive data have been established.\n\nGiven the widespread and increasing use of ICIs in real world, and the potential risk of SJS/TEN induced by ICIs, performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to estimate the risk of developing SJS/TEN related to ICIs. Furthermore, we also examine reported events of ICIs-associated SJS/TEN in clinical practice using real-world pharmacovigilance data from Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) [8].\n\n2 Methods\n\n2.1 Study design\n\nFirstly, we did a meta-analysis of RCTs to investigate the risk of SJS/TEN in patients treated with ICIs. Furthermore, a retrospective data mining analysis was conducted using the FDA FAERS database to further examine the risk of SJS/TEN in clinical practice. J. W. had full access to all the data in the study\n\n2.2 Systematic review procedures\n\nThis study was prospectively registered in PROSPERO (https://www.crd.york.ac.uk/PROSPERO/) (CRD42021232399). The meta-analysis was performed according to the PRISMA checklist [9]. A systematic literature review was performed in Pubmed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) [10], and the ClinicalTrials.gov website to identify randomized clinical trials of immune checkpoint inhibitors (up to 12 January 2021), with no language restriction. Terms related to immune checkpoint inhibitors (nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, ipilimumab and tremelimumab) and study design (RCT) were used. RCTs that compared immune checkpoint inhibitors versus placebo or active controls in cancer patients and reported adverse events of SJS/TEN were eligible for inclusion.\n\nData were collected by two authors (J.Z. and G.C.) independently, and discrepancies were resolved by a third investigator (Z.H.). The number of patients with SJS/TEN events classified according to the Cancer Therapy Evaluation Program (CTEP) in trials reported on ClinicalTrials.gov was extracted [11]. We further collected SJS/TEN events according to the Common Terminology Criteria for Adverse Events (CTCAE) in published RCTs [12], if data were not available on ClinicalTrials.gov. For each included trial, additional data including NCT number, trial name, study design, ICIs regimen, control arm regimen, median age, median follow-up, sample size, and tumor type was also extracted. The risk of bias of all included RCTs was examined by two reviewers (Y.Z. and S.G.) concurrently according to the recommendations outlined in the Cochrane Handbook [13].\n\nThe primary outcome was the summary risk of SJS/TEN related to immune checkpoint inhibitors, we performed a meta-analysis to compute Peto odds ratios (ORs) with 95% CIs. Between-study heterogeneity was determined by using the inconsistency index I2, with I2 values over 50% suggest substantial between-study heterogeneity [14]. Prespecified subgroup analyses were done according to the type of ICIs (ICIs treatment schedule), case of events (SJS vs TEN) or source of data (published paper vs ClinicalTrials.gov). In addition, if more than 10 studies were included in one meta-analysis, we also accessed the publication bias represented by the Egger's test [15,16]. A two-sided p value of less than 0.05 in all analyses was considered statistically significant. Statistical analyses were performed using Stata software (version 12.0).\n\n2.3 Pharmacovigilance study procedures\n\nReal-world pharmacovigilance data from FAERS were searched for SJS/TEN events from January 1, 2011 to December 31, 2020, with the MedDRA (version 23.1) preferred terms “Stevens-Johnson syndrome” (Preferred Term) and “toxic epidermal necrolysis” (Preferred Term), generic name of ICIs (nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, ipilimumab and tremelimumab) were used to identify cases notified as suspected to be caused by ICIs [17]. When available, data of clinical characteristics was also collected: reporter (health-care professional or non-health-care professional), sex, age, report countries, indication, reporting year, ICIs characteristics (regimen, start and end date, and treatment modifications), and SJS/TEN characteristics (date of event and reaction outcome). To avoid bias, data mining was performed by independent researchers by using the OpenVigil FDA tool [18]. Before performing statistical analysis, duplicate reports were removed by reviewing the unique ID and the case characteristics.\n\nTwo data mining methods using proportional reports reporting odds ratio (ROR) and Bayesian confidence propagation neural networks of information components (IC) were used to preform disproportionality analysis [14,19], with all other drugs/events recorded in FAERS as a comparator. For ROR, the lower limit of the 95% confidence interval (CI) of the ROR (ROR025) >1 with at least three case indicate a significant signal. For IC, the lower end of a 95% CI of the IC(IC025) >0 suggest a significant signal. Data analyses were performed using the Microsoft Excel (2010, Microsoft).\n\n2.4 Role of the funding source\n\nThe funder had no role in the study design, data collection, data analysis, data interpretation, and writing of the report.\n\n3 Results\n\nOf 4574 articles obtained from the initial search of the databases, 20 RCTs were included in the final analysis (Fig 1). Detailed baseline characteristics of the included trials are summarised in Table 1. Six trials were conducted in patients with lung cancer, 4 in patients with melanoma, 2 in patients with renal cell carcinoma, 2 in patients with multiple myeloma, 2 in patients with urothelial carcinoma, 2 in patients with gastroesophageal, one in head and neck, and one in hepatocellular carcinoma patients. Nivolumab used in 7 trials, ipilimumab used in 5 trials, pembrolizumab used in 5 trials, atezolizumab in 3 trials, durvalumab in 2 trials, and tremelimumab in 2 trials. Five trials used a combination of anti-PD-1/PDL-1 plus CTLA-4 treatment. The duration of the follow-up ranged from 9 to 61.6 months. Events of SJS/TEN collected from 9 published trials (supplementary material p.1), and the others were from ClinicalTrials.gov. Seven studies used blinding methods were judged to have a low risk of bias according to the Cochrane instrument (supplementary material p.2-p.3).Fig 1 Flow diagram of trial selection.\n\nFig 1\n\nTable 1 Characteristics of included randomised controlled trials.\n\nTable 1Study\tIntervention\tCancer type\tSex, Male\tSample Size\tAge years Mean\n(Standard Deviation)\tMedian follow-up\tEvents reported\t\nNCT02576509\tNivolumab\tHepatocellular Carcinoma\t84.9%\t367\t63.9 (10.61)\t3.5y\tClinicalTrials.gov\t\n\tSorafenib\t\t\t363\t64.5 (10.91)\t\t\t\nNCT02231749\tNivolumab + Ipilimumab\tRenal Cell Carcinoma\t73.7%\t547\t61.1 (9.76)\t31m\tClinicalTrials.gov\t\n\tSunitinib\t\t\t535\t60.7 (10.10)\t\t\t\nNCT02481830\tNivolumab\tSmall-cell Lung Cancer\t61.7%\t282\t61.5 (9.2)\tNR\tClinicalTrials.gov\t\n\tChemotherapy\t\t\t265\t61.6 (8.4)\t\t\t\nNCT02041533\tNivolumab\tNSCLC\t61.4%\t267\t62.8 (10.25)\t18m\tClinicalTrials.gov\t\nCarbone 2017\tChemotherapy\t\t\t263\t63.4 (9.63)\t\tCarbone 2017\t\nNCT03215706\tNivolumab + Ipilimumab + Chemotherapy\tNSCLC\t70.1%\t358\t65.0 (8.3)\t23m\tClinicalTrials.gov\t\n\tChemotherapy\t\t\t349\t65.0 (10.3)\t\t\t\nNCT03950674\tNivolumab + Chemotherapy\tNSCLC\t77.5%\t25\t59.6 (12.7)\tNR\tClinicalTrials.gov\t\n\tChemotherapy\t\t\t15\t60.9 (11.8)\t\t\t\nNCT02579863\tPembrolizumab + Lenalidomide + Dexamethasone\tMultiple Myeloma\t46.5%\t154\t74.4 (6.0)\t30m\tUsmani 2019\t\nUsmani 2019\tLenalidomide + Dexamethasone\t\t\t148\t74.3 (5.9)\t\t\t\nNCT02576977\tPembrolizumab+Pomalidomide+Dexamethasone\tMultiple Myeloma\t62.5%\t122\t65.5 (9.3)\t33m\tMateos 2019\t\n\tPomalidomide+Dexamethasone\t\t\t123\t66.4 (10.0)\t\t\t\nNCT02494583\tPembrolizumab + Chemotherapy\tGastric or Gastroesophageal Junction\t72.6%\t250\t60.9 (11.6)\t42m\tClinicalTrials.gov\t\n\tPembrolizumab\t\t\t254\t59.9 (11.6)\t\t\t\n\tChemotherapy\t\t\t244\t60.7 (12.7)\t\t\t\nNCT02252042\tPembrolizumab\tHead and Neck\t83.2%\t246\t60.3 (9.8)\t27m\tCohen 2019\t\n\tStandard Treatment\t\t\t234\t60.2 (8.6)\t\t\t\nNCT01704287\tPembrolizumab 2 mg/kg\tMelanoma\t60.6%\t178\t59.5 (14.9)\t75 m\tClinicalTrials.gov\t\n\tPembrolizumab 10 mg/kg\t\t\t179\t60.1 (13.3)\t\t\t\n\tChemotherapy\t\t\t171\t60.5 (12.7)\t\t\t\nNCT02302807\tAtezolizumab 1200mg every 21d\tUrothelial Bladder\t77.1%\t459\t65.9 (9.6)\t46m\tPowles 2018\t\n\tChemotherapy\t\t\t443\t66.1 (9.3)\t\t\t\nNCT02420821\tAtezolizumab + Bevacizumab\tRenal Cell Carcinoma\t73.1%\t\t\t\tClinicalTrials.gov\t\n\tSunitinib\t\t\t\t\t\t\t\nNCT02908672\tAtezolizumab + Cobimetinib + Vemurafenib\tMelanoma\t58.2%\t230\t54.0 (14.2)\t9m\tClinicalTrials.gov\t\n\tCobimetinib + Vemurafenib\t\t\t281\t53.2 (14.1)\t\t\t\nNCT00094653\tIpilimumab Plus gp100\tMelanoma\t59.3%\t380\t55.6\t61.6m\tClinicalTrials.gov\t\n\tIpilimumab\t\t\t131\t56.8\t\t\t\n\tgp100\t\t\t132\t57.4\t\t\t\nNCT02516241\tDurvalumab±tremelimumab\tUrothelial carcinoma\t75.5%\t340\t67\t41.2m\tPowles 2020\t\nPowles 2020\tDurvalumab\t\t\t348\t67\t\t\t\n\tChemotherapy\t\t\t313\t68\t\t\t\nNCT03043872\tDurvalumab±tremelimumab +Chemotherapy\tSCLC\t71.6%\t266\t63\t25.1m\tGoldman 2021\t\n\tDurvalumab +Chemotherapy\t\t\t265\t62\t\t\t\n\tChemotherapy\t\t\t266\t63\t\t\t\nNCT02569242\tNivolumab\tOesophageal squamous cell carcinoma\t89%\t209\t64\t\tKato 2019\t\nKato 2019\tChemotherapy\t\t\t208\t67\t\t\t\nNCT02523313\tIpilimumab+Nivolumab\tMelanoma\t57%\t55\t52\t28.4m\tZimmer 2020\t\nZimmer 2020\tNivolumab\t\t\t56\t57\t\t\t\n\tPlacebo\t\t\t51\t58.5\t\t\t\nNCT00527735\tIpilimumab + Paclitaxel/Carboplatin\tNSCLC/SCLC\t74.6%\t222\t/\tNR\tClinicalTrials.gov\t\n\tPaclitaxel/Carboplatin\t\t\t109\t/\t\t\t\n\nPooled data from 20 trials, SJS/TEN occurred in 22 of 6638 participants randomized to the ICIs group and 2 of 4959 participants randomized to the control group. Meta-analysis showed that ICIs was associated with increased risk of SJS/TEN. The OR of SJS/TEN associated with ICIs was 4.33 (95% CI: 1.90–9.87, P < 0.001) with insignificant heterogeneity (I2 = 0%) (Fig 2). Results of subgroup analysis indicated that OR of SJS/TEN associated with ICIs did not vary significantly by type of ICIs (ICIs treatment schedule, Pinteraction=0.92), case of events (SJS vs TEN, Pinteraction=0.504) or source of data (published paper vs ClinicalTrials.gov, Pinteraction=0.703) (supplementary material p.4–p.6). No publication bias was observed among the included studies for the meta-analysis of SJS/TEN in the present study (Egger's test P = 0.974).Fig 2 Odds ratios of SJS/TEN in cancer patients treatment with ICIs compare with control.\n\nFig 2\n\nFrom January 1, 2011 to December 31, 2020, there were 10 840 246 total adverse reactions of any drug reported, with 101 328 related to ICIs. Of these reports with ICIs, 411 SJS/TEN reactions were reported. Patient characteristics are summarised in Table 2. Most cases were reported by health professionals (77.3%), with median onset age of 66 years, and the male cases were slightly more than female cases (58.7% vs 41.3%). Most cases were observed in patients with lung cancer (46.6%), melanoma (17.3%), renal cancer (8.1%), lymphoma (4.7%) and head and neck cancer (4.5%). The number of cases increased during the 2011–2020 period, mainly from United States, Japan and Europe. Life-threatening events were higher (All cases:37%, SJS:19.9%, TEN:61.6%), almost all patients discontinued use of ICIs when suffered from SJS/TEN (97.5%). The median onset time of SJS/TEN was 25.5 days (SJS:21.5 days; TEN:32 days).Table 2 Characteristics of ICIs related SJS/TEN cases from FAERs database.\n\nTable 2\tAll cases (n = 411)\tSJS(n = 253)\tTEN (n = 184)\t\nReporter\t\t\t\t\nTotal data\t406\t250\t181\t\nHealth-care professional\t314(77.3%)\t191(76.4%)\t141(77.9%)\t\nNon-health-care professional\t92(22.7%)\t59(23.6%)\t40(22.1%)\t\nSex\t\t\t\t\nTotal data\t361\t229\t155\t\nMale\t212(58.7%)\t139(60.7%)\t88(56.8%)\t\nFemale\t149(41.3%)\t90(39.3%)\t67(43.2%)\t\nAge\t\t\t\t\nTotal data\t305\t190\t132\t\nMedian\t66years\t65years\t66years\t\nRange\t32–89years\t32–87years\t36–89years\t\nIndication\t\t\t\t\nTotal data\t358\t217\t161\t\nLung cancer\t167(46.6%)\t101(46.5%)\t77(47.8%)\t\nMelanoma\t62(17.3%)\t31(14.3%)\t32(19.9%)\t\nRenal Cancer\t29(8.1%)\t15(6.9%)\t15(9.3%)\t\nLymphoma\t17(4.7%)\t7(3.2%)\t12(7.5%)\t\nHead And Neck Cancer\t16(4.5%)\t15(6.9%)\t2(1.2%)\t\nOther cancer/Unknown Indication\t67(18.7%)\t48(22.1%)\t23(14.3%)\t\nReport countries\t\t\t\t\nTotal data\t409\t251\t184\t\nJapan,JP\t119(29.1%)\t94(37.5%)\t31(16.8%)\t\nUnited States,US\t109(26.7%)\t75(29.9%)\t45(24.5%)\t\nGermany,DE\t35(8.6%)\t13(5.2%)\t26(14.1%)\t\nCanada, CA\t27(6.6%)\t7(2.8%)\t20(10.9%)\t\nUnited Kingdom,GB\t27(6.6%)\t6(2.4%)\t22(11.9%)\t\nOther countries\t92(22.5%)\t56(22.3%)\t40(21.7%)\t\nReporting year\t\t\t\t\nTotal data\t411\t253\t184\t\n2020\t132(32.1%)\t82(32.4%)\t61(33.2%)\t\n2019\t119(28.9%)\t70(27.7%)\t58(31.5%)\t\n2018\t68(16.5%)\t43(17%)\t26(14.1%)\t\n2017\t51(12.4%)\t34(13.4%)\t20(10.9%)\t\n2016\t26(6.3%)\t18(7.1%)\t10(5.4%)\t\n2015\t9(2.2%)\t3(1.2%)\t6(3.3%)\t\n2014\t1(0.2%)\t1(0.4%)\t0(0%)\t\n2013\t4(1%)\t1(0.4%)\t3(1.6%)\t\n2012\t0(0%)\t0(0%)\t0(0%)\t\n2011\t1(0.2%)\t1(0.4%)\t0(0%)\t\nReaction Outcome\t\t\t\t\nTotal data\t305\t176\t146\t\nRecovered/resolved\t77(25.2%)\t56(31.8%)\t24(16.4%)\t\nRecovering/resolving\t73(23.9%)\t50(28.4%)\t24(16.4%)\t\nNot recovered/not resolved\t39(12.8%)\t33(18.7%)\t7(4.8%)\t\nRecovered/resolved with sequelae\t3(1%)\t2(1.1%)\t1(0.7%)\t\nFatal\t113(37.0%)\t35(19.9%)\t90(61.6%)\t\nTreatment modifications\t\t\t\t\nTotal data\t201\t143\t67\t\nDrug withdrawn\t196(97.5%)\t140(97.9%)\t65(97.0%)\t\nDose reduced\t0(0%)\t0(0%)\t0(0%)\t\nDose not changed\t5(2.5%)\t3(2.1%)\t2(3.0%)\t\nLatency period\t\t\t\t\nTotal data\t190\t130\t70\t\nMedian\t25.5 days\t21.5days\t32days\t\nRange\t0-844 days\t0-844 days\t0-500 days\t\nWithin 3 weeks\t86(45.3%)\t65(50%)\t26(37.1%)\t\n<24 h\t7(3.7%)\t6(46.2%)\t1(1.4%)\t\n1–7 days\t31(16.3%)\t23(17.7%)\t11(15.7%)\t\n8-30days\t73(38.4%)\t54(41.5%)\t22(31.4%)\t\n31-60days\t38(20%)\t17(13.1%)\t24(34.3%)\t\n>61 days\t41(21.6%)\t30(23.1%)\t12(17.1%)\t\n\nFor all cases of SJS/TEN, ICIs as a class had an ROR of 2.88 (95% CI 2.61–3.17) and a IC of 1.49 (95% CI 1.35–1.65) compared with all other medications (Table 3, Fig. 3A). Significant associations were also observed for anti-PD-1 as a class, nivolumab, pembrolizumab, anti-PD-L1, atezolizumab, durvalumab, anti-CTLA-4 as a class, ipilimumab, and anti-PD-1/PDL-1 plus anti-CTLA-4, and not reported with tremelimumab.Table 3 Disproportionality analysis of ICIs and SJS/TEN.\n\nTable 3Category\tN. of case\tROR\tROR025\tROR975\tIC\tIC025\tIC975\t\nAll cases (SJS or TEN)\t\nICIs\t411\t2.88\t2.61\t3.17\t1.49\t1.35\t1.65\t\nAnti-PD-1\t356\t3.29\t2.96\t3.66\t1.69\t1.52\t1.87\t\nNivolumab\t175\t2.43\t2.09\t2.82\t1.26\t1.09\t1.46\t\nPembrolizumab\t183\t4.93\t4.26\t5.71\t2.27\t1.96\t2.62\t\nCemiplimab\t1\t2.80\t0.39\t19.96\t0.81\t0.11\t5.74\t\nAnti-PD-L1\t42\t1.99\t1.47\t2.70\t0.97\t0.72\t1.32\t\nAtezolizumab\t30\t2.20\t1.54\t3.15\t1.10\t0.77\t1.58\t\nAvelumab\t1\t0.47\t0.07\t3.31\t-0.82\t-0.11\t-5.80\t\nDurvalumab\t13\t2.42\t1.41\t4.18\t1.20\t0.70\t2.07\t\nAnti-CTLA-4\t71\t2.10\t1.66\t2.65\t1.05\t0.83\t1.33\t\nIpilimumab\t71\t2.10\t1.66\t2.65\t1.05\t0.83\t1.33\t\nTremelimumab\t/\t\t\t\t\t\t\t\nPD-1/PDL-1 plus CTLA-4\t56\t2.91\t2.24\t3.79\t1.51\t1.16\t1.96\t\nSJS\t\t\t\t\t\t\t\t\nICIs\t253\t2.71\t2.39\t3.07\t1.41\t1.24\t1.59\t\nAnti-PD-1\t212\t3.00\t2.61\t3.43\t1.55\t1.36\t1.78\t\nNivolumab\t108\t2.29\t1.90\t2.77\t1.18\t0.97\t1.42\t\nPembrolizumab\t106\t4.36\t3.60\t5.29\t2.09\t1.72\t2.53\t\nCemiplimab\t1\t4.29\t0.60\t30.61\t1.03\t0.14\t7.36\t\nAnti-PD-L1\t35\t2.55\t1.83\t3.55\t1.31\t0.94\t1.83\t\nAtezolizumab\t25\t2.81\t1.90\t4.16\t1.44\t0.97\t2.13\t\nAvelumab\t1\t0.72\t0.10\t5.08\t-0.34\t-0.05\t-2.41\t\nDurvalumab\t11\t3.14\t1.74\t5.68\t1.52\t0.84\t2.75\t\nAnti-CTLA-4\t39\t1.76\t1.29\t2.41\t0.80\t0.58\t1.10\t\nIpilimumab\t39\t1.76\t1.29\t2.41\t0.80\t0.58\t1.10\t\nTremelimumab\t/\t\t\t\t\t\t\t\nPD-1/PDL-1 plus CTLA-4\t31\t2.47\t1.73\t3.51\t1.26\t0.89\t1.80\t\nTEN\t\nICIs\t184\t2.82\t2.43\t3.26\t1.46\t1.26\t1.69\t\nAnti-PD-1\t166\t3.36\t2.88\t3.92\t1.71\t1.47\t2.00\t\nNivolumab\t73\t2.21\t1.76\t2.79\t1.13\t0.89\t1.42\t\nPembrolizumab\t93\t5.49\t4.47\t6.74\t2.40\t1.96\t2.95\t\nCemiplimab\t/\t\t\t\t\t\t\t\nAnti-PD-L1\t10\t1.04\t0.56\t1.93\t0.05\t0.03\t0.09\t\nAtezolizumab\t7\t1.12\t0.53\t2.35\t0.15\t0.07\t0.32\t\nAvelumab\t0\t\t\t\t\t\t\t\nDurvalumab\t3\t1.22\t0.39\t3.80\t0.25\t0.08\t0.76\t\nAnti-CTLA-4\t34\t2.20\t1.57\t3.08\t1.11\t0.79\t1.55\t\nIpilimumab\t34\t2.20\t1.57\t3.08\t1.11\t0.79\t1.55\t\nTremelimumab\t/\t\t\t\t\t\t\t\nPD-1/PDL-1 plus CTLA-4\t26\t2.96\t2.01\t4.35\t1.51\t1.03\t2.22\t\nSJS/TEN overlap*\t\t\t\t\t\t\t\t\nICIs\t26\t1.65\t1.12\t2.44\t0.70\t0.47\t1.03\t\nAnti-PD-1\t22\t1.85\t1.22\t2.82\t0.85\t0.56\t1.30\t\nNivolumab\t6\t0.76\t0.34\t1.69\t-0.37\t-0.17\t-0.82\t\nPembrolizumab\t16\t3.95\t2.41\t6.46\t1.85\t1.13\t3.02\t\nCemiplimab\t/\t\t\t\t\t\t\t\nAnti-PD-L1\t3\t1.31\t0.42\t4.06\t0.32\t0.10\t1.01\t\nAtezolizumab\t2\t1.35\t0.34\t5.39\t0.33\t0.08\t1.33\t\nAvelumab\t/\t\t\t\t\t\t\t\nDurvalumab\t1\t1.71\t0.24\t12.18\t0.47\t0.07\t3.33\t\nAnti-CTLA-4\t2\t0.54\t0.14\t2.17\t-0.74\t-0.19\t-2.98\t\nIpilimumab\t2\t0.54\t0.14\t2.17\t-0.74\t-0.19\t-2.98\t\nTremelimumab\t/\t\t\t\t\t\t\t\nPD-1/PDL-1 plus CTLA-4\t1\t0.48\t0.07\t3.38\t-0.79\t-0.11\t-5.63\t\n*SJS and TEN reported in the same case\n\nFig 3 ICIs and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), reporting odds ratios: A, all cases (SJS or TEN); B, SJS; C, TEN; D, SJS/TEN overlap.\n\nFig 3\n\nFor SJS, ICIs as a class had an ROR of 2.71 (95% CI 2.39–3.07) and a IC of 1.41 (95% CI 1.24–1.59) compared with all other medications (Table 3, Fig. 3B). Significant associations were also observed for anti-PD-1 as a class, nivolumab, pembrolizumab, anti-PD-L1, atezolizumab, durvalumab, anti-CTLA-4 as a class, ipilimumab, and anti-PD-1/PDL-1 plus anti-CTLA-4, and not reported with tremelimumab.\n\nFor TEN, ICIs as a class had an ROR of 2.82 (95% CI 2.43–3.26) and a IC of 1.46 (95% CI 1.26–1.69) compared with all other medications (Table 3, Fig. 3C). Significant associations were also observed for Anti-PD-1 as a class, nivolumab pembrolizumab, anti-CTLA-4, ipilimumab, anti-PD-1/PDL-1 plus anti-CTLA-4, but unassociated with anti-PD-L1, atezolizumab, durvalumab, and not reported with cemiplimab, avelumab, tremelimumab.\n\nFor SJS/TEN overlap, ICIs as a class had an ROR of 1.65 (95% CI 1.12–2.44) and a IC of 1.48 (95% CI 1.27–1.72) compared with all other medications (Table 3, Fig. 3D), it was also observed strongly associated with anti-PD-1 as a class and pembrolizumab.\n\n4 Discussion\n\nFollowing increasing use of ICIs, rare serious adverse events have been reported which prompted additional investigations. To our knowledge, the present study is the largest and most extensive analysis of SJS and TEN associated with ICIs collected data from both clinical trials and a worldwide pharmacovigilance database, and results suggested that ICIs was associated with significantly increased risk of SJS/TEN.\n\nDue to the rare incidence of SJS and TEN, early RCTs did not identify any concerning safety signals. A small number of case reports were published6-7, but no causal association of ICIs with SJS and TEN could be established. Our results, based on meta-analysis of 20 RCTS (11597 patients), suggested that ICIs as class significantly increased the risk of SJS/TEN. We also performed a real-world analysis of 411 cases from FAERS, and results indicated that ICIs had a statistically significant positive signal with SJS/TEN. Previous studies suggested that the safety profiles of anti-PD-1, anti-PD-L1 and anti-CTLA-4 differed. Our results observed the safety signal for SJS/TEN was differed between different ICI therapies, with pembrolizumab presented the strongest signal for both SJS (ROR=4.36) and TEN (ROR=5.49), and the signal of TEN was differed between anti-PD-1(ROR=3.36) and anti-PD-L1(ROR=1.04) (Pinteraction<0.01). However, our subgroup analysis of RCTs did not find significant difference between different ICI therapies. Inconsistent with previous studies [20], combination therapy seemed to increase the risk of immune related cutaneous adverse events was not observed in our analysis, but this could be confounded by the tumors where combination therapy is used. It is interesting that there were proportionately more cases from Japan from FAERS, this may reflect the differences in the reporting structure, since anti-PD-1 drug was first approved in Japan. However, we did a post-hot analysis by excluding reportes from Japan, the signal for SJS/TEN seems to remain robust (ROR=2.58; IC:1.34). Due to some drugs (cemiplimab, avelumab, tremelimumab) are approved later, it is difficult to compare the safety profiles of different ICI therapies. Future research needed to be further investigated.\n\nSJS/TEN are often triggered by particular medications, other medications that have been shown to increase these reactions include nonsteroidal antiinflammatory drugs, antiepileptic drugs, and certain antibiotics [21], [22], [23]. About 80% of the SJS/TEN cases occurred within the first 2 months of initiation treatment, with median onset time was 25.5 days (SJS:21.5 days; TEN:32 days), matching other studies [21], [22], [23]. Mortality rates of SJS/TEN among ICIs related cases (All cases:37%, SJS:19.9%, TEN:61.6%) seems to be higher than other medications, as previous study reported that mortality from SJS is approximately 5%, and mortality from TEN is approximately 30% [24]. One possible reason for this is the concurrent malignancy and older age as compared to other studies, which are specific predictor factors for mortality according to score for toxic epidermal necrolysis (SCORTEN) [25]. In addition, ICIs were mostly used as later line therapy in the past years, the mortality rate due to SJS/TEN may decrease with the increasing use of ICIs in first line and adjuvant therapy setting. Therefore, a high index of suspicion is necessary to identify SJS/TEN in its early stages in order to minimize the potential for both morbidity and mortality in patients using ICIs [7].\n\nThe mechanism of immune checkpoint inhibitor results to SJS/TEN is not clear. One mechanism is thought to be due to cytotoxicity induced by ICIs resulting in T-cell targeting of keratinocytes leading to apoptosis [5,26]. Currently, there is a consensus recommendation for permanent discontinuation of the offending drug, considering the high mortality rate associated with SJS/TEN. This was observed in our study, with 97.5% cases discontinue the ICIs. Serious skin toxicity usually requires systemic immunomodulating drugs, some evidence suggested that pulse steroids may have benefit [27]. Therefore, close collaboration between oncologists and dermatologists are encouraged in order to optimize treatment strategy, since immunomodulating drugs may impede the action of ICIs [27]. Subsequently, best supportive care should be provided to maintain fluid and electrolyte balance, minimize infectious, and prevent other complications risks. Further studies are needed to identify risk factors, pathogenesis and optimal management of SJS/TEN-like reactions to ICIs.\n\nThe present study has some limitations. Limitation for data from trials: First, adverse events generally reportable only up to 30 days following the last treatment date according to CTCAEs. Therefore, events occurring after 30 days following last treatment would not have been captured, which create a bias in the analysis [28]. Second, We collected events of SJS and TEN from both published data (from published literature) and unpublished data (from ClinicalTrials.gov), we chose to include events from the ClinicalTrials.gov, as it comprehensively reports all serious adverse events and updates events reporting even after publication [29].There might be bias surrounding the inclusion of unpublished data, as this data was not peer-reviewed. Our subgroup analysis by data source showed no significant difference, possibly explained by SJS and TEN being considered as serious conditions in almost every case. However, the interpretation of results from subgroup analyses should be cautious, in view of limited patients included, and subgroup analysis according to study quality was not performed. Limitation for pharmacovigilance data: First, the actual incidence of SJS/TEN due to ICIs cannot be determined, as the total number of patients using these medications is undetermined [30]. A high number of reported cases for SJS/TEN in the FAERS database were from healthcare providers (77.3%), which may improve the quality of reporting. Second, due to the voluntary nature of reporting to FAERS, the relationship between target drug and suspected adverse event was not clear and definite [30]. Third, drugs with frequent adverse events can increase the total number of reaction reports and therefore influence the value of ROR and IC [30]. Therefore, the magnitude and statistical significance of these associations may change with more reports are submitted. In addition, misclassification bias is highly probable for the definition of SJS/TEN, and data on SCORTEN score was not provided.\n\nIn conclusion, both meta-analysis of RCT's and real-world FAERS pharmacovigilance data suggested that the ICIs may increase the risk of SJS/TEN. Further studies are needed to identify risk factors and optimal management of SJS/TEN-like reactions to ICIs.\n\nAuthor contributions\n\nJunyan Wu had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.\n\nStudy concept and design: Jianhong Zhu and Junyan Wu.\n\nAcquisition of data: Jianhong Zhu, Guanghui Chen and Zhichao He\n\nAnalysis and interpretation of data: Jianhong Zhu, Guanghui Chen, Zhichao He, Yayuan Zheng, Siyuan Gao, Jianfang Li, Yin Ling, Xiaoxia Yu, Kaifeng Qiu, Junyan Wu.\n\nDrafting of the manuscript: Jianhong Zhu, Guanghui Chen, Zhichao He, Yayuan Zheng, Siyuan Gao, Jianfang Li, Yin Ling, Xiaoxia Yu, Kaifeng Qiu, Junyan Wu.\n\nStatistical analysis: Jianhong Zhu, Guanghui Chen, Zhichao He, Yayuan Zheng, Siyuan Gao.\n\nData sharing statement\n\nData from the meta-analysis are freely and publicly available on published literature and ClinicalTrials.gov. Data of retrospective pharmacovigilance study are collected from the FDA Adverse Event Reporting System, and can be gained via the OpenVigil website (http://openvigil.pharmacology.uni-kiel.de/openvigilfda.php).\n\nDeclaration of Competing Interest\n\nDr. Wu reports grants from Research Fund of Guangdong Pharmaceutical Association (2018LR18), during the conduct of the study. Dr. Zhu reports grants from Research Fund of Guangdong Pharmaceutical Association (2021ZX01), during the conduct of the study, the funder had no role in the study design, data collection, data analysis, data interpretation, and writing of the report. All other authors have nothing to declare.\n\nAppendix Supplementary materials\n\nImage, application 1\n\nFunding\n\nResearch Fund of Guangdong Pharmaceutical Association (2021ZX01; 2018LR18).\n\nSupplementary material associated with this article can be found in the online version at doi:10.1016/j.eclinm.2021.100951.\n==== Refs\nReferences\n\n1 Johnson D.B. 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Data mining differential clinical outcomes associated with drug regimens using adverse event reporting data Nat Biotechnol 34 7 2016 697 700 Jul 12 27404875\n9 Liberati A. Altman D.G. Tetzlaff J. Mulrow C. Gøtzsche P.C. Ioannidis J.P. Clarke M. Devereaux P.J. Kleijnen J. Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration BMJ 339 2009 b2700 Jul 21 19622552\n10 Tudor Car L. Li L. Smith H. Atun R. Cochrane review: search strategies to identify observational studies in MEDLINE and EMBASE J Evid Based Med 12 3 2019 225 226 Aug 31441237\n11 National Cancer Institute. NCI guidelines: adverse event reporting requirements. Sept 16, 2013. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf\n12 National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0. 2010 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf).\n13 Higgins J.P. Altman D.G. Gøtzsche P.C. Jüni P. Moher D. Oxman A.D. Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials BMJ 343 2011 d5928 Oct 18 22008217\n14 Zheng Y. Zhu J. Liu Y. Lai W. Lin C. Qiu K. Wu J. Yao W. Triple therapy in the management of chronic obstructive pulmonary disease: systematic review and meta-analysis BMJ 363 2018 k4388 Nov 6 30401700\n15 Zhu J. Yu X. Zheng Y. Li J. Wang Y. Lin Y. He Z. Zhao W. Chen C. Qiu K. Wu J. Association of glucose-lowering medications with cardiovascular outcomes: an umbrella review and evidence map Lancet Diabetes Endocrinol 8 3 2020 192 205 Mar 32006518\n16 Guyatt G. Oxman A.D. Akl E.A. Kunz R. Vist G. Brozek J. Norris S. Falck-Ytter Y. Glasziou P. DeBeer H. Jaeschke R. Rind D. Meerpohl J. Dahm P. Schünemann H.J. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables J Clin Epidemiol 64 4 2011 383 394 Apr 21195583\n17 Zhai Y. Ye X. Hu F. Xu J. Guo X. Zhuang Y. He J. Endocrine toxicity of immune checkpoint inhibitors: a real-world study leveraging US Food and Drug Administration adverse events reporting system J Immunother Cancer 7 1 2019 286 Nov 6 31694698\n18 Böhm R. von Hehn L. Herdegen T. Klein H.J. Bruhn O. Petri H. OpenVigil FDA – inspection of U.S. American adverse drug events pharmacovigilance data and novel clinical applications PLoS One 11 6 2016 e0157753 Jun 21\n19 Norén G.N. Hopstadius J. Bate A. Shrinkage observed-to-expected ratios for robust and transparent large-scale pattern discovery Stat Methods Med Res 22 1 2013 57 69 21705438\n20 Khoja L. Day D. Wei-Wu Chen T. Siu L.L. Hansen A.R. Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review Ann Oncol 28 10 2017 2377 2385 Oct 1 28945858\n21 Barvaliya M. Sanmukhani J. Patel T. Paliwal N. Shah H. Tripathi C. Drug-induced Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS-TEN overlap: a multicentric retrospective study J Postgrad Med 57 2 2011 115 119 Apr-Jun 21654132\n22 Oshikoya K.A. Ogunyinka I.A. Ogar C.K. Abiola A. Ibrahim A. Oreagba I.A. Severe cutaneous adverse drug reactions manifesting as Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the national pharmacovigilance center in Nigeria: a database review from 2004 to 2017 Ther Adv Drug Saf 11 2020 2042098620905998 Feb 12\n23 Abe J. Umetsu R. Mataki K. Kato Y. Ueda N. Nakayama Y. Hane Y. Matsui T. Hatahira H. Sasaoka S. Motooka Y. Hara H. Kato Z. Kinosada Y. Inagaki N. Nakamura M. Analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis using the Japanese Adverse Drug Event Report database J Pharm Health Care Sci 2 2016 14 Jun 21 27330825\n24 Bastuji-Garin S. Fouchard N. Bertocchi M. Roujeau J.C. Revuz J. Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis J Invest Dermatol 115 2 2000 149 153 Aug 10951229\n25 Goldinger S.M. Stieger P. Meier B. Micaletto S. Contassot E. French L.E. Dummer R. Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy Clin Cancer Res 22 16 2016 4023 4029 Aug 15 26957557\n26 Apalla Z. Papageorgiou C. Lallas A. Delli F. Fotiadou C. Kemanetzi C. Lazaridou E. Cutaneous adverse events of immune checkpoint inhibitors: a literature review Dermatol Pract Concept 11 1 2021 e2021155 Jan 29\n27 Zhu J. Wu J. Li G. Li J. Lin Y. He Z. Su C. Zhao W. Wu Q. Chen Z. Qiu K. Meta-analysis of randomized controlled trials for the incidence and risk of fatal adverse events in cancer patients treated with ipilimumab Expert Opin Drug Saf 16 4 2017 423 428 Apr 28276859\n28 Morice P.M. Leary A. Dolladille C. Chrétien B. Poulain L. González-Martín A. Moore K. O'Reilly E.M. Ray-Coquard I. Alexandre J. Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: a safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database Lancet Haematol 8 2 2021 e122 e134 Feb 33347814\n29 Borrelli E.P. Lee E.Y. Descoteaux A.M. Kogut S.J. Caffrey A.R. Stevens-Johnson syndrome and toxic epidermal necrolysis with antiepileptic drugs: an analysis of the US Food and Drug Administration Adverse Event Reporting System Epilepsia 59 12 2018 2318 2324 Dec 30395352\n\n",
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"title": "Stevens-Johnson syndrome/toxic epidermal necrolysis in patients treated with immune checkpoint inhibitors: A safety analysis of clinical trials and FDA pharmacovigilance database.",
"title_normalized": "stevens johnson syndrome toxic epidermal necrolysis in patients treated with immune checkpoint inhibitors a safety analysis of clinical trials and fda pharmacovigilance database"
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"abstract": "Transurethral resection of the prostate is currently the gold standard for the surgical treatment of the benign prostatic hyperplasia. This surgery may lead transurethral resection of the prostate (TURP) syndrome and in some cases, acute tubular necrosis can develop. We report a patient who developed hyponatremia, hemolysis and oliguric acute renal failure as a major complication following TURP using glycine as irrigating fluid.A 64-year-old man was admitted for a prostate resection procedure. Physical examination revealed a healthy elderly man. Preoperative laboratory data showed serum sodium 140 mEq/L, blood urea nitrogen (BUN) 0.6 g/L, creatinine 0.7 mg/dL and hemoglobin 12.9 g/dL. Few hours after, the patient becomes incoherent and developed oliguria, nausea and vomiting. The laboratory data revealed rapidly elevating BUN and creatinine levels (BUN 2.4 g/L; creatinine 6.1 mg/dL), the serum sodium concentration decreased by 14 meq/L. A decreased hemoglobin level (7.4 g/dL) with an elevated lactate dehydrogenase level (665 U/L) was observed. Renal ultrasonography was normal. The diagnosis of acute tubular necrosis complicating TURP syndrome was retained. The hyponatremia was slowly corrected to 132 mmol/L by diuresis and fluid restriction. The renal function recovered after four hemodialysis sessions. Using glycine as an irrigant for TURP may cause hyponatremia, hemolysis and also acute renal failure, especially in patients with longer resection time. It is necessary to carry out every effort to shorten resection time and avoid extravasation during surgery.",
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"authors": "Rais|Lamia|L|;El Ati|Zohra|Z|;Ben Fatma|Lilia|L|;Kheder|Rania|R|;Jebali|Hela|H|;Smaoui|Wided|W|;Krid|Madiha|M|;Ben Hamida|Fethi|F|;Ben Moussa|Fatma|F|;Beji|Soumaya|S|;Zouaghi|Mohamed Karim|MK|",
"chemical_list": "D005998:Glycine",
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"mesh_terms": "D058186:Acute Kidney Injury; D005998:Glycine; D006801:Humans; D007010:Hyponatremia; D007683:Kidney Tubular Necrosis, Acute; D008297:Male; D008875:Middle Aged; D011470:Prostatic Hyperplasia; D013577:Syndrome; D007507:Therapeutic Irrigation; D020728:Transurethral Resection of Prostate",
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"title": "Acute tubular necrosis following transurethral resection of the Prostate using Glycine as irrigating fluid.",
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"abstract": "Here we report a case of a young male who developed full blown iatrogenic Cushing's syndrome after use of superpotent clobetasol propionate cream 0.05% for long duration to suppress psoriatic skin lesions. He also developed osteoporosis and hypogonadism. This case demonstrates that injudicious use of topical steroids can have disastrous consequences.",
"affiliations": "Department of Endocrinology, Nilratan Sircar Medical College, Kolkata, West Bengal, India.;Department of Dermatology, Nilratan Sircar Medical College, Kolkata, West Bengal, India.;Department of Endocrinology, Nilratan Sircar Medical College, Kolkata, West Bengal, India.;Department of Endocrinology, Nilratan Sircar Medical College, Kolkata, West Bengal, India.",
"authors": "Sahana|Pranab Kumar|PK|;Sarma|Nilendu|N|;Sengupta|Nilanjan|N|;Somani|Prashant Subhash|PS|",
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"fulltext": "\n==== Front\nIndian J DermatolIndian J DermatolIJDIndian Journal of Dermatology0019-51541998-3611Medknow Publications & Media Pvt Ltd India IJD-60-420c10.4103/0019-5154.160514E-IJD Case ReportA Florid Case of Iatrogenic Cushing's Syndrome Induced by Topical Steroid with Osteoporosis and Hypogonadism Sahana Pranab Kumar Sarma Nilendu 1Sengupta Nilanjan Somani Prashant Subhash From the Department of Endocrinology, Nilratan Sircar Medical College, Kolkata, West Bengal, India1 Department of Dermatology, Nilratan Sircar Medical College, Kolkata, West Bengal, IndiaAddress for correspondence: Dr. Pranab Kumar Sahana, 171 A Ramesh Dutta Street, Kolkata - 700 006, West Bengal, India. E-mail: pranabsahana@gmail.comJul-Aug 2015 60 4 420 420 12 2013 3 2014 Copyright: © Indian Journal of Dermatology2015This 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.Here we report a case of a young male who developed full blown iatrogenic Cushing's syndrome after use of superpotent clobetasol propionate cream 0.05% for long duration to suppress psoriatic skin lesions. He also developed osteoporosis and hypogonadism. This case demonstrates that injudicious use of topical steroids can have disastrous consequences.\n\nIatrogenic Cushing'spsoriasistopical steroid\n==== Body\nWhat was known?\n\nIatrogenic Cushing's is a well-documented phenomenon with prolonged use of high dose oral and inhaled corticosteroids.\n\nIntroduction\nThe availability of topical glucocorticosteroids is the most important milestone in dermatologic therapy ever achieved, owing to potent anti-inflammatory and antiproliferative effects. However, the same mechanisms of action responsible for the improvement of dermatologic inflammatory conditions can cause adverse effects.\n\nWhen reaching pharmacological levels, exogenous corticosteroids often lead to complete Cushing's syndrome causing skin manifestations, suppression of the hypothalamic-pituitary-adrenal (HPA) axis and growth retardation in children exposed to long-term potent and super potent topical formulations of steroids.[123] We report this case of a young male who developed iatrogenic Cushing's syndrome after use of topical clobetasol propionate.\n\nCase Report\nA 15-year-old young male presented with generalized pustular psoriasis along with extensive striae all over the body. He also complained of progressive weight gain, body ache, and generalized weakness. History as obtained from the parents and the past documents revealed that initial presentation at about 5 years back was suggestive of psoriasis vulgaris that slowly progressed to involve wider regions of the body. Past treatments included occasional courses of low dose oral methotrexate (2.5 mg every 12 h for two to three doses every week). However, potent topical corticosteroids like clobetasol propionate cream 0.05% usually with salicylic acid was repeatedly advised during this period. It was revealed that the same was continued almost continuously since then with or without the advice of the doctor over wide body surfaces to suppress the disease aggravation that was a regular occurrence after every attempt to withdraw the topical medication.\n\nOn examination, his height was 136 cm (<3rd percentile) and weight was 68 kg (>97th percentile). He had plethoric face, prominent neck hump, pink striae, easy bruising, and vellous hypertrichosis [Figure 1]. There was erythroderma studded with small pustules. Pustules were found to be present in small groups or along the margins of some scaly plaques typical of psoriasis vulgaris, especially on the back. On healing, pustules left prominent scaling patches. Some pustules merged with others and formed lakes of pus. They were mostly present on trunk and limbs, but few pustules were also noted on face.\n\nFigure 1 Moon face with plethora\n\nBroad pink striae were present over the abdomen and thighs along with psoriatic skin lesions [Figure 2]. He had bilateral gynecomastia and bilateral small testis (3 ml) and Tanner stage 2 pubic hair. He had significant proximal muscle weakness of lower limbs with preservation of deep tendon reflexes.\n\nFigure 2 Typical broad pink striae and gynecomastia\n\nOn investigation, testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were low [Table 1]. Serum cortisol (<1 μg/dl) and adrenocorticotropic hormone (ACTH) were also very low [Table 1]. Other routine laboratory parameters were normal. Dual energy X-ray absorptiometry (DEXA) scan of spine revealed significant osteoporosis (T score - 3.2).\n\nTable 1 Hormonal profile of the patient\n\nDiscussion\nChildren are more prone to the development of systemic reactions to topically applied corticosteroid medication because of their higher ratio of total body surface area to body weight, but rare in adults. Prolonged use of topical corticosteroids causes systemic adverse effects including Cushing's syndrome and HPA axis suppression, growth impairment in children, and cataract.[4] These side effects may occur if topical corticosteroids are absorbed in significant amounts through the inflamed skin, particularly when applied to large skin areas,[5] although is less common than that of the oral or parenteral route. At least 43 cases with iatrogenic Cushing syndrome from very potent topical steroid usage (clobetasol) in children and adult have been published over the last 35 years particularly in developing countries. In the children group (n = 22), most are infants with diaper dermatitis. For the adult group (n = 21), the most common purpose of steroid use was for treatment of psoriasis.[6]\n\nExcess glucocorticoids leads to short stature due to suppression of growth hormone releasing hormone (GHRH) and GH release from the hypothalamus and pituitary, respectively. Our patient had poor height gain probably due to same reason.[7]\n\nExogenous glucocorticoids suppress luteinizing hormone releasing hormone (LHRH) from hypothalamus and LH and FSH from pituitary resulting in hypogonadotropic hypogonadism. Our case had the same picture as also demonstrated by Luton et al.[8]\n\nOsteoporosis is a common and severe adverse effect of glucocorticoid excess and one of the major limitations to long-term glucocorticoid therapy. A significant number of patients on long-term steroid therapy will have at least some loss of bone density, and oral and inhaled corticosteroid use are associated with increased bone fractures.[910] The bone loss caused by glucocorticoids tends to be in trabecular bone as opposed to cortical bone. Therefore, most loss is in the vertebrae and ribs of the axial skeleton.\n\nThis case exemplifies severe iatrogenic Cushing's syndrome with hypogonadotropic hypogonadism and osteoporosis in children induced by injudicious use of potent topical steroids (clobetasol) to suppress recurrent flare of psoriatic skin lesions and therefore, we physicians should always be cautious about it.\n\nWhat is new?\n\nIatrogenic Cushing's is also caused by potent topical corticosteroids, when used for long duration over large inflamed skin areas.\n\nSource of support: Nil\n\nConflict of Interest: Nil.\n==== Refs\n1 Katar S Akdeniz S Ozbek MN Yaramiş A Infantile iatrogenic Cushing's syndrome Indian J Dermatol 2008 53 190 1 19882032 \n2 Abma EM Blanken R De Heide LJ Cushing's syndrome caused by topical steroid therapy for psoriasis Neth J Med 2002 60 148 50 12164372 \n3 Ermis B Ors R Tastekin A Ozkan B Cushing's syndrome secondary to topical corticosteroids abuse Clin Endocrinol (Oxf) 2003 58 795 6 12780758 \n4 Kristmundsdottir F David TJ Growth impairment in children with actopic eczema J R Soc Med 1987 80 9 12 3560137 \n5 Carruthers JA August PJ Staughton RC Observations on systemic effects of topical clobetasol propionate (Dermovate) Br Med J 1975 4 203 4 1191997 \n6 Tempark T Phatarakijnirund V Chatproedprai S Watcharasindhu S Supornsilchai V Wananukul S Exogenous Cushing's syndrome due to topical corticosteroid application: Case report and review of literature Endocrine 2010 38 328 34 20972726 \n7 Takasashi H Bando H Zhang C Yamasaki R Saito S Mechanism of impaired growth hormone secretion in patients with Cushing's disease Acta Endocrinol (Copenh) 1992 127 13 7 1519417 \n8 Luton JP Thiebolt P Valcke JC Mahoudeau JA Bricaire H Reversible gonadotropin deficiency in male Cushing disease J Clin Endocrinol Metab 1977 45 488 95 198424 \n9 Millard TP Antoniades L Evans AV Smith HR Spector TD Barker JN Bone mineral density of patients with chronic plaque psoriasis Clin Exp Dermatol 2001 26 446 8 11488836 \n10 Nymann P Kollerup G Jemec GB Grossmann E Decreased bone mineral density in patients with pustulosis Palmaris et plantaris Dermatology 1996 192 307 11 8864362\n\n",
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"journal": "Indian journal of dermatology",
"keywords": "Iatrogenic Cushing's; psoriasis; topical steroid",
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"title": "A Florid Case of Iatrogenic Cushing's Syndrome Induced by Topical Steroid with Osteoporosis and Hypogonadism.",
"title_normalized": "a florid case of iatrogenic cushing s syndrome induced by topical steroid with osteoporosis and hypogonadism"
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"abstract": "Histoplasmosis is an endemic mycosis in the Ohio and Mississippi River valleys and can cause disseminated infection in immunocompromised hosts. Disseminated histoplasmosis is often respiratory in nature and most cases in transplant patients occur within 2 years post-transplantation. A 32-year-old male on mycophenolate and tacrolimus who underwent an orthotopic liver transplantation 10 years prior presented with generalized body aches, fevers, mild congestion, dysuria and elevated transaminases. Liver biopsy revealed epithelioid granulomas with narrow-based budding yeast, suggesting histoplasma. Liver involvement in disseminated histoplasmosis is well characterized however the disease is usually pulmonary in origin. Only three other case reports describe isolated granulomatous hepatitis, and this is the first to our knowledge to occur in a liver transplant allograft. A high index of suspicion is essential for diagnosis and prompt treatment of histoplasmosis in transplant patients considering their immunocompromised state.",
"affiliations": "Baylor College of Medicine, Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Houston, TX 77030, USA.;Baylor College of Medicine, Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Houston, TX 77030, USA.;Baylor College of Medicine, Department of Pathology & Immunology, Houston, TX 77030, USA.;Baylor College of Medicine, Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Houston, TX 77030, USA.;Baylor College of Medicine, Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Houston, TX 77030, USA.",
"authors": "Washburn|Laura|L|;Galván|N Thao|NT|;Dhingra|Sadhna|S|0000-0003-0436-033X;Rana|Abbas|A|;Goss|John A|JA|",
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"fulltext": "\n==== Front\nJ Surg Case RepJ Surg Case RepjscrJournal of Surgical Case Reports2042-8812Oxford University Press 2925031010.1093/jscr/rjx232rjx232Case ReportHistoplasmosis hepatitis after orthotopic liver transplantation Washburn Laura 1Galván N Thao 1http://orcid.org/0000-0003-0436-033XDhingra Sadhna 2Rana Abbas 1Goss John A 11 \nBaylor College of Medicine, Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Houston, TX 77030, USA2 \nBaylor College of Medicine, Department of Pathology & Immunology, Houston, TX 77030, USACorrespondence address. Baylor College of Medicine, Division of Abdominal Transplantation, 6620 Main St. Suite 1425, Houston, TX 77030, USA. Tel: +1-832-255-1400; E-mail: laura.washburn@bcm.edu12 2017 11 12 2017 11 12 2017 2017 12 rjx23222 8 2017 10 10 2017 07 11 2017 Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author 2017.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nHistoplasmosis is an endemic mycosis in the Ohio and Mississippi River valleys and can cause disseminated infection in immunocompromised hosts. Disseminated histoplasmosis is often respiratory in nature and most cases in transplant patients occur within 2 years post-transplantation. A 32-year-old male on mycophenolate and tacrolimus who underwent an orthotopic liver transplantation 10 years prior presented with generalized body aches, fevers, mild congestion, dysuria and elevated transaminases. Liver biopsy revealed epithelioid granulomas with narrow-based budding yeast, suggesting histoplasma. Liver involvement in disseminated histoplasmosis is well characterized however the disease is usually pulmonary in origin. Only three other case reports describe isolated granulomatous hepatitis, and this is the first to our knowledge to occur in a liver transplant allograft. A high index of suspicion is essential for diagnosis and prompt treatment of histoplasmosis in transplant patients considering their immunocompromised state.\n==== Body\nINTRODUCTION\nHistoplasmosis is the most common endemic mycosis in the USA as well as certain areas of Latin America and, of the endemic mycoses, is one of the most fatal. The increasing use of immunosuppressive medications, such as tumor necrosis factor and calcineurin inhibitors, has resulted in rising incidence of the fungal infection, which is particularly relevant to the transplant population [1]. It is intensely endemic to the Ohio and Mississippi River valleys, and found in bird and bat guano. Infection usually involves inhaling an inoculum of Histoplasmacapsulatum and with the inactivation of T lymphocytes by calcineurin inhibitors, macrophages are not initiated to inhibit the growth of the fungal infection, leading to increased fungal burden and mortality [2]. Here we describe a case of Histoplasmosis hepatitis in a liver transplant recipient 10 years out from his transplantation, with histopathology illustrating the yeast-like fungal elements.\n\nCASE REPORT\nThe patient is a 32-year-old man who, in 2006, underwent an orthotopic liver transplantation for Glycogen Storage Disease Type 3. He had been doing well since transplant until 2012 when he was found to have slightly elevated transaminases (AST 156 U/L, reference range 5-34 U/L) (ALT 107, reference range 6-55 U/L) on mycophenolate and tacrolimus. Ultrasound imaging showed a normal liver transplant allograft with excellent perfusion. A percutaneous fine needle liver biopsy revealed no acute cellular rejection, but with nonspecific and minimal minute foci of necrosis and minimal lymphocytic cholangitis. Because he had aphthous ulcers, his mycophenolate was decreased. His mildly elevated transaminases persisted in a hepatocellular pattern through the years, up to the 200 s U/L. A subsequent biopsy in April 2015 was equally equivocal with minimal lobular spotty necrosis and bile ductular proliferation, yet no signs of rejection. In October 2016, another liver biopsy showed mild lobular inflammation with mild portal inflammation and focal mild bile duct damage. The progressive findings in the liver biopsies were described as minimal and nonspecific but a differential diagnosis included drug-induced liver injury, viral hepatitis, or acute cellular rejection. Because this could be an atypical pattern of acute cellular rejection, steroid therapy was added.\n\nIn March 2017, the patient presented with 2 weeks of generalized body aches, fevers, mild congestion and dysuria. His transaminases worsened—AST 360 U/L, ALT 387 U/L. Blood, urine and sputum cultures grew no organisms and the patient had a normal chest radiograph and abdominal ultrasound. CT sinus, obtained to rule out sinusitis, remarked on few mucous retention cysts of the maxillary sinuses, but was otherwise negative for any other pathology. However, further interrogation found that the patient had significant opportunistic infection exposure risk; the patient was a butcher at a local grocery store, and owned a new rabbit, several parakeets and four dogs. A repeat liver biopsy was performed, and this time, was found to have predominantly lobular, and occasionally portal, epithelioid granulomas (Fig. 1) with intracellular yeast-like elements (Fig. 2). These were described as narrow-based budding yeasts favoring histoplasma (Fig. 3). No portal based features of acute rejection were noted and bile ducts were preserved in the majority of portal tracts. Urine histoplasma antigen testing corroborated the histology finding—the patient had progressive disseminated histoplasmosis manifested as granulomatous hepatitis. He completed an 11-day course of liposomal amphotericin B and will continue itraconazole therapy for a year. His immunosuppression regimen was significantly decreased and mycophenolate was stopped. The most recent liver biopsy in May 2017 revealed a persistent—though significantly decreased—lobular inflammation, microgranulomas and budding yeast elements. His transaminases remain elevated at AST 265 U/L and ALT 259 U/L. He will continue close follow up to ensure further improvement on current therapy and resolution of Histoplasmosis.\n\n\nFigure 1: Liver parenchyma with multiple discrete portal and lobular granulomas. Hematoxylin and Eosin stain ×100.\n\nFigure 2: Portal granuloma with histiocytes containing multiple intracytoplasmic yeast-like fungi. Hematoxylin and Eosin stain ×400.\n\nFigure 3: Grocott methanamine silver stain showing yeast-like fungi with narrow-based budding, consistent with histoplasma ×400.\n\nDISCUSSION\nSymptoms of Histoplasmosis are often respiratory in nature, as it is a predominantly confined to the lungs. However, once the pathogen disseminates extracellularly through blood or lymph, macrophages or neutrophils, it becomes a progressive disseminated histoplasmosis with symptoms that reflect diverse end organ effects, as in this case [3]. Histoplasmosis in transplant patients has been well described, often as an early diagnosis, with more than two-third of cases described within the first 2 years of transplantation [1]. This case, contracted 10 years later, serves as the first to our knowledge that illustrates granulomas and intracytoplasmic yeast-like fungi within the liver parenchyma of the transplant allograft. Furthermore, only three other reports are of isolated granulomatous hepatitis, and ours serves as the only one to report this finding in a liver transplant allograft [4–6]. Immunocompetent hosts can often develop antigen-specific CD4 T lymphocyte-mediated immune response which can limit the disease. However, H. capsulatum can establish a quiescent phase indefinitely, and so for the immunocompromised host, reactivation will continue to serve as a threat, as in this case [7]. Our patient will need to continue antifungal therapy, likely for a year, with surveillance of his antigenuria, which has been suggested to correlate with fungal burden [2].\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n==== Refs\nREFERENCES\n1 \nAssi M , Martin S , Wheat LJ , et al \nHistoplasmosis after solid organ transplant . Clin Infect Dis 2013 ;57 :1542 –9 .24046304 \n2 \nKauffman CA \nHistoplasmosis: a clinical and laboratory update . Clin Microbiol Rev 2007 ;20 :115 –32 .17223625 \n3 \nCuellar-Rodriguez J , Avery RK , Lard M , et al \nHistoplasmosis in solid organ transplant recipients: 10 years of experience at a large transplant center in an endemic area . Clin Infect Dis 2009 ;49 :710 –6 .19635026 \n4 \nKibria R , Bari K , Ali SA , Barde CJ \n‘Ohio river valley fever’ presenting as isolated granulomatous hepatitis: a case report . South Med J 2009 ;102 :656 –8 .19434026 \n5 \nLanza FL , Nelson RS , Somayaji BN \nAcute granulomatous hepatitis due to histoplasmosis . Gastroenterology 1970 ;58 :392 –6 .5437993 \n6 \nRihana NA , Kandula M , Velez A , Dahal K , O’Neill EB \nHistoplasmosis presenting as granulomatous hepatitis: case report and review of the literature . Case Rep Med 2014 ;2014 :879535 .25013413 \n7 \nWoods JP \nRevisiting old friends: developments in understanding histoplasma capsulatum pathogenesis . J Microbiol 2016 ;54 :265 –76 .26920886\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2042-8812",
"issue": "2017(12)",
"journal": "Journal of surgical case reports",
"keywords": null,
"medline_ta": "J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101560169",
"other_id": null,
"pages": "rjx232",
"pmc": null,
"pmid": "29250310",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports",
"references": "19635026;25013413;19434026;24046304;17223625;5437993;26920886",
"title": "Histoplasmosis hepatitis after orthotopic liver transplantation.",
"title_normalized": "histoplasmosis hepatitis after orthotopic liver transplantation"
} | [
{
"companynumb": "US-ASTELLAS-2017US056031",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nGemcitabine (GEM) is widely used as a chemotherapeutic agent. However, pulmonary toxicity has been rarely observed with GEM use. This article aims to determine the incidence and causes of drug-induced pulmonary toxicity, and to classify the high-resolution computed tomography (HRCT) findings for antitumor therapy-associated pulmonary toxicity based on characteristic patterns and pathological considerations, with a special focus on GEM-associated pulmonary toxicity (GAPT).\n\n\nMETHODS\nMedical records of all patients with drug-induced pulmonary toxicity seen at Kyorin University hospital between April 2006 and December 2011 were retrospectively reviewed. The study examined correlations between HRCT and the assessed pathological or clinical findings, with a specific focus on antitumor drugs.\n\n\nRESULTS\nWe identified 66 patients with drug-induced pulmonary toxicity. Among the antitumor drugs, GEM was the primary offending agent (n = 8) for pulmonary toxicity followed by docetaxel and gefitinib. HRCT patterns for the eight GAPT patients included the non-specific interstitial pneumonia (NSIP; n = 5) and the hypersensitivity pneumonitis (HP)-like pattern (n = 3). In contrast, four patients in the study were found to have the HP-like pattern, with three cases associated with GEM and one case associated with imatinib mesylate. The transbronchial lung biopsy or video-assisted thoracic surgery specimens for these patients showed granuloma or organizing tissue with a random distribution that was independent of the respiratory bronchiole. These results appeared to correspond to the HRCT-determined centrilobular nodules.\n\n\nCONCLUSIONS\nGEM was the leading cause of drug-induced pulmonary toxicity in the patients examined in this study. This toxicity appears as NSIP or an HP-like pattern during HRCT examinations. This HP-like pattern may be useful for diagnosing GEM-induced pulmonary toxicity, as well as demonstrating granuloma or organizing tissue during lung pathology examinations.",
"affiliations": "Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, Japan.",
"authors": "Tamura|Masaki|M|;Saraya|Takeshi|T|;Fujiwara|Masachika|M|;Hiraoka|Sayuki|S|;Yokoyama|Takuma|T|;Yano|Kinuko|K|;Ishii|Haruyuki|H|;Furuse|Junji|J|;Goya|Tomoyuki|T|;Takizawa|Hajime|H|;Goto|Hajime|H|",
"chemical_list": "D000970:Antineoplastic Agents; D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; D000077156:Gefitinib",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2012-0248",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "18(4)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000542:Alveolitis, Extrinsic Allergic; D000970:Antineoplastic Agents; D001706:Biopsy; D000077143:Docetaxel; D005260:Female; D000077156:Gefitinib; D006099:Granuloma; D006801:Humans; D008168:Lung; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011799:Quinazolines; D012189:Retrospective Studies; D043823:Taxoids; D020775:Thoracic Surgery, Video-Assisted; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "454-9",
"pmc": null,
"pmid": "23404815",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": "12844017;21735750;14748759;20208334;18594001;18195376;14606719;18252919;11823707;1691067;10992538;12201493",
"title": "High-resolution computed tomography findings for patients with drug-induced pulmonary toxicity, with special reference to hypersensitivity pneumonitis-like patterns in gemcitabine-induced cases.",
"title_normalized": "high resolution computed tomography findings for patients with drug induced pulmonary toxicity with special reference to hypersensitivity pneumonitis like patterns in gemcitabine induced cases"
} | [
{
"companynumb": "JP-ACCORD-026168",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nUndifferentiated round cell sarcomas are a heterogeneous group, and include tumors that resemble the Ewing sarcoma family. Although a subset defined by recurrent CIC-DUX4 gene fusion has been recently characterized, data regarding the cytomorphologic features are currently limited. Two recent fine-needle aspiration (FNA) cases prompted review of the spectrum of round cell tumors in the differential diagnosis to determine distinctive diagnostic features.\n\n\nMETHODS\nTwo genetically confirmed FNA cases were identified. Cytomorphologic features were evaluated on FNA smears and hematoxylin and eosin-stained cell block and concurrent needle biopsy sections, and immunohistochemical studies performed on cell block and biopsy sections were reviewed.\n\n\nRESULTS\nThe 2 patients were a 24-year-old man with a posterior mediastinal mass and a 69-year-old woman with a gluteal mass. FNA smears were cellular with tumor cells present in large groups and singly dispersed. Tumor cells had large, round-to-ovoid, hyperchromatic nuclei with irregular membranes, frequent large nucleoli, and a moderate amount of vacuolated cytoplasm. Both cases demonstrated necrosis, and one case had prominent myxoid stroma. Immunohistochemistry demonstrated focal-to-multifocal CD99 positivity and diffuse nuclear staining for WT1; staining for cytokeratin, desmin, S-100, CD34, CD45, and TdT were negative. Fluorescence in situ hybridization demonstrated CIC-DUX4 fusion in both cases.\n\n\nCONCLUSIONS\nCIC-DUX4 round cell sarcoma differs from Ewing sarcoma in that it has more atypical cytologic features and lacks the diffuse membranous CD99 staining pattern characteristic of Ewing sarcoma. The differential diagnosis is broad, and requires the judicious use of ancillary studies. Focal-to-multifocal CD99 immunoreactivity and diffuse nuclear WT1 positivity is characteristic of CIC-DUX4 sarcoma, and should prompt molecular testing. Cancer Cytopathol 2016;124:350-61. © 2016 American Cancer Society.",
"affiliations": "Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.;James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.",
"authors": "Chebib|Ivan|I|;Jo|Vickie Y|VY|",
"chemical_list": "D014408:Biomarkers, Tumor; C574694:CIC-DUX4 fusion protein, human; D015514:Oncogene Proteins, Fusion",
"country": "United States",
"delete": false,
"doi": "10.1002/cncy.21685",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1934-662X",
"issue": "124(5)",
"journal": "Cancer cytopathology",
"keywords": "capicua transcriptional repressor-double homeobox 4 (CIC-DUX4); fine-needle aspiration; round cell; sarcoma; soft tissue",
"medline_ta": "Cancer Cytopathol",
"mesh_terms": "D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D044963:Biopsy, Fine-Needle; D001859:Bone Neoplasms; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D015514:Oncogene Proteins, Fusion; D012512:Sarcoma, Ewing; D018228:Sarcoma, Small Cell; D055815:Young Adult",
"nlm_unique_id": "101499453",
"other_id": null,
"pages": "350-61",
"pmc": null,
"pmid": "26800124",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Round cell sarcoma with CIC-DUX4 gene fusion: Discussion of the distinctive cytomorphologic, immunohistochemical, and molecular features in the differential diagnosis of round cell tumors.",
"title_normalized": "round cell sarcoma with cic dux4 gene fusion discussion of the distinctive cytomorphologic immunohistochemical and molecular features in the differential diagnosis of round cell tumors"
} | [
{
"companynumb": "US-ACTAVIS-2016-11856",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nTransplantation-mediated alloimmune thrombocytopenia (TMAT) is a rare complication affecting the recipient of an organ from a donor with immune thrombocytopenia (ITP).\n\n\nMETHODS\nWe present a case of TMAT following liver transplantation successfully treated by retransplantation, along with a review of previously published cases.Clinical presentation: The liver donor had lupus and ITP and died from an intracranial hemorrhage. The recipient's platelet count fell to 2x109/L on postoperative day 2. Due to the lack of response to medical treatment, emergency retransplantation was undertaken with a steady recovery of the platelet count within a few days.\n\n\nCONCLUSIONS\nSix additional cases of transplantation-mediated alloimmune thrombocytopenia after liver transplantation have been reported. In all cases, severe thrombocytopenia ensued within 3 days after liver transplantation. Four patients suffered hemorrhagic complications. Three patients died. Early retransplantation was needed in three out of four patients receiving a graft from a donor with ITP and splenectomy. All recovered shortly after the new graft was in place.\n\n\nCONCLUSIONS\nSevere refractory transplantation-mediated alloimmune thrombocytopenia can develop in liver recipients from donors with ITP, especially those with previous splenectomy. Early retransplantation should be considered if there is no rapid response to medical therapy.",
"affiliations": "General and Digestive Surgery Department, Hospital Universitario Cruces, Bizkaia, Spain.;General and Digestive Surgery Department, Hospital Universitario Cruces, Bizkaia, Spain.;General and Digestive Surgery Department, Hospital Universitario Cruces, Bizkaia, Spain.;Department of Internal Medicine, University of The Basque Country, The Basque Country, Spain.;General and Digestive Surgery Department, Hospital Universitario Cruces, Bizkaia, Spain.;General and Digestive Surgery Department, Hospital Universitario Cruces, Bizkaia, Spain.",
"authors": "Aranda Escaño|Elena|E|https://orcid.org/0000-0001-9760-5425;Prieto Calvo|Mikel|M|;Perfecto Valero|Arkaitz|A|;Ruiz Irastorza|Guillermo|G|https://orcid.org/0000-0001-9760-5425;Gastaca Mateo|Mikel|M|;Valdivieso López|Andrés|A|",
"chemical_list": "D016824:Antigens, Human Platelet",
"country": "England",
"delete": false,
"doi": "10.1177/0961203320983450",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "30(4)",
"journal": "Lupus",
"keywords": "Immune thrombocytopenia; TMAT; liver transplantation; passenger lymphocyte syndrome; transplantation-mediated alloimmune thrombocytopenia",
"medline_ta": "Lupus",
"mesh_terms": "D016824:Antigens, Human Platelet; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016031:Liver Transplantation; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic; D012086:Reoperation; D013156:Splenectomy; D013921:Thrombocytopenia; D014019:Tissue Donors; D066027:Transplant Recipients; D016896:Treatment Outcome",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "669-673",
"pmc": null,
"pmid": "33407046",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transplantation-mediated alloimmune thrombocytopenia successfully treated by retransplantation.",
"title_normalized": "transplantation mediated alloimmune thrombocytopenia successfully treated by retransplantation"
} | [
{
"companynumb": "ES-LFBP-2021000464",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "OBJECTIVE\nTo review the efficacy and safety of transitioning from dexmedetomidine to clonidine to facilitate weaning of patients from sedation with dexmedetomidine. There is a paucity of data describing dexmedetomidine withdrawal syndrome (DWS) as well as clonidine's place in therapy for DWS. This review will describe and analyze current literature to provide clinical recommendations.\n\n\nCONCLUSIONS\nA MEDLINE literature search was performed to identify original research articles describing DWS and/or transitioning from dexmedetomidine to clonidine for the purpose of weaning patients from sedation with dexmedetomidine. Four case reports describing DWS, 3 case reports describing the use of clonidine to treat DWS, and 3 observational studies describing the use of clonidine to facilitate dexmedetomidine weaning were identified. The incidence of and risk factors for DWS are unknown; factors including patient age and dexmedetomidine infusion rate, loading dose, and discontinuation strategy have inconsistent associations with DWS. All cases of DWS have been associated with infusion durations greater than 72 hours. While there are limited data describing clonidine use for the treatment of dexmedetomidine withdrawal, clonidine appears to be beneficial for dexmedetomidine weaning and its use for that purpose has been well described. Clonidine dosages that have been assessed for discontinuing dexmedetomidine vary from 0.1 to 0.3 mg orally or enterally every 6 to 8 hours; one study assessed use of transdermal clonidine (100 µg/24 h patch). Patients with extensive cardiac comorbidities may be more susceptible to adverse effects of clonidine, which may limit the drug's use for DWS intervention.\n\n\nCONCLUSIONS\nDespite limited supportive data, clonidine provides a promising option for sedation management in adult ICU patients, with successful transitions from dexmedetomidine reported within 24 hours after clonidine initiation.",
"affiliations": "University of the Incarnate Word Feik School of Pharmacy, San Antonio, TX, and UCHealth Memorial Hospital, Colorado Springs, CO.;University of the Incarnate Word Feik School of Pharmacy, San Antonio, TX, and UT Health San Antonio, San Antonio, TX.;UT Health San Antonio, San Antonio, TX, and University Health System, San Antonio, TX.",
"authors": "Glaess|Shelley S|SS|;Attridge|Rebecca L|RL|;Christina Gutierrez|G|G|",
"chemical_list": "D058647:Adrenergic alpha-2 Receptor Agonists; D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine; D003000:Clonidine",
"country": "England",
"delete": false,
"doi": "10.1093/ajhp/zxaa013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "77(7)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": "critical care; sedatives; sympatholytics; withdrawal",
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D058647:Adrenergic alpha-2 Receptor Agonists; D000328:Adult; D003000:Clonidine; D016638:Critical Illness; D020927:Dexmedetomidine; D004305:Dose-Response Relationship, Drug; D057915:Drug Substitution; D006801:Humans; D006993:Hypnotics and Sedatives; D012307:Risk Factors; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "515-522",
"pmc": null,
"pmid": "32086509",
"pubdate": "2020-03-24",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Clonidine as a strategy for discontinuing dexmedetomidine sedation in critically ill patients: A narrative review.",
"title_normalized": "clonidine as a strategy for discontinuing dexmedetomidine sedation in critically ill patients a narrative review"
} | [
{
"companynumb": "JP-HQ SPECIALTY-JP-2020INT000043",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXMEDETOMIDINE HYDROCHLORIDE"
},
"dru... |
{
"abstract": "Since 2014 several direct-acting antivirals (DAAs) have been made available, allowing interferon-free antiviral treatments with high sustained virological response rates. Side effects are, however, a real challenge during treatment. Sarkar et al. recently published a case of colitis following initiation of sofosbuvir and simeprevir for genotype 1 hepatitis C. We report the case of a patient with no prior history of inflammatory bowel disease, who developed significant bloody diarrhea within 3 weeks of sofosbuvir/simeprevir/ribavirin initiation. Colonoscopy and biopsy suggested a drug-induced colitis.",
"affiliations": "University Department of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy. izzo.ilaria@hotmail.it.;University Department of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;University Department of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;University Department of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;Spedali Civili General Hospital, Pathology Institute, Brescia, Italy.;Spedali Civili General Hospital, Pathology Institute, Brescia, Italy.;University Department of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;University Department of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;University Department of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.",
"authors": "Izzo|Ilaria|I|http://orcid.org/0000-0001-9611-6160;Zanotti|Paola|P|;Chirico|Claudia|C|;Casari|Salvatore|S|;Villanacci|Vincenzo|V|;Salemme|Marianna|M|;Biasi|Luciano|L|;Festa|Elena|E|;Castelli|Francesco|F|",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin; D000069616:Simeprevir; D000069474:Sofosbuvir",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-016-0915-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "44(6)",
"journal": "Infection",
"keywords": "Drug-induced colitis; HCV; New direct-acting antiviral agents",
"medline_ta": "Infection",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D003092:Colitis; D004359:Drug Therapy, Combination; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D012254:Ribavirin; D000069616:Simeprevir; D000069474:Sofosbuvir",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "811-812",
"pmc": null,
"pmid": "27311809",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17066158;23518807;25639479;22919260;26839638;26504877;23172780",
"title": "Colitis during new direct-acting antiviral agents (DAAs) therapy with sofosbuvir, simeprevir and ribavirin for genotype 1b hepatitis C.",
"title_normalized": "colitis during new direct acting antiviral agents daas therapy with sofosbuvir simeprevir and ribavirin for genotype 1b hepatitis c"
} | [
{
"companynumb": "IT-JNJFOC-20160622456",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"d... |
{
"abstract": "Peripheral neuropathy (PN) caused by bortezomib is an important complication of multiple myeloma. Subcutaneous injection of bortezomib reduced PN, but 24% of cases were grade 2 PN and 6% of cases were grade 3 PN. PN higher than grade 2 was not resolved by subcutaneous injection. PN higher than grade 3 has serious dose limiting toxicity and is the cause of discontinuing bortezomib treatment. Lafutidine is an H2-blocker with gastroprotective activity and is thought to function by increasing mucosal blood flow via capsaicin sensitive neurons. The same activity of lafutidine is considered to improve glossodynia and taxane induced PN. We hypothesized that lafutidine prevents or improves PN that is caused by bortezomib. In the current study, bortezomib was administered in the usual manner (intravenous administration of bortezomib 1.3 mg/m(2), twice a week for 2 weeks, followed by 1 week without treatment) for up to four cycles to compare our data with other studies. Lafutidine was administered orally at a dose of 10 mg twice daily. In our eight evaluated cases, the total occurrence of PN was four out of eight patients (50%). There were only grade 1 PN (4 out of 8) cases, and no cases higher than grade 2. We conclude that (1) the total occurrence of PN was not improved, (2) there was no PN after the first course, (3) there were only grade 1 cases and there were no cases higher than grade 2, and (4) no cases discontinued bortezomib treatment because of PN. This is the first report showing that lafutidine is useful for the amelioration of bortezomib induced PN.",
"affiliations": "Department of Hematology, Sakai City Hospital, Osaka, Japan.",
"authors": "Tsukaguchi|Machiko|M|;Shibano|Masaru|M|;Matsuura|Ai|A|;Mukai|Satoru|S|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/JBM.S44127",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1179-2736",
"issue": "4()",
"journal": "Journal of blood medicine",
"keywords": "bortezomib induced peripheral neuropathy; calcitonin gene-related peptide; capsaicin sensitive neurons; lafutidine; multiple myeloma; transient receptor potential 1",
"medline_ta": "J Blood Med",
"mesh_terms": null,
"nlm_unique_id": "101550884",
"other_id": null,
"pages": "81-5",
"pmc": null,
"pmid": "23874126",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": "8387040;1498331;18414063;12826635;15958804;18753647;21507715;19170677;16549052;9516404;11872748;22193964;20924731;11740957;1852779;20886379;18574024;20874823;17214983;10535466;22750259;15867381;2311873;16473643;17970782;7563973",
"title": "The protective effects of lafutidine for bortezomib induced peripheral neuropathy.",
"title_normalized": "the protective effects of lafutidine for bortezomib induced peripheral neuropathy"
} | [
{
"companynumb": "JP-MPIJNJ-2013-05998",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": null,
"... |
{
"abstract": "Human Immunodeficiency Virus (HIV)-related Opportunistic Infections (OI), including Pneumocystis jiroveci pneumonia (PCP), have become much less commonplace with anti-retroviral therapy (ART). Despite this, OIs are still common and it is important to remain vigilant for their presence and be aware of how ART and OI chemoprophylaxis may lead to atypical disease presentations. We present the case of a 51-year-old woman with HIV and CD4+ T helper lymphocytes cell count > 200 cells/ul on both ART and trimethoprim/sulfamethoxazole prophylaxis who presented with cavitating lung masses, mediastinal lymphadenopathy and pleural effusions. Negative bronchoalveolar lavage (BAL) and transbronchial biopsy (TBBx) prompted a second diagnostic procedure with a transthoracic core needle biopsy; the final diagnosis was granulomatous PCP. This case showcases a very rare presentation of PCP, with both large cavitating lung masses on imaging and granulomatous reaction on pathology, as well as the challenge of a potentially missed diagnosis with negative BAL and TBBx requiring transthoracic core needle biopsy for a final diagnosis.",
"affiliations": "Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.",
"authors": "Diaz-Abad|Montserrat|M|;Robinett|Kathryn S|KS|;Lasso-Pirot|Anayansi|A|;Legesse|Teklu B|TB|;Khambaty|Mariam|M|",
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"doi": "10.2174/1874306402115010019",
"fulltext": "\n==== Front\nOpen Respir Med J\nOpen Respir Med J\nTORMJ\nThe Open Respiratory Medicine Journal\n1874-3064\nBentham Science Publishers\n\nTORMJ-15-19\n10.2174/1874306402115010019\nRespiratory Medicine\nGranulomatous Pneumocystis jiroveci Pneumonia in an HIV-Positive Patient on Antiretroviral Therapy: A Diagnostic Challenge\nDiaz-Abad Montserrat 1*\nRobinett Kathryn S. 1\nLasso-Pirot Anayansi 2\nLegesse Teklu B. 3\nKhambaty Mariam 1\n1 Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA\n2 Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA\n3 Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA\n* Address correspondence to this author at the Department of Medicine, University of Maryland School of Medicine; 100 North Greene Street, Room 204, Baltimore, Maryland 21201, USA; Tel: 410-706-4771; Fax: 410-706-0345; E-mail: mdiaz@som.umaryland.edu.\n18 6 2021\n2021\n15 1922\n15 1 2021\n16 2 2021\n7 3 2021\n© 2021 Diaz-Abad et al.\n2021\nDiaz-Abad\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nHuman Immunodeficiency Virus (HIV)-related Opportunistic Infections (OI), including Pneumocystis jiroveci pneumonia (PCP), have become much less commonplace with anti-retroviral therapy (ART). Despite this, OIs are still common and it is important to remain vigilant for their presence and be aware of how ART and OI chemoprophylaxis may lead to atypical disease presentations. We present the case of a 51-year-old woman with HIV and CD4+ T helper lymphocytes cell count > 200 cells/ul on both ART and trimethoprim/sulfamethoxazole prophylaxis who presented with cavitating lung masses, mediastinal lymphadenopathy and pleural effusions. Negative bronchoalveolar lavage (BAL) and transbronchial biopsy (TBBx) prompted a second diagnostic procedure with a transthoracic core needle biopsy; the final diagnosis was granulomatous PCP. This case showcases a very rare presentation of PCP, with both large cavitating lung masses on imaging and granulomatous reaction on pathology, as well as the challenge of a potentially missed diagnosis with negative BAL and TBBx requiring transthoracic core needle biopsy for a final diagnosis.\n\nKeywords\n\nPneumocystis jiroveci pneumonia\nHuman immunodeficiency virus\nGranulomatous\nDiagnosis\nBiopsy\nAntiretroviral therapy\nLung mass\n==== Body\n1 INTRODUCTION\n\nBeing the most common cause of death in human immunodeficiency virus (HIV)-related diseases, opportunistic infections (OI), including Pneumocystis jiroveci pneumonia (PCP), are becoming much less commonplace with the advent of potent and more readily available anti-retroviral therapy (ART). Prior to the availability of highly-active ART and PCP prophylaxis, it is estimated that up to 75% of people living with AIDS developed PCP in the US [1]. That number fell precipitously throughout the decades from 3.5 between 2003 to 2007 [2] to less than 1 case per 100 person-years [3]. In 2017, an estimated 10,590 patients were hospitalized with PCP [4]. Indeed, the spectrum of HIV-related diseases that patients are hospitalized for is very different compared to 10 or 15 years ago, with prolonged patient survival now reported due to improved medication efficacy and decreased toxicities [5].\n\nDespite this, OIs are still common and it is important to remain vigilant for their presence and be aware of how ART and OI chemoprophylaxis may contribute to atypical disease presentations. We present the case of a 51-year-old woman with HIV and CD4+ T helper lymphocytes (CD4) cell count > 200 cells/ul, on both ART and trimethoprim/sulfamethoxazole (TMP/SMX) chemoprophylaxis, who presented with cavitating lung masses, mediastinal lymphadenopathy and pleural effusions, and was diagnosed with granulomatous PCP with transthoracic core needle biopsies, a very rare presentation of this infection.\n\n2 CASE PRESENTATION\n\nA 51-year-old woman was admitted with 3 weeks of cough, initially dry then productive of a small amount of clear sputum, and 6 days of subjective fevers, chills and dyspnea on exertion. On the day prior to admission, she experienced worsening malaise, fatigue and dyspnea. Her past medical history included HIV infection diagnosed 2 years earlier, with a CD4 cell count of 220 cells/ul measured 2 months prior to admission, cervical dysplasia with cone biopsy 8 months earlier and chronic anemia. She reported no recent travel history or sick exposures. Her ART regimen was lamivudine/zidovudine plus lopinavir/ritonavir, with TMP/SMX 800/160 mg 3 times weekly for PCP prophylaxis.\n\nOn physical examination, the patient was in no acute distress. She was febrile at 102 °F, pulse was 84 beats/minute, and respirations were 22 breaths/minute. Blood pressure was 86/50 mm Hg and oxygen saturation was 99% on room air. Lungs were clear, with bilateral breath sounds. There was no palpable lymphadenopathy. Laboratory values were significant for a lactate dehydrogenase level of 217 U/L (100-190), albumin 2.0 g/dl, hemoglobin 10.7g/dl, and white blood cell count 7.9 cells/ul, with differential: 71.1% neutrophils, 15.9% lymphocytes, 12.1% monocytes, 0.4% eosinophils and 0.8% basophils.\n\nComputed Tomography (CT) of the chest revealed subcarinal, prevascular and right hilar lymphadenopathy. Multiple masses and nodules were scattered throughout both lungs, the largest cavitating and abutting the major fissure in the left upper lobe measuring 4.2 x 4.2 cm, with another large mass at the right cardiophrenic angle measuring 2.2 x 4.6 cm. There were also bilateral pleural effusions with associated compressive atelectasis of the lower lobes and fibrotic changes in the left apical region, (Fig. 1).\n\nThe patient was admitted with the diagnosis of pneumonia of uncertain etiology, placed on airborne isolation for tuberculosis, and was started on ceftriaxone 1g Intravenous (IV) daily, azithromycin 500 mg IV daily and TMP/SMX 2 double strength tablets orally every 8 hours. Sputum Gram stain and bacterial culture, 3 Acid-Fast Bacilli sputum smears and purified protein derivative testing were negative. The patient continued to have intermittent fevers 101-102 °F for the next 4 days, then became afebrile and started feeling overall better. She experienced nausea and vomiting as a side effect of TMP/SMX.\n\nFive days after admission, the patient underwent fiberoptic bronchoscopy under moderate sedation. There were no abnormalities in the airways, and Bronchoalveolar Lavage (BAL) of the lingula as well as 5 Transbronchial Biopsies (TBBx) of the left upper lobe were performed. All cultures and smears were negative. Cytology was negative for malignancy and PCP. The TBBx of the left upper lobe showed benign bronchial tissue and a fragment of lung parenchyma with interstitial fibrosis. TMP/SMX was discontinued in view of negative results for PCP while azithromycin and ceftriaxone were continued. Three days later, fever and malaise restarted, and because of suspicion for nocardiosis, TMP/SMX was restarted. CT of the head showed maxillary, frontal and ethmoid sinus disease, without other pathology. That day, 2 transthoracic core needle biopsies were performed in the left upper lung cavitating pleural-based mass. Pathology revealed lung parenchyma and bronchial tissue with acute inflammation and fibrosis, and granulomas with coagulation necrosis with organisms within morphologically consistent with Pneumocystis jiroveci noted on Gomori methenamine silver (GMS) stain by direct microscopy, and negative Acid-Fast Bacilli stain, (Fig. 2).\n\nAzithromycin and ceftriaxone were stopped. The patient was restarted on oral TMP/SMX and again became afebrile; malaise and fatigue improved. Due to persistent nausea and vomiting, therapy was switched to IV formulation. She continued to improve and felt back to baseline and was discharged 1 week later on oral clindamycin and primaquine. CT of the chest 3 months later revealed nearly complete resolution of the previous findings, with a significantly improved cavitating left upper lobe nodule, multiple peripheral bilateral sub-cm non calcified pulmonary nodules, and resolution of bilateral pleural effusions and mediastinal lymphadenopathy (Fig. 1).\n\n3 RESULTS AND DISCUSSION\n\nThe present case showcases a very rare presentation of PCP, with large cavitating lung masses, mediastinal lymphadenopathy and pleural effusions on CT imaging and granulomatous reaction on pathology, as well as the challenge of a potentially missed diagnosis, with both negative BAL and TBBx requiring transthoracic core needle biopsy for final diagnosis. The patient had a moderate level of immunity and was also on both ART and PCP chemoprophylaxis, which likely contributed to this atypical presentation.\n\nThe BAL and TBBx failed to reveal the Pneumocystis jiroveci organisms in this case. While BAL and TBBx have been reported to be highly sensitive for this organism, and the diagnostic yield for TBBx has been reported as 97% [6], patients who have failed PCP chemoprophylaxis have a smaller burden of organisms and an increased frequency of false-negative results on BAL [7]. The patient required transthoracic core needle biopsy for the diagnosis, and at one moment, the appropriate therapy with TMP-SMX was stopped due to the unlikely possibility of PCP with the prior negative results, with prompt recurrence of symptoms. There was almost complete resolution of the CT findings with therapy, which points to appropriate diagnosis and therapy.\n\nThis patient presented with lung masses, nodules and cavitation, mediastinal lymphadenopathy and pleural effusions, a presentation that is very uncommon. The classic radiographic appearance of PCP pneumonia is that of bilateral alveolar infiltrates that begin in the perihilar areas and progress to diffusely involve the lungs, and CT of the chest usually shows ground-glass attenuation or opacities. Atypical presentations of PCP on CT are less common and include focal, segmental or lobar consolidation, nodules and cavitating lesions, a military pattern, pleural effusions, lymphadenopathy, cystic spaces, bullae and pneumothorax [8-13].\n\nThe biopsy, in this case, reported granulomatous lesions with caseating necrosis with the organisms within. The typical histologic appearance of PCP consists of intra-alveolar foamy eosinophilic exudates, which contain trophozoites and cysts of the organism. The atypical granulomatous reaction can be proven only by finding the cysts on Gomori’s Methenamine Silver staining in the absence of other organisms on appropriate stains and cultures [14, 15]. Granulomatous inflammation in PCP is unusual [11, 12]. It can be seen in about 5% of patients, usually when immunodeficiency is more limited [15], and can be seen on CT of the chest as a solitary nodule, multiple nodules of varying sizes, or even a mass mimicking lung carcinoma [16]. PCP with a granulomatous reaction has also been reported as part of an immune reconstitution inflammatory syndrome [15, 17, 18]. In granulomatous PCP without alveolitis, BAL may be negative because the cysts are trapped in the necrosis of the granulomas, or there are fewer organisms in the granulomas. Patients with HIV have a T-cell deficiency and, due to this, have difficulty in mounting a granulomatous reaction [19]. It is possible that the relatively lower immunodeficiency in this case -CD4 cell count of 220 cell/ul- allowed for the development of the granulomatous reaction.\n\nThere have been several reports of unusual presentations of PCP in patients with HIV. One case had pleural based masses, nodules and mediastinal lymphadenopathy in a patient on chemoprophylaxis but without ART or a granulomatous reaction. The diagnosis was made initially by transthoracic fine needle biopsy [20]. A patient on ART but not compliant with chemoprophylaxis presented with multiple pulmonary nodules. BAL and TBBx were negative, and the diagnosis was made with a thoracoscopic lung biopsy showing well-formed necrotizing granulomas with Pneumocystis organisms [21]. In another case, the patient presented after starting ART with multiple lung nodules, some cavitating, CD4 count > 250 cell/ul and off chemoprophylaxis. BAL, TBBx and transthoracic needle biopsy were negative, requiring a thoracoscopic lung biopsy that revealed necrotizing granulomas containing Pneumocystis organisms [17].\n\nTo our knowledge, this is the first case of PCP that reunites together in one patient all these atypical CT imaging and histologic findings, along with both a negative BAL and TBBx while receiving ART and chemoprophylaxis at the time of admission and with a CD4 count > 200 cell/ul. PCP should be in the differential diagnosis of patients with HIV who present with a lung mass. There have been increasing numbers of unusual presentations of PCP in HIV patients, leading to delayed diagnosis and appropriate treatment [22]. The spectrum of imaging abnormalities associated with PCP now includes abnormalities of the lung parenchyma, airways, lymph nodes, and pleura [23]. Multiple diagnostic tests may be required in these patients for a definitive diagnosis. Concomitant ART and chemoprophylaxis do not rule out PCP and may actually contribute to more atypical presentations, highlighting the need for increased awareness of these unusual presentations when patients with HIV are receiving these treatment regimens.\n\nACKNOWLEDGEMENTS\n\nDeclared none.\n\nLIST OF ABBREVIATIONS\n\nHIV = Human Immunodeficiency Virus\n\nOI = Opportunistic Infections\n\nPCP = Pneumocystis jiroveci Pneumonia\n\nART = Anti-Retroviral Therapy\n\nCD4 = CD4+ T Helper Lymphocytes\n\nTMP/SMX = Trimethoprim/Sulfamethoxazole\n\nCT = Computed Tomography (CT)\n\nIV = Intravenous\n\nTBBx = Transbronchial Biopsies\n\nETHICS APPROVAL AND CONSENT TO PARTICIPATE\n\nNot applicable.\n\nHUMAN AND ANIMAL RIGHTS\n\nNot applicable.\n\nCONSENT FOR PUBLICATION\n\nInformed consent was taken from all the participants when they were enrolled.\n\nAVAILABILITY OF DATA AND MATERIALS\n\nNot applicable.\n\nFUNDING\n\nNone.\n\nSTANDARDS OF REPORTING\n\nCARE guidelines have been followed.\n\nCONFLICT OF INTEREST\n\nThe authors declare that there is no conflict of interest regarding the publication of this article.\n\nFig. (1) Admission Computed Tomography scan (CT) of the chest, showing: (A) Pleural based large cavitating lung mass in the left upper lobe measuring 4.2 x 4.2 cm; and (B) Multiple masses and nodules scattered throughout both lungs. CT of the chest 3 months later, showing: (C) Persistent but much smaller cavitating left upper lobe nodule, and (D) Nearly complete resolution of the previous nodules and masses, with multiple peripheral bilateral sub-cm non-calcified pulmonary nodules.\n\nFig. (2) Transthoracic core needle biopsies histology. (A) Granulomatous inflammation with epithelioid cell aggregates and lymphoplasmacytic infiltrates. The granulomas in some areas are not well-formed (Hematoxylin and Eosin, Low magnification). (B) Granulomatous inflammation with aggregates of epithelioid cells and scattered Langhans type multinucleated giant cells (Hematoxylin and Eosin, medium magnification). (C) Necrotic center of the granuloma with surrounding loose epithelioid cell aggregates (Hematoxylin and Eosin, High magnification). (D) Scattered cysts of Pneumocystis jiroveci in the center of necrotic granuloma (Gomori methenamine silver, high magnification).\n==== Refs\nREFERENCES\n\n1 Hay J.W. Osmond D.H. Jacobson M.A. Projecting the medical costs of AIDS and ARC in the United States. J Acquir Immune Defic Syndr (1988) 1988 1 5 466 485 3065476\n2 Buchacz K. Baker R.K. Palella F.J. Jr Chmiel J.S. Lichtenstein K.A. Novak R.M. Wood K.C. Brooks J.T. HOPS Investigators AIDS-defining opportunistic illnesses in US patients, 1994-2007: A cohort study. AIDS 2010 24 10 1549 1559 10.1097/QAD.0b013e32833a3967 20502317\n3 Buchacz K. Lau B. Jing Y. Bosch R. Abraham A.G. Gill M.J. Silverberg M.J. Goedert J.J. Sterling T.R. Althoff K.N. Martin J.N. Burkholder G. Gandhi N. Samji H. Patel P. Rachlis A. Thorne J.E. Napravnik S. Henry K. Mayor A. Gebo K. Gange S.J. Moore R.D. Brooks J.T. North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA Incidence of aids-defining opportunistic infections in a multicohort analysis of hiv-infected persons in the United States and Canada, 2000-2010. J. Infect. Dis. 2016 214 6 862 872 10.1093/infdis/jiw085 27559122\n4 Benedict K. Jackson B.R. Chiller T. Beer K.D. Estimation of direct healthcare costs of fungal diseases in the United States. Clin. Infect. Dis. 2019 68 11 1791 1797 10.1093/cid/ciy776 30204844\n5 Antiretroviral Therapy Cohort Collaboration Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV 2017 4 8 e349 e356 10.1016/S2352-3018(17)30066-8 28501495\n6 Mones J.M. Saldana M.J. Oldham S.A. Diagnosis of Pneumocystis carinii pneumonia. Roentgenographic-pathologic correlates based on fiberoptic bronchoscopy specimens from patients with the acquired immunodeficiency syndrome. Chest 1986 89 4 522 526 10.1378/chest.89.4.522 3485514\n7 Jules-Elysee K.M. Stover D.E. Zaman M.B. Bernard E.M. White D.A. Aerosolized pentamidine: Effect on diagnosis and presentation of Pneumocystis carinii pneumonia. Ann. Intern. Med. 1990 112 10 750 757 10.7326/0003-4819-112-10-750 2331119\n8 Doppman J.L. Geelhoed G.W. De Vita V.T. Atypical radiographic features in Pneumocystis carinii pneumonia. Radiology 1975 114 1 39 44 10.1148/114.1.39 1082150\n9 Doppman J.L. Geelhoed G.W. Atypical radiographic features in Pneumocystis carinii pneumonia. Natl. Cancer Inst. Monogr. 1976 43 89 97 1087962\n10 Suster B. Akerman M. Orenstein M. Wax M.R. Pulmonary manifestations of AIDS: Review of 106 episodes. Radiology 1986 161 1 87 93 10.1148/radiology.161.1.3489955 3489955\n11 Kuhlman J.E. Kavuru M. Fishman E.K. Siegelman S.S. Pneumocystis carinii pneumonia: Spectrum of parenchymal CT findings. Radiology 1990 175 3 711 714 10.1148/radiology.175.3.2343118 2343118\n12 Kennedy C.A. Goetz M.B. Atypical roentgenographic manifestations of Pneumocystis carinii pneumonia. Arch. Intern. Med. 1992 152 7 1390 1398 10.1001/archinte.1992.00400190032008 1627019\n13 Block B.L. Mehta T. Ortiz G.M. Ferris S.P. Vu T.H. Huang L. Cattamanchi A. Unusual radiographic presentation of Pneumocystis pneumonia in a patient with AIDS. Case Rep. Infect. Dis. 2017 2017 3183525 10.1155/2017/3183525 29362681\n14 Saldana M.J. Mones J.M. Cavitation and other atypical manifestations of Pneumocystis carinii pneumonia. Semin. Diagn. Pathol. 1989 6 3 273 286 2678337\n15 Travis W.D. Pittaluga S. Lipschik G.Y. Ognibene F.P. Suffredini A.F. Masur H. Feuerstein I. Kovacs J. Pass H.I. Condron K.S. Shelhamer J.H. Atypical pathologic manifestations of Pneumocystis carinii pneumonia in the acquired immune deficiency syndrome. Review of 123 lung biopsies from 76 patients with emphasis on cysts, vascular invasion, vasculitis, and granulomas. Am. J. Surg. Pathol. 1990 14 7 615 625 10.1097/00000478-199007000-00002 2192568\n16 Kanne J.P. Yandow D.R. Meyer C.A. Pneumocystis jiroveci pneumonia: high-resolution CT findings in patients with and without HIV infection. AJR Am. J. Roentgenol. 2012 198 6 W555-61 10.2214/AJR.11.7329 22623570\n17 Sabur N. Kelly M.M. Gill M.J. Ainslie M.D. Pendharkar S.R. Granulomatous Pneumocystis jiroveci pneumonia associated with immune reconstituted HIV. Can. Respir. J. 2011 18 6 e86 e88 10.1155/2011/539528 22187692\n18 Taeb A.M. Sill J.M. Derber C.J. Hooper M.H. Nodular granulomatous Pneumocystis jiroveci pneumonia consequent to delayed immune reconstitution inflammatory syndrome. Int. J. STD AIDS 2018 29 14 1451 1453 10.1177/0956462418787603 30114992\n19 Perlman D.C. El-Helou P. Salomon N. Tuberculosis in patients with human immunodeficiency virus infection. Semin. Respir. Infect. 1999 14 4 344 352 10638514\n20 Sundar K. Rosado-Santos H. Reimer L. Murray K. Michael J. Unusual presentation of thoracic Pneumocystis carinii infection in a patient with acquired immunodeficiency syndrome. Clin. Infect. Dis. 2001 32 3 498 501 10.1086/318504 11170960\n21 Winn R.A. Stoeckli T.C. Wilson M.L. Burman W. Schwarz M.I. Chan E.D. Multiple pulmonary nodules in an HIV-positive man on highly active antiretroviral therapy. Chest 2002 122 5 1840 1843 10.1378/chest.122.5.1840 12426290\n22 Sarkar S. Dubé M.P. Jones B.E. Sattler F.R. Pneumocystis carinii pneumonia masquerading as tuberculosis. Arch. Intern. Med. 1997 157 3 351 355 10.1001/archinte.1997.00440240117017 9040304\n23 Boiselle P.M. Crans C.A. Jr Kaplan M.A. The changing face of Pneumocystis carinii pneumonia in AIDS patients. AJR Am. J. Roentgenol. 1999 172 5 1301 1309 10.2214/ajr.172.5.10227507 10227507\n\n",
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"keywords": "Antiretroviral therapy; Biopsy; Diagnosis; Granulomatous; Human immunodeficiency virus; Lung mass; Pneumocystis jiroveci pneumonia",
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"title": "Granulomatous Pneumocystis jiroveci Pneumonia in an HIV-Positive Patient on Antiretroviral Therapy: A Diagnostic Challenge.",
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"abstract": "Metformin could have benefits on cardiovascular disease and kidney disease progression but is often withheld from individuals with diabetes and chronic kidney disease (CKD) because of a concern that it may increase the risk of lactic acidosis.\n\n\n\nAll-cause mortality, cardiovascular death, cardiovascular events (death, hospitalization for heart failure, myocardial infarction, stroke or myocardial ischemia), end stage renal disease (ESRD) and the kidney disease composite (ESRD or death) were compared in metformin users and non-users with diabetes and CKD enrolled in the Trial to Reduce Cardiovascular Events with Aranesp (darbepoeitin-alfa) Therapy (TREAT) (NCT00093015). Outcomes were compared after propensity matching of users and non-users and in multivariable proportional hazards models.\n\n\n\nThere were 591 individuals who used metformin at baseline and 3447 non-users. Among propensity-matched users, the crude incidence rate for mortality, cardiovascular mortality, cardiovascular events and the combined endpoint was lower in metformin users than in non-users, but ESRD was marginally higher (4.0% vs 3.6%). Metformin use was independently associated with a reduced risk of all-cause mortality (HR, 0.49; 95% CI, 0.36-0.69), cardiovascular death (HR, 0.49; 95% CI, 0.32-0.74), the cardiovascular composite (HR, 0.67, 95% CI, 0.51-0.88) and the kidney disease composite (HR, 0.77; 95% CI, 0.61-0.98). Associations with ESRD (HR, 1.01; 95% CI, 0.65-1.55) were not significant. Results were qualitatively similar in adjusted analyses of the full population. Two cases of lactic acidosis were observed.\n\n\n\nMetformin may be safer for use in CKD than previously considered and may lower the risk of death and cardiovascular events in individuals with stage 3 CKD.",
"affiliations": "Nephrology Division, Department of Medicine, NYU Langone Medical Center, New York, New York.;Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.;Renal Division, Northwestern University, Chicago, Illinois.;Division of Nephrology, L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy and Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.;Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia.;Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri.;Division of Endocrinology, Metabolism and Lipid Research, Rigshospitalet Copenhagen University Hospital, Copehnahgen, Denmark.;Division of Nephrology, Health Sciences Centre, St. John's, Canada.;Nephrology Division, Department of Medicine, NYU Langone Medical Center, New York, New York.;Division of Nephrology, University of Sao Paulo Medical School, Sao Paulo, Brazil.;Division of Nephrology, Tufts Medical Center, Boston, Massachusetts.;Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.;Division of Cardiology, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.;Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.;Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.;Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.;Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.;Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.",
"authors": "Charytan|David M|DM|0000-0002-7695-3583;Solomon|Scott D|SD|;Ivanovich|Peter|P|;Remuzzi|Giuseppe|G|;Cooper|Mark E|ME|;McGill|Janet B|JB|;Parving|Hans-Henrik|HH|;Parfrey|Patrick|P|;Singh|Ajay K|AK|;Burdmann|Emmanuel A|EA|;Levey|Andrew S|AS|;Eckardt|Kai-Uwe|KU|;McMurray|John J V|JJV|0000-0002-6317-3975;Weinrauch|Larry A|LA|;Liu|Jiankang|J|;Claggett|Brian|B|;Lewis|Eldrin F|EF|;Pfeffer|Marc A|MA|",
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"journal": "Diabetes, obesity & metabolism",
"keywords": "cardiovascular disease; diabetes complications; diabetic nephropathy; metformin",
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"mesh_terms": "D000368:Aged; D002318:Cardiovascular Diseases; D002423:Cause of Death; D000068256:Darbepoetin alfa; D003924:Diabetes Mellitus, Type 2; D003925:Diabetic Angiopathies; D003928:Diabetic Nephropathies; D005260:Female; D006333:Heart Failure; D006801:Humans; D008297:Male; D008687:Metformin; D008875:Middle Aged; D009026:Mortality; D051436:Renal Insufficiency, Chronic; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke",
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"title": "Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease.",
"title_normalized": "metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease"
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"companynumb": "US-AMNEAL PHARMACEUTICALS-2019AMN00379",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"dru... |
{
"abstract": "Clozapine is the most effective anti-psychotic medication for treatment refractory schizophrenia. A growing number of case reports have linked infection to high clozapine levels and associated adverse outcomes. We present a systematic review of published cases to clarify the relationship between infection and elevated clozapine levels. The case reports were located through PubMed and Embase. In addition, 8 new cases from two Australian states were included. Demographics, psychiatric diagnoses and medical morbidities, medications, clinical symptoms, clozapine levels, inflammatory markers and final clinical outcome were extracted. 40 cases were identified in 23 publications that demonstrated elevated clozapine levels associated with infection. Infections were commonly respiratory in origin. Adverse events, typically sedation, were associated with raised clozapine levels during infection. In many cases the signs of infection such as fever and white blood cell count were reduced. Severe adverse effects were uncommon, with one case each of seizure, myocarditis and neutropenia. The relationship between infection, clozapine levels and adverse events is complex and multi-factorial. Monitoring of clozapine levels is essential during hospitalisation for infection and consideration should be given to gradual dose reduction to minimise dose related side effects.",
"affiliations": "University of Adelaide, Department of Psychiatry, Adelaide, SA 5005, Australia.;Metro South Addiction and Mental Health Service, Brisbane, QLD 4012, Australia; University of Queensland, School of Medicine, Brisbane, QLD 4072, Australia. Electronic address: n.warren@uq.edu.au.;University of Adelaide, Department of Psychiatry, Adelaide, SA 5005, Australia.;Southern Adelaide Local Health Network, Adelaide, South Australia 5042, Australia.;University of Adelaide, Department of Psychiatry, Adelaide, SA 5005, Australia; Northern Adelaide Local Health Network, Adelaide, South Australia 5112, Australia.;Metro South Addiction and Mental Health Service, Brisbane, QLD 4012, Australia; University of Queensland, School of Medicine, Brisbane, QLD 4072, Australia.;Princess Alexandra Hospital, Brisbane, QLD 4012, Australia.;University of Adelaide, Department of Psychiatry, Adelaide, SA 5005, Australia.;Metro South Addiction and Mental Health Service, Brisbane, QLD 4012, Australia; University of Queensland, School of Medicine, Brisbane, QLD 4072, Australia.",
"authors": "Clark|Scott R|SR|;Warren|Nicola S|NS|;Kim|Gajin|G|;Jankowiak|David|D|;Schubert|Klaus Oliver|KO|;Kisely|Steve|S|;Forrester|Tori|T|;Baune|Bernhard T|BT|;Siskind|Dan J|DJ|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.schres.2017.03.045",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-9964",
"issue": "192()",
"journal": "Schizophrenia research",
"keywords": "Clozapine; Infection; Inflammation; Levels; Schizophrenia; Toxicity",
"medline_ta": "Schizophr Res",
"mesh_terms": "D014150:Antipsychotic Agents; D003024:Clozapine; D006801:Humans; D007239:Infections; D012559:Schizophrenia",
"nlm_unique_id": "8804207",
"other_id": null,
"pages": "50-56",
"pmc": null,
"pmid": "28392207",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Elevated clozapine levels associated with infection: A systematic review.",
"title_normalized": "elevated clozapine levels associated with infection a systematic review"
} | [
{
"companynumb": "AU-ACCORD-050705",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Purpose: Cytarabine is considered the standard of care for induction therapy in patients with acute myeloid leukemia (AML) who are preparing for bone marrow transplant. Summary: We report a case of a 72-year-old female presenting to the intensive care unit with hepatic failure after high-dose cytarabine (HiDAC) for the treatment of relapsed AML. The patient's liver function tests (LFTs) were elevated acutely, with a mildly elevated bilirubin and a normal alkaline phosphatase. HiDAC was discontinued but her LFTs remained high for 9 days post discontinuation, and the patient eventually expired due to sepsis and multiple organ failure. We estimated the probability of the hepatotoxicity observed with HiDAC as probable based on a score of 5 on the Naranjo scale. Conclusion: Clinicians should be aware of the potential hepatotoxicity associated with HiDAC for patients with AML, specifically in the elderly population.",
"affiliations": "University of Kentucky College of Pharmacy, Lexington, USA.;University of Kentucky College of Pharmacy, Lexington, USA.;University of Kentucky College of Pharmacy, Lexington, USA.",
"authors": "Fu|Samuel H|SH|;Flannery|Alexander H|AH|;Thompson Bastin|Melissa L|ML|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0018578718779763",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-5787",
"issue": "54(3)",
"journal": "Hospital pharmacy",
"keywords": "cytarabine; hepatotoxicity; liver failure",
"medline_ta": "Hosp Pharm",
"mesh_terms": null,
"nlm_unique_id": "0043175",
"other_id": null,
"pages": "160-164",
"pmc": null,
"pmid": "31205325",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "10327034;1464366;1554959;16473644;23671007;26471735;28573946;3457102;3589690;4879053;4956026;6594185;7249508;7350020;8634416;8874180",
"title": "Acute Hepatotoxicity After High-Dose Cytarabine for the Treatment of Relapsed Acute Myeloid Leukemia: A Case Report.",
"title_normalized": "acute hepatotoxicity after high dose cytarabine for the treatment of relapsed acute myeloid leukemia a case report"
} | [
{
"companynumb": "US-MYLANLABS-2018M1009815",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MICAFUNGIN SODIUM"
},
"drugadditional": null,... |
{
"abstract": "Mitochondrial dynamics such as fission and fusion play a vital role in normal brain development and neuronal activity. DNM1L encodes a dynamin-related protein 1 (Drp1), which is a GTPase essential for proper mitochondrial fission. The clinical phenotype of DNM1L mutations depends on the degree of mitochondrial fission deficiency, ranging from severe encephalopathy and death shortly after birth to initially normal development and then sudden onset of refractory status epilepticus with very poor neurologic outcome. We describe a case of a previously healthy 3-year-old boy with a mild delay in speech development until the acute onset of a refractory status epilepticus with subsequent epileptic encephalopathy and very poor neurologic outcome. The de novo missense mutation in DNM1L (c.1207C > T, p.R403C), which we identified in this case, seems to determine a unique clinical course, strikingly similar to four previously described patients in literature with the identical de novo heterozygous missense mutation in DNM1L.",
"affiliations": "Department of Pediatrics, Kinderklinik Muenchen Schwabing, Klinikum Schwabing, StKM GmbH und Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.;Institute of Human Genetics, Technical University Munich, Munich, Germany.;Department of Pediatrics, Kinderklinik Muenchen Schwabing, Klinikum Schwabing, StKM GmbH und Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.;Department of Pediatrics, Kinderklinik Muenchen Schwabing, Klinikum Schwabing, StKM GmbH und Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.;Department of Pediatrics, Klinikum Reutlingen, Reutlingen, Germany.;Schoen Klinik Vogtareuth, Epilepsy Center for Children and Adolescents, Hospital for Neuropediatrics and Neurological Rehabilitation, Vogtareuth, Germany.;Department of Social Pediatrics and Developmental Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.;Department of Pediatrics, Kinderklinik Muenchen Schwabing, Klinikum Schwabing, StKM GmbH und Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.;Department of Pediatrics, Kinderklinik Muenchen Schwabing, Klinikum Schwabing, StKM GmbH und Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.",
"authors": "Schmid|S J|SJ|;Wagner|M|M|;Goetz|C|C|;Makowski|C|C|;Freisinger|P|P|;Berweck|S|S|;Mall|V|V|;Burdach|S|S|;Juenger|H|H|",
"chemical_list": "C110768:DNM1L protein, human; D034281:Dynamins",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0039-1685217",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0174-304X",
"issue": "50(3)",
"journal": "Neuropediatrics",
"keywords": null,
"medline_ta": "Neuropediatrics",
"mesh_terms": "D001927:Brain Diseases; D002675:Child, Preschool; D034281:Dynamins; D004829:Epilepsy, Generalized; D006801:Humans; D008297:Male; D009154:Mutation; D013226:Status Epilepticus",
"nlm_unique_id": "8101187",
"other_id": null,
"pages": "197-201",
"pmc": null,
"pmid": "30939602",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A De Novo Dominant Negative Mutation in DNM1L Causes Sudden Onset Status Epilepticus with Subsequent Epileptic Encephalopathy.",
"title_normalized": "a de novo dominant negative mutation in dnm1l causes sudden onset status epilepticus with subsequent epileptic encephalopathy"
} | [
{
"companynumb": "DE-TEVA-2019-DE-1070519",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": "3",
"... |
{
"abstract": "BACKGROUND\nEfavirenz, widely used as part of antiretroviral drug regimens in the treatment of paediatric human immunodeficiency virus infection, has central nervous system side effects. We describe four children presenting with serious, persistent central nervous system adverse events who were found to have elevated plasma efavirenz concentrations as a result of carrying CYP2B6 single nucleotide polymorphisms, known to play a role in the metabolism of EFV. None of the children had a CYP2B6 wildtype haplotype. We believe this is the first case of cerebellar dysfunction associated with efavirenz use to be described in children.\n\n\nMETHODS\nFour black African children, between the ages of 4 and 8 years presenting between 1 and 20 months post-efavirenz initiation, are described. Cerebellar dysfunction, generalised seizures and absence seizures were the range of presenting abnormalities. Plasma efavirenz levels ranged from 20-60 mg/L, 5-15 times the upper limit of the suggested reference range. All abnormal central nervous system manifestations abated after efavirenz discontinuation.\n\n\nCONCLUSIONS\nEfavirenz toxicity should always be considered in human immunodeficiency virus-infected children with unexplained central nervous system abnormalities. Our findings further our understanding of the impact of genetic variants on antiretroviral pharmacokinetics in children across various ethnic groups. Screening for potential EFV-toxicity based on the CYP2B6 c.516 SNP alone, may not be adequate.",
"affiliations": "Empilweni Services and Research Unit (ESRU), Rahima Moosa Mother and Child Hospital, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.;Pharmacogenetics and Cancer Research Group, Division of Human Genetics, Department of Pathology & Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.;Pharmacogenetics and Cancer Research Group, Division of Human Genetics, Department of Pathology & Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.;Empilweni Services and Research Unit (ESRU), Rahima Moosa Mother and Child Hospital, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.;Gertrude H. Sergievsky Center, College of Physicians and Surgeons; and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.;Empilweni Services and Research Unit (ESRU), Rahima Moosa Mother and Child Hospital, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.;Empilweni Services and Research Unit (ESRU), Rahima Moosa Mother and Child Hospital, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.;ICAP, Mailman School of Public Health, and College of Physicians & Surgeons Columbia University, 722 W168th street, New York, NY, 10032, USA. eja1@columbia.edu.",
"authors": "Pinillos|Francoise|F|;Dandara|Collet|C|;Swart|Marelize|M|;Strehlau|Renate|R|;Kuhn|Louise|L|;Patel|Faeezah|F|;Coovadia|Ashraf|A|;Abrams|Elaine|E|",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-016-1381-x",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 26831894138110.1186/s12879-016-1381-xCase ReportCase report: Severe central nervous system manifestations associated with aberrant efavirenz metabolism in children: the role of CYP2B6 genetic variation Pinillos Francoise 1Dandara Collet 2Swart Marelize 2Strehlau Renate 1Kuhn Louise 3Patel Faeezah 1Coovadia Ashraf 1http://orcid.org/0000-0001-7938-8981Abrams Elaine 212 342 0543eja1@columbia.edu 41 Empilweni Services and Research Unit (ESRU), Rahima Moosa Mother and Child Hospital, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 2 Pharmacogenetics and Cancer Research Group, Division of Human Genetics, Department of Pathology & Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa 3 Gertrude H. Sergievsky Center, College of Physicians and Surgeons; and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY USA 4 ICAP, Mailman School of Public Health, and College of Physicians & Surgeons Columbia University, 722 W168th street, New York, NY 10032 USA 2 2 2016 2 2 2016 2016 16 5631 10 2015 25 1 2016 © Pinillos et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nEfavirenz, widely used as part of antiretroviral drug regimens in the treatment of paediatric human immunodeficiency virus infection, has central nervous system side effects. We describe four children presenting with serious, persistent central nervous system adverse events who were found to have elevated plasma efavirenz concentrations as a result of carrying CYP2B6 single nucleotide polymorphisms, known to play a role in the metabolism of EFV. None of the children had a CYP2B6 wildtype haplotype. We believe this is the first case of cerebellar dysfunction associated with efavirenz use to be described in children.\n\nCase presentation\nFour black African children, between the ages of 4 and 8 years presenting between 1 and 20 months post-efavirenz initiation, are described. Cerebellar dysfunction, generalised seizures and absence seizures were the range of presenting abnormalities. Plasma efavirenz levels ranged from 20-60 mg/L, 5–15 times the upper limit of the suggested reference range. All abnormal central nervous system manifestations abated after efavirenz discontinuation.\n\nConclusion\nEfavirenz toxicity should always be considered in human immunodeficiency virus-infected children with unexplained central nervous system abnormalities. Our findings further our understanding of the impact of genetic variants on antiretroviral pharmacokinetics in children across various ethnic groups. Screening for potential EFV-toxicity based on the CYP2B6 c.516 SNP alone, may not be adequate.\n\nKeywords\nEfavirenzPaediatricsCYP2B6HIVPaediatric HIVAntiretroviral treatmentCNSSeizuresCerebellumEunice Kennedy Shriver National Institutes of Child Health and Human DevelopmentHD061255Kuhn Louise issue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nEfavirenz (EFV) is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) used as part of combination antiretroviral (ARV) regimens in the treatment of paediatric and adult human immunodeficiency virus (HIV) infection. Central nervous system (CNS) complications associated with EFV use have been well characterised in adults, but are less commonly described in children. We report on four children who presented with serious, persistent CNS adverse effects attributed to EFV toxicity while receiving standard recommended weight-based EFV dosing as per South African guidelines. All four children were found to have plasma EFV concentrations above the suggested therapeutic range and carried CYP2B6 single nucleotide polymorphisms (SNPs), CYP2B6 c.516G > T, CYP2B6 c.785A > G and CYP2B6 c.983 T > C, which are associated with reduced CYP2B6 function and decreased EFV metabolism Table 1.Table 1 Case detail summary\n\n\t[Case 1]b\n\t[Case 2]b\n\t[Case 3]a\nb\n\t[Case 4]b\n\t\nCNS Adverse Event\tGeneralised tonic-clonic seizures Aggressive behavior\tAcute progressive ataxia, with cerebellar signs Anti-social behavior\tGeneralised tonic-clonic seizures Progressively poor school performance\tAbsence seizures\t\nEvent Described\tGeneralised tonic-clonic seizure\tCerebellar dysfunction\tGeneralised tonic-clonic seizure\tAbsence seizure\t\nSex\tMale\tFemale\tFemale\tFemale\t\nStarting ART Regimen\tLPV/r, 3TC, d4T\tLPV/r, 3TC, d4T\tLPV/r, 3TC, d4T\tRTV, 3TC, d4T\t\nAge at ART start (months)\t4.9\t2.4\t16.7\t4\t\nART regimen at first event\tEFV, 3TC, ABC\tEFV, 3TC, ABC\tEFV, 3TC, ABC\tEFV, 3TC, d4T\t\nTime on EFV at first event (months)\t3.3\t19.8\t13.7\t0.9\t\nAge at first event\t4 years 6 months\t4 years 10 months\t7 years 6 months\t4 years 7 months\t\nEFV dose at first event (mg/kg/dose)\t21 mg/kg/dose\t21 mg/kg/dose\t15 mg/kg/dose\t21 mg/kg/dose\t\nAge at second event\t5 years\t4 years 11 months\t9 years 5 months\tN/A\t\nTime on EFV at second event (months)\t9.6\t21.3\t37.9\tN/A\t\nTime on EFV at time of drug level (months)\t10.1\t23.5\t49.7\t1.2\t\nEFV level mg/L (reference range)\t20 mg/L (1-4 mg/L)\t60.54 mg/L (Ref > 1 mg/L)\t51.23 mg/L (1-4 mg/L)\t19.62 mg/L (1-4 mg/L)\t\nTime since last dose prior to levels (hours)\t13 h post dose\t13 h post dose\t14 h post dose\t15 h post dose\t\nGenotype\tHeterozygous CYP2B6 516G/T\n\nHeterozygous CYP2B6 785A/G\n\tHeterozygous CYP2B6 516G/T\n\nHeterozygous CYP2B6 983 T/C\n\tHeterozygous CYP2B6 516G/T Heterozygous CYP2B6 983 T/C\n\tHomozygous CYP2B6 516 T/T\n\t\n\naNeverest 2 clinical trial (ClinicalTrials.gov, NCT00117728) [3] was a NVP-conserving strategy, aiming to preserve regimens for children exposed to NVP as part of Prevention of Mother-to-Child Transmission (PMTCT). Children were either randomized to continue on a protease inhibitor (PI) or switch to NVP\n\n\nbNeverest 3 clinical trial (ClinicalTrials.gov, NCT01146873) [1] evaluated PI-sparing treatment strategies among NVP-exposed HIV infected children initially treated with lopinavir/ritonavir (LPV/r), but were either randomized to stay on LPV/r or switch to EFV\n\nAbbreviations: LPV/r (lopinavir/ritonavir), 3TC (lamivudine), d4T (stavudine), EFV (efavirenz), RTV (ritonavir), ABC (abacavir), CYP2B6 (Cytochrome P450 2B6), G (guanine), T (thymine), A (adenine), C (cytosine)\n\n\n\n\nCase presentation\nCase-1 [Generalised tonic-clonic seizures]\nA 4-year-6-month-old black South African male with perinatal HIV infection presented with generalised tonic-clonic seizures, 3 months after initiation of EFV-based antiretroviral treatment (ART).\n\nThe child’s initial ARV regimen, started at 5 months of age, consisted of lamivudine (3TC), stavudine (d4T), and lopinavir/ritonavir (LPV/r) twice daily (bd). At 4 years of age he was enrolled in a treatment strategy trial evaluating ART switches in virologically suppressed children undertaken at Rahima Moosa Mother and Child Hospital in Johannesburg, South Africa (ClinicalTrials.gov, NCT01146873) [1]. Abacavir (ABC) was substituted for d4T and LPV/r was switched to EFV 8 weeks thereafter. EFV dosing was prescribed according to standard recommended weight-based dosing as per South African guidelines [2]. Baseline assessment for neuropsychiatric symptoms and neurological examination revealed no abnormalities.\n\nThree months post-EFV initiation, the child was hospitalised for seizures. The mother reported that the child had multiple seizure episodes over a 3-day period with pyrexia. No further information was provided. Lumbar puncture (LP) showed no abnormalities and the child was discharged the following day on an unknown oral antibiotic and paracetamol. After the episode, the mother described the child’s behavior as becoming progressively more aggressive; fighting with his siblings; defiant towards his parents, but never violent. Routine clinical examinations revealed no CNS abnormalities.\n\nTen months after switching to EFV, the child experienced a generalised tonic-clonic seizure while being seen at a routinely scheduled study visit. The seizure lasted for approximately 1 minute, with no urination, tongue-biting, hypersalivation or obvious postictal confusion. The child had been seizure-free and clinically well since his prior hospital admission. In addition to EFV-based ART, tetryzoline (Spersallerg®) eye drops had been prescribed for allergic conjunctivitis. No known allergies or intolerances were reported.\n\nAfter the witnessed seizure the child was hospitalised, and investigations including a chest x-ray (CXR), urine dipstick, septic blood work-up and LP revealed no abnormalities. The child was discharged the following day with a diagnosis of idiopathic childhood epilepsy and started on an antiepileptic drug (AED), sodium valproate, 15 mg/kg/dose once daily (od). Outpatient electroencephalogram (EEG) revealed no abnormalities and a contrast Computed Tomography brain (CTB) scan showed normal developmental structures, with no lesions or mass effect.\n\nPlasma EFV levels were subsequently measured and genotyping performed as part of clinical care in an attempt to understand the nature of the presenting problem. The plasma EFV level, 13 h post dose, was >20.0 mg/L (suggested reference range: 1–4 mg/L) [3] as a result of the genetic characterisation which showed the child to be heterozygous for both CYP2B6 c.516G/T and c.785A/G genotypes. Consequently, EFV was discontinued and LPV/r restarted. The AED was stopped after 7 weeks. No further seizures have been reported, 30 months post-EFV discontinuation, and the aggressive behavior has improved.\n\nCase-2 [Cerebellar dysfunction]\nA 4-year-10-month-old black Zimbabwean female with perinatal HIV infection presented with clinical findings consistent with cerebellar dysfunction, 20 months after being switched to an EFV-based ART regimen.\n\nShe was initiated on 3TC, d4T and LPV/r bd at 10 weeks of age. Achieving and maintaining viral suppression, at 37 months of age she was enrolled in the same clinical trial described above [1] and randomised to substitute ABC for d4T and EFV for LPV/r 1 month thereafter. EFV dosing was prescribed according to standard recommended weight-based dosing as per South African guidelines [2]. Baseline assessment for neuropsychiatric symptoms and neurological examination revealed no abnormalities.\n\nNineteen months after switching to EFV-based ART the child presented with ataxia and tremors. The EFV dose had been increased from 200 mg to 300 mg od 1 week prior to presentation, as part of routine weight-based dose adjustment. At this event, antibiotics were prescribed for a urinary tract infection, and an outpatient CTB scheduled, but was never performed.\n\nSix weeks after the initial presentation the child was noted as having progressively worsening ataxia, marked upper and lower limb tremors and head bobbing. She also complained of epigastric pain and post-prandial vomiting. Examination on hospital admission revealed an ataxic gait, titubation, dysarthria, intention tremor, increased tone with cog-wheel rigidity in all limbs, and truncal hypotonia. Power and reflexes in upper and lower limbs were assessed as normal.\n\nAn urgent CTB scan revealed no abnormalities and a follow-up Magnetic Resonance Imaging scan was within normal limits. Laboratory findings including urea, electrolytes, full blood count, C-reactive protein (CRP) all reported within normal limits, and blood culture results showed no bacterial growth. Cerebrospinal fluid analysis was within normal limits. Further investigations, including screening for inborn errors of metabolism, were unable to be carried out as the parents refused further hospital admission.\n\nFollow-up 2 months post-admission showed persistence of the CNS signs and symptoms. At this time, EFV toxicity was considered as a possible cause of the cerebellar dysfunction, drug levels and genotyping were obtained and EFV was replaced with LPV/r.\n\nMid-dosing plasma EFV levels, taken 13 h post dose, were reported at 60.54 mg/L (suggested reference range: 1-4 mg/L) [3] resulting from CYP2B6 genotyping, where the child was found to be heterozygous carrying both CYP2B6 c.516G/T and c.983 T/C genotypes.\n\nUpon EFV discontinuation, significant improvement of the cerebellar signs and symptoms was noted. Follow up was for a period of 2 months, when the family relocated, 1 month of clinical observation with the caregivers reporting continued clinical improvement telephonically thereafter.\n\nCase-3 [Generalised tonic-clonic seizures]\nA 7-year-6-month-old black South African female with perinatal HIV infection presented with generalised tonic-clonic seizures 14 months after starting an EFV-based regimen.\n\nThe child was enrolled in an earlier trial at the same site (ClinicalTrials.gov, NCT00117728) [4] and initiated on 3TC, d4T and LPV/r at 17 months of age. Having achieved viral suppression, she was randomised to substitute NVP for LPV/r 7 months after ART initiation. The diagnosis of pulmonary tuberculosis necessitated discontinuation of NVP and re-introduction of LPV/r at age 3 years 10 months. She was subsequently enrolled in a follow up trial [1] and at age 6 years 4 months, where LPV/r was randomised to EFV. EFV dosing was prescribed according to standard recommended weight-based dosing as per South African guidelines [2]. Baseline assessment for neuropsychiatric symptoms and neurological examination revealed no abnormalities.\n\nThirteen months after starting EFV-based ART, the child was hospitalised with generalised tonic-clonic seizures and a suspected diagnosis of meningoencephalitis and tonsillitis. Neurologically she had a diminished level of consciousness (Glasgow coma scale of 10/15), meningism, increased tone, and brisk reflexes globally. An urgent CTB scan revealed no abnormalities. Besides an elevated CRP, her blood and LP results were within normal limits. On reassessment the following day she was awake, alert and fully cooperative with no meningism, and normal tone and reflexes.\n\nAnti-epileptic therapy, sodium valproate controlled release (CR) tablets 200 mg bd, were started and EFV was continued. She was also discharged on paracetamol and multivitamin. Sodium valproate CR was stopped when the prescription was inadvertently discontinued after 1 month.\n\nThe child was admitted 2 years later with her second seizure episode having taken EFV-based ART for a 3-year period. Although two further seizure episodes were reported since her prior admission, no medical attention had been sought. Seizures were described by the caregiver as generalised tonic-clonic in nature accompanied by urinary incontinence and a distinct postictal period. On admission the child was apyrexial with a normal physical examination except for enlarged uninfected tonsils. An elevated CRP and white blood cell count were noted, but other investigations were within normal limits. No LP was performed. She was restarted on anticonvulsants, but defaulted treatment after 2 months. An outpatient CTB was found to be normal.\n\nPlasma EFV concentration was measured as a suspected cause of the seizure activity. Plasma EFV level, 14 h post-dose, was 51.23 mg/L (suggested reference range 1-4 mg/L) [3] as a result of CYP2B6 genotyping revealing heterozygosity for CYP2B6 c.516G/T and c.983 T/C genotypes. EFV was discontinued and replaced with LPV/r. Follow-up, 14 months post EFV-discontinuation, has revealed no abnormalities and no further seizures were reported.\n\nCase-4 [Absence seizures]\nAs previously described by Strehlau et al., a 4-year-7-month-old black South African female presented with new onset absence seizures and behavioral changes 1 month after starting an EFV-based regimen [5].\n\nConclusions\nFor more than a decade, EFV, in combination with a non-nucleoside reverse transcriptase inhibitor backbone, has been recommended as part of the first-line ART regimen for adults and children older than 3 years in South Africa [2, 6–8]. EFV is an attractive drug for the management of children infected with HIV owing to once-daily dosing, high potency, child-friendly formulations, palatability, and alignment with adult regimens. When compared to NVP in a meta-analysis of adults and children on first-line therapy, EFV was observed to result in fewer treatment discontinuations despite some patients presenting with severe CNS effects [9]. In addition to cutaneous side effects, EFV is most commonly associated with early, mild, transient nervous system side effects in both adults [3, 9–15] as well as children [9, 12, 16]. Dizziness, headaches, nightmares and difficulty sleeping, tend to resolve spontaneously within the first month of treatment. Severe CNS adverse events appear to be infrequent and are not well described in children.\n\nA number of cases of severe adverse CNS side effects associated with EFV use in children have been reported. A 10-year-old girl experienced one episode of generalised seizures 6 weeks after switching from a PI-based to an EFV-based regimen. It was noted that the patient had a strong family history of epilepsy, although she had not previously experienced seizures. ART was not interrupted, she was not initiated on anticonvulsants and the seizures did not recur [17]. Another reported case of a 12-year-old girl presenting with psychosis associated with long term EFV use with genetic analysis showing a heterozygous CYP2B6 c.516G/T genotype [18]. Two of the 33 children (6 %) reported on in an EFV pharmacokinetics study, presented with adverse events, namely a psychotic reaction and seizures, with no further details provided [19].\n\nIn this case series, we describe severe CNS adverse events in four children between 4 and 8 years of age presenting between 1 and 20 months post-EFV initiation. In all four cases the plasma EFV levels were substantially higher than the upper limit of the therapeutic range (1–4 mg/L) [3]. Children in this series presented with a variety of abnormal CNS signs and symptoms – absence seizures, generalised seizures, and cerebellar dysfunction. We believe this is the first case of cerebellar dysfunction associated with EFV treatment to be described in a child. Furthermore, in three of the cases, CNS sequelae manifested late, 3–20 months, after switching to EFV. All four cases showed significant improvement, and even resolution of the CNS abnormalities, once EFV treatment was discontinued.\n\nEFV is primarily metabolised by the CYP2B6 enzyme and to a lesser extent by CYP3A5, CYP3A4, CYP2A6 and CYP1A2 isoforms of the cytochrome P450 system in the liver [20, 21]. The gene coding for CYP2B6 is highly polymorphic and the CYP2B6 c.516G > T SNPs [11, 21–32] and CYP2B6 c.983 T > C SNPs [23, 25, 33–37] have been reportedly associated with reduced EFV oral clearance resulting in increased plasma EFV concentrations. The single nucleotide variant CYP2B6\n c.516 T is linked to a CYP2B6 mRNA splice variant that lacks exons four to six and consequently lower levels of functional CYP2B6 enzyme [24], while the CYP2B6 c.983C variant causes a non-synonymous amino acid change from isoleucine to threonine at position 328 in exon 7 and, thus, reduced CYP2B6 activity [37]. Furthermore it is known that significant differences in allele frequencies between different populations exist, for example the frequency of the CYP2B6 c.516 T allele ranges from 14 % in Koreans [38] to 27–30 % in Caucasians [36], 49 % in Africans [39] and 62 % in Papua New Guineans [40]. The CYP2B6 c.983C allele is, however, not observed in Asian or Caucasian individuals, but is present in 4–9 % of Africans and African-Americans [41].\n\nThe child in case 4 was homozygous for CYP2B6 c.516 T/T which has been shown to be associated with substantially decreased CYP2B6 mRNA expression and therefore higher plasma EFV levels leading to an increased risk of CNS toxicity [3]. In a study done by Swart et al. [36], the frequencies of CYP2B6 c.516G/T and T/T genotypes among healthy, black South Africans were 0.48 and 0.13, respectively. In the same study 88 % of patients with the CYP2B6 c.516 T/T genotype presented with plasma EFV concentrations above the therapeutic range. A significant number of South African HIV-infected patients could potentially benefit from EFV dosage optimisation or reduction.\n\nBoth children in cases 2 and 3 carried CYP2B6 c.516G/T and c.983 T/C genotypes, and individuals with dual c.516G/T – c.983 T/C heterozygosity are CYP2B6 slow metabolisers, because CYP2B6 c.516 T and CYP2B6 c.983C variants reside on mutually exclusive haplotypes. [42] Carriers of both the CYP2B6 c.516 T and c.983C variants are more likely to present with high plasma EFV levels and exhibit poorer CNS responses [23, 25, 33, 37]. CYP2B6 c.983 T/C and C/C genotypes are present in 5–11 % and 0–2 %, respectively, of black South Africans [36]. Swart et al. [36], reported on nine adult patients with both the c.516G/T and c.983 T/C genotypes with an average plasma EFV concentrations >12 mg/L.\n\nThe child described in case 1 was heterozygous for CYP2B6 c.516G > T and the CYP2B6 c.785A > G SNP. Similar to other populations, CYP2B6 c.516G > T SNP is in tight linkage disequilibrium with the c.785A > G SNP. Genotyping for the c.785A > G SNP, which is located in exon 5 of CYP2B6, is thus not necessary [43, 44]. Studies have reported a gene-dose effect with EFV clearance following the pattern T/T < G/T < G/G and EFV levels following the pattern T/T > G/T > G/G [27, 29]. This could explain the lower EFV level in this case, however, genotyping for CYP2B6 c.983 T/C was not performed.\n\nEFV use has been well studied in adult populations, but less so among children where physiological changes may further complicate drug metabolism. For example, hepatic enzyme activity is increased between the ages of 1–4 years, potentially impacting drug metabolism [45]. Findings from Saitoh et al. [27], suggest that age may need to be considered when evaluating the impact of genetic variants on antiretroviral pharmacokinetics in children.\n\nWith the increasing use of ART resulting in HIV becoming a chronic disease, and the extended duration perinatally infected children will remain on treatment, reducing long-term ART-related side effects is a priority. A reduced EFV dose of 400 mg from 600 mg in adults was found to be non-inferior with a modest improvement in adverse events [46]. Similarly, an EFV pharmacokinetics study in Ugandan adults suggested that a daily EFV dose of 300 mg may be adequate for individuals carrying the CYP2B6 c.516 T/T genotype [47]. Ter Heine et al. [28], showed that children carrying the CYP2B6 c516G/G genotype had a 50–70 % probability of developing sub-therapeutic EFV concentrations, pointing towards the need for dose optimisation in both adults and children. Cases 1, 2 and 3, as compared to case 4, carried not only the CYP2B6 c. 516G > T SNP but additional heterozygous SNP’s conferring impaired CYP2B6 activity resulting in higher plasma EFV concentrations. Thus, screening for potential EFV-toxicity based on the CYP2B6 516 SNP alone would fail to predict the patients with severely impaired EFV metabolism. We hypothesize that genotype-assisted EFV dose optimisation could possibly assist with a reduction in severe CNS toxicities. Both CYP2B6 c.516G > T and c.983 T > C SNP’s should be considered in predicting EFV plasma levels pronounced effects, in decreasing the enzyme activity and frequencies of the allelic variants among African populations. While further research characterising the full spectrum of adverse events associated with EFV are needed, clinical vigilance and a high level of suspicion with any reported neurobehavioral or CNS abnormalities for children receiving EFV-based regimens are needed.\n\nConsent\nGenetic characterization was performed as part of the clinical evaluation in each case. Verbal informed consent was obtained from patients’ caregivers before testing. Written informed consent was obtained from all patients’ caregivers to collate and publish information found in this case report. A copy of the written consent is available for review by the editor of this journal.\n\nAbbreviations\n3TClamivudine\n\nAadenine\n\nABCabacavir\n\nAEDanti-epileptic drug\n\nARTantiretroviral therapy\n\nARVantiretroviral\n\nbdtwice-daily dosing\n\nCcytosine\n\nCNScentral nervous system\n\nCRcontrolled release\n\nCRPC-reactive protein\n\nCTBcomputed tomography brain\n\nCXRchest x-ray\n\nCYP2B6cytochrome P450 2B6\n\nd4Tstavudine\n\nEEGelectroencephalogram\n\nEFVefavirenz\n\nGguanine\n\nHIVhuman immunodeficiency virus\n\nLPlumbar puncture\n\nLPV/rlopinavir/ritonavir\n\nNNRTInon-nucleoside reverse transcriptase inhibitor\n\nodonce-daily dosing\n\nSNPsingle nucleotide polymorphism\n\nTthymine\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nFP was involved in acquisition of data and drafting of final manuscript. CD and MS carried out genotyping analysis and interpretation, drafting of manuscript and critical revision of manuscript for important intellectual content. RS involved in data acquisition, drafting and reviewing of manuscript. LK conceived of the studies participated in and involved in the reviewing of the manuscript. FP involved in data acquisition, drafting and reviewing of manuscript. AC involved in reviewing of the manuscript. EA was involved in drafting of the manuscript, critical revision of the manuscript for important intellectual content and senior overseer. All authors read and approved the final manuscript.\n\nThe study was supported by grants (HD061255) from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development (NICHD).\n==== Refs\nReferences\n1. Coovadia A Abrams E Strehlau R Shiau S Pinillos F Martens L Virologic efficacy of efavirenz maintanance therapy in neviripine prophylaxis-exposed children 2014 Boston 21st CROI \n2. 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Klein K Lang T Saussele T Barbosa-Sicard E Schunck WH Eichelbaum M Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz Pharmacogenet Genomics 2005 15 12 861 73 10.1097/01213011-200512000-00004 16272958 \n42. Haas DW Kwara A Richardson DM Baker P Papageorgiou I Acosta EP Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes J Antimicrob Chemother 2014 69 8 2175 82 10.1093/jac/dku110 24729586 \n43. Haas DW Gebretsadik T Mayo G Menon UN Acosta EP Shintani A Associations between CYP2B6 polymorphisms and pharmacokinetics after a single dose of nevirapine or efavirenz in African americans J Infect Dis 2009 199 6 872 80 10.1086/597125 19239339 \n44. Leger P Dillingham R Beauharnais CA Kashuba AD Rezk NL Fitzgerald DW CYP2B6 variants and plasma efavirenz concentrations during antiretroviral therapy in Port-au-Prince, Haiti J Infect Dis 2009 200 6 955 64 10.1086/605126 19659438 \n45. Hoody DW Fletcher CV Pharmacology considerations for antiretroviral therapy in human immunodeficiency virus (HIV)-infected children Semin Pediatr Infect Dis 2003 14 4 286 94 10.1053/j.spid.2003.09.004 14724793 \n46. Puls R Amin J Losso M Phanuphak P Nwizu C Orrell C Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial Lancet 2014 383 9927 1474 82 10.1016/S0140-6736(13)62187-X 24522178 \n47. Mukonzo JK Owen JS Ogwal-Okeng J Kuteesa RB Nanzigu S Sewankambo N Pharmacogenetic-based efavirenz dose modification: suggestions for an African population and the different CYP2B6 genotypes PLoS One 2014 9 1 e86919 10.1371/journal.pone.0086919 24497997\n\n",
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"mesh_terms": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D002490:Central Nervous System; D002648:Child; D002675:Child, Preschool; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D015658:HIV Infections; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide",
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"pmid": "26831894",
"pubdate": "2016-02-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Case report: Severe central nervous system manifestations associated with aberrant efavirenz metabolism in children: the role of CYP2B6 genetic variation.",
"title_normalized": "case report severe central nervous system manifestations associated with aberrant efavirenz metabolism in children the role of cyp2b6 genetic variation"
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"abstract": "This multicenter, randomized, open-label study evaluated the efficacy, safety, and pharmacokinetics of a single subcutaneous pegfilgrastim injection with daily subcutaneous filgrastim administration in pediatric patients receiving myelosuppressive chemotherapy for sarcoma. PATIENTS AND METHODS Forty-four patients with previously untreated, biopsy-proven sarcoma stratified into three age groups (0-5, 6-11, and 12-21 years) were randomly assigned in a 6:1 randomization ratio to receive a single pegfilgrastim dose of 100 microg/kg (n = 38) or daily filgrastim doses of 5 microg/kg (n = 6) after chemotherapy (cycles 1 and 3: vincristine-doxorubicin-cyclophosphamide; cycles 2 and 4: ifosfamide-etoposide). The duration of grade 4 neutropenia, time to neutrophil recovery, incidence of febrile neutropenia, and adverse events were recorded. Results Pegfilgrastim and filgrastim were similar for all efficacy and safety end points, and their pharmacokinetic profiles were consistent with those in adults. Younger children experienced more protracted neutropenia and had higher median pegfilgrastim exposure than older children. CONCLUSION A single dose of pegfilgrastim at 100 microg/kg administered once per chemotherapy cycle is comparable to daily injections of filgrastim at 5 microg/kg for pediatric sarcoma patients receiving myelosuppressive chemotherapy.",
"affiliations": "Department of Oncology, St Jude Children's Research Hospita, Universityof Tennessee Health Sciences Center, Memphis, TN 38105-3678, USA. sheri.spunt@stjude.org",
"authors": "Spunt|Sheri L|SL|;Irving|Helen|H|;Frost|Jami|J|;Sender|Leonard|L|;Guo|Matthew|M|;Yang|Bing-Bing|BB|;Dreiling|Lyndah|L|;Santana|Victor M|VM|",
"chemical_list": "D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim",
"country": "United States",
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"doi": "10.1200/JCO.2009.24.8872",
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"issue": "28(8)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001315:Australia; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007279:Injections, Subcutaneous; D009503:Neutropenia; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012509:Sarcoma; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "1329-36",
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"pmid": "20142595",
"pubdate": "2010-03-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "16246977;5216294;2458748;11448927;11408506;15067712;16282899;8622038;11821454;12362934;9389686;17264759;10856103;7691119;2452983;12488289;18616811;1711156;1381626;19484756;18641682;12560443;10893282;9849455;2362188;10641590;12594313;1697646;1833556;16096530;16809800;9187068;12123336;8605328;2480603;10741300",
"title": "Phase II, randomized, open-label study of pegfilgrastim-supported VDC/IE chemotherapy in pediatric sarcoma patients.",
"title_normalized": "phase ii randomized open label study of pegfilgrastim supported vdc ie chemotherapy in pediatric sarcoma patients"
} | [
{
"companynumb": "US-JNJFOC-20130609138",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "The aim of this study was to evaluate specific medications and patient characteristics as risk factors of falling in the hospital.\n\n\n\nThis is a case-control study comparing demographic, health, mobility, and medication data for 228 patients who fell between June 29, 2007, and November 14, 2007, at a large tertiary care hospital and 690 randomly selected control patients. Logistic regression was used to identify fall risk factors.\n\n\n\nIndependent risk factors of falling included history of falls (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.8-4.2); needing an assistive device (OR, 3.2; 95% CI, 1.5-6.8) or person assistance (OR, 2.1; 95% CI, 1.3-3.3) to ambulate; being underweight (OR, 2.4; 95% CI, 1.2-4.7) or obese (OR, 1.6; 95% CI, 1.0-2.5); confusion (OR, 2.4; 95% CI, 1.5-4.0); dizziness (OR, 2.1; 95% CI, 1.1-4.3); incontinence (OR, 1.5; 95% CI, 1.0-2.3); and an order for a hydantoin (OR, 3.3; 95% CI, 1.3-8.0) or benzodiazepine anticonvulsant (OR, 2.2; 95% CI, 1.5-3.3), haloperidol (OR, 2.8; 95% CI, 1.2-6.8), tricyclic antidepressant (OR, 2.4; 95% CI, 1.2-4.9), or insulin (OR, 1.5; 95% CI, 1.0-2.1). Female sex (OR, 0.8; 95% CI, 0.6-1.0), proton pump inhibitors (OR, 0.6; 95% CI, 0.4-0.9), and muscle relaxants (OR, 0.4; 95% CI, 0.3-0.7) were associated with lower risk for falling.\n\n\n\nThis study identified medications and patient characteristics associated with increased risk for falling in the hospital. High-risk medications identified in this study may serve as targets for medication review or adjustment, which have been recommended as a component of multifaceted fall prevention programs.",
"affiliations": null,
"authors": "OʼNeil|Caroline A|CA|;Krauss|Melissa J|MJ|;Bettale|Jon|J|;Kessels|Anthony|A|;Costantinou|Eileen|E|;Dunagan|W Claiborne|WC|;Fraser|Victoria J|VJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PTS.0000000000000163",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1549-8417",
"issue": "14(1)",
"journal": "Journal of patient safety",
"keywords": null,
"medline_ta": "J Patient Saf",
"mesh_terms": "D000058:Accidental Falls; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003710:Demography; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006304:Health Status; D006760:Hospitalization; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011446:Prospective Studies; D012307:Risk Factors",
"nlm_unique_id": "101233393",
"other_id": null,
"pages": "27-33",
"pmc": null,
"pmid": "25782559",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "8213744;11750195;11811346;11961367;17785615;15836543;15768548;7633010;2738307;9726185;9920227;20558479;9505576;7594153;9366729;9744971;19245414;16433876;8132920;20215495;17634322;19300076;17158580;14960426;9122555;16750473;11146268;12624858;10025306;9920228;7625418",
"title": "Medications and Patient Characteristics Associated With Falling in the Hospital.",
"title_normalized": "medications and patient characteristics associated with falling in the hospital"
} | [
{
"companynumb": "US-JNJFOC-20191007420",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LOPERAMIDE HYDROCHLORIDE"
},
"drugadditional": "3... |
{
"abstract": "The effects of medication on neuropsychological performance have yet to be fully investigated, particularly in older patients. As such, the present case study was undertaken to examine the specific impact of benzodiazepine use on neuropsychological performance by providing a comparison of the test-retest data of an 81-year-old patient taking lorazepam. A comprehensive neuropsychological evaluation was conducted: (a) during the initial referral, while the patient had been taking high doses of lorazepam for approximately 3 years; and (b) 6 months after complete titration, which was 1 year after the initial evaluation. Normative scores derived from the 2 trials were compared via calculation of Reliable Change Indexes. Neuropsychological performance during both evaluations was indicative of dementia, including similar degrees of impairment in delayed memory, verbal fluency, and olfaction. However, scores obtained during the second evaluation were somewhat higher, with significant improvements observed in immediate memory, visuospatial/construction abilities, language function, abstract concept formation, and set shifting. Results of the current case study suggest that several neuropsychological domains may be particularly sensitive to chronic benzodiazepine use. Although the overall diagnostic picture in the present study remained unaltered, clinicians should be cognizant of such medication effects and the potential for these neuropsychological alterations to obscure differential diagnosis.",
"affiliations": "a Department of Counseling & Psychology , The University of Texas at Tyler , Tyler , Texas.;a Department of Counseling & Psychology , The University of Texas at Tyler , Tyler , Texas.;a Department of Counseling & Psychology , The University of Texas at Tyler , Tyler , Texas.",
"authors": "Scott|Bonnie M|BM|;Schmitt|Andrew L|AL|;Livingston|Ronald B|RB|",
"chemical_list": "D006993:Hypnotics and Sedatives; D008140:Lorazepam",
"country": "United States",
"delete": false,
"doi": "10.1080/23279095.2015.1030017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2327-9095",
"issue": "23(3)",
"journal": "Applied neuropsychology. Adult",
"keywords": "Benzodiazepine; dementia; neuropsychological assessment; older adults",
"medline_ta": "Appl Neuropsychol Adult",
"mesh_terms": "D000369:Aged, 80 and over; D003072:Cognition Disorders; D003704:Dementia; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D008137:Longitudinal Studies; D008140:Lorazepam; D009483:Neuropsychological Tests; D016896:Treatment Outcome",
"nlm_unique_id": "101584082",
"other_id": null,
"pages": "167-71",
"pmc": null,
"pmid": "26507010",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neuropsychological performance of a patient suspected of dementia taking lorazepam and retested 1 year later following titration.",
"title_normalized": "neuropsychological performance of a patient suspected of dementia taking lorazepam and retested 1 year later following titration"
} | [
{
"companynumb": "US-BAUSCH-BL-2017-017176",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LORAZEPAM"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nCorticosteroids remain an important component of immunosuppressive regimens in high-risk kidney transplants. In this study, we investigated the efficacy of early steroid withdrawal with basiliximab and rituximab in ABO-blood type incompatible (ABO-i) recipients of kidney transplants.\n\n\nMETHODS\nBetween 2008 and 2019, 15 patients underwent ABO-i kidney transplantation. Seven of the 15 patients were treated with a steroid maintenance protocol and the remaining 8 with an early steroid withdrawal protocol. The immunosuppressive protocol consisted of tacrolimus, mycophenolate mofetil, and methylprednisolone (MP), with basiliximab administered as induction therapy. Rituximab was administered as a single 200-mg dose 1 to 4 weeks before kidney transplantation. Two to 4 sessions of either double-filtration plasmapheresis or regular plasmapheresis or both were performed to remove anti-AB antibodies before transplantation. During surgery, MP was administered at a dose of 500 mg; thereafter, the dosage was tapered rapidly, and the drug was discontinued on day 14 post transplant.\n\n\nRESULTS\nIn the steroid maintenance group, 2 patients experienced acute antibody-mediated rejection (AMR). One patient with severe AMR had graft loss on postoperative day 4. Patient and graft survival rates in the steroid maintenance group were 100% and 86%, respectively. MP was successfully withdrawn in the steroid withdrawal group. In this group, there was no biopsy-proven rejection. Patient and graft survival rates were 100%, and when last measured, serum creatinine level ± SD was 1.6 ± 0.8 mg/dL.\n\n\nCONCLUSIONS\nOur protocol successfully enabled the early withdrawal of steroids in recipients of ABO-i grafts; however, further follow-up is necessary to confirm our results.",
"affiliations": "Department of Transplant Surgery, International University of Health and Welfare, Atami Hospital, Shizuoka, Japan. Electronic address: tojimbara@iuhw.ac.jp.;Department of Transplant Surgery, International University of Health and Welfare, Atami Hospital, Shizuoka, Japan.;Department of Transplant Surgery, International University of Health and Welfare, Atami Hospital, Shizuoka, Japan.;Department of Transplant Surgery, International University of Health and Welfare, Atami Hospital, Shizuoka, Japan.;Department of Surgery, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan.;Department of Surgery, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan.",
"authors": "Tojimbara|Tamotsu|T|;Yashima|Jun|J|;Shirai|Hiroyuki|H|;Yamazaki|Tomotaka|T|;Koyama|Ichiro|I|;Nakajima|Ichiro|I|",
"chemical_list": "D000017:ABO Blood-Group System; D000305:Adrenal Cortex Hormones; D007155:Immunologic Factors; D000069283:Rituximab; D000077552:Basiliximab; D009173:Mycophenolic Acid; D016559:Tacrolimus; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.01.139",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "52(6)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000017:ABO Blood-Group System; D000305:Adrenal Cortex Hormones; D000328:Adult; D000077552:Basiliximab; D001787:Blood Group Incompatibility; D001788:Blood Grouping and Crossmatching; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007155:Immunologic Factors; D007668:Kidney; D016030:Kidney Transplantation; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D009173:Mycophenolic Acid; D010956:Plasmapheresis; D000069283:Rituximab; D016559:Tacrolimus; D019737:Transplants; D016896:Treatment Outcome; D028761:Withholding Treatment",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1705-1708",
"pmc": null,
"pmid": "32444132",
"pubdate": "2020",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Early Steroid Withdrawal Protocol With Basiliximab and Rituximab in ABO-Incompatible Kidney Transplant Recipients.",
"title_normalized": "early steroid withdrawal protocol with basiliximab and rituximab in abo incompatible kidney transplant recipients"
} | [
{
"companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2020-02481",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
... |
{
"abstract": "Background: Radiation therapy (RT) plays an important role in management of pediatric central nervous system (CNS) malignancies. Centers are increasingly utilizing pencil beam scanning proton therapy (PBS-PT). However, the risk of brainstem necrosis has not yet been reported. In this study, we evaluate the rate of brainstem necrosis in pediatric patients with CNS malignancies treated with PBS-PT.Material and methods: Pediatric patients with non-hematologic CNS malignancies treated with PBS-PT who received dose to the brainstem were included. All procedures were approved by the institutional review board. Brainstem necrosis was defined as symptomatic toxicity. The actuarial rate was analyzed by the Kaplan Meier method.Results: One hundred and sixty-six consecutive patients were reviewed. Median age was 10 years (range 0.5-21 years). Four patients (2.4%) had prior radiation. Median maximum brainstem dose in the treated course was 55.4 Gy[RBE] (range 0.15-61.4 Gy[RBE]). In patients with prior RT, cumulative median maximum brainstem dose was 98.0 Gy [RBE] (range 17.0-111.0 Gy [RBE]). Median follow up was 19.6 months (range, 2.0-63.0). One patient who had previously been treated with twice-daily radiation therapy and intrathecal (IT) methotrexate experienced brainstem necrosis. The actuarial incidence of brainstem necrosis was 0.7% at 24 months (95% CI 0.1-5.1%).Conclusion: The rate of symptomatic brainstem necrosis was extremely low after treatment with PBS-PT in this study. Further work to clarify clinical and dosimetric parameters associated with risk of brainstem necrosis after PBS-PT is needed.",
"affiliations": "Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.;Radiation Oncology, The Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Radiation Oncology, The Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Radiation Oncology, The Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Radiation Oncology, The Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Radiation Oncology, The Hospital of the University of Pennsylvania, Philadelphia, PA, USA.",
"authors": "Vogel|J|J|;Grewal|A|A|;O'Reilly|S|S|;Lustig|R|R|;Kurtz|G|G|;Minturn|J E|JE|;Shah|A C|AC|;Waanders|A J|AJ|;Belasco|J B|JB|;Cole|K A|KA|;Fisher|M J|MJ|;Phillips|P C|PC|;Balamuth|N J|NJ|;Storm|P B|PB|;Hill-Kayser|C E|CE|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/0284186X.2019.1659996",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0284-186X",
"issue": "58(12)",
"journal": "Acta oncologica (Stockholm, Sweden)",
"keywords": null,
"medline_ta": "Acta Oncol",
"mesh_terms": "D000293:Adolescent; D001254:Astrocytoma; D001933:Brain Stem; D016543:Central Nervous System Neoplasms; D002648:Child; D002675:Child, Preschool; D004806:Ependymoma; D005260:Female; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D008527:Medulloblastoma; D009336:Necrosis; D061766:Proton Therapy; D011829:Radiation Dosage; D011832:Radiation Injuries; D000069475:Re-Irradiation; D055815:Young Adult",
"nlm_unique_id": "8709065",
"other_id": null,
"pages": "1752-1756",
"pmc": null,
"pmid": "31512931",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk of brainstem necrosis in pediatric patients with central nervous system malignancies after pencil beam scanning proton therapy.",
"title_normalized": "risk of brainstem necrosis in pediatric patients with central nervous system malignancies after pencil beam scanning proton therapy"
} | [
{
"companynumb": "US-SILVERGATE PHARMACEUTICALS, INC.-2019SIL00050",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drug... |
{
"abstract": "Leukocytoclastic vasculitis is an uncommon but important complication of aromatase inhibitor use which may have cosmetic and systemic ramifications. We present a case in which this reaction was observed and aim to compare the characteristics of patients and trajectory of disease in order to assist with early identification and treatment.",
"affiliations": "St George Hospital, Sydney, New South Wales, Australia.;Coffs Coast Dermatology, Coffs Harbour, New South Wales, Australia.;Mid-North Coast Cancer Institute, Coffs Harbour Health Campus, Coffs Harbour, New South Wales, Australia.",
"authors": "Woodford|Rachel G|RG|;Becker|Gerrie J|GJ|;Jain|Ankit|A|",
"chemical_list": "D047072:Aromatase Inhibitors; D000077289:Letrozole",
"country": "Australia",
"delete": false,
"doi": "10.1111/imj.14422",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1444-0903",
"issue": "49(9)",
"journal": "Internal medicine journal",
"keywords": "aromatase inhibitor; breast cancer; drug reaction; hormonal therapy; leukocytoclastic vasculitis",
"medline_ta": "Intern Med J",
"mesh_terms": "D047072:Aromatase Inhibitors; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D018366:Vasculitis, Leukocytoclastic, Cutaneous",
"nlm_unique_id": "101092952",
"other_id": null,
"pages": "1162-1167",
"pmc": null,
"pmid": "31507048",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Leukocytoclastic vasculitis associated with use of aromatase inhibitors.",
"title_normalized": "leukocytoclastic vasculitis associated with use of aromatase inhibitors"
} | [
{
"companynumb": "AU-INDICUS PHARMA-000659",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditional": "3",
... |
{
"abstract": "We describe the case of a 6.5-year-old girl with central precocious puberty (CPP), which signifies the onset of secondary sexual characteristics before the age of eight in females and the age of nine in males as a result of stimulation of the hypothalamic-pituitary-gonadal axis. Her case is likely related to her adoption, as children who are adopted internationally have much higher rates of CPP. She had left breast development at Tanner Stage 2, adult body odor, and mildly advanced bone age. In order to halt puberty and maximize adult height, she was prescribed a gonadotropin releasing hormone analog, the first line treatment for CPP. She was administered Lupron (leuprolide acetate) Depot-Ped (3 months) intramuscularly. After her second injection, she developed swelling and muscle pain at the injection site on her right thigh. She also reported an impaired ability to walk. She was diagnosed with muscle fibrosis. This is the first reported case of muscle fibrosis resulting from Lupron injection.",
"affiliations": "Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA ; Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.;Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA ; Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.;Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA ; Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.;Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA ; Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.;Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA ; Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.;Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA ; Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.;Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA ; Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.;Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA ; Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.",
"authors": "Everest|Erica|E|0000-0002-4686-9225;Tsilianidis|Laurie A|LA|;Raissouni|Nouhad|N|0000-0002-8774-5712;Ballock|Tracy|T|;Blatnik|Terra|T|0000-0002-1098-4862;Haider|Anzar|A|;Rogers|Douglas G|DG|;Schweiger|B Michelle|BM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2015/938264",
"fulltext": "\n==== Front\nCase Rep PediatrCase Rep PediatrCRIPECase Reports in Pediatrics2090-68032090-6811Hindawi Publishing Corporation 10.1155/2015/938264Case ReportPostinjection Muscle Fibrosis from Lupron http://orcid.org/0000-0002-4686-9225Everest Erica \n1\n\n2\n\n*\nTsilianidis Laurie A. \n1\n\n2\nhttp://orcid.org/0000-0002-8774-5712Raissouni Nouhad \n1\n\n2\nBallock Tracy \n1\n\n2\nhttp://orcid.org/0000-0002-1098-4862Blatnik Terra \n1\n\n2\nHaider Anzar \n1\n\n2\nRogers Douglas G. \n1\n\n2\nSchweiger B. Michelle \n1\n\n2\n1Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA2Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA*Erica Everest: ericaeverest@gmail.comAcademic Editor: Giovanni Montini\n\n2015 25 5 2015 2015 93826414 3 2015 13 5 2015 Copyright © 2015 Erica Everest et al.2015This 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.We describe the case of a 6.5-year-old girl with central precocious puberty (CPP), which signifies the onset of secondary sexual characteristics before the age of eight in females and the age of nine in males as a result of stimulation of the hypothalamic-pituitary-gonadal axis. Her case is likely related to her adoption, as children who are adopted internationally have much higher rates of CPP. She had left breast development at Tanner Stage 2, adult body odor, and mildly advanced bone age. In order to halt puberty and maximize adult height, she was prescribed a gonadotropin releasing hormone analog, the first line treatment for CPP. She was administered Lupron (leuprolide acetate) Depot-Ped (3 months) intramuscularly. After her second injection, she developed swelling and muscle pain at the injection site on her right thigh. She also reported an impaired ability to walk. She was diagnosed with muscle fibrosis. This is the first reported case of muscle fibrosis resulting from Lupron injection.\n==== Body\n1. Background\nLupron (leuprorelin acetate) is a gonadotropin releasing hormone analog (GnRHa). GnRH is normally released in a pulsatile manner, which can be interrupted by a constant serum level of an agonist. Resultant downregulation of the GnRH receptors reduces the amounts of estradiol and testosterone produced [1]. This medication is indicated for prostate cancer, endometriosis, uterine fibroids, and central precocious puberty, the condition of our patient [2]. GnRHas are the first-line treatment for central precocious puberty (CPP) [3].\n\nPrecocious puberty is early sexual maturation, before the age of eight in girls and the age of nine in boys [4]. There are two types: central (gonadotropin-dependent) and peripheral (gonadotropin-independent) types. CPP results from premature activation of the hypothalamic-pituitary-gonadal axis. CPP is concerning, because premature fusion of the epiphyseal growth plates decreases adult height and because early development may cause psychosocial issues [5, 6]. Interestingly, CPP is more prevalent in children who were adopted internationally, which is the case for our patient. These children are ten to twenty times more likely to develop precocious puberty. It is hypothesized that early nutritional deficits followed by rapid weight gain after adoption trigger the endocrine changes and physical growth of puberty prematurely [7, 8] However, the condition may still be idiopathic in nature, because idiopathic central precocious puberty makes up 90% of cases in females. Males are more likely to have pathological causes for central precocious puberty [1].\n\n\nEstablished Facts\nGonadotropin releasing hormone analogs are the standard of care for central precocious puberty [3].\n\nInjection site reactions are common from Lupron administration [9].\n\n\n\n\n\nNovel Insights\nThis is the first reported case of muscle fibrosis from a Lupron injection.\n\n\n\n\nWe report a case of a seven-year-old girl with muscle fibrosis of the right thigh following an injection of Lupron to treat her precocious puberty. A review of the literature reveals no previous reports of muscle fibrosis resulting from an intramuscular injection of Lupron.\n\n2. Case Presentation\nA six-year-eleven-month-old female presented to the Pediatric Endocrinology Clinic with signs of early puberty. Her mother noticed her daughter having adult body odor two months prior and development of her left breast (Tanner Stage 2) one month prior to the appointment. The patient denied any vaginal bleeding or discharge. She also denied pubic and axillary hair development, as well as any acne. Review of systems revealed increased thirst, while her physical exam was unremarkable. Her height and weight were at the 64th percentile for her age. This is an increase from the 14th percentile at the age of four, at which time she was adopted internationally. An X-ray to determine bone age was performed and showed bones between seven years ten months and eight years ten months of age by standards of Greulich and Pyle [10].\n\nLaboratory data showed that the testosterone level was elevated at 12 ng/dL (0–9 ng/dL for Tanner Stage 1 females), and the hydroxyprogesterone level was elevated at 1.4 ng/mL (0.0–0.3 ng/mL). (A hydroxyprogesterone under 2 ng/mL and a testosterone that is not substantially higher than normal make congenital adrenal hyperplasia unlikely. However, the body odor suggested testing). The luteinizing hormone level of 2.0 mU/mL was consistent with CPP (diagnostic criteria is LH > 0.3 mU/mL). Follicle stimulating hormone was elevated at 4.5 mU/mL (0.0–4.0 mU/mL in prepubescent females) and estradiol 17B was also in the pubertal range at 39 pg/mL (<30 pg/mL). DHEA-S was normal at 28.6 ug/dL (0.0–37.0 ug/dL).\n\nGiven her increased growth velocity, thelarche, body odor, mildly advanced bone age, and gonadotropins and estradiol in pubertal ranges, she was diagnosed with CPP. She was given an MRI of her pituitary gland to rule out intracranial pathology as the cause of her precocious puberty (see Figure 1). The posterior T1 bright spot was present. The pituitary was homogenous in signal but was enlarged at 8 mm in the craniocaudal dimension. It had a convex superior margin, and no mass effect was noted. Overall, the pituitary gland was enlarged, but with no lesions to suggest an adenoma. We recommended injections of Lupron to halt puberty and prescribed Lupron Depot-Ped, 3 months 11.25 mg. We planned for her to return in five months, at which point she would have received two Lupron injections.\n\nShe received her first Lupron injection two weeks after the appointment. It was administered IM in the right vastus lateralis muscle. The patient tolerated the injection well, and she returned for a second injection in three months in the same location in her right thigh. At the time, the patient appeared to tolerate this injection well also. However, three weeks after the second injection, the patient had an appointment with a pediatric orthopedic surgeon. The reason for the visit was a lump on and swelling of her right thigh at the injection site. The lump measured 5 × 5 cm and was not tender to palpation. She reports pain in her right leg and trouble walking. She rated the pain as a 5 on a 0 to 10 scale with daily activities and with exercise. Her knee flexion was only fifteen degrees. Her right extremity showed no deformity. Ultrasound revealed no cellulitis or abnormal fluid collection at the injection site on her right thigh (see Figure 2). The lack of fluid indicated that this was not an abscess. She was diagnosed with muscle fibrosis based on the severe restriction of knee flexion due to lack of muscle excursion following the injection, as well as the presence of a mass at the injection site. She was instructed to have physical therapy.\n\n3. Discussion\nMuscle fibrosis and contracture following an intramuscular injection occurs most commonly in the anterior and lateral thigh [11]. Muscle fibrosis usually presents as atrophy, dimpling, reduced range of motion, and abnormal gait [12]. The major symptoms are recurrent dislocation of the patella and limitation of flexion of the knee. The contractures may form within weeks but also may take months to years after an injection [11]. These deformities may be coming later in our patient, since the diagnosis was merely weeks after the injection. For cases in which the diagnosis is made early or the fibrosis is mild, physical therapy and casting may be helpful [13]. However, these treatments are usually unhelpful in established cases. Surgery is often required and can create substantial improvement, especially when performed before there is permanent damage to the knee joint [14]. Since our patient was diagnosed quickly and began physical therapy, it is possible that this will prevent the muscle deformity from ever happening.\n\nThus far, there have been no reported cases of muscle fibrosis following an injection of Lupron. Treatment-related adverse effects occurred in 29% of patients dosed at 11.25 mg over three years in a long-term safety and efficacy study [9]. Common side effects at the injection site are pain and abscess, which occur in 5–15% of patients [5]. Also, there is the potential for acne, rash, blisters, facial swelling, weight gain, altered mood, headache, flushes and sweating, and vaginal symptoms, such as vaginitis, bleeding, and discharge [2].\n\nThe depot suspension of leuprolide acetate consists of microspheres of the drug within a biodegradable copolymer of lactic and glycolic acids [15]. With regard to the adverse effects of sterile abscess formation, it is believed that the cause is a reaction to the inert polymer rather than to the drug itself. The chance of having a reaction to these materials is estimated to be 3 to 13 per 100 children [16]. Given that patients have been successfully treated with the daily non-depot form of leuprolide acetate following an adverse reaction to the depot form, it seems as if the polymer was the component causing the problem [17]. However, there also have been cases reported of people with prostate cancer who have become resistant to GnRHa therapy following a sterile abscess formation [18, 19].\n\nAlthough muscle fibrosis is a rare side effect of the Lupron depot injection, there are a substantial number of adverse effects reported at the injection site. Parents should be advised to monitor their child's injection site for abnormalities, even up to a few weeks or months afterward. Moreover, if they report any symptoms that resemble muscle fibrosis, they should be advised to seek medical care promptly.\n\n4. Conclusion\nThis report describes the first case of muscle fibrosis of the thigh following an injection of Lupron Depot-Ped. The patient is a seven-year-old female being treated for central precocious puberty.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Figure 2\n==== Refs\n1 Fuqua J. S. Treatment and outcomes of precocious puberty: an update Journal of Clinical Endocrinology and Metabolism 2013 98 6 2198 2207 10.1210/jc.2013-1024 2-s2.0-84878483008 23515450 \n2 Lupron Depot leuprolide acetate for depot suspension, 2013, http://www.lupron.com/ \n3 Johnson S. R. Nolan R. C. Grant M. T. Sterile abscess formation associated with depot leuprorelin acetate therapy for central precocious puberty Journal of Paediatrics and Child Health 2012 48 3 E136 E139 10.1111/j.1440-1754.2011.02083.x 2-s2.0-84858439021 21564386 \n4 Menon P. S. N. Vijayakumar M. Precocious puberty—perspectives on diagnosis and management Indian Journal of Pediatrics 2014 81 1 76 83 10.1007/s12098-013-1177-6 2-s2.0-84898876651 24014184 \n5 Carel J. C. Eugster E. A. Rogol A. Ghizzoni L. Palmert M. R. Consensus statement on the use of gonadotropin-releasing hormone analogs in children Pediatrics 2009 123 4 e752 e762 10.1542/peds.2008-1783 2-s2.0-65349104762 19332438 \n6 Carel J.-C. Lahlou N. Roger M. Chaussain J. L. Precocious puberty and statural growth Human Reproduction Update 2004 10 2 135 147 10.1093/humupd/dmh012 2-s2.0-1942440920 15073143 \n7 Soriano-Guillén L. Corripio R. Labarta J. I. Central precocious puberty in children living in Spain: incidence, prevalence, and influence of adoption and immigration Journal of Clinical Endocrinology and Metabolism 2010 95 9 4305 4313 10.1210/jc.2010-1025 2-s2.0-77956567064 20554707 \n8 Teilmann G. Pedersen C. B. Skakkebæk N. E. Jensen T. K. Increased risk of precocious puberty in internationally adopted children in Denmark Pediatrics 2006 118 2 391 399 10.1542/peds.2005-2939 2-s2.0-33751428399 \n9 Lee P. Klein K. Mauras N. 36-month treatment experience of 2 doses of leuprolide acetate 3-month depot for children with central precocious puberty The Journal of Clinical Endocrinology & Metabolism 2014 99 3153 3159 24926950 \n10 Greulich W. W. Pyle S. I. Radiographic Atlas of Skeletal Development of Hand Wrist 1971 2 Stanford, Calif, USA Stanford University Press \n11 Bergeson P. S. Singer S. A. Kaplan A. M. Intramuscular injections in children Pediatrics 1982 70 6 944 948 2-s2.0-0020420771 6755373 \n12 Mir N. A. Ahmed S. M. Bhat J. A. Post-injection gluteal fibrosis: a neglected problem JK Science 2002 4 3 144 146 2-s2.0-0036652542 \n13 Jerotic R. Rikolic G. Rejie S. Rehabilitation of post-injection contractures in children Srpski Arhiv za Celokupno Lekarstvo 1975 103 p. 59 \n14 Alvarez E. V. Munters M. Lavine L. S. Manes H. Waxman J. Quadriceps myofibrosis: a complication of intramuscular injections The Journal of Bone & Joint Surgery—American Volume 1980 62 1 58 60 2-s2.0-0018905213 7351417 \n15 Abbott Laboratories Lupron Depot Ped (leuprolide acetate for depot suspension) 2008 North Chicago, Ill, USA Abbott Laboratories http://www.rxabbvie.com/pdf/lupronpediatric.pdf \n16 Tonini G. Marinoni S. Forleo V. Rustico M. Neely E. K. Wilson D. M. Local reactions to luteinizing hormone releasing hormone analog therapy The Journal of Pediatrics 1995 126 1 159 160 2-s2.0-0028795465 7815213 \n17 Neely E. K. Hintz R. L. Parker B. Two-year results of treatment with depot leuprolide acetate for central precocious puberty Journal of Pediatrics 1992 121 4 634 640 10.1016/S0022-3476(05)81162-X 2-s2.0-0026774837 1403402 \n18 Daskivich T. J. Oh W. K. Failure of gonadotropin-releasing hormone agonists with and without sterile abscess formation at depot sites: insight into mechanisms? Urology 2006 67 5 1084.e15 1084.e17 10.1016/j.urology.2005.11.015 2-s2.0-33646844914 16698377 \n19 Curry E. A. III Sweeney C. J. Resistance to luteinizing hormone releasing hormone agonist therapy for metastatic prostate cancer Journal of Urology 2002 168 1 p. 193 10.1016/S0022-5347(05)64864-1 2-s2.0-0036282985\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2015()",
"journal": "Case reports in pediatrics",
"keywords": null,
"medline_ta": "Case Rep Pediatr",
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"nlm_unique_id": "101581030",
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"pages": "938264",
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"pmid": "26101682",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "7815213;20554707;23515450;24926950;19332438;15073143;16698377;6755373;7351417;24014184;12050525;21564386;16882780;1403402;2118858;1170645",
"title": "Postinjection Muscle Fibrosis from Lupron.",
"title_normalized": "postinjection muscle fibrosis from lupron"
} | [
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"companynumb": "US-ABBVIE-16P-163-1776050-00",
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{
"abstract": "A patient was 60-year-old man. In March 2011, the small bowel tumor with perforation was found and the partial resection of small intestine was urgently performed. KIT of resected specimen was positive. Then, diagnosis as GIST was defined. Oral administration of imatinib was started, but it was finished in 5 months because of development of the systemic edema. In February 2013, the abdominal CT revealed a tumor of 20 cm in size in the pelvis. Upon laparotomy, we detected the GIST recurrence generated at the region of small intestine anastomosis where manipulated previously, then resected all of tumor and partially small intestine. Afterward, we diagnosed as a recurrence of GIST. In March 2014, the abdominal CT found 4 cm sized mesenteric tumor and 2 cm sized abdominal wall tumor. The laparotomy was performed and we found 5 disseminated nodules intraperitoneally. We confirmed that all of these disseminated nodules were successfully removed. We defined them as re-recurrence of GIST. Six years and 5 months have elapsed since the first operation was performed, but there is no sign of three times recurrence.",
"affiliations": "Dept. of Surgery, Japanese Red Cross Hadano Hospital.",
"authors": "Koumori|Keisuke|K|;Watanabe|Takuo|T|;Kakazu|Ayano|A|;Fujikawa|Yoshiko|Y|;Mikayama|Yo|Y|;Jin|Yasuyuki|Y|;Hasuo|Kimiatsu|K|;Masuda|Munetaka|M|",
"chemical_list": "D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate",
"country": "Japan",
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"issue": "45(1)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000970:Antineoplastic Agents; D017024:Chemotherapy, Adjuvant; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D000068877:Imatinib Mesylate; D007414:Intestinal Neoplasms; D007416:Intestinal Perforation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012008:Recurrence; D013997:Time Factors",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "145-147",
"pmc": null,
"pmid": "29362336",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case Survived Long Period after Repeated Operation against the Small Intestinal GIST with Perforation.",
"title_normalized": "a case survived long period after repeated operation against the small intestinal gist with perforation"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-170311",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB"
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{
"abstract": "Kaposi sarcoma inflammatory cytokine syndrome (KICS) is a newly-described condition affecting individuals who are HIV-positive and are infected with human herpesvirus 8 (HHV-8). This is a syndrome that in some ways mimics severe sepsis with associated acute respiratory distress syndrome, possibly requiring a ventilator and vasopressor support. However, unlike severe sepsis, antibiotics provide no benefit. Management of KICS has not been fully elucidated because of its high mortality rate. However, the syndrome has been successfully treated in some cases with immunomodulatory therapy. It is crucial for oncologists to be able to recognize this syndrome and to institute the appropriate therapy. 2017;22:623-625.",
"affiliations": "New York Medical College, Valhalla, New York, USA karass.michael@gmail.com.;Emory University, Atlanta, Georgia, USA.;American University of Beirut, Beirut, Lebanon.;Morehouse School of Medicine, Atlanta, Georgia, USA.;Emory University, Atlanta, Georgia, USA.",
"authors": "Karass|Michael|M|;Grossniklaus|Emily|E|;Seoud|Talal|T|;Jain|Sanjay|S|;Goldstein|Daniel A|DA|",
"chemical_list": "D016207:Cytokines; D004317:Doxorubicin",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2016-0237",
"fulltext": null,
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"issn_linking": "1083-7159",
"issue": "22(5)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D016207:Cytokines; D004317:Doxorubicin; D006678:HIV; D015658:HIV Infections; D019288:Herpesvirus 8, Human; D006801:Humans; D056747:Immunomodulation; D007249:Inflammation; D008297:Male; D012514:Sarcoma, Kaposi; D055815:Young Adult",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "623-625",
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"pmid": "28424322",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11755839;25843728;25331113;7632932;15578375;16392092;22403576;18077835;20583924;2384605;17522245;19025493;26658701",
"title": "Kaposi Sarcoma Inflammatory Cytokine Syndrome (KICS): A Rare but Potentially Treatable Condition.",
"title_normalized": "kaposi sarcoma inflammatory cytokine syndrome kics a rare but potentially treatable condition"
} | [
{
"companynumb": "US-PFIZER INC-2020128210",
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"occurcountry": "US",
"patient": {
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{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
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{
"abstract": "Deep brain stimulation of the posteromedial hypothalamus (PMH DBS) appears to be an effective treatment for drug-resistant aggressiveness. Weaver syndrome (WS) is a rare genetic disorder in which patients develop some degree of intellectual disability and rarely severe behavioral alterations that may benefit from this procedure.\n\n\n\nWe present the case of a 26-yr-old man diagnosed with WS presenting with uncontrollable self and heteroaggressiveness and disruptive behavior refractory to pharmacological treatment and under severe physical and mechanical restraining measures. The patient was successfully treated with bilateral PMH DBS resulting in affective improvement, greater tolerance for signs of affection, regularization in his sleep pattern and appetite disturbances at 12-mo follow-up. A detailed description and video of the procedure are presented, and a review of the clinical characteristics of WS and the utility and benefits of PMH DBS for refractory aggressiveness are reviewed.\n\n\n\nTo our knowledge, this is the first case of refractory aggressiveness described in WS as well as the first patient with WS successfully treated with PMH DBS.",
"affiliations": "Department of Neurosurgery, La Princesa University Hospital, Madrid, Spain.;Department of Neurosurgery, La Princesa University Hospital, Madrid, Spain.;Department of Psychiatry, San Juan de Dios Centre, Ciempozuelos, Spain.;Department of Psychiatry, San Juan de Dios Centre, Ciempozuelos, Spain.;Department of Psychiatry, La Princesa University Hospital, Madrid, Spain.;Department of Psychiatry, La Princesa University Hospital, Madrid, Spain.;Department of Clinical Neurophysiology, La Princesa University Hospital, Madrid, Spain.;Department of Clinical Neurophysiology, La Princesa University Hospital, Madrid, Spain.;Department of Neurosurgery, La Princesa University Hospital, Madrid, Spain.",
"authors": "Blasco García de Andoain|Guillermo|G|;Navas García|Marta|M|;González Aduna|Óscar|Ó|;Bocos Portillo|Alvaro|A|;Ezquiaga Terrazas|Elena|E|;Ayuso-Mateos|José Luis|JL|;Pastor|Jesús|J|;Vega-Zelaya|Lorena|L|;Torres|Cristina V|CV|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ons/opab149",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2332-4252",
"issue": "21(3)",
"journal": "Operative neurosurgery (Hagerstown, Md.)",
"keywords": "Aggressiveness; Deep brain stimulation; Functional neurosurgery; Posteromedial hypothalamus; Psychosurgery; Weaver syndrome",
"medline_ta": "Oper Neurosurg (Hagerstown)",
"mesh_terms": "D000015:Abnormalities, Multiple; D000374:Aggression; D003409:Congenital Hypothyroidism; D019465:Craniofacial Abnormalities; D046690:Deep Brain Stimulation; D006228:Hand Deformities, Congenital; D006801:Humans; D007031:Hypothalamus; D008297:Male",
"nlm_unique_id": "101635417",
"other_id": null,
"pages": "165-171",
"pmc": null,
"pmid": "34017998",
"pubdate": "2021-08-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Posteromedial Hypothalamic Deep Brain Stimulation for Refractory Aggressiveness in a Patient With Weaver Syndrome: Clinical, Technical Report and Operative Video.",
"title_normalized": "posteromedial hypothalamic deep brain stimulation for refractory aggressiveness in a patient with weaver syndrome clinical technical report and operative video"
} | [
{
"companynumb": "ES-TEVA-2021-ES-1986845",
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"occurcountry": "ES",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe presented study is a retrospective evaluation of switching therapy from ranibizumab and/or bevacizumab to aflibercept in neovascular age-related macular degeneration in patients who had previously given an insufficient response to therapy with ranibizumab and/or bevacizumab.\n\n\nMETHODS\n96 eyes with neovascular age-related macular degeneration (AMD) were included, which had been pretreated with ranibizumab and/or bevacizumab (T&E), but had responded insufficiently. An injection interval of less than six weeks or permanently persisting intra- and/or subretinal fluid or persistent pigment epithelial detachments (PED) were defined as an insufficient response. The patients were followed for 12 months after switching therapy to aflibercept. The change in central retinal thickness (CRT) was defined as the primary endpoint. Other endpoints were the axial height of PEDs and the injection interval.\n\n\nRESULTS\nThe primary endpoint, the average CRT, was significantly decreased twelve months after switching therapy to aflibercept (Wilcoxon Nemenyi-McDonald-Thompson post-hoc analysis - 31.36 µm; SD ± 70.64 µm; p < 0.001). Another morphological endpoint, the average axial height of PEDs, also decreased significantly (- 34.10 µm; SD ± 91.90 µm, p < 0.001) from 207.82 µm (SD ± 148.12 µm) at baseline to 173.72 µm (SD ± 132.30 µm) at month 12. Moreover, the average injection interval increased significantly (p < 0.001; Friedman test) from 1.30 months (SD ± 0.19 months) before switching therapy to 1.67 months (SD ± 0.19 months) at month 12 after switching therapy to aflibercept. However, the best corrected visual acuity (BCVA) as a functional endpoint did not significantly improve (+ 0.36 ETDRS letters = 0.0972 p; SD ± 16.94 ETDRS letters).\n\n\nCONCLUSIONS\nIn patients with neovascular AMD, who had initially exhibited an inadequate response to ranibizumab and/or bevacizumab, switching therapy to aflibercept improves clinical outcome measures. Besides morphological improvements, such as the decrease of the CRT and the axial height of PEDs, the average injection interval was prolonged. However, visual acuity did not improve.",
"affiliations": "Augenklinik, Universitätsklinikum Bonn.;Augenklinik, Stadtspital Triemli, Zürich, Schweiz.;Augenklinik, Stadtspital Triemli, Zürich, Schweiz.;Augenklinik, Stadtspital Triemli, Zürich, Schweiz.;Augenklinik, Stadtspital Triemli, Zürich, Schweiz.;Augenklinik, Stadtspital Triemli, Zürich, Schweiz.;Augenklinik, Stadtspital Triemli, Zürich, Schweiz.",
"authors": "Pfau|M|M|;Fassnacht-Riederle|H M|HM|;Freiberg|F J|FJ|;Wons|J B|JB|;Wirth|M|M|;Becker|M D|MD|;Michels|S|S|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0042-101348",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-2165",
"issue": "233(8)",
"journal": "Klinische Monatsblatter fur Augenheilkunde",
"keywords": null,
"medline_ta": "Klin Monbl Augenheilkd",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D004334:Drug Administration Schedule; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D012189:Retrospective Studies; D012307:Risk Factors; D013557:Switzerland; D016896:Treatment Outcome; D014792:Visual Acuity; D057135:Wet Macular Degeneration",
"nlm_unique_id": "0014133",
"other_id": null,
"pages": "945-50",
"pmc": null,
"pmid": "27123887",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Switching Therapy from Ranibizumab and/or Bevacizumab to Aflibercept in Neovascular Age-Related Macular Degeneration (AMD): One-Year Results.",
"title_normalized": "switching therapy from ranibizumab and or bevacizumab to aflibercept in neovascular age related macular degeneration amd one year results"
} | [
{
"companynumb": "DE-REGENERON PHARMACEUTICALS, INC.-2016-17318",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PHENPROCOUMON"
},
"druga... |
{
"abstract": "The combined immunotherapy of nivolumab and ipilimumab causes a variety of autoimmune-related adverse events (irAEs). The current report details a 70-year-old woman with clear cell renal cell carcinoma metastasis in the lung. Two weeks after two courses of treatment, the patient complained of headache, dizziness and nausea. Cerebrospinal fluid (CSF) analysis revealed an elevated protein level of 195 mg/dl and a significantly elevated white blood cell (WBC) count of 830/mm3 (lymphocytes, 825/mm3; neutrophils, 5/mm3). The results excluded malignancy and infection. The patient was diagnosed with aseptic meningitis and was administered intravenous prednisolone (1 mg/kg/day). On the 49th day of the 2nd course of treatment, no recurrence of clinical symptoms was exhibited during maintenance oral steroid treatment (prednisolone 10 mg/day) and CSF analysis revealed that the WBC count had dropped to 44/mm3 (lymphocytes only). Therefore, the 3rd course of treatment was readministered the next day. After two weeks, the patients again complained of nausea, anorexia and fatigue. CSF analysis demonstrated that the WBC count was not increased from the result obtained previously. However, brain MRI scans revealed the mild diffuse enlargement of the pituitary and endocrine system tests revealed reduced adrenocorticotropic hormone (ACTH; 2.0 pg/ml) and cortisol (1.12 µg/dl) levels. The patient was diagnosed with isolated ACTH deficiency and oral hydrocortisone was administered after prednisolone cessation. On the 25th day of the 3rd course of treatment, the patient complained of headache and anorexia. CSF examination revealed that the WBC count had increased a second time (53/mm3; lymphocytes only) and laboratory data revealed hepatic dysfunction. The patient was then diagnosed with relapse of aseptic meningitis and liver dysfunction. While continuing oral hydrocortisone treatment, the administration of intravenous prednisolone was started. The observed liver dysfunction and aseptic meningitis gradually improved. The current report may be useful for avoiding delays in the diagnosis and treatment of this life-threatening and uncommon irAE, in which CSF examinations are useful for diagnosis and management.",
"affiliations": "Department of Urology, National Hospital Organization Kyushu Cancer Center, Fukuoka 811-1395, Japan.;Department of Urology, National Hospital Organization Kyushu Cancer Center, Fukuoka 811-1395, Japan.;Department of Urology, National Hospital Organization Kyushu Cancer Center, Fukuoka 811-1395, Japan.;Department of Urology, National Hospital Organization Kyushu Cancer Center, Fukuoka 811-1395, Japan.;Department of Urology, National Hospital Organization Kyushu Cancer Center, Fukuoka 811-1395, Japan.;Department of Urology, National Hospital Organization Kyushu Cancer Center, Fukuoka 811-1395, Japan.;Department of Urology, National Hospital Organization Kyushu Cancer Center, Fukuoka 811-1395, Japan.",
"authors": "Takamatsu|Dai|D|;Furubayashi|Nobuki|N|;Negishi|Takahito|T|;Ieiri|Kosuke|K|;Inoue|Tomohiro|T|;Tsukino|Keiji|K|;Nakamura|Motonobu|M|",
"chemical_list": null,
"country": "England",
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"doi": "10.3892/mco.2019.1929",
"fulltext": "\n==== Front\nMol Clin OncolMol Clin OncolMCOMolecular and Clinical Oncology2049-94502049-9469D.A. Spandidos 10.3892/mco.2019.1929MCO-0-0-1929ArticlesRelapse of aseptic meningitis induced by ipilimumab and nivolumab therapy for metastatic renal cell carcinoma: A case report Takamatsu Dai Furubayashi Nobuki Negishi Takahito Ieiri Kosuke Inoue Tomohiro Tsukino Keiji Nakamura Motonobu Department of Urology, National Hospital Organization Kyushu Cancer Center, Fukuoka 811-1395, JapanCorrespondence to: Dr Nobuki Furubayashi, Department of Urology, National Hospital Organization Kyushu Cancer Center, Notame 3‑1‑1, Minami‑ku, Fukuoka 811‑1395, Japan, E-mail: furubayashi-jua@umin.ac.jp12 2019 03 10 2019 03 10 2019 11 6 590 594 06 6 2019 12 9 2019 Copyright: © Takamatsu et al.2019This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.The combined immunotherapy of nivolumab and ipilimumab causes a variety of autoimmune-related adverse events (irAEs). The current report details a 70-year-old woman with clear cell renal cell carcinoma metastasis in the lung. Two weeks after two courses of treatment, the patient complained of headache, dizziness and nausea. Cerebrospinal fluid (CSF) analysis revealed an elevated protein level of 195 mg/dl and a significantly elevated white blood cell (WBC) count of 830/mm3 (lymphocytes, 825/mm3; neutrophils, 5/mm3). The results excluded malignancy and infection. The patient was diagnosed with aseptic meningitis and was administered intravenous prednisolone (1 mg/kg/day). On the 49th day of the 2nd course of treatment, no recurrence of clinical symptoms was exhibited during maintenance oral steroid treatment (prednisolone 10 mg/day) and CSF analysis revealed that the WBC count had dropped to 44/mm3 (lymphocytes only). Therefore, the 3rd course of treatment was readministered the next day. After two weeks, the patients again complained of nausea, anorexia and fatigue. CSF analysis demonstrated that the WBC count was not increased from the result obtained previously. However, brain MRI scans revealed the mild diffuse enlargement of the pituitary and endocrine system tests revealed reduced adrenocorticotropic hormone (ACTH; 2.0 pg/ml) and cortisol (1.12 µg/dl) levels. The patient was diagnosed with isolated ACTH deficiency and oral hydrocortisone was administered after prednisolone cessation. On the 25th day of the 3rd course of treatment, the patient complained of headache and anorexia. CSF examination revealed that the WBC count had increased a second time (53/mm3; lymphocytes only) and laboratory data revealed hepatic dysfunction. The patient was then diagnosed with relapse of aseptic meningitis and liver dysfunction. While continuing oral hydrocortisone treatment, the administration of intravenous prednisolone was started. The observed liver dysfunction and aseptic meningitis gradually improved. The current report may be useful for avoiding delays in the diagnosis and treatment of this life-threatening and uncommon irAE, in which CSF examinations are useful for diagnosis and management.\n\nrenal cell carcinomaipilimumabnivolumabmeningitisimmune-related adverse events\n==== Body\nIntroduction\nIn recent years, combination therapy with nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor antibody, and ipilimumab, an anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, have demonstrated clinical efficacy in the treatment of metastatic RCC (mRCC) patients (1). These results led to the United State Food and Drug Administration approving the combination of ipilimumab and nivolumab in treatment-naïve patients with intermediate- or poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria in April 2018 (2,3). In Japan, this combination therapy has also been approved since August 2018. However, it is often associated with a wide variety of immune-related adverse events (irAEs) that can affect almost any organ site (1,4).\n\nWe herein report a patient with metastatic renal cell carcinoma who developed the uncommon irAE of aseptic meningitis as well as isolated ACTH deficiency and liver dysfunction during ipilimumab and nivolumab therapy.\n\nCase report\nA 70-year-old Japanese woman was referred to our institution for the evaluation of a right renal tumor that had been detected by abdominal ultrasonography at a screening examination in July 2018. She had a history of hypertension. She was diagnosed with right renal cell carcinoma (cT1bN0M0) by computed tomography (CT) and underwent right nephrectomy in the same month. Two months later, multiple lung metastases were observed by CT (Fig. 1A). Therefore, she was diagnosed as ‘intermediate risk’ according to the IMDC criteria [she had one prognostic factor (<1 year since the diagnosis)].\n\nCombination therapy (once every 3 weeks, intravenously) of ipilimumab (1 mg/kg) and nivolumab (240 mg/body) was administered as the first-line therapy in September 2018. On the 14th day of the 2nd course, she complained of nonspecific clinical symptoms, such as headaches, dizziness and nausea, and was admitted to our hospital. However, she did not complain of or develop any other specific clinical features pertaining to the central nervous system. She also did not report any neck stiffness. Brain magnetic resonance imaging (MRI) was preformed, but there were no brain metastases or any findings suggestive of encephalitis or meningitis (Fig. 2A). However, meningitis could not be ruled out clinically, so a cerebrospinal fluid (CSF) test was performed.\n\nThe examination of the CSF revealed normal glucose levels but an elevated protein level at 195 mg/dl and a significantly elevated white blood cell (WBC) count of 830/mm3 (lymphocytes 825/mm3, neutrophils 5/mm3; Table I). In addition, CSF cytology showed no malignant cells, and the CSF analysis was negative for bacteria and viruses (cytomegalovirus, herpes simplex virus, varicella-zoster virus and human herpes virus type 6). Based on these results, she was diagnosed with aseptic meningitis induced by ipilimumab and nivolumab therapy, and prednisolone (1 mg/kg/day) was started intravenously. After a few days, her clinical symptoms improved rapidly, as did the CSF analysis findings, so prednisolone was tapered gradually. On the 49th day of the 2nd course, she had no recurrence of clinical symptoms on maintenance oral steroid treatment (prednisolone 10 mg/day), and a CSF analysis showed that the WBC count had dropped to 44/mm3 (only lymphocytes; Table I). After delivering a sufficient explanation of the risks and benefits to the patient, the 3rd course of the combination therapy was readministered the next day.\n\nTwo weeks later, she complained of nausea, anorexia and fatigue. A relapse of meningitis was suspected, but the CSF showed that the WBC count was not marked elevated compared to before (Table I). Although CT was performed to investigate the cause, no abnormal findings were found. However, all multiple lung metastases had disappeared, and a complete response was considered to have been achieved (Fig. 1B). The MRI of the brain showed mild diffuse enlargement of the pituitary (Fig. 2B). Her laboratory data showed a low sodium value (122 mmol/l). Based on the clinical symptoms, examination values and MRI findings, adrenocorticotropic hormone (ACTH) deficiency was suspected, and the administration of oral hydrocortisone 20 mg/day (Cortril®; morning 15 mg, evening 5 mg) was started after stopping prednisolone.\n\nTwo days later, her symptoms dramatically improved. The results of the endocrine system tests revealed that her ACTH (2.0 pg/ml) and cortisol (1.12 µg/dl) levels were lower than normal. The levels of other anterior pituitary hormones (prolactin, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone) were not low (Table II). Based on these findings, the diagnosis was isolated ACTH deficiency induced by combination therapy of ipilimumab and nivolumab.\n\nOn the 25th day of the 3rd course, she complained of headache and anorexia. The CSF examination showed that the WBC count had increased again (53/mm3, only lymphocytes), and her laboratory data showed hepatic dysfunction and elevated aspartate aminotransferase at 155 U/l and alanine aminotransferase at 244 U/l (Tables I and II). She had no history of infection with hepatitis B and C virus, and abdominal echography showed no remarkable findings in her liver. She was diagnosed with liver dysfunction and relapse of aseptic meningitis induced by combination therapy of ipilimumab and nivolumab.\n\nWhile continuing the administration of oral hydrocortisone 20 mg/day, the administration of intravenous prednisolone (total 1 mg/kg/day) was started additionally. The liver dysfunction and aseptic meningitis gradually improved (Table II). Three months later, CT showed that the multiple lung metastases had not reappeared. However, she had been taking oral hydrocortisone 20 mg/day for isolated ACTH deficiency and prednisolone 2.5 mg/day for liver dysfunction. Therefore, the immunotherapy was not restarted.\n\nDiscussion\nAnti-CTLA-4 antibody and anti-PD-1 antibody have different working points and mechanisms of activity, and their combination brings about a synergetic effect on the tumor reduction effect and overall survival (1,5). However, the frequency and severity of irAEs is also synergistically affected. Although the patient backgrounds differed between these studies, grade 3 or 4 treatment-related AEs occurred in 18.7% of patients treated with nivolumab alone for mRCC (6), whereas such AEs occurred in 45.7% of patients treated with nivolumab plus ipilimumab for mRCC (1). The most frequently reported irAEs in the RCC population are skin events (59.6% of patients), endocrine events (40.4% of patients), gastrointestinal events (44.7% of patients), hepatic events (27.7%), renal events (12.8%) and pulmonary events (10.6 %) (7). Neurologic side-effects are rare but include cases of immune polyneuropathies, Guillain Barré syndrome, myasthenia gravis, posterior reversible encephalopathy syndrome, aseptic meningitis, enteric neuropathy, transverse myelitis as well as immune encephalitis (8). In a pooled analysis of nearly 1,500 patients with melanoma treated with ipilimumab, the incidence of neurologic irAEs was 0.1% (9,10).\n\nWe herein report a 70-year-old woman with mRCC receiving combination nivolumab and ipilimumab therapy who developed aseptic meningitis, isolated ACTH deficiency and hepatic dysfunction that were probably induced by an auto-immune related mechanism. As meningitis and encephalitis were suspected based on clinical symptoms, lumber puncture proved extremely helpful for making a diagnosis because there were no findings on brain MRI. CSF abnormalities with an elevated proteins level associated with lymphocytic pleocytosis supported the presence of inflammatory-mediated disease. General bacterial meningitis was initially excluded because of the lymphocyte-dominated findings on CSF. Tuberculous meningitis has also been reported to have lymphocyte-dominated findings. However, in modern Japan, tuberculosis infection itself is so rare that it was not considered as a differential diagnosis. A CSF analysis was the most useful examination for supporting the relationship between the aseptic meningitis status and the response to steroid treatment. Aseptic meningitis fortunately responded well to high-dose steroid therapy, and her irAEs also improved to Grade 1 promptly. The early improvement of the patient's symptoms and CSF analysis findings by steroid treatment ruled out tuberculous meningitis. There were no sequelae, and the prednisolone dose was able to be reduced to 10 mg/day within 1 month after the start of steroid therapy.\n\nWhether or not to resume immune checkpoint inhibitor treatment after neurological recovery is a matter of debate, and a careful analysis of the risks and benefits should be done on a case by case basis. The therapeutic effect was a complete response after only 2 courses. However, the durability of the response to this combination therapy for mRCC still remains unclear and this combination immunotherapy is only allowed in the first-line setting for mRCC in Japan. Steroid treatment therapy for this irAE foutunately demonstrated a good response, so the combination therapy was re-administered after both the risks and benefits were sufficiently explained to the patient. However, isolated ACTH deficiency occurred with the oral administration of steroids. Furthermore, relapse of aseptic meningitis and liver dysfunction also occurred. An autopsy analysis of the pituitary glands of patients with cancer treated by CTLA-4 blockade described type II and IV hypersensitivity reactions and a strong CTLA-4 expression in the pituitary gland (11). Therefore, this hypophysitis with pituitary enlargement hypothetically could have been caused by type II hypersensitivity reactions, such as complement activation and infiltration with macrophages and phagocytosis, and type IV hypersensitivity reactions, such as infiltration with autoreactive T lymphocytes. Although the study was conducted in a melanoma population, it was reported that approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of AEs. However, the efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue the treatment because of AEs (12). In the present case, re-administration of nivolumab and ipilimumab therapy occurred not only other irAEs but also relapse of aseptic meningitis. Therefore, we decided to resume immunotherapy when the disease progressed.\n\nNo standard treatment has yet been defined for neurological irAEs. A commonly used protocol is oral prednisone at roughly 1 mg/kg/day. A neurological irAE management algorithm has been proposed (5,8). However, further studies are necessary in order to establish the precise framework regarding the dose, timing of tapering and administration period of steroid treatment. In the present case, a longer tapering period for steroids might have been needed in order to prevent recurrent irAEs. Indeed, it was reported that neurological irAEs are not always reversible (13), highlighting the importance of optimizing treatment regimens.\n\nWith the increasing use of immune checkpoint inhibitors in cancer treatment, practicing oncologists need to be aware of the potential risks of neurologic irAEs and be able to provide prompt treatment for this uncommon but potentially serious class of AEs. Treatment algorithms for relatively frequent AEs have been established, and there are many case reports of relatively frequent AEs that can be referenced (14,15). The present case of aseptic meningitis is a rare AE, and the diagnosis and treatment of such events can be facilitated by the publication of detailed clinical case reports. Proper testing based on the careful observation of patients' clinical symptoms and intervention with steroids will enable the effective treatment at an earlier point in the clinical course.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nAll data generated or analyzed during the present study are included in this published article.\n\nAuthors' contributions\nDT, NF and TN participated, conceived and designed the present case report, analyzed and interpreted the data and wrote the manuscript. DT, KI, TI and KT evaluated the patient and participated in therapy. KI and MN evaluated radiological images. TN and MN supervised the study and critically reviewed the manuscript. All authors have read and approved the final version of the manuscript.\n\nEthics approval and consent to participate\nThe present case report was approved by the Institutional Review Board of National Hospital Organization Kyushu Cancer Center (approval no. 2014-99). Written informed consent was obtained from the patient.\n\nPatient consent for publication\nThe patient provided written informed consent for the publication of any associated data and accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1. Chest CT. (A) Chest CT revealed metastatic lung tumors in the bilateral lobe prior to ipilimumab and nivolumab combinational therapy (white arrow). (B) Following the 3rd course of therapy, CT images revealed that the lung metastasis had disappeared.\n\nFigure 2. Brain MRI. (A) A sagittal section of a contrast-enhanced T1-weighted brain MRI scan revealed no abnormality. (B) A sagittal section of a contrast-enhanced T1-weighted brain MRI scan presented mild diffuse enlargement of the pituitary (white arrow).\n\nTable I. CSF analysis and blood glucose data of the case study.\n\nCSF examination\tReference value\tC2D14\tC2D23\tC2D49\tC3D10\tC3D25\t\nGlucose, mg/dl\t45-80\t46\t74\t67\t66\t66\t\nProtein, mg/dl\t<45\t195\t97\t41\t52\t48\t\nWBC, n/mm3\t<5\t830\t217\t44\t34\t53\t\n Lymphocyte, n/mm3\t0\t825\t215\t44\t34\t53\t\n Neutrophil, n/mm3\t0\t5\t2\t0\t0\t0\t\nBlood glucose, mg/dl\t73-109\t106\t–\t–\t148\t141\t\nBlood to CSF glucose ratio\t\t0.43\t–\t–\t0.45\t0.47\t\nCSF, cerebrospinal fluid; C, course; D, day; WBC, white blood cell.\n\nTable II. Patient laboratory data.\n\nLaboratory data\tReference value\tC3D10\tC3D15\tC3D25\tC3D27\tC3D29\tC3D50\t\nWBC, n\t3,300-8,600/µl\t11,000\t9,000\t9,170\t8,850\t19,030\t16,920\t\nEosino (%)\t0.4–8.6\t0.5\t1.3\t0.3\t0.6\t0.1\t0.2\t\nAST, U/l\t13-30\t35\t50\t131\t155\t69\t20\t\nALT, U/l\t10-42\t41\t57\t204\t244\t176\t44\t\nNa, mmol/l\t138-145\t133\t122\t127\t131\t134\t–\t\nCRP, mg/dl\t0-0.14\t3.12\t6.45\t0.36\t0.27\t<0.07\t–\t\nACTH, pg/ml\t7.2–63.3\t15.7\t2\t<1.5\t–\t–\t–\t\nCortisol, µg/dl\t6.24–18.0\t3.18\t1.12\t38.1\t–\t–\t–\t\nTSH, µIU/ml\t0.49–4.67\t–\t0.31\t2.5\t–\t–\t–\t\nF-T4, ng/ml\t0.71–1.85\t–\t0.91\t0.89\t–\t–\t–\t\nPRL, ng/ml\t4.29–13.69\t–\t60.5\t–\t–\t–\t–\t\nLH, mIU/ml\t0.79–5.72\t–\t8.08\t–\t–\t–\t–\t\nFSH, mIU/l\t2.00–8.30\t–\t30.54\t–\t–\t–\t–\t\nCertain data are not provided, as these parameters did not require follow-up at these stages. WBC, white blood cell; Eosino, eosinophil ratio; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CRP, C-reactive protein; ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone; F-T4, thyroxine; PRL, prolactin; LH, luteinizing hormone; FSH, follicle-stimulating hormone; C, course; D, day.\n==== Refs\nReferences\n1 Motzer RJ Tannir NM McDermott DF Arén Frontera O Melichar B Choueiri TK Plimack ER Barthélémy P Porta C George S Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma N Engl J Med 378 1277 1290 2018 10.1056/NEJMoa1712126 29562145 \n2 Heng DY Xie W Regan MM Warren MA Golshayan AR Sahi C Eigl BJ Ruether JD Cheng T North S Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a large, multicenter study J Clin Oncol 27 5794 5799 2009 10.1200/JCO.2008.21.4809 19826129 \n3 Heng DY Xie W Regan MM Harshman LC Bjarnason GA Vaishampayan UN Mackenzie M Wood L Donskov F Tan MH External validation and comparison with other models of the international metastatic renal-cell carcinoma database consortium prognostic model: A population-based study Lancet Oncol 14 141 148 2013 10.1016/S1470-2045(12)70559-4 23312463 \n4 Ardolino L Joshua A Immune checkpoint inhibitors in malignancy Aust Prescr 42 62 67 2019 10.18773/austprescr.2019.012 31048940 \n5 Postow MA Chesney J Pavlick AC Robert C Grossmann K McDermott D Linette GP Meyer N Giguere JK Agarwala SS Nivolumab and ipilimumab versus ipilimumab in untreated melanoma N Engl J Med 372 2006 2017 2015 10.1056/NEJMoa1414428 25891304 \n6 Motzer RJ Escudier B McDermott DF George S Hammers HJ Srinivas S Tykodi SS Sosman JA Procopio G Plimack ER Nivolumab versus everolimus in advanced renal-cell carcinoma N Engl J Med 373 1803 1813 2015 10.1056/NEJMoa1510665 26406148 \n7 Hammers HJ Plimack ER Infante JR Rini BI McDermott DF Lewis LD Voss MH Sharma P Pal SK Razak ARA Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: The CheckMate 016 study J Clin Oncol 35 3851 3858 2017 10.1200/JCO.2016.72.1985 28678668 \n8 Hottinger AF Neurologic complications of immune checkpoint inhibitors Curr Opin Neurol 29 806 812 2016 10.1097/WCO.0000000000000391 27653290 \n9 Tarhini A Immune-mediated adverse events associated with ipilimumab ctla-4 blockade therapy: The underlying mechanisms and clinical management Scientifica (Cairo) 2013 857519 2013 24278787 \n10 Ibrahim RA Berman DM DePril V Humphrey RW Chen T Messina K M Chin M Liu HY Bielefield M Hoos A Ipilimumab safety profile: Summary of findings from completed trials in advanced melanoma J Clin Oncol 29 15 Suppl S8583 2011 10.1200/jco.2011.29.15_suppl.8583 \n11 Caturegli P Di Dalmazi G Lombardi M Grosso F Larman HB Larman T Taverna G Cosottini M Lupi I Hypophysitis secondary to cytotoxic T-lymphocyte-associated protein 4 blockade: Insights into pathogenesis from an autopsy series Am J Pathol 186 3225 3235 2016 10.1016/j.ajpath.2016.08.020 27750046 \n12 Schadendorf D Wolchok JD Hodi FS Chiarion-Sileni V Gonzalez R Rutkowski P Grob JJ Cowey CL Lao CD Chesney J Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: A pooled analysis of randomized phase II and III trials J Clin Oncol 35 3807 3814 2017 10.1200/JCO.2017.73.2289 28841387 \n13 Spain L Walls G Julve M O'Meara K Schmid T Kalaitzaki E Turajlic S Gore M Rees J Larkin J Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: A single centre experience and review of the literature Ann Oncol 28 377 385 2017 28426103 \n14 National Comprehensive Cancer Network Guidelines on Management of Immune Checkpoint Inhibitor-Related Toxicities Version 2, 2019 https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf/ 6 3 2019 \n15 Brahmer JR Lacchetti C Schneider BJ Atkins MB Brassil KJ Caterino JM Chau I Ernstoff MS Gardner JM Ginex P Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline J Clin Oncol 36 1714 1768 2018 10.1200/JCO.2017.77.6385 29442540\n\n",
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"issue": "11(6)",
"journal": "Molecular and clinical oncology",
"keywords": "immune-related adverse events; ipilimumab; meningitis; nivolumab; renal cell carcinoma",
"medline_ta": "Mol Clin Oncol",
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"pages": "590-594",
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"pubdate": "2019-12",
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"references": "26406148;27750046;29442540;19826129;24278787;28426103;29562145;28841387;25891304;27653290;23312463;28678668;31048940",
"title": "Relapse of aseptic meningitis induced by ipilimumab and nivolumab therapy for metastatic renal cell carcinoma: A case report.",
"title_normalized": "relapse of aseptic meningitis induced by ipilimumab and nivolumab therapy for metastatic renal cell carcinoma a case report"
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"abstract": "Our case report discusses the usefulness of administering romiplostim as a second-line treatment before splenectomy in a cirrhotic patient with immune thrombocytopenia who developed corticosteroid-induced Cushing's syndrome. Corticosteroids were tapered and consequently withdrawn. The patient made a full recovery postsplenectomy.",
"affiliations": "Gastroenterology Service Hepatitis and Liver Transplant Unit IDIBELL Hospital Universitari de Bellvitge Feixa Llarga s/n L'Hospitalet de Llobregat 08907 Barcelona Spain.;Gastroenterology Service Hepatitis and Liver Transplant Unit IDIBELL Hospital Universitari de Bellvitge Feixa Llarga s/n L'Hospitalet de Llobregat 08907 Barcelona Spain.",
"authors": "Casanovas Taltavull|Teresa|T|;Peña-Cala|Maria Carmen|MC|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.667CCR3667Case ReportCase ReportsRomiplostim therapy as a second‐line treatment before splenectomy for refractory immune thrombocytopenia in a cirrhotic patient with iatrogenic Cushing syndrome secondary to corticosteroids T. Casanovas Taltavull & M. C. Peña‐CalaCasanovas Taltavull Teresa teresacasan@gmail.com \n1\nPeña‐Cala Maria Carmen \n1\n1 Gastroenterology ServiceHepatitis and Liver Transplant UnitIDIBELLHospital Universitari de BellvitgeFeixa Llarga s/nL'Hospitalet de Llobregat08907BarcelonaSpain* Correspondence\n\nTeresa Casanovas Taltavull, Gastroenterology Service, Hepatitis and Liver Transplant Unit, IDIBELL, Hospital Universitari de Bellvitge, Feixa Llarga s/n, L'Hospitalet de Llobregat, Barcelona 08907, Spain. Tel: + 34‐93‐3357011 ext 2826; Fax: +34‐93‐2607533; E‐mail: teresacasan@gmail.com\n23 1 2017 2 2017 5 2 10.1002/ccr3.2017.5.issue-2159 163 18 10 2015 09 6 2016 24 7 2016 © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nOur case report discusses the usefulness of administering romiplostim as a second‐line treatment before splenectomy in a cirrhotic patient with immune thrombocytopenia who developed corticosteroid‐induced Cushing's syndrome. Corticosteroids were tapered and consequently withdrawn. The patient made a full recovery postsplenectomy.\n\nChronic liver diseasehypersplenismiatrogenic Cushing syndromeimmune thrombocytopeniaromiplostimsplenectomy source-schema-version-number2.0component-idccr3667cover-dateFebruary 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.0.4 mode:remove_FC converted:03.02.2017\n==== Body\nIntroduction\nThis case report describes the clinical case of a patient with chronic liver disease (CLD) who suffered chronic immune thrombocytopenia (ITP), for more than one year which defines a chronic evolution.\n\nChronic ITP is an acquired immune disorder characterized by isolated thrombocytopenia. The diagnosis of ITP is established by the exclusion of other causes of low platelets count such as bone marrow failure, especially malignancy, infections, alcohol excess, or drug induced.\n\nSevere clinical manifestations may be observed associated with ITP. Patients can suffer: gastrointestinal bleeding, extensive skin, mucosal, or intracranial hemorrhage. On physical examination, you can find splenomegaly and hepatomegaly. In our patient, these findings were attributed initially to his concomitant chronic liver disease. Our patient had compensated cirrhosis, Child A status, according to the prognostic classification of cirrhosis. His analytical parameters had only mild abnormalities severe; however, severe thrombocytopenia was observed which is not usually secondary to portal hypertension.\n\nThe patient received the first‐line treatments proposed by the clinical guidelines with intravenous immunoglobulins and prednisone. Despite showing no signs of improvement, the administration of prednisone was continued in the long term and the patient developed iatrogenic Cushing's syndrome. Because the patient failed to respond to first‐line treatment, a bone marrow examination was carried out. This test is usually not performed as an initial investigation if the history and clinical examination fit with the diagnosis of ITP.\n\nThe second line of recommended treatment is to perform a splenectomy, but the deteriorated clinical condition and comorbidities of our patient precluded it. At present, the recommendation for a second line of treatment is the administration of a thrombopoietin receptor agonists (TPO), romiplostim, or eltrombopag. In our patient, romiplostim was administered while tapering and suspending prednisone. When the patient was stabilized, splenectomy could be performed with the expected normalization of clinical situation and platelet count. Splenectomy is one of the second‐line treatments for adults with ITP.\n\nCase Presentation\nIn 2002, the patient, a 64‐year‐old male, presented at the emergency room with severe thrombocytopenia and a self‐limited intestinal hemorrhage of unknown origin and was diagnosed with chronic liver disease, Child A status. The cause of cirrhosis was attributed to alcohol consumption in the past. A bone marrow examination was performed and showed normal megakaryocytes, and as a result, hematological diseases were excluded. Thrombocytopenia persisted and was considered secondary to hypersplenism. The initial laboratory values are shown in Table 1, highlighting the severity of thrombocytopenia.\n\nTable 1 Initial laboratory values\n\nLaboratory tests\tValue\tNormal range\t\nWhite blood cell count (cells/mm3)\t3\t3.9–10\t\nMean corpuscular volume (fL)\t91\t81–96\t\nPlatelets (cells/mm3)\t\n13\n\t\n135–333\n\t\nHemoglobin level (g/L)\t120\t126–166\t\nBone marrow examination\tShowed no disorders\tNot applicable\t\nInternational normalized ratio (INR)\t1.2\t0.8–1.2\t\nCreatinine (μmol/L)\t80\t<111\t\nAspartate amino transferase (μKat/L)\t0.51\t<0.50\t\nAlanine amino transferase (μKat/L)\t0.38\t<0.73\t\nAlkaline phosphatase (μKat/L)\t1.3\t<1.5\t\nTotal bilirubin (mmol/L)\t19\t<18\t\nGamma‐glutamyl transpeptidase (μKat/L)\t1.7\t<1.11\t\nAlbumin (g/L)\t38\t33–50\t\nGlucose (mmol/L)\t5.6\t4.1–6.9\t\nCobalamin/Folate (pmol/L/pmol/L)\t291.9/6.8\t≥122/>45.4\t\nLactate dehydrogenase (LDH) μKat/L\t6.3\t<3.4\t\nStandard urinalysis\tAll within normal limits\tNot applicable\t\nHepatitis B virus and hepatitis C virus Ab\tNegative\tNegative\t\nHepatitis autoimmune Ab (antinuclear, antimitochondrial, antismooth muscle, and anti‐KLM)\tNegative\tNegative\t\n\nμmol/L, micromoles per Liter; μKat/L, microkat per Liter; mmol/L, millimoles per Liter; pmol/L, picomol per Liter; Ab, antibodies.\n\nBold values means severity of low platelets count.\n\nJohn Wiley & Sons, LtdDuring the period 2005–2009, he suffered from repeated hemorrhages. Hence, he was treated with the first‐line therapy which is IV IgG and prednisone. During these years, he needed emergency treatments and was hospitalized on several occasions. In spite of standard therapies, hemorrhages persisted but he did not develop liver decompensation.\n\nIn June 2009, he was hospitalized for ecchymoses, rectal bleeding, and severe thrombocytopenia requiring blood transfusions, IV IgG, and high doses of prednisone (1 mg per kilogram of body weight per day). A bone marrow exam was repeated, and no abnormalities were detected.\n\nIn August, October, and November 2009, he needed to be re‐hospitalized for epistaxis and intestinal hemorrhage and his platelet count was 1.000–3.000 cells/mm3. Long‐term high doses of prednisone, 100 mg/day, were administered from June 2009 to April 2010. Hemorrhages were clinically stabilized, but the patient's clinical situation deteriorated.\n\nIn November 2009, he was referred to our clinic for evaluation of his chronic liver disease. He had developed iatrogenic Cushing syndrome with cardiovascular complications (shortness of breath, swollen extremities, weight increase). Table 2 shows the values of the patient's vital signs. General and specific analysis and abdominal doppler ultrasound were performed. Symptomatic treatment was established while tapering prednisone.\n\nTable 2 Patient's vital sign values pretreatment with romiplostim\n\nBlood pressure\t180/90\t\nPulse (bpm)\t67\t\nWeight (Kg)/Height (cm)\t102/168\t\nBMI (Body Mass Index)\t36.1\t\nJohn Wiley & Sons, LtdIn March 2010, he started romiplostim treatment as a bridge for splenectomy. Taking into account his chronic liver disease and risk of vascular thrombosis, the target platelet count range was an average of 50,000–90,000 cells/mm3. Efficacy and safety were assessed weekly, during each visit. Figure 1 shows the platelet count during this period.\n\nFigure 1 Platelet count level over time and correlation with medical treatment and splenectomy.\n\nIn December 2010, prednisone was totally stopped and this allowed the patient to be considered for splenectomy. He was given an antipneumoccocal, meningococcal, and hemophilus influenzae vaccinations and underwent computed axial tomography (CAT) (Fig. 2) and abdominal ultrasound test. In addition, a nuclear medicine study was carried out of the liver–spleen image with 99 mTc‐labeled colloid, confirming enlarged spleen and a reduced platelet half‐life with a pattern of increased splenic destruction.\n\nFigure 2 Abdominal CT scan lobular liver, suggesting cirrhosis without nparenchimal, biliary or vascular lesions, normal portal vein and enlarged spleen (19 cm.). Kidney of normal size and morphology. No retroperitoneal or lymphadenopathy and no free peritoneal fluid were observed.\n\nIn May 2011, open laparotomy with splenectomy was performed with a liver biopsy specimen obtained preoperatively, which showed advanced fibrosis without steatosis or other features. After the surgery, the patient showed full recovery.\n\nToday, after 5 years of follow‐up, the patient only requires vitamin supplements and standard ambulatory checkups every 6 months. His liver function remains stable, and platelet count is maintained at normal range.\n\nDiscussion\nWe present the clinical case of a patient with chronic liver disease (CLD) and severe thrombocytopenia 1 who after 9 years of suffering repeated hemorrhages developed iatrogenic Cushing syndrome secondary to high doses of prednisone. He received romiplostim as a second line of immune thrombocytopenia (ITP) therapy 2 for a period of nine months while prednisone was tapered before a splenectomy could be indicated.\n\nIn CLD patients, thrombocytopenia is a common clinical problem associated with hypersplenism but ITP disorder is rarely encountered 1.\n\nThrombocytopenia in liver cirrhosis is typically less severe than that found in ITP, which may be secondary to hematological diseases, chemotherapy, some drugs, hepatitis C‐related, and myelodysplastic syndromes 3. In our patient, secondary causes of ITP were ruled out and the diagnosis of ITP was well established.\n\nTreatment of ITP in our patient was a challenge due to the risks associated with liver disease and also to the Cushing Syndrome and cardiovascular complications observed 4. Therefore, our major concern while decreasing the doses of prednisone was how to treat the underlying thrombocytopenia and hypercortisolism with heart failure and hypertension avoiding steroid withdrawal syndrome.\n\nNowadays, clinical guidelines for ITP in newly diagnosed adults recommend rituximab, thrombopoietin receptor agonist (TPO), TPO‐RA (romiplostim or eltrombopag), or splenectomy for patients who are unresponsive or who have relapsed after initial IV IgG and corticosteroid therapies. Splenectomy is one of the second‐line treatment for adults with ITP. 5, 6.\n\nIt is important to note that in case of resistance to the first‐line therapy, as was observed in our patient, other options such as splenectomy should be considered. However, in patients with CLD, portal hypertension and thrombocytopenia represent obstacles to surgical procedures.\n\nSplenectomy has been the standard second‐line treatment for adults with ITP and remains a good option 7. Due to the deleterious effects of long‐term use of high doses of prednisone, our patient's clinical condition was severely deteriorated, and this was a cause for deterring and contraindicating the splenectomy that should have been performed once clinicians realized that the patient was nonresponding to the first‐line treatment. Doctors may be hesitant to indicate splenectomy as some adults improve over time or spontaneously or as a result of medical treatment.\n\nAvoiding or delaying splenectomy is usual and is evidenced by a decrease in the rate of splenectomies performed in recent years.\n\nHowever, the majority of groups accept splenectomy as a second‐line treatment after failure of steroids and in the absence of contraindication. Failure is defined by a remaining platelet count of less than 10,000–30,000, active bleeding, or high steroid requirement 8.\n\nAlthough romiplostim had not been tested specifically in chronic liver disease, after examining the pros and cons, it was indicated.\n\nMany recent clinical case reports have shown a possible role of romiplostim in the preparation preliver transplant or prior for invasive therapeutic procedure 9, 10, 11.\n\nThrombocytopenia associated with advanced liver disease has a multifactorial origin. Usually a combination of causes can be implicated, producing an imbalance between production and destruction of platelets. A reduction of synthesis of TPO, which is produced exclusively by the liver, has been observed and also an increased splenic sequestration as a consequence of portal hypertension 12.\n\nThe etiology of thrombocytopenia in our patient was attributed to hypersplenism, although since the beginning a component of ITP could not be discarded. Despite performing a scintigraphic evaluation which confirmed the platelet sequestration and destruction in the spleen, these results are not totally predictive 13. Complications related to romiplostim treatment have been described: thrombotic events related to an elevated number of platelets, lack of response due to fibrous tissue deposition in bone marrow, worsening thrombocytopenia due to a rebound effect etc. 14.\n\nIt is worthwhile presenting this patient because not only did treatment with romiplostim improves platelet count but it also enabled a clinical improvement, thus allowing him to be splenectomised 15.\n\nDue to the presence of iatrogenic Cushing syndrome with cardiovascular complications in our patient, there were some concerns regarding the impact of romiplostim on his management. Nevertheless, romiplostim was well tolerated. However, the possibility of severe complications, especially in patients with decompensated cirrhosis, should be considered.\n\nThe outcome after splenectomy was uneventful. Cirrhosis was not decompensated during the treatment period, and a Child A status was maintained indicating a relatively good liver function and a good prognosis for surgery.\n\nConclusion\nThis case report emphasizes the hazards of long‐term administration of prednisone, which in our patient resulted in Cushing's syndrome, and shows how romiplostim was used to maintain a safe platelet count while tapering prednisone to prepare the patient for splenectomy.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\n1 \n\nAfdhal , N. \n, \nJ. \nMcHutchison \n, \nR. \nBrown \n, \nL. \nJacobson \n, \nM. \nManns \n, \nF. \nPoordad \n, et al. 2008 \nThrombocytopenia associated with chronic liver disease . J. Hepatol. \n48 :1000 –1007 .18433919 \n2 \n\nFrampton , J. E. \n, and \nA. \nLyseng‐Williamson \n. 2009 \nRomiplostim drugs . Drugs \n69 :307 –317 .19275274 \n3 \n\nLakshmanan , S. \n, and \nA. \nCuker \n. 2012 \nContemporary management of primary immune thrombocytopenia (ITP) in adults . J. Thromb. Haemost. \n10 :1988 –1998 .22863415 \n4 \n\nFardet , L. \n, \nI. \nPetersen \n, and \nI. \nNazareth \n. 2012 \nRisk of cardiovascular events in people prescribed glucocorticoids with iatrogenic Cushing's syndrome: cohort study . BMJ \n345 :e4928 .22846415 \n5 \n\nProvan , D. \n, \nR. \nStasi \n, \nA. C. \nNewland \n, \nV. S. \nBlanchette \n, \nP. \nBolton‐Maggs \n, \nJ. B. \nBussel \n, et al. 2010 \nInternational consensus report on the investigation and management of primary immune thrombocytopenia . Blood \n115 :168 –186 .19846889 \n6 \n\nNeunert , C. \n, \nW. \nLim \n, \nM. \nCrowther \n, \nA. \nCohen \n, \nL. Jr , Solberg \n, \nM. A. \nCrowther \n, American Society of Hematology \n. 2011 \nThe American Society of Hematology 2011 evidence‐based practice guideline for immune thrombocytopenia . Blood \n117 :4190 –4207 .21325604 \n7 \n\nVianelli , N. \n, \nF. \nPalandri \n, \nN. \nPolverelli \n, \nR. \nStasi \n, \nJ. \nJoelsson \n, \nE. \nJohansson \n, et al. 2013 \nSplenectomy as a curative treatment for immune thrombocytopenia: a retrospective analysis of 233 patients with a minimum follow up of 10 years . Haematologica \n98 :875 –880 .23144195 \n8 \n\nGhanima , W. \n, \nB. \nGodeau \n, \nD. B. \nCines \n, and \nJ. B. \nBussel \n. 2012 \nHow I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second‐line treatment . Blood \n120 :960 –969 .22740443 \n9 \n\nDultz , G. \n, \nB. \nKronenberger \n, \nA. \nAzizi \n, \nU. \nMihm \n, \nT. J. \nVogl \n, \nU. \nSarrazin \n, et al. 2011 \nPortal vein thrombosis as complication of romiplostim treatment in a cirrhotic patient with hepatitis C‐associated immune thrombocytopenic purpura . J. Hepatol. \n55 :229 –232 .21310200 \n10 \n\nSivera , P. \n, \nM. \nRuella \n, \nA. \nGueli \n, \nH. \nHu \n, \nM. \nWade \n, \nC. \nTarella \n, et al. 2012 \nUse of the novel thrombopoietin receptor‐agonist romiplostim, in combination with steroids and immunoglobulins for the increase of platelets prior to splenectomy, in refractory immune thrombocytopenia: a case report . Blood Coagul. Fibrinolysis \n23 :331 –334 .22343685 \n11 \n\nMoussa , M. M. \n, and \nN. \nMowafy \n. 2013 \nPreoperative use of romiplostim in thrombocytopenic patients with chronic hepatitis C and liver cirrhosis . J. Gastroenterol. Hepatol. \n28 :335 –341 .22849409 \n12 \n\nWitters , P. \n, \nK. \nFreson \n, \nC. \nVerslype \n, \nK. \nPeerlinck \n, \nM. \nHoylaerts \n, \nF. \nNevens \n, et al. 2008 \nReview article: blood platelet number and function in chronic liver disease and cirrhosis . Aliment. Pharmacol. Ther. \n27 :1017 –1029 .18331464 \n13 \n\nKinuya , K. \n, \nS. \nMatano \n, \nH. \nNakashima \n, and \nS. \nTaki \n. 2003 \nScintigraphic prediction of therapeutic outcomes of splenectomy in patients with thrombocytopenia . Ann. Nucl. Med. \n17 :161 –164 .12790368 \n14 \n\nMitchell , W. B. \n, and \nJ. B. \nBussel \n. 2015 \nThrombopoietin receptor agonists: a critical review . Semin. Hematol. \n52 :46 –52 .25578419 \n15 \n\nThota , S. \n, \nG. \nKistangari \n, \nH. \nDaw \n, and \nT. \nSpiro \n. 2012 \nImmune thrombocytopenia in adults: an update . Clev. Clin. J. Med. \n79 :641 –650 .\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "5(2)",
"journal": "Clinical case reports",
"keywords": "Chronic liver disease; hypersplenism; iatrogenic Cushing syndrome; immune thrombocytopenia; romiplostim; splenectomy",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "159-163",
"pmc": null,
"pmid": "28174643",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports",
"references": "19275274;22740443;18433919;21310200;25578419;21325604;22949345;23144195;22343685;12790368;22846415;18331464;22863415;22849409;19846889",
"title": "Romiplostim therapy as a second-line treatment before splenectomy for refractory immune thrombocytopenia in a cirrhotic patient with iatrogenic Cushing syndrome secondary to corticosteroids.",
"title_normalized": "romiplostim therapy as a second line treatment before splenectomy for refractory immune thrombocytopenia in a cirrhotic patient with iatrogenic cushing syndrome secondary to corticosteroids"
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"companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-135297",
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"abstract": "OBJECTIVE\nWe assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS).\n\n\nMETHODS\nWe extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications.\n\n\nRESULTS\nDILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (<1 week) was detected in 46% of patients (47% and 44%, respectively).\n\n\nCONCLUSIONS\nThe disproportionality signal for rivaroxaban calls for further comparative population-based studies to characterize and quantify the actual DILI risk of NOACs, taking into account drug- and patient-related risk factors. As DILI is unpredictable, our findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals of DILI through FAERS and other data sources, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of NOACs when they diagnose a liver injury.",
"affiliations": "Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.;Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.;Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.;University of Bordeaux, U657, F33000, Bordeaux, France.;University of Bordeaux, U657, F33000, Bordeaux, France.;Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.;Department of Public Health and Community Medicine, University of Verona, Verona, Italy.;University of Bordeaux, U657, F33000, Bordeaux, France.;Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.",
"authors": "Raschi|Emanuel|E|;Poluzzi|Elisabetta|E|;Koci|Ariola|A|;Salvo|Francesco|F|;Pariente|Antoine|A|;Biselli|Maurizio|M|;Moretti|Ugo|U|;Moore|Nicholas|N|http://orcid.org/0000-0003-1212-2817;De Ponti|Fabrizio|F|",
"chemical_list": "D000925:Anticoagulants",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.12611",
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"issn_linking": "0306-5251",
"issue": "80(2)",
"journal": "British journal of clinical pharmacology",
"keywords": "FAERS; disproportionality; hepatotoxicity; liver injury; novel oral anticoagulants; spontaneous reporting system",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000284:Administration, Oral; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000925:Anticoagulants; D056486:Chemical and Drug Induced Liver Injury; D016208:Databases, Factual; D006801:Humans; D011358:Product Surveillance, Postmarketing; D014481:United States; D014486:United States Food and Drug Administration",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "285-93",
"pmc": null,
"pmid": "25689417",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23619611;25155865;17506785;23571771;24841749;21848575;19358225;20486732;24837361;24476812;23474284;23673817;20020269;21658092;7836716;24681117;22967190;24369077;24178291;21332248;24925091;24879979;15733826;25232453;23377696;15317031;15246210;23305158;10327225;15782397;21039764;23294275;22759198;24644100;23451769",
"title": "Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system.",
"title_normalized": "liver injury with novel oral anticoagulants assessing post marketing reports in the us food and drug administration adverse event reporting system"
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"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2013-BI-25243BP",
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"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
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"abstract": "Tyrosine kinase inhibitors (TKIs) aid in prolonging life in patients with advanced locoregional thyroid malignancy. Such patients may undergo total laryngectomy for local disease control and tracheoesophageal puncture (TEP) for speech rehabilitation. Enlargement of TEP fistulas is usually attributed to wound healing issues and leads to major complications. Four laryngectomies with TEP were performed between 2015 and 2016 and subsequently placed on a TKI. Three patients developed a complication after TKI treatment, and 2 patients had a tracheoesophageal fistula. Patients should be counseled about possible wound healing risks associated with TKIs.",
"affiliations": "Department of Otolaryngology, Loyola University Medical Center, Chicago, IL, USA.;Department of Otolaryngology, Johns Hopkins University, Baltimore, MD, USA.",
"authors": "Britt|Christopher J|CJ|;Russell|Jonathon O|JO|",
"chemical_list": "D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011804:Quinolines; C531958:lenvatinib; C452423:N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine",
"country": "United States",
"delete": false,
"doi": "10.1177/0145561319839805",
"fulltext": null,
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"issn_linking": "0145-5613",
"issue": "98(8)",
"journal": "Ear, nose, & throat journal",
"keywords": "TEP; TKI; biologics; laryngectomy; prosthesis; thyroid cancer; thyroid carcinoma; thyroidectomy; tracheoesophageal fistula; tyrosine kinase inhibitor; wound healing",
"medline_ta": "Ear Nose Throat J",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D004947:Esophagus; D005260:Female; D006801:Humans; D007825:Laryngectomy; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011677:Punctures; D011799:Quinazolines; D011804:Quinolines; D013064:Speech Disorders; D000072836:Surgical Wound; D013964:Thyroid Neoplasms; D014132:Trachea; D014945:Wound Healing",
"nlm_unique_id": "7701817",
"other_id": null,
"pages": "510-512",
"pmc": null,
"pmid": "30974994",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tyrosine Kinase Inhibitor Use and Wound Healing in Tracheoesophageal Punctures.",
"title_normalized": "tyrosine kinase inhibitor use and wound healing in tracheoesophageal punctures"
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{
"companynumb": "US-EISAI MEDICAL RESEARCH-EC-2019-064962",
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"activesubstancename": "LENVATINIB"
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"abstract": "We present a case of malignant change of an ovarian mature cystic teratoma. Our patient was a 48-year-old woman and she visited a primary care doctor presenting with abdominal pain. At her first visit, her pelvic tumor measured 70 × 50 mm by ultrasonography. She was diagnosed as rupture of the malignant tumor occurred secondary to mature cystic teratoma and she took the surgery (abdominal total hysterectomy, bilateral oophorectomy and partial omentectomy). Pathologic diagnosis was squamous cell carcinoma (SCC) occurred secondary to mature cystic teratoma. Treatment with paclitaxel/carboplatin (TC chemotherapy) and gemcitabine hydrochloride/carboplatin (GC chemotherapy) after operation was not effective, and the refractory ileus resulting from rapid progression of the disease continued. She was died of disease progression 7 months after the diagnosis of ovarian cancer. We discuss about the clinical characteristics of malignant transformation of mature cystic teratoma and considered about the treatment of the ovarian SCC.",
"affiliations": "Department of Obstetrics and Gynecology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Obstetrics and Gynecology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Obstetrics and Gynecology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Obstetrics and Gynecology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Obstetrics and Gynecology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Obstetrics and Gynecology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Obstetrics and Gynecology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Obstetrics and Gynecology, Nagasaki University Hospital, Nagasaki, Japan.",
"authors": "Shimada|Takako|T|https://orcid.org/0000-0003-3793-693X;Higashijima|Ai|A|;Fukushima|Ai|A|;Komatsu|Nahoko|N|;Noguchi|Masashi|M|;Ohashi|Kazuaki|K|;Hasegawa|Yuri|Y|;Miura|Kiyonori|K|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.14043",
"fulltext": null,
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"issn_linking": "1341-8076",
"issue": "45(9)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "chemotherapy in gynecological cancer; epithelial cancer of the ovary; gynecologic oncology",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D002294:Carcinoma, Squamous Cell; D002471:Cell Transformation, Neoplastic; D005260:Female; D006801:Humans; D008875:Middle Aged; D010048:Ovarian Cysts; D010051:Ovarian Neoplasms; D010053:Ovary; D013724:Teratoma",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "1957-1960",
"pmc": null,
"pmid": "31215124",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Malignant transformation from mature cystic teratoma of the ovary.",
"title_normalized": "malignant transformation from mature cystic teratoma of the ovary"
} | [
{
"companynumb": "JP-MYLANLABS-2019M1093736",
"fulfillexpeditecriteria": "1",
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"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Buprenorphine Extended-Release (BUP-XR) is an FDA approved, monthly subcutaneous injection for opioid use disorder. This formulation provides an alternative for patients who have difficulty adhering to daily sublingual buprenorphine; however, its cost may be prohibitive compared to other medication alternatives.\nThe objective of this project was to evaluate the effectiveness of BUP-XR and provide a rationale for its utilization in health care facilitates.\nAcross two VA outpatient clinics, twenty-six (22 male, 4 female) clinically complex patients received at least one BUP-XR injection between December 1, 2018 and April 1, 2020. The sample was high risk for hospital admission and mortality. Data was collected retrospectively from the medical records. Outcomes examined included: medication adherence, urine drug and alcohol screenings, emergency department visits, hospital admissions, and housing status. Within-subject comparisons were made between the six month period prior to and following the first injection.\nTreatment retention was robust, as 81% of the sample received six or more monthly BUP-XR injections. Most patients (77%) maintained 300 mg dosage and a majority (70%) missed or were late for at least one injection. BUP-XR was associated with reduction in: emergency department visits, days of hospitalization, non-prescribed opioid use, and homelessness. Mortality rate was 23%.\nBUP-XR with a flexible dosing schedule and a nonstandard default dose of 300 mgs resulted in robust retention, provided effective treatment of OUD, and reduced health care utilization for these complex patients with high mortality risk. However, due to the lack of statistical significance generalization of these findings is limited.",
"affiliations": "Addiction Treatment Center, U.S. Department of Veterans Affairs Puget Sound Health Care System, Seattle, USA.;Addiction Treatment Center, U.S. Department of Veterans Affairs Puget Sound Health Care System, Seattle, USA.;Addiction Treatment Center, U.S. Department of Veterans Affairs Puget Sound Health Care System, Seattle, USA.;Addiction Treatment Center, U.S. Department of Veterans Affairs Puget Sound Health Care System, Seattle, USA.",
"authors": "Cotton|Ann J|AJ|0000-0001-7141-4890;Lo|Katelyn|K|;Kurtz|Fiona B|FB|;Waldbauer|LeAnna|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/00952990.2021.1992773",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0095-2990",
"issue": null,
"journal": "The American journal of drug and alcohol abuse",
"keywords": "BUP-XR; effectiveness; opioid use disorder; veterans",
"medline_ta": "Am J Drug Alcohol Abuse",
"mesh_terms": null,
"nlm_unique_id": "7502510",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "34780319",
"pubdate": "2021-11-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Extended-release buprenorphine outcomes among treatment resistant veterans.",
"title_normalized": "extended release buprenorphine outcomes among treatment resistant veterans"
} | [
{
"companynumb": "US-INDIVIOR US-INDV-132082-2021",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"abstract": "Prosthetic joint infections (PJIs) remain a major complication of arthroplasty, most of which are caused by Staphylococcus aureus and gram-negative bacteria. Unfortunately, cultures are false negative in upward of 7 percent of patients with suspected PJIs, and commonly in infections caused by rare rapidly growing mycobacterium (RGM) species. Guidelines recommend 6 months of antimycobacterial therapy for bone diseases caused by RGM, with empiric therapy consists of an oral macrolide (clarithromycin or azithromycin) plus tobramycin and imipenem-cilastatin. Definitive treatment of PJI due to RGM should be guided by antimicrobial susceptibility, however, most microbiology laboratories are unable to differentiate between M. chelonae and M. abscessus. Furthermore, treatment of M. chelonae PJI is challenging due to multidrug resistance and the dearth of oral antibiotics for therapy. This case report investigates a patient with PJI caused by M. chelonae and M. abscessus. The initial treatment with imipenem-cilastatin was complicated by drug induced seizures, further limiting therapy options.",
"affiliations": "Pharmacy Practice, 306709Howard University College of Pharmacy, Washington, DC, USA.;20814Howard University Hospital, Washington, DC, USA.;12232Howard University College of Medicine, Washington, DC, USA.;20814Howard University Hospital, Washington, DC, USA.",
"authors": "Singh|Divita|D|https://orcid.org/0000-0003-1934-3399;Johnson|Mikayla|M|;Kitchens|Caleah S|CS|;Boone|Andrew|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0897190020977757",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": null,
"journal": "Journal of pharmacy practice",
"keywords": "Mycobacterium abscessus; Mycobacterium chelonae; prosthetic joint infections; rapidly growing mycobacterium",
"medline_ta": "J Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "897190020977757",
"pmc": null,
"pmid": "33280512",
"pubdate": "2020-12-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Challenges in Treating Mycobacterium chelonae/abscessus Prosthetic Joint Infection.",
"title_normalized": "challenges in treating mycobacterium chelonae abscessus prosthetic joint infection"
} | [
{
"companynumb": "US-BAYER-2020-283999",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
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"drugadditional": null,
... |
{
"abstract": "Ibrutinib represents extraordinary progress in the treatment of chronic lymphocytic leukemia (CLL). However, treatment-related adverse events limit the benefit of this agent. This observational, multicenter study focused on the incidence, risk factors, and prognostic impact of infections in 494 patients with CLL treated with an ibrutinib-based treatment. Ibrutinib was given to 89 (18%) previously untreated patients (combined with rituximab, 24) and 405 (82%) relapsed/refractory patients. Pneumonia (PN), grade ≥3 non-opportunistic infections (NOI), and opportunistic infections (OI) were recorded in 32% of patients with an overall incidence rate per 100 person-year of 15.3% (PN, 10%; NOI, 3.3%; OI, 2%). Infections were the reason for the permanent discontinuation of ibrutinib in 9% of patients. Patients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free (p < 0.0001). A scoring system based on the three factors associated with a significant and independent impact on infections-PN or severe infection in the year before starting ibrutinib, chronic obstructive pulmonary disease, ≥2 prior treatments-identified patients with a two- to threefold increase in the rate of infections. In conclusion, the results of this study highlight the adverse impact of infectious events on the outcomes of CLL patients treated with ibrutinib.",
"affiliations": "Hematology, Department of Translational and Precision Medicine, \"Sapienza\" University, 00161 Rome, Italy.;Biostatistic Unit, Regina Elena National Cancer Institute, IRCCS, 00144 Rome, Italy.;Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, 35121 Padua, Italy.;Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.;Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine, University of Perugia, 06129 Perugia, Italy.;Deptartment of Hematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy.;Division of Hematology, Ferrarotto Hospital, 95123 Catania, Italy.;Hematology Unit, Careggi Hospital, 50139 Firenze, Italy.;Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.;Institute of Haematology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.;Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy.;Haematology and Stem Cell Transplantation Unit, Ospedale Oncologico A. Businco, AO Brotzu, 09134 Cagliari, Italy.;Hematology Unit, Hematology and Oncology Department, 87100 Cosenza, Italy.;Hematology, Department of Medical Sciences, St. Anna University Hospital, 44124 Ferrara, Italy.;Haematology Unit, A. Pugliese Hospital, Azienda Ospedaliera Pugliese Ciaccio, 88100 Catanzaro, Italy.;Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, 70124 Bari, Italy.;Hematology, Department of Biomedicine and Prevention, University Tor Vergata, 00133 Rome, Italy.;Division of Hematology, Azienda Ospedaliera Bianchi-Melacrino-Morelli, 89124 Reggio Calabria, Italy.;Hematology, Department of Translational and Precision Medicine, \"Sapienza\" University, 00161 Rome, Italy.;Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.;Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine, University of Perugia, 06129 Perugia, Italy.;Haematology Unit, A. Pugliese Hospital, Azienda Ospedaliera Pugliese Ciaccio, 88100 Catanzaro, Italy.;Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.;Deptartment of Hematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy.;Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy.;Hematology, Department of Medical Sciences, St. Anna University Hospital, 44124 Ferrara, Italy.;Hematology, Department of Translational and Precision Medicine, \"Sapienza\" University, 00161 Rome, Italy.;Hematology, Department of Translational and Precision Medicine, \"Sapienza\" University, 00161 Rome, Italy.;Hematology, Department of Translational and Precision Medicine, \"Sapienza\" University, 00161 Rome, Italy.;Hematology, Department of Translational and Precision Medicine, \"Sapienza\" University, 00161 Rome, Italy.;Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, 35121 Padua, Italy.",
"authors": "Mauro|Francesca Romana|FR|;Giannarelli|Diana|D|0000-0002-6085-1195;Visentin|Andrea|A|0000-0003-0271-7200;Reda|Gianluigi|G|;Sportoletti|Paolo|P|0000-0002-5630-9862;Frustaci|Anna Maria|AM|;Chiarenza|Annalisa|A|;Ciolli|Stefania|S|;Vitale|Candida|C|0000-0002-2592-8724;Laurenti|Luca|L|0000-0002-8327-1396;De Paoli|Lorenzo|L|;Murru|Roberta|R|;Gentile|Massimo|M|0000-0002-5256-0726;Rigolin|Gian Matteo|GM|0000-0002-8370-5190;Levato|Luciano|L|;Giordano|Annamaria|A|;Del Poeta|Giovanni|G|;Stelitano|Caterina|C|;Ielo|Claudia|C|;Noto|Alessandro|A|;Guarente|Valerio|V|0000-0002-2001-8000;Molica|Stefano|S|;Coscia|Marta|M|0000-0003-2123-7675;Tedeschi|Alessandra|A|;Gaidano|Gianluca|G|0000-0002-4681-0151;Cuneo|Antonio|A|;Foà|Robin|R|;Martelli|Maurizio|M|;Girmenia|Corrado|C|;Gentile|Giuseppe|G|0000-0002-1105-5256;Trentin|Livio|L|0000-0003-1222-6149",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/cancers13133240",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694\nMDPI\n\n34209515\n10.3390/cancers13133240\ncancers-13-03240\nArticle\nPrognostic Impact and Risk Factors of Infections in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib\nMauro Francesca Romana 1*\nhttps://orcid.org/0000-0002-6085-1195\nGiannarelli Diana 2\nhttps://orcid.org/0000-0003-0271-7200\nVisentin Andrea 3\nReda Gianluigi 4\nhttps://orcid.org/0000-0002-5630-9862\nSportoletti Paolo 5\nFrustaci Anna Maria 6\nChiarenza Annalisa 7\nCiolli Stefania 8\nhttps://orcid.org/0000-0002-2592-8724\nVitale Candida 9\nhttps://orcid.org/0000-0002-8327-1396\nLaurenti Luca 10\nDe Paoli Lorenzo 11\nMurru Roberta 12\nhttps://orcid.org/0000-0002-5256-0726\nGentile Massimo 13\nhttps://orcid.org/0000-0002-8370-5190\nRigolin Gian Matteo 14\nLevato Luciano 15\nGiordano Annamaria 16\nDel Poeta Giovanni 17\nStelitano Caterina 18\nIelo Claudia 1\nNoto Alessandro 4\nhttps://orcid.org/0000-0002-2001-8000\nGuarente Valerio 5\nMolica Stefano 15\nhttps://orcid.org/0000-0003-2123-7675\nCoscia Marta 9\nTedeschi Alessandra 6\nhttps://orcid.org/0000-0002-4681-0151\nGaidano Gianluca 11\nCuneo Antonio 14\nFoà Robin 1\nMartelli Maurizio 1\nGirmenia Corrado 1\nhttps://orcid.org/0000-0002-1105-5256\nGentile Giuseppe 1\nhttps://orcid.org/0000-0003-1222-6149\nTrentin Livio 3\nRobak Tadeusz Academic Editor\nEfremov Dimitar Academic Editor\n1 Hematology, Department of Translational and Precision Medicine, “Sapienza” University, 00161 Rome, Italy; claudia.ielo@uniroma1.it (C.I.); rfoa@bce.uniroma1.it (R.F.); martelli@bce.uniroma1.it (M.M.); girmenia@bce.uniroma1.it (C.G.); gentile@bce.uniroma1.it (G.G.)\n2 Biostatistic Unit, Regina Elena National Cancer Institute, IRCCS, 00144 Rome, Italy; diana.giannarelli@ifo.gov.it\n3 Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, 35121 Padua, Italy; andrea.visentin@aopd.veneto.it (A.V.); livio.trentin@unipd.it (L.T.)\n4 Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; gianluigi.reda@policlinico.mi.it (G.R.); alessandro.noto@policlinico.mi.it (A.N.)\n5 Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine, University of Perugia, 06129 Perugia, Italy; paolo.sportoletti@unipg.it (P.S.); valerio.guarente@studenti.unipg.it (V.G.)\n6 Deptartment of Hematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy; annamaria.frustaci@ospedaleniguarda.it (A.M.F.); alessandra.tedeschi@ospedaleniguarda.it (A.T.)\n7 Division of Hematology, Ferrarotto Hospital, 95123 Catania, Italy; annalisa.chiarenza@gmail.com\n8 Hematology Unit, Careggi Hospital, 50139 Firenze, Italy; ciollis@aou.careggi.toscana.it\n9 Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; candida.vitale@unito.it (C.V.); marta.coscia@unito.it (M.C.)\n10 Institute of Haematology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; Luca.Laurenti@unicatt.it\n11 Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy; lorenzo.depaoli@med.uniupo.it (L.D.P.); gianluca.gaidano@med.uniupo.it (G.G.)\n12 Haematology and Stem Cell Transplantation Unit, Ospedale Oncologico A. Businco, AO Brotzu, 09134 Cagliari, Italy; roberta.murru@tiscali.it\n13 Hematology Unit, Hematology and Oncology Department, 87100 Cosenza, Italy; massim.gentile@tiscali.it\n14 Hematology, Department of Medical Sciences, St. Anna University Hospital, 44124 Ferrara, Italy; rglgmt@unife.it (G.M.R.); cut@unife.it (A.C.)\n15 Haematology Unit, A. Pugliese Hospital, Azienda Ospedaliera Pugliese Ciaccio, 88100 Catanzaro, Italy; leluc13@alice.it (L.L.); smolica@libero.it (S.M.)\n16 Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, 70124 Bari, Italy; annamaria.giordano1977@gmail.com\n17 Hematology, Department of Biomedicine and Prevention, University Tor Vergata, 00133 Rome, Italy; g.delpoeta@tin.it\n18 Division of Hematology, Azienda Ospedaliera Bianchi-Melacrino-Morelli, 89124 Reggio Calabria, Italy; caterinastelitano27@gmail.com\n* Correspondence: mauro@bce.uniroma1.it; Tel.: +39-06-499741; Fax: +39-06-44241984\n29 6 2021\n7 2021\n13 13 324016 5 2021\n13 6 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nSimple Summary\n\nIbrutinib demonstrated superior efficacy compared to chemoimmunotherapy in patients with chronic lymphocytic leukemia. However, adverse events are a frequent reason for treatment discontinuation. This study was aimed to evaluate the incidence, risk factors, and prognostic impact of infections in a large series of patients with chronic lymphocytic leukemia who received an ibrutinib-based therapy. Approximately one-third of patients developed pneumonia or a severe infection with an overall rate of 15.3% infections per 100 person-year. Patients who experienced a severe infection in the year before starting ibrutinib, those with chronic obstructive pulmonary disease, and those heavily pretreated showed greater vulnerability to infection. A scoring system based on these factors identified patients with a two- to threefold increase in the rate of infections. Infections showed an unfavorable impact in terms of treatment discontinuation and inferior survival. Our results demonstrate that infections are a relevant reason for treatment failure in patients treated with ibrutinib.\n\nAbstract\n\nIbrutinib represents extraordinary progress in the treatment of chronic lymphocytic leukemia (CLL). However, treatment-related adverse events limit the benefit of this agent. This observational, multicenter study focused on the incidence, risk factors, and prognostic impact of infections in 494 patients with CLL treated with an ibrutinib-based treatment. Ibrutinib was given to 89 (18%) previously untreated patients (combined with rituximab, 24) and 405 (82%) relapsed/refractory patients. Pneumonia (PN), grade ≥3 non-opportunistic infections (NOI), and opportunistic infections (OI) were recorded in 32% of patients with an overall incidence rate per 100 person-year of 15.3% (PN, 10%; NOI, 3.3%; OI, 2%). Infections were the reason for the permanent discontinuation of ibrutinib in 9% of patients. Patients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free (p < 0.0001). A scoring system based on the three factors associated with a significant and independent impact on infections—PN or severe infection in the year before starting ibrutinib, chronic obstructive pulmonary disease, ≥2 prior treatments—identified patients with a two- to threefold increase in the rate of infections. In conclusion, the results of this study highlight the adverse impact of infectious events on the outcomes of CLL patients treated with ibrutinib.\n\nchronic lymphocytic leukemia\nibrutinib\ninfection\nprognosis\n==== Body\n1. Introduction\n\nChronic lymphocytic leukemia (CLL) is the most common leukemia in the adult population. According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (SEER) [1], the estimated number of new cases of CLL in the United States in 2021 is 21,250. The incidence rapidly increases with increasing age, and the median age at diagnosis is about 70. The CLL-IPI combines genetic, biochemical, and clinical parameters into a prognostic model, discriminating four prognostic subgroups with 5-year survival probabilities ranging from 93% to 23% [2].\n\nSeveral randomized trials have demonstrated the superiority of the B-cell receptor pathway inhibitor ibrutinib over chemotherapy in patients with chronic lymphocytic leukemia (CLL). [3,4,5,6]. The remarkable activity and the favorable tolerability profile have favored the widespread use of ibrutinib for the upfront treatment of patients with CLL. However, treatment discontinuation due to specific off-target toxicities of this agent, such as bleeding events and atrial fibrillation, is not negligible, although some treatment-related adverse events are now better managed [7,8,9,10,11,12,13,14,15].\n\nIt is well known that defects in humoral and cellular immunity due to CLL itself and chemoimmunotherapy result in an increased risk of infections that are a significant cause of morbidity and mortality in CLL patients [16]. Recently, an increased rate of infections has also been described in patients treated with ibrutinib, particularly in R/R patients. As a lower risk of infectious events was expected with targeted agents than chemoimmunotherapy, several reports have focused on infections in patients treated with ibrutinib [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34]. Although several inhibitory effects exerted by ibrutinib on immune effector cells have been described to explain the increased fragility to infections (particularly fungal infections [35,36,37,38,39,40,41,42]), little is known about the prognostic impact of infections in patients treated with ibrutinib. Moreover, the role of clinical and biological factors in favoring infections in patients treated with ibrutinib should be better defined.\n\nThis retrospective, multicenter study was carried out to define the incidence of pneumonia and severe infections in a large series of patients with CLL treated with ibrutinib. This study was also aimed at investigating risk factors and the impact of infections on treatment discontinuation and survival of patients receiving ibrutinib.\n\n2. Materials and Methods\n\nThis study analyzed retrospectively the characteristics of 494 patients with CLL treated with ibrutinib at 16 Italian institutions, 12 academic centers, and four hospitals.\n\nInclusion criteria were CLL diagnosis according to the iwCLL criteria [43] and front-line or advanced-line treatment with ibrutinib-based therapy having started between February 2013 and February 2019. Exclusion criteria included known transformation from CLL to an aggressive lymphoma (i.e., Richter transformation) and clinically significant comorbidities potentially interfering with the regular administration of treatment.\n\nData of patients were collected from medical records by the referring physician and included demographics, comorbidities, infectious events within 12 months before starting ibrutinib, prior treatment, serum IgG level, antimicrobial prophylaxis, concomitant use of steroids for more than four weeks, the IGHV andTP53 mutation status, and the FISH profile.\n\nThree types of infections were considered: pneumonia (PN), grade ≥ 3 non-opportunistic infections (NOIs), and opportunistic infections (OIs). When available, the etiologic agent was recorded. Infections of non-bacterial etiology with lung involvement were classified as NOI or OI, according to the identified agent. The severity of infections was graded according to the Common Terminology Criteria for Adverse Events, version 4.0.\n\nThe primary endpoint of this study was the incidence of PN, NOIs, and OIs in patients receiving ibrutinib. The secondary endpoints were the impact of infections on treatment discontinuation, survival, and factors associated with an increased rate of infectious events.\n\nThe database was locked on March 30, 2020, for analysis. The person-year duration of ibrutinib exposure was defined for each patient as the time from the start of ibrutinib to the last taken dose, last follow-up, or death. The person-year incidence rate of infections was defined as the number of infectious events observed during treatment divided by the total person-years of ibrutinib exposure. Survival was calculated from the start of treatment to the infectious event, disease progression, Richter syndrome, or the last follow-up or death. Survival curves were calculated according to the Kaplan and Meier method and differences in survival using the log-rank test in univariate analysis and the Cox regression model in multivariate analysis, after the assessment of the proportionality of hazards. Variables associated with a significant and independent increase in the infection rate were selected using a stepwise forward method, based on Wald statistics [44]. A scoring system to assess the risk of infections was developed by assigning to each significant variable in the final model a weighted point based on its hazard ratio, proportional to the regression β coefficient. The bootstrap method was used to validate the model. Prediction performance has been evaluated by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. Confidence intervals (CIs) have been calculated at the 95% level. All statistical tests were two-sided. A p-value of less than 0.05 has been considered significant. All analyses have been performed in SPSS v26.\n\nThis observational study was conducted in accordance with the Declaration of Helsinki and approved by the institutional review board and ethical committee.\n\n3. Results\n\n3.1. Clinical Characteristics of Patients\n\nThe baseline characteristics of the 494 CLL patients included in this study are detailed in Table 1. The median time on ibrutinib was 35 months (range, 4–85 months) and the median duration of the exposure to ibrutinib per patient was 2.6 years. The median age of patients was 69 years (range, 32–92 years). A CIRS >6 was observed in 24% of patients and creatinine clearance <70 mL/min in 37.4%. A chronic obstructive pulmonary disease was recorded in 16% of patients, and 24% had a grade ≥3 severe infection or a pneumonia event in the year before starting ibrutinib. Twenty-one percent of patients showed IgG levels ≤ 400 mg/dl and were on immunoglobulin support and 8% had a baseline granulocyte count <1 × 109/L. Rai stage III-IV was present in 53% of patients, unmutated IGHV status in 73.5%, and TP53 disruption (del17p, and or TP53 mutation) in 55.2%.\n\nEighty-nine (18%) of the patients received front-line therapy with ibrutinib, 420 mg once daily given continuously and 24 received also rituximab, 375 mg/sqm, weekly on day 1 of month 1 and then on day 1 of months 2–6. After a median number of one prior treatment (range, 1–9), 405 (82%) relapsed/refractory patients received ibrutinib single agent, 420 mg once daily given continuously. Concomitant steroids have been administered to 17% of patients.\n\nInfection prophylaxis did not follow common guidelines but rather the guidelines of each institution. Seventy-four percent of patients were on Pneumocystis jirovecii (PJ) prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX), and 53 (8%) patients with a known risk of hepatitis B reactivation (HBc+ and, or HBsAg+) received lamivudine.\n\n3.2. Incidence of Infections\n\nOne hundred and fifty-six (32%) patients experienced at least one infectious event and 35 (7%) had an additional infection. The total number of infections we recorded was 193 with an overall incidence rate of 15.3% infections per 100 person-year. Pneumonia was the most common infection with an incidence per 100-person per year of 10%, while it was 3.3% for grade ≥3 non-opportunistic infections, and 2.0% for opportunistic infections. The median time from the start of ibrutinib and the onset of infections was six months, seven for pneumonia events, nine for grade ≥3 non-opportunistic infections, and three for opportunistic infections (Table 2).\n\n3.3. Type of Infections\n\nThe incidence and type of infections are described in detail in Table S1.\n\nOne hundred (20%) patients experienced at least a pneumonia event, 32 (6.5%) a grade ≥3 non-opportunistic infection, and 24 (5%) a grade ≥3 opportunistic infection. Among the 32 patients who developed a grade ≥3 non-opportunistic infection, 7 viral infections were recorded. HBV reactivation was described in three patients in whom the serological profile for HBV had not been evaluated at baseline while none of the 41 patients on HBV prophylaxis due to a known risk for HBV reactivation developed an HBV reactivation. Symptomatic COVID-19 pneumonia was diagnosed in two young patients with hypogammaglobulinemia and was fatal in one. Fungal infections were the most frequent type of opportunistic infection (14/24; 58%), and, in turn, Aspergillus infection was the most frequent type of fungal infection (11/14; 79%). Aspergillus infection was associated with SNC involvement in three cases and was the direct cause of death for 6/11patients. Other opportunistic infections included Cryptococcus infection in two patients, CMV infection in three, disseminated HVZ infection in five. Pneumocystis jirovecii pneumonia (PJP) was diagnosed in a previously treated patient who received trimethoprim-sulfamethoxazole irregularly. This accounts for 0.8% (1/129) of PJP cases among patients who did not receive appropriate prophylaxis. Mycobacterium infection was described in two asymptomatic patients who underwent the biopsy of an isolated lung nodule. A fatal, progressive multifocal leukoencephalopathy was recorded in a 79-year-old man with advanced disease treated with ibrutinib and rituximab.\n\n3.4. Outcomes of Patients Who Developed Infections\n\nForty-three (9%) patients discontinued ibrutinib permanently due to an infection. Treatment discontinuation due to infection was an early event observed in 20 (4%) patients in the first year of treatment, in 10 (2%) in the second year, and 13 (3%) thereafter.\n\nThe other most frequent reasons leading to permanent ibrutinib discontinuation were disease progression in 16% of patients, Richter syndrome (RS) in 5%, atrial fibrillation in 5%, and second malignancies in 4% (Table S2).\n\nInfections were the direct cause of death for 29/494 (6%) patients (Table 2). Other causes of death were disease progression (6%) and Richter syndrome (5%) (Table S3).\n\nPatients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free (36-month OS: 82% vs. 63%; p < 0.0001; Figure 1A). The survival probability of patients who discontinued ibrutinib due to an infection or Richter syndrome was significantly inferior to that of those who discontinued treatment due to disease progression (median survival: 2 vs. 6 vs. 9 months; p = 0.006) (Figure 1B).\n\n3.5. Impact of Baseline Characteristics of Patients on Infections\n\nThe incidence rates per 100 person-year of infections according to patients’ clinical and biologic characteristics are summarized in Table 3. Baseline factors associated with a significantly higher rate of infections were chronic obstructive pulmonary disease (p <0.0001), pneumonia or grade ≥3 infection in the year before starting ibrutinib (p < 0.0001), IgG levels ≤400 mg/dl (p = 0.002), neutrophil count <1 × 109/L (p = 0.001), Rai stage III-IV (p < 0.0001), prior treatment (0 vs. ≥1, p = 0.004; 1 vs. ≥ 2; p < 0.0001), and the addition of steroids to ibrutinib (p = 0.002) (Table 3). The addition of rituximab to front-line therapy with ibrutinib, the IGHV mutational status, and the presence of TP53 aberrations did not reveal any impact on the infection rate.\n\nIn multivariate analysis, three factors maintained significance: a pneumonia event or a severe infection in the year before starting ibrutinib (HR, 2.69 (95% CI, 1.90–3.76)), the presence of a chronic obstructive pulmonary disease (HR, 1.52 (95% CI, 1.03–2.25)), two or more prior treatments (HR, 1.63 (95% CI, 1.17–2.28)) (Table 4).\n\nTo predict the risk of infections we designed a scoring system based on the HR values of factors with a significant and independent impact on infections. Two points were assigned for the presence of a pneumonia event or a severe infection in the year before starting ibrutinib, and one for chronic obstructive pulmonary disease, and two or more prior treatments. The sum of these scores showed an AUC of 0.65 (95% CI: 0.60–0.71). Three subgroups of patients were identified according to the score. The low-risk group (score, 0–1 points) identified 352 (71.2%) patients of whom 81 (23.0%) experienced an infectious event. The intermediate-risk group (score, 2 points) included 67 (13.6%) patients of whom 28 (41.8%) experienced an infection. Finally, the high-risk group (score, ≥3 points) identified 75 (15.2%) patients of whom 47 (62.7%) developed an infection. (Table 5).\n\n4. Discussion\n\nInfections are a well-known cause of morbidity and mortality in CLL patients treated with chemotherapy. This study was carried out to evaluate the prognostic impact of pneumonia and severe infections in patients who receive ibrutinib.\n\nOverall, with a median follow-up of 35 months, about a third of patients experienced at least one infectious event with an overall rate of 15.3% infections per 100 person-year. Given the large proportion of unselected and previously treated patients included in this study, the high infection-related morbidity was not unexpected as compared to that described in controlled trials [3,4,5,6,9,10,45,46]. Previous chemotherapy treatment revealed a significant impact in promoting greater fragility to infections in patients receiving ibrutinib.\n\nAs observed in other studies, infections were an early event that occurred after a median time of 7 months from starting ibrutinib [10,46]. This observation suggests careful monitoring of patients during the first months of treatment with ibrutinib. Pneumonia was recorded in 20% of patients with an incidence rate per 100 person-years of 10%. Variable rates of pneumonia events, ranging between 10% and 28%, have been reported and this could be related to the different characteristics and follow-up of patients included in other studies [3,4,5,6,9,32,34,46].\n\nTwo young, R/R patients with hypogammaglobulinemia developed symptomatic COVID-19 infection, discontinued treatment, and one did not survive the infection. The small number of patients with COVID-19 disease we recorded was due to the locking of the database for analysis before the pandemic became widespread in our country. At present, there is no agreement on the impact of ibrutinib on the outcomes of CLL patients who developed COVID-19 disease. Some studies report a lower number of COVID-19 infections than expected and more favorable outcomes in patients treated with ibrutinib [47,48,49,50,51]. However, the same favorable impact of ibrutinib has not been confirmed in a multicenter study [52].\n\nThe rate of opportunistic infections per 100 person-year recorded in this study, 2%, is in line with that reported by Rogers et al., 1.9% [23]. Consistent with other reports, the most common fungal infection was due to the Aspergillus fumigatus [24,25,26,27,28]. It has been argued that the inhibitory effects of ibrutinib on the activity of T-cells, natural killer cells, and macrophages may play a role in the development of these infections [36,37,38,39,40,41]. Given the relatively low incidence, routine prophylaxis of fungal infections has not been recommended. Similarly, the low incidence of PJP in this study, as well as in other studies [28,29], makes one also question the need for specific prophylaxis in patients receiving ibrutinib. However, the presence of an opportunistic infection should be kept in mind, in patients who develop clinical signs of a severe infection.\n\nTreatment discontinuations due to infections were more frequently observed than those due to other treatment-related adverse events, such as atrial fibrillation and bleeding events. Patients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free. Moreover, patients who developed pneumonia or a severe infection showed a significantly inferior survival than those who progressed. These findings underline the unfavorable impact of infections and the need to identify factors associated with a higher risk of infectious events. Three baseline factors revealed a significant and independent impact on the infection risk. The first one, an infectious event in the year preceding the start of ibrutinib, emphasizes the impact of a pre-existing immunodeficiency in predisposing further infections. The second, the presence of a concomitant chronic obstructive pulmonary disease, is a well-known risk factor for respiratory infections. Finally, the third factor, heavy pretreatment, is also a well-known clinical condition associated with an increased risk of infections. In this study, pretreated patients showed double the incidence of infections compared to treatment-naive patients. Earlier use of ibrutinib can result in a lower rate of infectious events.\n\nConcerns about infectious events led several scientific groups to recommend more attention to the infection risk of patients treated with BTK inhibitors and other targeted molecules [12,13,14,15,53]. Other BTK inhibitors, acalabrutinib, zanubrutinib, show a more favorable safety profile [54,55]. Interestingly, in contrast to ibrutinib, tirabrutinib does not show inhibition of T lymphocyte function and this could result in less susceptibility to infections [56].\n\nThe scoring system we designed requires an external validation cohort to confirm its predictive value. However, it identified about 30% of patients with a two- to threefold increase in the rate of infectious events. These more vulnerable patients could benefit from measures to prevent and mitigate the harmful impact of infections.\n\n5. Conclusions\n\nThe results of this study show that infections are still a critical issue in the treatment management of CLL patients who receive ibrutinib and highlight the adverse impact of infectious events on treatment discontinuation and survival.\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/article/10.3390/cancers13133240/s1, Table S1. Infections recorded in patients treated with ibrutinib ± rituximab, Table S2. Events leading to permanent treatment discontinuation in 2% of patients treated with ibrutinib ± rituximab, Table S3. Cause of death in patients treated with ibrutinib ± rituximab.\n\nClick here for additional data file.\n\nAuthor Contributions\n\nF.R.M. and L.T.: study design, study co-ordination, data collection, results analysis and interpretation, and manuscript writing; D.G.: data extraction, statistical analyses, results interpretation, manuscript revision; A.V., G.R., P.S., A.M.F., A.C. (Annalisa Chiarenza), S.C., C.V., L.L. (Luca Laurenti), L.D.P., R.M., M.G., G.M.R., L.L. (Luciano Levato), A.G., G.D.P., C.S., C.I., A.N., V.G.: data collection, results, and manuscript revision; S.M., M.C., A.T., G.G. (Giuseppe Gentile), A.C. (Antonio Cuneo), R.F., M.M., C.G., G.G. (Gianluca Gaidano): data and manuscript revision. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nPlease add: This research was supported by the 2016 Fellowship Program of Gilead and by the 2018 Ateneo Project of the ‘Sapienza’ University of Rome, Italy.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of the Università Sapienza (Rif. 5278- 07/02/19).” Informed consent was obtained from patients involved in the study.\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nData may be made available request for consideration to the study corresponding author and establishment of the data transfer agreement.\n\nConflicts of Interest\n\nF.R.M. received research funding from Gilead, advisory board participation fees from AbbVie, Gilead, Janssen, AstraZeneca, Takeda, Roche; speaker bureau fees from Gilead, Janssen, and Abbvie. A.V. received advisory board participation fees from Gilead, Janssen, Italfarmaco, speaker bureau fees from Janssen and Abbvie. G.R. received advisory board participation fees from Gilead, Janssen, Abbvie, and AstraZeneca; speaker bureau fees from Gilead, Janssen, and Abbvie. P.S. received research funding from Gilead, advisory board participation fees from AbbVie, Janssen. S.C. received an honorarium for an advisory board or lecturing for AbbVie, Janssen, AstraZeneca; speaker bureau fees from Janssen and Abbvie. C.V. received consulting fees and advisory board participation fees from Janssen. L.L. (Luca Laurenti) aurenti received research funding from Abbvie and Roche; advisory board participation fees from AbbVie, Janssen, AstraZeneca; speaker bureau fees from Gilead, Janssen, Abbvie, AstraZeneca, Roche. L.D.P received advisory board participation fees from Amgen, Gilead, Janssen, Takeda, Celgene-Bristol, and consulting fees from Amgen. R.M. received grants from AbbVie, Gilead, Janssen. M.G. received advisory board participation fees from Amgen, Abvvie, Astra Zeneca, Celgene, Janssen, Takeda. G.M.R. received research funding from Gilead, speaker bureau fees from Gilead and Abbvie. S.M. received advisory board participation fees from Roche, Gilead, Janssen, Abbvie, AstraZeneca, and consulting fees from Janssen. M.C. received research funding from Janssen and Karyopharm, advisory board participation fees from AbbVie, Gilead, Janssen, Shire-Takeda. A.T. received advisory board participation fees from AbbVie, Gilead, Janssen, AstraZeneca, Beigene. G.G. (Gianluca Gaidano) received advisory board participation fees from AbbVie, Janssen, AstraZeneca: speaker bureau fees from Gilead, Janssen, and Abbvie. C.G. received advisory board participation fees from MSD, Celgene, Novartis; speaker bureau fees from Gilead, Pfizer, MSD. G.G. (Giuseppe Gentile) received advisory board participation fees from MSD, Gilead, Pfizer. L.T. received research funding from Gilead and Janssen, advisory board participation fees from AbbVie, Shire, Roche. D.G., A.M. L.L. (Luciano Levato), A.G., G.D.P., C.S., C.I., A.N., V.G., A.C. (Annalisa Chiarenza), A.C. (Antonio Cuneo). RF: no disclosures.\n\nFigure 1 (A) Survival in patients with and without an infectious event. (B). Survival probability from the time of disease progression (DP), infection (INF), Richter syndrome (RS).\n\ncancers-13-03240-t001_Table 1 Table 1 Baseline characteristics of CLL patients treated with ibrutinib ± rituximab.\n\n\tn (%)\t\nNumber of patients\t494 (79.7)\t\nMedian duration of exposure to ibrutinib, months (range)\t35 (4–85)\t\nGender male\nGender female\t338 (68.4)\n156(31.6)\t\nMedian age, years (range)\t69 (32–92)\t\nMedian time from CLL diagnosis, years (range)\t6 (3–34)\t\nMedian CIRS, (range)\t4 (0–16)\t\nPatients with CIRS > 6\t185 (37.4)\t\nPatients with CrCl < 70 mL/min\t167 (33.8)\t\nPatients with COPD\t78 (15.8)\t\nSmokers\t123 (24.9)\t\nPatients with diabetes\t78 (15.8)\t\nPneumonia or grade ≥3 infections within 1 year before starting ibrutinib\t118 (23.9)\t\nMedian IgG levels, mg/dL (range)\t625 (82–5220)\t\nPatients with IgG levels ≤ 400 mg/dL on Ig support\t99/472 (21.0)\t\nMedian Hb × 109/L (range)\t12.0 (3.8–17.4)\t\nMedian neutrophil count × 109/L (range)\t3.2 (0.11–9.9)\t\nPatients with neutrophil count < 1 × 109/L\t39 (8)\t\nMedian lymphocyte count × 109/L (range)\t36.7 (0.5–99.1)\t\nRai stage III-IV\t260 (52.6)\t\nDel17p and/or TP53 mutation\t228/413 (55.2)\t\nUnmutated IGHV\t319/434 (73.5)\t\nMutated IGHV\t115/434 (26.5)\t\nCD38 ≥ 30%\t130/335 (38.8)\t\nUntreated patients (1)\t89 (18.0)\t\nPreviously treated patients\t405 (82)\t\nMedian number of prior treatments (range)\t1 (0–9)\t\nPrior treatments = 1\t169 (34.2)\t\nPrior treatments = 2\t101 (20.4)\t\nPrior treatments > 2\t135 (27.4)\t\nPatients on TMP-SMX prophylaxis\t365 (73.9)\t\nPatients on HBV prophylaxis\t41 (8.3)\t\nPatients on fungal prophylaxis\t1 (0.2)\t\nPatients on concomitant steroids\t83 (16.8)\t\nAbbreviations: CIRS, Cumulative Illness Rating Scale; CrCL, creatinine clearance; COPD, chronic obstructive pulmonary disease; TMP-SMX, trimethoprim-sulfamethoxazole; IGHV, immunoglobulin heavy chain variable region genes; HBV, hepatitis B virus. (1) Ibrutinib single agent, 65 patients; ibrutinib+rituximab, 24 patients.\n\ncancers-13-03240-t002_Table 2 Table 2 Incidence and outcomes of pneumonia and grade ≥3 infectious events in patients treated with ibrutinib ± rituximab.\n\n\tn = 494 (%)\t\nIbrutinib exposure, person-years\t1264\t\nMedian exposure to ibrutinib per patient, years\t2.6\t\nPatients with at least pneumonia or grade ≥3 infection events\t156 (32)\t\nTotal pneumonia or grade ≥3 infection events\t193\t\nIR per 100 person-years\t15.3\t\nMedian time to onset of the first infection, months (range) [IQR]\t6 (0–54) (2–13)\t\nNumber of patients with pneumonia or grade ≥3 infections who discontinued ibrutinib\t43 (9)\t\nNumber of patients with fatal pneumonia or grade ≥3 infections\t29 (6)\t\nPatients with pneumonia\t\t\nNumber of patients with at least one pneumonia event\t100 (20)\t\nTotal pneumonia events\t126\t\nIR of pneumonia events per 100 person-years\t10.0\t\nMedian time to pneumonia, months (range) [IQR]\t7 (0–51) [3,4,5,6,7,8,9,10,11,12]\t\nNumber of patients with pneumonia who discontinued ibrutinib\t19 (4)\t\nNumber of patients with a fatal pneumonia\t17(3.5)\t\nPatients with grade ≥3 non-opportunistic infections\t\t\nNumber of patients with at least a grade ≥3 non-opportunistic infection\t32 (6.5)\t\nTotal grade ≥3 non-opportunistic infections\t42\t\nIR of grade ≥3 non-opportunistic infections per 100 person-years\t3.3\t\nMedian time to grade ≥3 non-opportunistic infections, months, (range) [IQR]\t9 (1–48) [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22]\t\nNumber of patients with a grade ≥3 non-opportunistic infections who discontinued ibrutinib\t10 (2)\t\nNumber of patients with a fatal grade ≥3 non-opportunistic infections\t3 (0.6)\t\nPatients with grade ≥3 opportunistic infections\t\t\nNumber of patients with at least a grade ≥3 opportunistic infections\t24 (5)\t\nTotal grade ≥3 opportunistic infections\t25\t\nIR of grade ≥3 opportunistic infections per 100 person-years\t2.0\t\nMedian time to grade ≥3 opportunistic infections, months, (range) [IQR]\t3 (0–54) [1,2,3,4,5,6,7,8,9,10]\t\nNumber of patients with a grade ≥3 opportunistic infection who discontinued ibrutinib\t14 (3)\t\nNumber of patients with a fatal grade ≥3 opportunistic infection\t9 (2)\t\nAbbreviations: IR, incidence rate; IQR, interquartile range.\n\ncancers-13-03240-t003_Table 3 Table 3 Incidence rate per 100 person-years of pneumonia or grade ≥3 infections according to the clinical and biologic characteristics of patients treated with ibrutinib ± rituximab.\n\n\tNumber of Patients n = 494\tNumber of Infections\nn = 193\n(IR per 100 Person-Years = 15.3)\tp Value\t\nGender M\nGender F\t338\n156\t127 (14.6)\n66 (16.7)\t0.38\t\nAge ≥ 70 years\t228\t83 (14.7)\t0.65\t\nAge < 70 years\t266\t110 (15.7)\t\nCIRS ≥ 6\t185\t86 (17.8)\t0.07\t\nCIRS < 6\t309\t107 (13.7)\t\nCrCl ≥ 70 mL/min\t327\t124 (14.4)\t0.23\t\nCrCl < 70 mL/min\t167\t69 (17.2)\t\nSmokers\t123\t42 (14.0)\t0.53\t\nNon-smokers\t371\t151 (15.7)\t\nPatients with diabetes\t78\t32 (17.2)\t0.46\t\nPatients without diabetes\t416\t161 (14.9)\t\nPatients with COPD\t78\t56 (27.7)\t<0.0001\t\nPatients without COPD\t416\t137 (12.9)\t\nPneumonia or a grade ≥3 infection 1 year before starting ibrutinib presentabsent\t118\n376\t84 (32.3)\n109 (10.9)\t<0.0001\t\nPatients on TMP-SMX prophylaxis\t365\t134 (14.4)\t0.21\t\nPatients not on TMP-SMX prophylaxis\t129\t59 (17.6)\t\nPatients with IgG levels ≤ 400 mg/dL\t99\t56 (22.1)\t0.002\t\nPatients with IgG levels > 400 mg/dL\t373\t129 (13.2)\t\nNeutrophil count >1000 ×109/L\t416\t156 (14.0)\t0.001\t\nNeutrophil count ≤1000 × 109/L\t49\t28 (28.6)\t\nRai stage 0–II\t234\t71 (10.7)\t<0.0001\t\nRai stage III–IV\t260\t122 (20.2)\t\nDel17p and/or Tp53 mutation present\t228\t94 (16.5)\t0.29\t\nDel17p and Tp53 mutation absent\t250\t92 (14.1)\t\nIGHV unmutated\t319\t126 (15.3)\t0.98\t\nIGHV mutated\t115\t46 (15.2)\t\nPrior treatments 0\t89\t20 (8.8)\t0.003\t\nPrior treatments ≥ 1\t405\t173 (16.7)\t\nPrior treatments ≤ 1\t258\t69 (10.6)\t<0.0001\t\nPrior treatments ≥ 2\t236\t124 (20.2)\t\nFront-line ibrutinib\t65\t16 (10.5)\t0.23\t\nFront-line ibrutinib+rituximab\t24\t4 (5.3)\t\nPatients with concomitant steroids\t83\t45 (23.2)\t0.003\t\nPatients without concomitant steroids\t411\t148 (13.7)\t\nAbbreviations: IR, incidence rate; CIRS, Cumulative Illness Rating Scale; CrCL, creatinine clearance; COPD, chronic obstructive pulmonary disease; TMP-SMX, trimethoprim-sulfamethoxazole; IGHV, immunoglobulin heavy chain variable region genes; HBV, Hepatitis B.\n\ncancers-13-03240-t004_Table 4 Table 4 Impact of baseline factors on the time to pneumonia or grade ≥3 infectious events in patients treated with ibrutinib ± rituximab: univariate and multivariate analysis.\n\n\tUnivariate Analysis\nHR (95%CI)\tMultivariate Analysis\nHR (95%CI)\tBootstrap Validated Coefficients\nHR (95% CI)\t\nPneumonia or grade ≥3 infections 1 year before starting ibrutinib\n(yes vs. no)\t3.09 (2.24–4.27)\t2.72 (1.94–3.81)\t2.72 (1.93–3.91)\t\nChronic obstructive pulmonary disease\n(yes vs. no)\t2.23 (1.55–3.21)\t1.49 (1.01–2.19)\t1.49 (1.01–2.22)\t\nNumber of prior treatments\n(≤1 vs. ≥2)\t1.88 (1.36–2.59)\t1.67 (1.20–2.33)\t1.67 (1.21–2.37)\t\nNumber of prior treatments\n(0 vs. ≥1)\t1.99 (1.20–3.29)\tNS\t\t\nNeutrophil count\n(≤1000 vs. >1000 × 109/L)\t1.83 (1.16–2.88)\tNS\t\t\nIgG levels\n(<400 vs. >400 mg/dL)\t1.71 (1.20–2.43)\tNS\t\t\nSteroids\n(yes vs. no)\t1.60 (1.09–2.34)\tNS\t\t\nRAI stage\n(III–IV vs. 0–I–II)\t1.48 (1.08–2.05)\tNS\t\t\n\ncancers-13-03240-t005_Table 5 Table 5 Scoring system to assess the risk of infections in CLL patients treated with ibrutinib ± rituximab.\n\nVariables\tRisk Points\t\t\t\nPneumonia or gr ≥3 infections 1 year before starting ibrutinib\t2\t\t\t\nPrior treatments ≥ 2\t1\t\t\t\nCOPD (1)\t1\t\t\t\nRisk Group\tRisk Score\t% Patients (n)\t% Patients with\nInfections (n)\t\nLow\t0–1\t71.2\n(352)\t23.0\n(81)\t\nIntermediate\t2\t13.6\n(67)\t41.8\n(28)\t\nHigh\t≥3\t15.2\n(75)\t62.7\n(47)\t\n(1) COPD, chronic obstructive pulmonary disease.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 2021 Report of the Surveillance, Epidemiology, and End Results (SEER) Program National Cancer Institute, Division of Cancer Control and Population Sciences (DCCPS) Available online: https://seer.cancer.gov/ (accessed on 16 May 2021)\n2. International CLL-IPI Working Group An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): A meta-analysis of individual patient data Lancet Oncol. 2016 17 779 790 10.1016/S1470-2045(16)30029-8 27185642\n3. Burger J.A. Barr P.M. Robak T. Owen C. Ghia P. Tedeschi A. Bairey O. Hillmen P. Coutre S.E. Devereux S. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study Leukemia 2020 34 787 798 10.1038/s41375-019-0602-x 31628428\n4. Woyach J.A. Ruppert A.S. Heerema N.A. Zhao W. Booth A.M. Ding W. Bartlett N.L. Brander D.M. Barr P.M. Rogers K.A. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL N. Engl. J. Med. 2018 379 2517 2528 10.1056/NEJMoa1812836 30501481\n5. Moreno C. Greil R. Demirkan F. Tedeschi A. Anz B. Larratt L. Simkovic M. Samoilova O. Novak J. Ben-Yehuda D. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukemia (iLLUMINATE): A multicentre, randomized, open-label, phase 3 trial Lancet Oncol. 2019 20 43 56 10.1016/S1470-2045(18)30788-5 30522969\n6. Shanafelt T.D. Wang X.V. Kay N.E. Hanson C.A. O’Brien S. Barrientos J. Jelinek D.F. Braggio E. Leis J.F. Zhang C.C. Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia N. Engl. J. Med. 2019 381 432 443 10.1056/NEJMoa1817073 31365801\n7. Jain P. Keating M. Wierda W. Estrov Z. Ferrajoli A. Jain N. George B. James D. Kantarjian H. Burger J. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib Blood 2015 125 2062 2067 10.1182/blood-2014-09-603670 25573991\n8. Maddocks K.J. Ruppert A.S. Lozanski G. Heerema N.A. Zhao W. Abruzzo L.V. Lozanski A. Davis M. Gordon A.L. Smith L.L. Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients with Chronic Lymphocytic Leukemia JAMA Oncol. 2015 1 80 87 10.1001/jamaoncol.2014.218 26182309\n9. Mato A.R. Nabhan C. Thompson M.C. Lamanna N. Brander D.M. Hill B. Howlett C. Skarbnik A. Cheson B.D. Zent C. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: A real-world analysis Haematologica 2018 103 874 879 10.3324/haematol.2017.182907 29419429\n10. O’Brien S.M. Byrd J.C. Hillmen P. Coutre S. Brown J.R. Barr P.M. Barrientos J.C. Devereux S. Robak T. Reddy N.M. Outcomes with ibrutinib by line of therapy and post-ibrutinib discontinuation in patients with chronic lymphocytic leukemia: Phase 3 analysis Am. J. Hematol. 2019 94 554 562 10.1002/ajh.25436 30767298\n11. Parikh S.A. Achenbach S.J. Call T.G. Rabe K.G. Ding W. Leis J.F. Kenderian S.S. Chanan-Khan A.A. Koehler A.B. Schwager S.M. The impact of dose modification and temporary interruption of ibrutinib on outcomes of chronic lymphocytic leukemia patients in routine clinical practice Cancer Med. 2020 9 3390 3399 10.1002/cam4.2998 32187452\n12. Brown J.R. How I treat CLL patients with ibrutinib Blood 2018 25 379 386 10.1182/blood-2017-08-764712 29255067\n13. Gribben J.G. Bosch F. Cymbalista F. Geisler C.H. Ghia P. Hillmen P. Moreno C. Stilgenbauer S. Optimising outcomes for patients with chronic lymphocytic leukaemia on ibrutinib therapy: European recommendations for clinical practice Br. J. Haematol. 2018 180 666 679 10.1111/bjh.15080 29318593\n14. Stephens D.M. Byrd J.C. How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia Blood 2019 133 1298 1307 10.1182/blood-2018-11-846808 30642919\n15. Lasica M. Tam C.S. Management of Ibrutinib Toxicities: A Practical Guide Curr. Hematol. Malign Rep. 2020 15 177 186 10.1007/s11899-020-00576-3\n16. Morrison V.A. Infections in Patients with Leukemia and Lymphoma Cancer Treat. Res. 2014 161 319 349 10.1007/978-3-319-04220-6_11 24706230\n17. Peri A.M. Rossio R. Tafuri F. Benzecry V. Grancini A. Reda G. Bandera A. Peyvandi F. Atypical primary cutaneous cryptococcosis during ibrutinib therapy for chronic lymphocytic leukemia Ann. Hematol. 2019 98 2847 2849 10.1007/s00277-019-03837-1 31741032\n18. Koehler A.B. Vijayvargiya P. Ding W. Probable Invasive Pulmonary Cryptococcosis and Possible Cryptococcal Empyema in CLL Treated with Frontline Ibrutinib Mayo Clin. Proc. 2019 94 915 917 10.1016/j.mayocp.2019.02.002 31054610\n19. Giridhar K.V. Shanafelt T. Tosh P.K. Parikh S.A. Call T.G. Disseminated herpes zoster in chronic lymphocytic leukemia (CLL) patients treated with B-cell receptor pathway inhibitors Leuk. Lymphoma 2016 58 1973 1976 10.1080/10428194.2016.1267352 27960571\n20. Lutz M. Schulze A.B. Rebber E. Wiebe S. Zoubi T. Grauer O.M. Keßler T. Kerkhoff A. Lenz G. Berdel W.E. Progressive Multifocal Leukoencephalopathy after Ibrutinib Therapy for Chronic Lymphocytic Leukemia Cancer Res. Treat. 2017 49 548 552 10.4143/crt.2016.110 27456945\n21. Raisch D.W. Rafifi J.A. Chen C. Bennett C.L. Detection of cases of progressive multifocal leukoencephalopathy associated with new biologicals and targeted cancer therapies from the FDA’s adverse event reporting system Expert. Opin. Drug Saf. 2016 15 1003e11 10.1080/14740338.2016.1198775 27268272\n22. Wang S.-Y. Ebert T. Jaekel N. Schubert S. Niederwieser D. Al-Ali H.K. Miliary tuberculosis after initiation of ibrutinib in chronic lymphocytic leukemia Ann. Hematol. 2015 94 1419 1420 10.1007/s00277-015-2385-0 25903044\n23. Rogers K.A. Mousa L. Zhao Q. Bhat S.A. Byrd J.C. El Boghdadly Z. Guerrero T. Levine L.B. Lucas F. Shindiapina P. Incidence of opportunistic infections during ibrutinib treatment for B-cell malignancies Leukemia 2019 33 2527 2530 10.1038/s41375-019-0481-1 31086260\n24. Ghez D. Calleja A. Protin C. Baron M. LeDoux M.-P. Damaj G. Dupont M. Dreyfus B. Ferrant E. Herbaux C. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib Blood 2018 131 1955 1959 10.1182/blood-2017-11-818286 29437588\n25. Ruchlemer R. Ben-Ami R. Bar-Meir M. Brown J.R. Malphettes M. Mous R. Tonino S.H. Soussain C. Barzic N. Messina J.A. Ibrutinib-associated invasive fungal diseases in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: An observational study Mycoses 2019 62 1140 1147 10.1111/myc.13001 31520441\n26. Varughese T. Taur Y. Cohen N. Palomba M.L. Seo S.K. Hohl T.M. Redelman-Sidi G. Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Cancer Clin. Infect. Dis. 2018 67 687 692 10.1093/cid/ciy175 29509845\n27. Zarakas M.A. Desai J.V. Chamilos G. Lionakis M.S. Fungal Infections with Ibrutinib and Other Small-Molecule Kinase Inhibitors Curr. Fungal Infect. Rep. 2019 13 86 98 10.1007/s12281-019-00343-9 31555394\n28. Ahn I.E. Jerussi T. Farooqui M. Tian X. Wiestner A. Gea-Banacloche J. Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib Blood 2016 128 1940 1943 10.1182/blood-2016-06-722991 27503501\n29. Ryan C.E. Cheng M.P. Issa N.C. Brown J.R. Davids M.S. Pneumocystis jirovecii pneumonia and institutional prophylaxis practices in CLL patients treated with BTK inhibitors Blood Adv. 2020 4 1458 1463 10.1182/bloodadvances.2020001678 32282880\n30. Herishanu Y. Katchman H. Polliack A. Severe hepatitis B virus reactivation related to ibrutinib monotherapy Ann. Hematol. 2017 96 689 690 10.1007/s00277-016-2917-2 28058492\n31. Hammond S. Chen K. Pandit A. Davids M.S. Issa N.C. Marty F.M. Risk of hepatitis B virus reactivation in patients treated with ibrutinib Blood 2018 131 1987 1989 10.1182/blood-2018-01-826495 29490923\n32. Williams A.M. Baran A.M. Meacham P.J. Feldman M.M. Valencia H.E. Newsom-Stewart C. Gupta N. Janelsins M.C. Barr P.M. Zent C.S. Analysis of the risk of infection in patients with chronic lymphocytic leukemia in the era of novel therapies Leuk. Lymphoma 2018 59 625 632 10.1080/10428194.2017.1347931 28696801\n33. Tillman B.F. Pauff J.M. Satyanarayana G. Talbott M. Warner J.L. Systematic review of infectious events with the Bruton tyrosine kinase inhibitor ibrutinib in the treatment of hematologic malignancies Eur. J. Haematol. 2018 100 325 334 10.1111/ejh.13020 29285806\n34. Coutre S.E. Byrd J.C. Hillmen P. Barrientos J.C. Barr P.M. Devereux S. Robak T. Kipps T.J. Schuh A. Moreno C. Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies Blood Adv. 2019 3 1799 1807 10.1182/bloodadvances.2018028761 31196847\n35. Ball S. Das A. Vutthikraivit W. Edwards P.J. Hardwicke F. Short N.J. Borthakur G. Maiti A. Risk of Infection Associated with Ibrutinib in Patients With B-Cell Malignancies: A Systematic Review and Meta-analysis of Randomized Controlled Trials Clin. Lymphoma Myeloma Leuk. 2020 20 87 97 10.1016/j.clml.2019.10.004 31787589\n36. Kohrt H.E. Sagiv-Barfi I. Rafiq S. Herman S.E.M. Butchar J.P. Cheney C. Zhang X. Buggy J.J. Muthusamy N. Levy R. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity Blood 2014 123 1957 1960 10.1182/blood-2014-01-547869 24652965\n37. Borge M. Almejún M.B. Podaza E. Colado A. Grecco H.F. Cabrejo M. Bezares R.F. Giordano M. Gamberale R. Ibrutinib impairs the phagocytosis of rituximab-coated leukemic cells from chronic lymphocytic leukemia patients by human macrophages Haematologica 2015 100 e140 e142 10.3324/haematol.2014.119669 25616578\n38. Herbst S. Shah A. Moya M.M. Marzola V. Jensen B. Reed A. Birrell M.A. Saijo S. Mostowy S. Shaunak S. Phagocytosis-dependent activation of a TLR 9- BTK -calcineurin- NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus EMBO Mol. Med. 2015 7 240 258 10.15252/emmm.201404556 25637383\n39. Bercusson A. Colley T. Shah A. Warris A. Armstrong-James D. Ibrutinib blocks Btk-dependent NF-ĸB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis Blood 2018 132 1985 1988 10.1182/blood-2017-12-823393 30021784\n40. Woyach J.A. Ibrutinib and Aspergillus: A Btk-targeted risk Blood 2018 132 1869 1870 10.1182/blood-2018-08-865659 30385492\n41. Maffei R. Maccaferri M. Arletti L. Fiorcari S. Benatti S. Potenza L. Luppi M. Marasca R. Immunomodulatory effect of ibrutinib: Reducing the barrier against fungal infections Blood Rev. 2020 40 100635 10.1016/j.blre.2019.100635 31699465\n42. Blez D. Blaize M. Soussain C. Boissonnas A. Meghraoui-Kheddar A. Menezes N. Portalier A. Combadière C. Leblond V. Ghez D. Ibrutinib induces multiple functional defects in the neutrophil response against Aspergillus fumigatus Haematologica 2019 105 478 489 10.3324/haematol.2019.219220\n43. Hallek M. Cheson B.D. Catovsky D. Caligaris-Cappio F. Dighiero G. Döhner H. Hillmen P. Keating M. Montserrat E. Chiorazzi N. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL Blood 2018 131 2745 2760 10.1182/blood-2017-09-806398 29540348\n44. Ward M.D. Ahlquist J.S. Maximum Likelihood for Social Science: Strategies for Analysis Cambridge University Press Cambridge, UK 2018 36 978-1-316-63682-4\n45. Byrd J.C. Hillmen P. O’Brien S. Barrientos J.C. Reddy N.M. Coutre S. Tam C.S. Mulligan S.P. Jaeger U. Barr P.M. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab Blood 2019 133 2031 2042 10.1182/blood-2018-08-870238 30842083\n46. Byrd J.C. Furman R.R. Coutre S.E. Flinn I.W. Burger J.A. Blum K.A. Sharman J.P. Wierda W. Zhao W. Heerema N.A. Ibrutinib Treatment for First-Line and Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Analysis of the Pivotal Phase Ib/II PCYC-1102 Study Clin. Cancer Res. 2020 26 3918 3927 10.1158/1078-0432.CCR-19-2856 32209572\n47. Treon S.P. Castillo J.J. Skarbnik A.P. Soumerai J.D. Ghobrial I.M. Guerrera M.L. Meid K.E. Yang G. The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19–infected patients Blood 2020 135 1912 1915 10.1182/blood.2020006288 32302379\n48. Cuneo A. Scarfò L. Reda G. Varettoni M. Quaglia F.M. Marchetti M. de Paoli L. Re F. Pietrasanta D. Rigolin G.M. Chronic lymphocytic leukemia management in Italy during the COVID-19 pandemic: A Campus CLL report Blood 2020 136 763 766 10.1182/blood.2020006854 32559271\n49. Reda G. Noto A. Cassin R. Zamprogna G. Borella C. Scarfò L. Farina L. Molteni A. Ghia P. Tedeschi A. Reply to “CLL and COVID-19 at the Hospital Clinic of Barcelona: An interim report” Analysis of six hematological centers in Lombardy Leukemia 2020 34 2531 2532 10.1038/s41375-020-0966-y 32753689\n50. Baumann T. Delgado J. Montserrat E. CLL and COVID-19 at the Hospital Clinic of Barcelona: An interim report Leukemia 2020 34 1954 1956 10.1038/s41375-020-0870-5 32433507\n51. Scarfò L. Chatzikonstantinou T. Rigolin G.M. Quaresmini G. Motta M. Vitale C. Garcia-Marco J.A. Hernández-Rivas J. Ángel; Mirás, F.; Baile, M.; et al. COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: A joint study by ERIC, the European Research Initiative on CLL, and CLL Campus Leukemia 2020 34 2354 2363 10.1038/s41375-020-0959-x 32647324\n52. Mato A.R. Roeker L.E. Lamanna N. Allan J.N. Leslie L. Pagel J.M. Patel K. Osterborg A. Wojenski D. Kamdar M. Outcomes of COVID-19 in patients with CLL: A multicenter international experience Blood 2020 136 1134 1143 10.1182/blood.2020006965 32688395\n53. Maschmeyer G. de Greef J. Mellinghoff S.C. Nosari A. Thiebaut-Bertrand A. Bergeron A. Franquet T. Blijlevens N.M.A. Maertens J.A. Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology. A position paper by the European Conference on Infections in Leukemia (ECIL) Leukemia 2019 33 844 862 10.1038/s41375-019-0388-x 30700842\n54. Byrd J.C. Hillmen P. Ghia P. Kater A.P. Chanan-Khan A.A.A. Furman R.R. O’Brien S.M. Yenerel M.N. Illés Á. Kay N.E. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia J. Clin. Oncol. 2021 39 7500 10.1200/JCO.2021.39.15_suppl.7500\n55. Tam C.S. Trotman J. Opat S. Burger J.A. Cull G. Gottlieb D. Harrup R. Johnston P.B. Marlton P. Munoz J. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL Blood 2019 134 851 859 10.1182/blood.2019001160 31340982\n56. Hofland T. de Weerdt I. Ter Burg H. de Boer R. Tannheimer S. Tonino S.H. Kater A.P. Eldering E. Dissection of the Effects of JAK and BTK Inhibitors on the Functionality of Healthy and Malignant Lymphocytes J. Immunol. 2019 203 2100 2109 10.4049/jimmunol.1900321 31511358\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2072-6694",
"issue": "13(13)",
"journal": "Cancers",
"keywords": "chronic lymphocytic leukemia; ibrutinib; infection; prognosis",
"medline_ta": "Cancers (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101526829",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34209515",
"pubdate": "2021-06-29",
"publication_types": "D016428:Journal Article",
"references": "32688395;31511358;32647324;29509845;27185642;29437588;29318593;25637383;29490923;30021784;30501481;31741032;25616578;31555394;28696801;31340982;32187452;29285806;31365801;32302379;31628428;29540348;31196847;30522969;31171644;32753689;30642919;29419429;28058492;30767298;31086260;30842083;31054610;32433507;25903044;32415406;30385492;31699465;25573991;31787589;26182309;27960571;24652965;27456945;32559271;27503501;27268272;32209572;31520441;24706230;30700842;29255067;32282880",
"title": "Prognostic Impact and Risk Factors of Infections in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib.",
"title_normalized": "prognostic impact and risk factors of infections in patients with chronic lymphocytic leukemia treated with ibrutinib"
} | [
{
"companynumb": "IT-ABBVIE-21K-083-3995786-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
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{
"abstract": "Pure osteosarcoma arising from the uterus is extremely rare. Only 15 cases of this type of cancer have been reported to date. Most patients showed local or lung metastasis early after surgery and died within a year of treatment initiation, regardless of multimodality therapy, indicating that this tumor is aggressive with a poor prognosis. Herein, we report the first clinical experience treated with a combination of docetaxel and gemcitabine for local and lung metastasis from primary osteosarcoma of the uterus. Although the disease was considered stable after three cycles of treatment, new metastatic lesions appeared in the lungs after six cycles. The patient was asymptomatic for 13 months; however, she died two months after symptom recurrence. Our case demonstrates that a combined regimen of docetaxel and gemcitabine may be a sound therapeutic option to control primary osteosarcoma of the uterus.",
"affiliations": "Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.;Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan. moriman@koto.kpu-m.ac.jp.;Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.;Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.;Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.;Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.",
"authors": "Tsukasaki|Nanami|N|;Mori|Taisuke|T|;Yasukawa|Satoru|S|;Konishi|Eiichi|E|;Kokabu|Tetsuya|T|;Kitawaki|Jo|J|",
"chemical_list": "D000970:Antineoplastic Agents; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C056507:gemcitabine",
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.13079",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "42(11)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "docetaxel; extraskeletal osteosarcoma; gemcitabine; uterine osteosarcoma",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D003841:Deoxycytidine; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007044:Hysterectomy; D008175:Lung Neoplasms; D008875:Middle Aged; D012516:Osteosarcoma; D043823:Taxoids; D016896:Treatment Outcome; D014594:Uterine Neoplasms",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "1604-1608",
"pmc": null,
"pmid": "27319757",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary osteosarcoma of the uterine corpus: A case report.",
"title_normalized": "primary osteosarcoma of the uterine corpus a case report"
} | [
{
"companynumb": "JP-CIPLA LTD.-2016JP08329",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPostoperative pain is an important factor affecting anesthesia and surgery.\n\n\nOBJECTIVE\nThe present study assessed the effects of 1200 mg gabapentin, an anticonvulsant drug that acts through voltage-dependent calcium channels, for the control of postoperative pain in patients undergoing abdominal hysterectomy.\n\n\nMETHODS\nFifty patients undergoing hysterectomy were enrolled in the present study. Subjects received either 1200 mg gabapentin or placebo 2 h before surgery. The amount of morphine consumption and level of postoperative pain at 2 h, 6 h, 12 h and 24 h after surgery were measured.\n\n\nRESULTS\nThere were no significant differences in age, duration of surgery and anesthesia, or body mass index between the two groups. The mean intensity of pain in the gabapentin group was significantly lower than in the placebo group. The mean amount of morphine used in the placebo group (5.2 ± 2.8 mg) was significantly higher than in gabapentin group (1.2 ± 0.29 mg; P=0.001). Nausea and vomiting in the placebo group was more common than in the gabapentin group (P=0.001). The time interval for initial ambulation after surgery was significantly shorter in the gabapentin group (12.24 ± 2.18 h) compared with the placebo group (15 ± 3.61 h; P=0.002).\n\n\nCONCLUSIONS\n1200 mg gabapentin reduced postoperative pain and the need for opioids, and enabled earlier ambulation of the patient. Significant side effects were not observed.",
"affiliations": "Department of Obstetrics and Gynecology, Kashan University of Medical Services, Iran.",
"authors": "Frouzanfard|Fatemeh|F|;Fazel|Mohammad Reza|MR|;Abolhasani|Azadeh|A|;Fakharian|Esmaeil|E|;Mousavi|Golmabas|G|;Moravveji|Alireza|A|",
"chemical_list": "D000588:Amines; D000700:Analgesics; D000701:Analgesics, Opioid; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin",
"country": "United States",
"delete": false,
"doi": "10.1155/2013/787401",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1203-6765",
"issue": "18(2)",
"journal": "Pain research & management",
"keywords": null,
"medline_ta": "Pain Res Manag",
"mesh_terms": "D000328:Adult; D000588:Amines; D000700:Analgesics; D000701:Analgesics, Opioid; D016009:Chi-Square Distribution; D003509:Cyclohexanecarboxylic Acids; D004334:Drug Administration Schedule; D005260:Female; D000077206:Gabapentin; D006801:Humans; D007044:Hysterectomy; D008875:Middle Aged; D010147:Pain Measurement; D010149:Pain, Postoperative; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D013997:Time Factors; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "9612504",
"other_id": null,
"pages": "94-6",
"pmc": null,
"pmid": "23662292",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": "15087630;8119268;9659873;16527792;12218520;8621444;15503108;9846777;14982565;12218517;21189848;20473044;15105217;16037731;15101847;15840990;17083725;10991921;12717156;9561320;10866910;17257177;11786502;17056969;15275765",
"title": "Effects of gabapentin on pain and opioid consumption after abdominal hysterectomy.",
"title_normalized": "effects of gabapentin on pain and opioid consumption after abdominal hysterectomy"
} | [
{
"companynumb": "IR-GLENMARK PHARMACEUTICALS INC, USA.-2014GMK012573",
"fulfillexpeditecriteria": "2",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drug... |
{
"abstract": "The etiology of autoimmune hepatitis (AIH) is unknown, though hepatotropic viruses may be potential triggers. Hepatitis E virus (HEV) infection, an increasingly recognized cause of acute hepatitis, has been misdiagnosed as AIH due to the occurrence of autoantibodies during its acute phase. It has also been suggested that HEV infection may lead to or unmask AIH. The HEV seroprevalence has been ascertained in patients with AIH, but the prevalence of AIH-related autoantibodies in patients with HEV infection has not been systematically tested. We aimed to investigate whether acute HEV infection is associated with the presence of AIH-relevant autoantibodies, following the liver autoimmune serology guidelines of the International AIH Group. We tested 48 patients with acute HEV infection. Half of them had at least one autoantibody, 17% two autoantibodies. Anti-nuclear antibody (ANA) were detected in 16 (33%), anti-smooth muscle antibody (SMA) in 10 (21%), and anti-neutrophil cytoplasmic antibody (ANCA) in 7 (14.6%). Of note, two patients showed SMA with VG or VGT patterns and five had ANA with homogeneous appearance, both being typical of AIH type 1. Other AIH-specific autoantibodies were negative. Atypical anti-mitochondrial antibody, without evidence of primary biliary cholangitis, was positive in one patient, disappearing at follow-up. Follow-up (median 12 months) serum was available from seven autoantibody positive patients: two became negative, while five remained positive, although no patient developed AIH to date. In conclusion, autoantibodies are frequently present during acute HEV infection, indicating that HEV should always be excluded before diagnosing AIH. Importantly, a minority of patients with acute hepatitis E develops AIH-specific autoantibodies, and, though they did not progress to autoimmune liver disease in the short-term, they warrant long-term monitoring.",
"affiliations": "Epatocentro Ticino, Lugano, Switzerland. Electronic address: benedetta.terziroli@hin.ch.;Neurocentro della Svizzera Italiana, Ospedale regionale di Lugano, Lugano, Switzerland.;Neurocentro della Svizzera Italiana, Ospedale regionale di Lugano, Lugano, Switzerland.;Epatocentro Ticino, Lugano, Switzerland.;Fondazione Epatocentro Ticino, Lugano, Switzerland.;Fondazione Epatocentro Ticino, Lugano, Switzerland.;Servizio di Epatologia EOC, Bellinzona, Switzerland.;LUM Autoimmunity and Allergy AUSL Bologna, Italy.;LUM Autoimmunity and Allergy AUSL Bologna, Italy.;LUM Autoimmunity and Allergy AUSL Bologna, Italy.;Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK.;Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK.;DIMEC, University of Bologna, Bologna, Italy.",
"authors": "Terziroli Beretta-Piccoli|Benedetta|B|;Ripellino|Paolo|P|;Gobbi|Claudio|C|;Cerny|Andreas|A|;Baserga|Adriana|A|;Di Bartolomeo|Claudia|C|;Bihl|Florian|F|;Deleonardi|Gaia|G|;Melidona|Laura|L|;Grondona|Ana Gabriela|AG|;Mieli-Vergani|Giorgina|G|;Vergani|Diego|D|;Muratori|Luigi|L|;|||",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D000974:Antibodies, Antinuclear; D001324:Autoantigens; D007106:Immune Sera",
"country": "England",
"delete": false,
"doi": "10.1016/j.jaut.2018.07.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0896-8411",
"issue": "94()",
"journal": "Journal of autoimmunity",
"keywords": "Acute hepatitis E; Autoimmune hepatitis; Autoimmune hepatitis-specific autoantibodies; Autoimmune liver serology",
"medline_ta": "J Autoimmun",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019268:Antibodies, Antineutrophil Cytoplasmic; D000974:Antibodies, Antinuclear; D001324:Autoantigens; D005260:Female; D005500:Follow-Up Studies; D016751:Hepatitis E; D016752:Hepatitis E virus; D019693:Hepatitis, Autoimmune; D006801:Humans; D007106:Immune Sera; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8812164",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "30336842",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Autoimmune liver disease serology in acute hepatitis E virus infection.",
"title_normalized": "autoimmune liver disease serology in acute hepatitis e virus infection"
} | [
{
"companynumb": "CH-TEVA-2018-CH-985782",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
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"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nColonic diverticular disease is rare in developing nations but common in Western and industrialized societies. Many studies show that heart and lung transplantation increase the risk of having severe diverticulitis, although the exact magnitude of this risk remain unclear because many of these studies have been small with short follow up. The term malignant diverticulitis has been employed to describe an extreme form of colon diverticulitis that is characterized by an extensive phlegmon and inflammatory reaction extending below the peritoneal reflection, with a tendency toward obstruction and fistula formation.\n\n\nMETHODS\nWe report a 57-year-old male, transplanted in our Institute for dilated cardiomyopathy due to previous myocardial ischemia, in whom, during the post-transplantation period, a malignant diverticulitis requiring an aggressive surgical approach was diagnosed, the diagnosis of diverticulosis was made during a colonoscopy in a pre-transplant work-up.\n\n\nCONCLUSIONS\nImmunosuppressed patients should be considered at high risk for developing a complicated malignant diverticular disease, and when diagnosed in a pre-transplant work-up, should be managed aggressively in terms of surgical approach when symptoms and signs suggest a diverticulitis.",
"affiliations": "Department of Abdominal and Transplantation Surgery, Mediterranean Institute for Transplantation and Advanced Specialized Therapies, University of Pittsburgh Medical Center in Italy, Palermo, Italy. dpagano@ismett.edu",
"authors": "Pagano|Duilio|D|;Cintorino|Davide|D|;Gruttadauria|Salvatore|S|;Spada|Marco|M|;Echeverri|Gabriel|G|;Botrugno|Ivan|I|;di Francesco|Fabrizio|F|;Li Petri|Sergio|S|;Gridelli|Bruno|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1425-9524",
"issue": "15(3)",
"journal": "Annals of transplantation",
"keywords": null,
"medline_ta": "Ann Transplant",
"mesh_terms": "D044683:Colon, Descending; D003113:Colonoscopy; D004239:Diverticulitis, Colonic; D043963:Diverticulosis, Colonic; D016027:Heart Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "9802544",
"other_id": null,
"pages": "71-4",
"pmc": null,
"pmid": "20877270",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Malignant diverticulitis of the left colon complicating heart transplantation.",
"title_normalized": "malignant diverticulitis of the left colon complicating heart transplantation"
} | [
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"companynumb": "PHHY2016IT068058",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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"actiondrug": "4",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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{
"abstract": "A 41-year-old woman was diagnosed with POEMS syndrome based on polyneuropathy, hepatosplenomegaly, sclerotic bone lesions, IgA-λ M-protein, and an elevated level of serum vascular endothelial growth factor. One month after the initiation of lenalidomide-dexamethasone with prophylactic aspirin, she developed facial paralysis, dysarthria, and left hemiplegia. Multiple cerebral infarctions and internal carotid artery stenosis were detected. Five months after switching to pomalidomide-dexamethasone, she again developed cerebral infarction. Progressed stenotic lesions in the bilateral internal carotid artery terminal portions were detected, showing a moyamoya disease-like appearance. Quasi-moyamoya disease can be an important phenotype of systemic vasculopathies of POEMS syndrome.",
"affiliations": "Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan.;Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan.;Center for Medical Genetics, Shinshu University Hospital, Japan.;Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan.;Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan.",
"authors": "Takahashi|Yusuke|Y|;Mochizuki|Yusuke|Y|;Nakamura|Katsuya|K|;Katoh|Nagaaki|N|;Sekijima|Yoshiki|Y|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.7701-21",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n34744103\n10.2169/internalmedicine.7701-21\nCase Report\nMoyamoya Disease-like Cerebrovascular Stenotic Lesions Are an Important Phenotype of POEMS Syndrome-associated Vasculopathy\nTakahashi Yusuke 1\nMochizuki Yusuke 1\nNakamura Katsuya 2\nKatoh Nagaaki 1\nSekijima Yoshiki 1\n1 Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan\n2 Center for Medical Genetics, Shinshu University Hospital, Japan\nCorrespondence to Dr. Nagaaki Katoh, nagaaki@shinshu-u.ac.jp\n\n6 11 2021\n15 5 2022\n61 10 16031608\n2 4 2021\n23 9 2021\nCopyright © 2022 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 41-year-old woman was diagnosed with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome based on polyneuropathy, hepatosplenomegaly, sclerotic bone lesions, IgA-λ M-protein, and an elevated level of serum vascular endothelial growth factor. One month after the initiation of lenalidomide-dexamethasone with prophylactic aspirin, she developed facial paralysis, dysarthria, and left hemiplegia. Multiple cerebral infarctions and internal carotid artery stenosis were detected. Five months after switching to pomalidomide-dexamethasone, she again developed cerebral infarction. Progressed stenotic lesions in the bilateral internal carotid artery terminal portions were detected, showing a moyamoya disease-like appearance. Quasi-moyamoya disease can be an important phenotype of systemic vasculopathies of POEMS syndrome.\n\ncerebral infarction\nIMiDs\nPOEMS syndrome\nquasi-moyamoya disease\nvasculopathy\n==== Body\npmcIntroduction\n\nPolyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is characterized by these chief symptoms, which are considered to be associated with an underlying plasma cell disorder and elevated levels of vascular endothelial growth factor (VEGF) (1). In addition to these five main symptoms, disease-related vasculopathy, including thrombosis (2,3), vascular stenosis (2-6), occlusion/infarction (2-5), and hemorrhage (4,5) have been reported in the limbs (2,3), visceral organs (2,3), and central nervous system (2-6). Although not well-recognized features, these POEMS syndrome-associated vasculopathies (PAV) are important complications. We herein report a case with recurrent cerebral infarctions due to moyamoya disease-like cerebrovascular stenotic lesions (quasi-moyamoya disease) as one of the main features of POEMS syndrome. Quasi-moyamoya disease is a very rare manifestation of POEMS syndrome with only two previous cases reported in the literature to date (4,5). However, this condition could be one of the phenotypes of PAV, and clinicians should pay attention to the possibility of this disease entity in patients with POEMS syndrome.\n\nCase Report\n\nA 41-year-old woman with no family history of neurological disorders, such as neuropathy or cerebrovascular disease, was referred to our hospital for further examination and treatment of polyneuropathy. Six months prior to presentation at our hospital, she developed muscle weakness in the legs when walking, and began to feel numbness and pain in her feet and lower legs at 4 months prior to presentation. At 3 months prior to presentation, she developed leg edema and visited a local hospital. Although her edema improved after the administration of diuretics, her neuropathic symptoms remained. One month prior to presentation, she was referred to the neurology department of the local hospital. She was suspected to have polyneuropathy based on muscle weakness in the legs, reduced tendon reflexes in the extremities, and decreased nerve conduction velocities, and was then admitted to our hospital.\n\nOn admission, the physical examination findings were not remarkable except for leg edema. There was no detectable hypertension, skin lesion, or palpable hepatosplenomegaly. Neurological examinations revealed distal dominant muscle weakness in her legs, absent tendon reflexes in the upper and lower extremities, decreased touch, pain, and vibration sensations in the distal legs, numbness and pain in the legs, and disturbed walking with a cane. Laboratory tests revealed an elevated platelet count (450,000 /μL, normal 158,000-348,000 /μL), IgA-λ M-protein, and elevated serum vascular endothelial growth factor (VEGF, 7,350.0 pg/mL). There was no hyperlipidemia or diabetes mellitus. The cardiac functions and dimensions were normal on echocardiography but mild pericardial effusion was detected. An enhanced computed tomography (CT) scan of the neck, chest, abdomen, pelvis, and femur detected hepatosplenomegaly and sclerotic bone lesions in the lower thoracic spine. No stenotic or occlusive arteriovenous vascular lesions were detected. A nerve conduction test detected lower extremity-dominant amplitude reduction in both motor and sensory nerves with decreased velocities, suggesting sensorimotor polyneuropathy with axonal degeneration. A sural nerve biopsy was performed and the histological findings of axonal degeneration with subperineurial edema were thus identified (Fig. 1). Taken together, a diagnosis of POEMS syndrome was made. Lenalidomide-dexamethasone (Rd) therapy with prophylactic aspirin was started. The affected free light chain (FLC) λ decreased from 34.4 mg/L to 17.7 mg/L after one cycle. Rd therapy was therefore considered to be effective and a second cycle was started as scheduled. On day 6 of the second cycle, she began to feel slight weakness in her left arm. On day 8, she noticed dysarthria and muscle weakness progression in her left arm and leg. These symptoms remained and she visited our hospital on day 9. A neurological examination revealed left unilateral facial paralysis, dysarthria, and mild left hemiplegia. Magnetic resonance imaging (MRI) was performed and multiple cerebral infarctions were detected in the right middle cerebral artery area (Fig. 2A, B). Dual antiplatelet therapy with aspirin and clopidogrel was started. In addition, stenotic lesions at the terminal portion of the bilateral internal carotid artery (ICA) were detected by magnetic resonance angiography (MRA) (Fig. 2C). Although almost all the results of carotid duplex ultrasonography were unremarkable, 1.6 mm intima media thickness was detected in the bifurcation portion of left common carotid artery. POEMS syndrome-associated vasculopathy (PAV) and possible side effects of Rd therapy were suspected, and chemotherapy was switched to pomalidomide-dexamethasone (Pd). After the Pd initiation, hematologic and clinical disease activities were maintained to be plateau state. Five months later, during the sixth cycle of Pd treatment, she developed speaking difficulty and apathy, and new cerebral infarctions were detected in both frontal lobes by MRI (Fig. 2D, E). A progression of stenotic lesions in both sides of ICA terminal portions was demonstrated by MRA, showing a moyamoya disease-like appearance (Fig. 2F). “Moyamoya vessels” (typical collateral vessels observed in moyamoya disease) were not evident in MRA (Fig. 2G). 123I-IMP cerebral blood flow scintigraphy revealed severely decreased tracer uptake in both lobes, especially in the frontotemporal lobe area (Fig. 3). As a result of screening tests for systemic arteriovenous vascular lesions, subclinical bilateral renal infarctions were detected by whole-body enhanced CT scan. Quasi-moyamoya disease, which developed in association with disease progression of PAV, was diagnosed. A direct sequence analysis of the RNF213 gene for the variant (NM_001256071.2:c.14429G＞A:p.Arg4810Lys) was performed and the patient was found to be heterozygous for this variant. The patient was referred to the neurosurgery department for further examination with cerebral angiography to discuss the indications for surgical revascularization. She underwent bilateral superficial temporal artery to MCA (STA-MCA) bypass operations successfully (Fig. 4). After the surgical intervention, she has been in a good clinical state without any new cerebral ischemia attacks or a progression of neuropathy under the additional chemotherapy including daratumumab, lenalidomide, and dexamethasone for 2 years and 5 months.\n\nFigure 1. Histopathological picture of a sural nerve biopsy (toluidine blue staining). The histological findings were highly suggestive of POEMS syndrome, such as myelin spheres, indicated distal axonal degeneration due to proximal demyelination, and subperineurial edema (§). Axonal loss was unclear. There was no evident thinning of the myelin sheath or onion bulb formation. Scale bar =100 μm.\n\nFigure 2. Diffusion-weighted brain magnetic resonance imaging (MRI) (A, B, D, E) and magnetic resonance angiography (MRA) (C, F, G). (A-C). Images taken at the first episode of stroke. Multiple infarctions in the right middle cerebral artery area (A, B) and stenotic lesion of bilateral internal carotid artery (ICA) in the terminal portion (C) are shown. (D-G). Images taken at the second episode of stroke 5 months after the first episode. These images revealed new cerebral infarctions in both frontal lobes (D, E) and significantly progressed stenotic lesions in the bilateral ICA terminal portions, showing moyamoya disease-like appearance (F). Although coronal maximum intensity projection (MIP) picture focusing on ICA terminal portion was also examined (G), typical collateral vessels (moyamoya vessels) were not evident.\n\nFigure 3. Axial rainbow color scale images of 123I-IMP cerebral blood flow scintigraphy. The results indicated a diffuse and severe decrease of the cerebral blood flow especially in the frontotemporal lobe area.\n\nFigure 4. Digital subtraction angiography (DSA) images of bilateral common carotid artery. DSA images of right (A, C) and left (B, D) common carotid angiography. Images of pre- (C, D) and post- (A, B) bilateral superficial temporal artery to MCA (STA-MCA) bypass operations are presented.\n\nDiscussion\n\nIn contrast to moyamoya disease that is defined by “idiopathic” steno-occlusion at the terminal portion of the internal carotid artery, quasi-moyamoya disease is characterized by the presence of underlying primary disease manifesting the same cerebrovascular lesions (7). Various inherited or acquired disorders and conditions have been reported as associated pathologies of quasi-moyamoya disease. A nationwide survey in Japan documented atherosclerosis (29%), Down syndrome (15.1%), von Recklinghausen disease (14%), brain tumor/irradiation (7.5%), autoimmune disease (7.5%), hyperthyroidism (7.5%), and other conditions as associated primary diseases (7).\n\nOn the other hand, PAV are regarded as specific types of arteriovenous vascular events, including thrombosis (2,3), vascular stenosis (2-6), occlusion/infarction (2-5), and hemorrhage (4,5) in the limbs (2,3), visceral organs (2,3), and central nervous system (2-6). The underlying mechanism of PAV has not yet been elucidated. Fu et al. suggested that vasculitis is the dominant mechanism of vasculopathy based on imaging studies showing contrast enhancement without pathological analysis (3). In contrast, some reports indicated that no vasculitis pathology on histological analysis (2,5). In an autopsy study, Sekiguchi et al. reported that the histological findings of PAV in quasi-moyamoya disease were similar to those of moyamoya disease, showing fibrous intimal thickening and tortuosity of the internal elastic lamina without vasculitis pathology (5).\n\nVEGF is known to play an important role in the vascular pathology of POEMS syndrome (1). Interestingly, some studies have demonstrated that there a number of angiogenic agents, including VEGF (8), basic fibroblast growth factor (bFGF) (8), hepatocyte growth factor (HGF) (8,9), transforming growth factor-β1 (TGF-β1) (8), and granulocyte-colony stimulating factor (G-CSF) (8), are also overexpressed in moyamoya disease. Therefore, some angiogenic agents, such as VEGF, could be associated with both diseases, with similar pathological effects in the vessels. This hypothesis would support the observations that the same histopathological findings of involved vasculature were seen in both diseases (5). On the other hand, different mechanisms were also suggested. As shown in the case presentation, rapid progression of ICA terminal stenosis had occurred in only a few months. It is possible to postulate that additional pathological mechanisms in POEMS syndrome have made vascular stenosis worsen more rapidly than in idiopathic moyamoya disease and a few months was not long enough for collateral circulation system to develop sufficiently.\n\nFurthermore, this immature collateral circulation system might have been affected by chemotherapy, resulting in the patient's pathology. Anti-plasma cell chemotherapy is considered to be effective for POEMS syndrome in principle (1). However, because VEGF is important in angiogenesis in POEMS syndrome (1), anti-plasma cell chemotherapy might have caused collapse of immature collateral circulation system by decreasing the serum level of VEGF and might have affected the ischemic mechanisms in the present case. Therefore, it may be important to discuss how to use optional anti-ischemic agents appropriately, such as antiplatelet, anticoagulant, and possible vasodilation agents, when administering the chemotherapeutic drugs for POEMS patient with stenotic vascular lesion(s).\n\nPOEMS syndrome-associated quasi-moyamoya disease is extremely rare, and only two cases have been reported to date (4,5). Yamaguchi et al. reported a 49-year-old woman with plasmacytoma-associated POEMS syndrome, who developed quasi-moyamoya disease-related intracranial hemorrhage during the disease remission period 5 years after radiation therapy for plasmacytoma (4). Sekiguchi et al. reported a 45-year-old man with plasmacytoma-associated POEMS syndrome, who developed quasi-moyamoya disease-related recurrent cerebral infarction while chemotherapy for POEMS syndrome failed because of adverse effects (5). These reports suggest that quasi-moyamoya disease can progress during the “treatment cessation period” (5) and can also progress during the “remission period” of POEMS syndrome (4), resulting in cerebral stroke. Therefore, our case is the first report of POEMS syndrome-associated quasi-moyamoya disease that progressed and resulted in recurrent cerebral infarction despite ongoing chemotherapy.\n\nOur patient was treated with immunomodulatory drugs (IMiDs), such as lenalidomide or pomalidomide. Thalidomide and its analogs, lenalidomide and pomalidomide, are referred to as IMiDs and have been reported to have multiple actions with direct and/or indirect antitumor effects (10,11). These actions include immunomodulatory, antiangiogenic, antiinflammatory, and antiproliferative effects (10,11). These IMiDs are currently considered to be fundamental antimyeloma agents with a high efficacy and are now widely used (12). Furthermore, as most POEMS syndrome patients have the same underlying plasma cell pathology as myeloma, IMiDs have also become promising key drugs for its treatment (1,13). Our patient, however, showed a progression of quasi-moyamoya disease and developed recurrent cerebral ischemic attacks despite effective treatment with IMiDs. As the 5-year risk of cerebral infarction in POEMS syndrome has been reported to be as high as 13.4% (14) and IMiDs therapy combined with dexamethasone is known to be associated with increased risk of venous thromboembolism (15), it is recommended to add antiplatelet therapy when treating patients with IMiDs (15). However, antithrombotic therapy may be insufficient to completely prevent cerebral infarction (6), because some reports have indicated that patient with POEMS syndrome could develop cerebral infarction despite prophylactic antithrombotic therapy during the period of treatment with IMiDs and/or dexamethasone (6,16). As in these cases, our patient also developed cerebral infarction even with prophylactic aspirin treatment. IMiDs therapy was therefore thought to be associated with the underlying mechanism of cerebral infarction in our patient to some degree. Hence, an appropriate assessment of systemic vascular status, including cerebral MRI/MRA before treatment initiation, is necessary for the risk management of PAV. Careful monitoring of vascular status after initiating treatment is also recommended, because treatment regimens with IMiDs are being used more frequently (1,13).\n\nAnother possible pathological mechanism of cerebrovasculopathy in this case might be associated with p.Arg4810Lys variant in RNF213 gene. Because this variant was known as susceptibility variant for Moyamoya disease (17) and other intracranial artery stenosis (18), progressive cerebrovasculopathies in this patient might have been attributable to this gene variant to some extent.\n\nIn conclusion, moyamoya disease-like cerebrovascular stenotic lesions (quasi-moyamoya disease) can be one phenotype of systemic vasculopathy of POEMS syndrome. A patient with this condition can develop cerebral infarction even during the period of ongoing effective chemotherapy with prophylactic antiplatelet agents. Screening cerebral MRI/MRA examinations at the diagnosis of POEMS syndrome and careful vascular monitoring after initiation of treatment are recommended for all patients, especially when treating patients with IMiDs.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Dispenzieri A . POEMS syndrome: 2019 update on diagnosis, risk-stratification, and management. Am J Hematol 94 : 812-827, 2019.31012139\n2. Lesprit P , Authier FJ , Gherardi R , et al . Acute arterial obliteration: a new feature of the POEMS syndrome? Medicine 75 : 226-232, 1996.8699962\n3. Fu FW , Rao J , Zheng YY , Wang HL , Yang JG , Zheng GQ . Ischemic stroke in patients with POEMS syndrome: a case report and comprehensive analysis of literature. Oncotarget 8 : 89406-89424, 2017.29179528\n4. Yamaguchi I , Satomi J , Yamamoto N , et al . Coexistence of quasi-moyamoya disease and POEMS syndrome in a patient with Intracranial Hemorrhage: a case report and literature review. NMC Case Rep J 4 : 5-9, 2017.28664017\n5. Sekiguchi T , Ishibashi S , Sasame J , et al . Recurrent stroke due to quasi-moyamoya disease associated with POEMS syndrome: an autopsy case. J Neurol Sci 412 : 116738, 2020.32092484\n6. Mitsutake A , Matsumoto H , Hatano K , Irie K , Tsukada N , Hashida H . Lenalidomide-induced ischemic cerebrovascular disease in polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome. J Stroke Cerebrovasc Dis 27 : e102-e103, 2018.29395638\n7. Hayashi K , Horie N , Izumo T , Nagata I . Nationwide survey on quasi-moyamoya disease in Japan. Acta Neurochir 156 : 935-940, 2014.24499994\n8. Weinberg DG , Arnaout OM , Rahme RJ , Aoun SG , Batjer HH , Bendok BR . Moyamoya disease: a review of histopathology, biochemistry, and genetics. Neurosurg Focus 30 : E20, 2011.21631222\n9. Takahashi A , Sawamura Y , Houkin K , Kamiyama H , Abe H . The cerebrospinal fluid in patients with moyamoya disease (spontaneous occlusion of the circle of Willis) contains high level of basic fibroblast growth factor. Neurosci Lett 160 : 214-216, 1993.8247356\n10. Quach H , Ritchie D , Stewart AK , et al . Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia 24 : 22-32, 2010.19907437\n11. Davies F , Baz R . Lenalidomide mode of action: linking bench and clinical findings. Blood Rev 24 : S13-S19, 2010.21126632\n12. van de Donk NWCT , Pawlyn C , Yong KL . Multiple myeloma. Lancet (London, England) 397 : 410-427, 2021.\n13. Misawa S , Sato Y , Katayama K , et al . Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 15 : 1129-1137, 2016.27496680\n14. Dupont SA , Dispenzieri A , Mauermann ML , Rabinstein AA , Brown RD Jr . Cerebral infarction in POEMS syndrome: incidence, risk factors, and imaging characteristics. Neurology 73 : 1308-1312, 2009.19841383\n15. Larocca A , Cavallo F , Bringhen S , et al . Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood 119 : 933-939, quiz 1093, 2012.21835953\n16. Sommer B , Schaumberg J . Therapeutic challenges in a patient with POEMS syndrome and recurrent stroke: presentation of a case and review of the literature. Acta Neurol Belg 112 : 9-13, 2012.22427283\n17. Kamada F , Aoki Y , Narisawa A , et al . A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet 56 : 34-40, 2011.21048783\n18. Miyawaki S , Imai H , Shimizu M , et al . Genetic variant RNF213 c.14576G＞A in various phenotypes of intracranial major artery stenosis/occlusion. Stroke 44 : 2894-2897, 2013.23970789\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": null,
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "IMiDs; POEMS syndrome; cerebral infarction; quasi-moyamoya disease; vasculopathy",
"medline_ta": "Intern Med",
"mesh_terms": null,
"nlm_unique_id": "9204241",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34744103",
"pubdate": "2021-11-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Moyamoya Disease-like Cerebrovascular Stenotic Lesions Are an Important Phenotype of POEMS Syndrome-associated Vasculopathy.",
"title_normalized": "moyamoya disease like cerebrovascular stenotic lesions are an important phenotype of poems syndrome associated vasculopathy"
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"companynumb": "JP-ALVOGEN-2021-ALVOGEN-117829",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "1",... |
{
"abstract": "OBJECTIVE\nEndoscopic repair of inguinal hernia can decrease the incidence of chronic groin pain. Staple mesh fixation is the surgical technique preferentially used but may also cause residual pain. Although a substantial number of specialists advocate no mesh fixations, concerns are that this could lead to an increase in recurrence rates. This study aimed to assess the safety and the effectiveness of fibrin sealant, as an alternative technique to staple mesh fixation after totally extraperitoneal (TEP) inguinal hernia repair.\n\n\nMETHODS\nA total of 472 patients underwent elective TEP inguinal hernia repair between February 2005 and July 2011. Mesh fixation was achieved using fibrin sealant. Patients were reviewed postoperatively at Week 2, Week 6, and Month 6. Patient satisfaction was assessed in a subgroup of 116 patients using a comprehensive scoring system designed for hernia repairs, and pain was assessed using a standard Visual Analog pain Scale.\n\n\nRESULTS\nNo conversion to open surgery was observed. There were two cases of major morbidities and no mortality. Three months after surgery, only three patients (0.6 %) experienced chronic groin or testicular discomfort. At Week 6, 98.9 % of the patients were either satisfied or very satisfied with their outcome, and 96.8 % denied any residual pain. Finally, only six hernia recurrences (0.9 %) were reported, of which five occurred during the first months of the study.\n\n\nCONCLUSIONS\nFibrin sealant is safe and reliable for mesh fixation of inguinal hernia during TEP repair with a very high satisfaction index and limited risk of developing chronic pain.",
"affiliations": "Bankstown-Lidcombe Hospital, University of New South Wales, Bankstown, NSW, 2200, Australia, berneycr@hotmail.com.",
"authors": "Berney|C R|CR|;Yeo|A E T|AE|",
"chemical_list": "D015718:Fibrin Tissue Adhesive; D014014:Tissue Adhesives",
"country": "France",
"delete": false,
"doi": "10.1007/s10029-012-1034-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1248-9204",
"issue": "17(6)",
"journal": "Hernia : the journal of hernias and abdominal wall surgery",
"keywords": null,
"medline_ta": "Hernia",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059350:Chronic Pain; D005260:Female; D015718:Fibrin Tissue Adhesive; D005500:Follow-Up Studies; D006552:Hernia, Inguinal; D059685:Herniorrhaphy; D006801:Humans; D010535:Laparoscopy; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D010149:Pain, Postoperative; D017060:Patient Satisfaction; D010537:Peritoneum; D011788:Quality of Life; D012008:Recurrence; D012189:Retrospective Studies; D013526:Surgical Mesh; D014014:Tissue Adhesives; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9715168",
"other_id": null,
"pages": "709-17",
"pmc": null,
"pmid": "23344667",
"pubdate": "2013-12",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": "17063297;22120101;12945086;15570845;21638171;17623239;15249343;21487873;17353992;16424986;9114802;20495842;20552368;11330384;21225439;11141220;16076322;15611452;15977079;21293897;18387468;15531621;22015810;21342387;23064991;22278103;20395851;17245175;16244540",
"title": "Mesh fixation with fibrin sealant during endoscopic totally extraperitoneal inguinal hernia approach: a review of 640 repairs.",
"title_normalized": "mesh fixation with fibrin sealant during endoscopic totally extraperitoneal inguinal hernia approach a review of 640 repairs"
} | [
{
"companynumb": "AU-BAXTER-2014BAX049410",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ENOXAPARIN"
},
"drugadditional": null,
... |
{
"abstract": "Calciphylaxis is a serious and potentially life-threatening disorder characterized by medial calcification of arterioles leading to subcutaneous ischemia and skin necrosis. It is most commonly seen in patients with end-stage renal disease or shortly after renal transplantation. We report an unusual case of calciphylaxis occurring 16 years after renal transplantation in a 48-year-old female with a failing graft, along with histological and striking radiological findings.",
"affiliations": "Department of Radiology, Norfolk & Norwich University Hospital NHS Trust, Colney Lane, Norwich, Norfolk, NR4 7UY, UK.",
"authors": "Smith|Sarahn|S|;Inaba|Akimichi|A|;Murphy|Joseph|J|;Campbell|Gary|G|;Toms|Andoni P|AP|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00256-013-1648-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0364-2348",
"issue": "42(11)",
"journal": "Skeletal radiology",
"keywords": null,
"medline_ta": "Skeletal Radiol",
"mesh_terms": "D002115:Calciphylaxis; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008875:Middle Aged; D017211:Treatment Failure",
"nlm_unique_id": "7701953",
"other_id": null,
"pages": "1623-6",
"pmc": null,
"pmid": "23754731",
"pubdate": "2013-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12495283;17338433;22841657;20024510;15711428;12514758;17581723;15575010;12602715;12028462;20040786;19380668;18417747;9426423;17141359",
"title": "A case report: radiological findings in an unusual case of calciphylaxis 16 years after renal transplantation.",
"title_normalized": "a case report radiological findings in an unusual case of calciphylaxis 16 years after renal transplantation"
} | [
{
"companynumb": "GB-AMGEN-GBRSP2021110968",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LANTHANUM CARBONATE"
},
"drugadditional": nul... |
{
"abstract": "OBJECTIVE\nTo report a case of extensive rash induced by orally administered pregabalin in a patient with neuropathic pain.\n\n\nMETHODS\nA 35-year-old white female with a diffuse, erythematous, maculopapular rash localized to her back and extremities presented to the preoperative holding area for planned exploratory nerve surgery. Prior to presentation, she had been receiving oral pregabalin 50 mg 3 times a day for approximately 2 weeks to treat her neuropathy. Prior to pregabalin therapy, the patient indicated that she had taken gabapentin for approximately 3 weeks for the pain, but had discontinued it due to adverse effects and perceived lack of efficacy. Pregabalin was discontinued and diphenhydramine and methylprednisolone were given to treat the rash. The rash almost completely resolved one week after pregabalin was discontinued.\n\n\nCONCLUSIONS\nPregabalin-induced rash was rarely reported in Phase 3 trials, and a clinical description of such events has not been published. Pregabalin exhibits pharmacokinetics different from those of most other antiepileptic agents. Presently, there are no clear mechanisms known for rash associated with pregabalin. The Naranjo probability scale indicates a probable relationship between the development of rash and use of pregabalin by our patient.\n\n\nCONCLUSIONS\nThere are currently no other available reports of the development of a rash coinciding with the use of pregabalin. As both Food and Drug Administration-approved and off-label use of this drug increases, further consideration of risk factors associated with the development of rash is needed.",
"affiliations": "College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.",
"authors": "Smith|Timothy L|TL|;Baldwin|Aaron|A|;Cunningham|Larry L|LL|;Cook|Aaron M|AM|",
"chemical_list": "D000700:Analgesics; D018926:Anti-Allergic Agents; D005938:Glucocorticoids; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D004155:Diphenhydramine; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1L305",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "42(12)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000700:Analgesics; D018926:Anti-Allergic Agents; D004155:Diphenhydramine; D003875:Drug Eruptions; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008775:Methylprednisolone; D009437:Neuralgia; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1899-902",
"pmc": null,
"pmid": "19001532",
"pubdate": "2008-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rash associated with pregabalin use.",
"title_normalized": "rash associated with pregabalin use"
} | [
{
"companynumb": "US-APOTEX-2020AP025078",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nSince its introduction in France, ketoprofen for topical use has been associated with a large number of cutaneous adverse effect reports. Therefore, the French Medicine Agency progressively introduced warnings and contraindications to its use. Despite this, serious adverse drug reactions (ADRs) still occur.\n\n\nOBJECTIVE\nTo describe clinical patterns and estimate costs of spontaneously reported cutaneous ADRs of topical ketoprofen.\n\n\nMETHODS\nAll cases of cutaneous ADRs of topical ketoprofen reported to the Bordeaux regional pharmacovigilance center between January 1989 and December 2006 were included. Clinical patterns, in respect of adherence to recommendations, causality, seriousness, and direct costs incurred by the ADRs, were assessed.\n\n\nRESULTS\nA total of 136 cases were reported (median age: 42 years, 55.9% women). Proper use of topical ketoprofen regarding indications, warnings, and contraindications was not respected by one-third of the patients. Almost all cases occurred during sunny months. Symptoms consisted predominantly of bullous eruptions (29.4%) or contact dermatitis (27.2%). Generalized lesions were observed in 37.5% of patients. Causality was considered at least possible for most of the cases (92.6%). These ADRs induced hospital admission in 15 cases (11.0%). The total estimated cost was euro 42,962 ($US 66,559), corresponding to euro 316 per case. This mean cost was nine times higher for serious ADRs.\n\n\nCONCLUSIONS\nTopical ketoprofen is used to treat benign symptoms but can be associated with serious and costly cutaneous ADRs. Furthermore, the number of cases and the calculated costs may have been greatly under-estimated in the present study.",
"affiliations": "Centre Régional de Pharmacovigilance, Département de Pharmacologie, Université Victor Segalen, Centre Hospitalier Universitaire, Bordeaux, France.",
"authors": "Noize|Pernelle|P|;Bénard-Laribière|Anne|A|;Aulois-Griot|Marine|M|;Moore|Nicholas|N|;Miremont-Salamé|Ghada|G|;Haramburu|Françoise|F|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007660:Ketoprofen",
"country": "New Zealand",
"delete": false,
"doi": "10.2165/11530160-000000000-00000",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1175-0561",
"issue": "11(2)",
"journal": "American journal of clinical dermatology",
"keywords": null,
"medline_ta": "Am J Clin Dermatol",
"mesh_terms": "D000279:Administration, Cutaneous; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002648:Child; D003875:Drug Eruptions; D004348:Drug Labeling; D005260:Female; D005602:France; D017048:Health Care Costs; D006760:Hospitalization; D006801:Humans; D007660:Ketoprofen; D008297:Male; D008875:Middle Aged; D012621:Seasons; D055815:Young Adult",
"nlm_unique_id": "100895290",
"other_id": null,
"pages": "131-6",
"pmc": null,
"pmid": "20141234",
"pubdate": "2010",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cutaneous adverse effects of ketoprofen for topical use: clinical patterns and costs.",
"title_normalized": "cutaneous adverse effects of ketoprofen for topical use clinical patterns and costs"
} | [
{
"companynumb": "FR-TEVA-2019-FR-1070278",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "KETOPROFEN"
},
"drugadditional": "3",
... |
{
"abstract": "Hereditary angioedema (HAE) is a disease manifested by repeated episodes of localized submucosal or subcutaneous edematous episodes, potentially triggered by emotional stress, mechanical trauma, or intake of estrogens. We present our experience managing two parturients with HAE. Multidisciplinary care is essential for planning and executing the specialized care of these patients, and management included extensive planning among obstetric, anesthesiology, and allergy and immunology teams. Pregnancy has been shown to have a variable effect on triggering HAE episodes. First-line treatment includes C1 esterase inhibitor concentrate, which can also be used for prophylaxis in high-risk patients. Neuraxial analgesia is recommended to avoid general anesthesia and was established early in both individuals. Vaginal delivery was well tolerated without need for emergent treatment for angioedema symptoms.",
"affiliations": "Departments of Anesthesiology and Perioperative Medicine.;Departments of Anesthesiology and Perioperative Medicine.;Departments of Anesthesiology and Perioperative Medicine.;Departments of Anesthesiology and Perioperative Medicine.;Medicine, Division of Allergic Diseases.;Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Departments of Anesthesiology and Perioperative Medicine.",
"authors": "Clark|Kathryn J|KJ|0000-0003-4908-5335;Sviggum|Hans P|HP|;Jacob|Adam K|AK|;Arendt|Katherine W|KW|;Volcheck|Gerald W|GW|;Szymanski|Linda M|LM|;Sharpe|Emily E|EE|",
"chemical_list": "D000777:Anesthetics; D050718:Complement C1 Inhibitor Protein",
"country": "England",
"delete": false,
"doi": "10.1093/pm/pnaa457",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-2375",
"issue": "22(8)",
"journal": "Pain medicine (Malden, Mass.)",
"keywords": "Anesthesia; Angioedema; C1 Esterase Inhibitor Deficiency; Epidural; Hereditary Angioedema; Pregnancy",
"medline_ta": "Pain Med",
"mesh_terms": "D000777:Anesthetics; D054179:Angioedemas, Hereditary; D050718:Complement C1 Inhibitor Protein; D005260:Female; D006801:Humans; D011247:Pregnancy",
"nlm_unique_id": "100894201",
"other_id": null,
"pages": "1878-1882",
"pmc": null,
"pmid": "33769522",
"pubdate": "2021-08-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Obstetric Anesthetic Management for Parturients with Hereditary Angioedema: A Case Report and Suggested Protocol.",
"title_normalized": "obstetric anesthetic management for parturients with hereditary angioedema a case report and suggested protocol"
} | [
{
"companynumb": "US-PHARMING-PHAUS2021000168",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN C1-ESTERASE INHIBITOR"
},
"drugadditi... |
{
"abstract": "Fanconi anemia (FA) is a genomic instability syndrome associated with bone marrow failure, myelodysplastic syndrome (MDS), and/or acute myeloid leukemia (AML) requiring hematopoietic stem cell transplantation (HSCT) to restore normal hematopoiesis. Although low-intensity fludarabine-based preparative regimens without radiation confer excellent outcomes in FA HSCTs with HLA-matched sibling donors, outcomes for FA patients with alternative donors are less encouraging, albeit improving. We present our experience with 17 FA patients who completed mismatched related or unrelated donor HSCT using a non-radiation fludarabine-based preparative regimen at Charité University Medicine Berlin. All patients engrafted; however, one patient had unstable chimerism in the setting of multi-viral infections that necessitated a stem cell boost to revert to full donor chimerism. Forty-seven percent of patients developed grade I acute graft-verus-host disease (aGVHD). No grade II-IV aGVHD or chronic graft-versus-host disease of any severity occurred. At a median follow-up of 30 months, 88 % of patients are alive with normal hematopoiesis. Two patients died of infections 4 months post-transplantation. These results demonstrate that short-term outcomes for FA patients with mismatched and unrelated donor HSCTs can be excellent using chemotherapy only conditioning. Viral reactivation, however, was a major treatment-related complication.",
"affiliations": "Department of Pediatric Hematology Oncology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany, chao.mwe@mh-hannover.de.",
"authors": "Chao|M M|MM|;Kuehl|J S|JS|;Strauss|G|G|;Hanenberg|H|H|;Schindler|D|D|;Neitzel|H|H|;Niemeyer|C|C|;Baumann|I|I|;von Bernuth|H|H|;Rascon|J|J|;Nagy|M|M|;Zimmermann|M|M|;Kratz|C P|CP|;Ebell|W|W|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-015-2370-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "94(8)",
"journal": "Annals of hematology",
"keywords": null,
"medline_ta": "Ann Hematol",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D005199:Fanconi Anemia; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D019172:Transplantation Conditioning; D016896:Treatment Outcome; D061349:Unrelated Donors; D055815:Young Adult",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1311-8",
"pmc": null,
"pmid": "25862235",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Outcomes of mismatched and unrelated donor hematopoietic stem cell transplantation in Fanconi anemia conditioned with chemotherapy only.",
"title_normalized": "outcomes of mismatched and unrelated donor hematopoietic stem cell transplantation in fanconi anemia conditioned with chemotherapy only"
} | [
{
"companynumb": "DE-SA-2016SA171875",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo determine the efficacy and safety of solifenacin for correcting the residual symptoms of an overactive bladder (OAB) in patients who were treated for a urinary tract infection (UTI).\n\n\nMETHODS\nUsing random sampling, 524 patients aged >60 years were selected (347 women, 66.2%, and 177 men, 33.8%). They denied the presence of any symptoms of detrusor overactivity in their medical history, but had a diagnosis of a UTI. At least 1 month after the end of treatment and a laboratory confirmation of the absence of infection, each patient completed an OAB-Awareness Tool questionnaire (OAB signs, total score 8 points), and a noninvasive examination of urinary function (uroflowmetry). Each day patients in group A took solifenacin 10 mg and those in group B took 5 mg, with patients in group C being given a placebo.\n\n\nRESULTS\nDuring the study 58.8% of patients had symptoms of an OAB at 1 month after the end of the treatment for a UTI, and normal laboratory markers. During treatment with the standard and higher dose of solifenacin, within 8 weeks most variables of the condition of the lower urinary tract reached a normal state or improved.\n\n\nCONCLUSIONS\nPatients aged >60 years who had been treated for a UTI have a high risk of developing symptoms of an OAB. Solifenacin in standard doses is an efficient and safe means of managing overactive detrusor symptoms after a UTI.",
"affiliations": "School of Humanities, Far Eastern Federal University, Russian Federation.;Department of Urology, City Polyclinic No. 3, Russian Federation.;Far Eastern Fisheries University, Russian Federation.;Department of the Functional Methods of Examination, Medical Association No. 2 of Vladivostok City, Vladivostok, Primorsky Region, Russian Federation.",
"authors": "Kosilov|Kirill V|KV|;Loparev|Sergay A|SA|;Ivanovskaya|Marina A|MA|;Kosilova|Liliya V|LV|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.aju.2015.07.003",
"fulltext": "\n==== Front\nArab J UrolArab J UrolArab Journal of Urology2090-598X2090-5998Elsevier S2090-598X(15)00076-510.1016/j.aju.2015.07.003Original ArticleThe efficacy of different doses of solifenacin in elderly patients after treating a urinary tract infection Kosilov Kirill V. oton2000@mail.rua⁎Loparev Sergay A. bIvanovskaya Marina A. cKosilova Liliya V. da School of Humanities, Far Eastern Federal University, Russian Federationb Department of Urology, City Polyclinic No. 3, Russian Federationc Far Eastern Fisheries University, Russian Federationd Department of the Functional Methods of Examination, Medical Association No. 2 of Vladivostok City, Vladivostok, Primorsky Region, Russian Federation⁎ Corresponding author at: St. 100-old Vladivostok 118-74, Vladivostok, Russian Federation. oton2000@mail.ru05 8 2015 9 2015 05 8 2015 13 3 203 208 11 3 2015 29 6 2015 2 7 2015 © 2015 Arab Association of Urology. Production and hosting by Elsevier B.V.2015Arab Association of UrologyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Objective\nTo determine the efficacy and safety of solifenacin for correcting the residual symptoms of an overactive bladder (OAB) in patients who were treated for a urinary tract infection (UTI).\n\nPatients and methods\nUsing random sampling, 524 patients aged >60 years were selected (347 women, 66.2%, and 177 men, 33.8%). They denied the presence of any symptoms of detrusor overactivity in their medical history, but had a diagnosis of a UTI. At least 1 month after the end of treatment and a laboratory confirmation of the absence of infection, each patient completed an OAB-Awareness Tool questionnaire (OAB signs, total score 8 points), and a noninvasive examination of urinary function (uroflowmetry).\n\nEach day patients in group A took solifenacin 10 mg and those in group B took 5 mg, with patients in group C being given a placebo.\n\nResults\nDuring the study 58.8% of patients had symptoms of an OAB at 1 month after the end of the treatment for a UTI, and normal laboratory markers. During treatment with the standard and higher dose of solifenacin, within 8 weeks most variables of the condition of the lower urinary tract reached a normal state or improved.\n\nConclusion\nPatients aged >60 years who had been treated for a UTI have a high risk of developing symptoms of an OAB. Solifenacin in standard doses is an efficient and safe means of managing overactive detrusor symptoms after a UTI.\n\nAbbreviations\nOAB, overactive bladderOAB-AT, OAB Awareness Tool (questionnaire)IE, incontinence episodesUE, urgency episodesLUT, lower urinary tractKeywords\nOveractive bladderElderly menSolifenacinUrinary tract infectionVOIDING DYSFUNCTION/FEMALE UROLOGY\n==== Body\nIntroduction\nUTIs in elderly men and women are common and the prevalence depends on numerous factors. The frequency of UTI depends on the place of residence, climate, age, the presence of urodynamic disorders, compliance with treatments for overactive bladder (OAB) symptoms, the immunological status, and many other factors [1–3]. The absence of a common approach (‘gold standard’) to the diagnostics and treatment of UTI complicates the well-timed detection and appropriate therapy of this disease. As a rule, existing principles of UTI management duplicate the recommendations for treating younger groups and, according to several studies, allow an excessive use of antibiotics [2–4]. Nevertheless, most specialists consider the availability of laboratory findings such as pyuria and a positive urine culture (>105 colony-forming units/mL) with no more than two uropathogens, and such clinical symptoms as fever, acute dysuria, urgency, increase in urinary frequency, pain or hypersensitivity in the area of bladder [4,5], to be sufficient to establish a diagnosis of UTI. Some of these symptoms are also the signs of an OAB [6,7]. Many researchers assume that, at least in some cases, OAB and UTI are interdependent processes and UTIs can be one of the reasons for the development of an OAB. Rodrigues et al. [8] reported involuntary detrusor contraction in 86.3% of patients with a UTI. Moore et al. [9] noted that despite the presence of different views on the mechanisms of formation of an OAB in cases of UTI, many researchers do not deny the cause-and-effect relationship between these conditions. It is common knowledge that OAB symptoms, especially frequency and imperative desire to urinate, cause involuntary urination that compromises the quality of life of elderly people, both men and women [10,11].\n\nNumerous studies have assessed solifenacin as a first-line drug for treating an OAB in elderly people [12,13]. Solifenacin is competitive inhibitor of M3 antimuscarinic receptors that comprise ⩾22% of all bladder cholinoreceptors, and play a key role in maintaining its normal physiological function [14]. Solifenacin is 3.6 times as selective for bladder receptors than for those in salivary glands. The indisputable advantages of this drug include the absence of addiction and a lasting result during long periods of use [15–17].\n\nAll these properties give a high efficacy and tolerability of solifenacin in elderly men and women, while taking this drug in increased dosages generally does not increase the number of adverse effects [18–21].\n\nPreviously we reported success in controlling the symptoms of OAB using standard and increased dosages of solifenacin and trospium in elderly persons [22–24]. Given these conditions, in the present study we assessed the efficacy and safety of solifenacin for treating residual symptoms of OAB in patients who had been treated for a UTI.\n\nPatients and methods\nThis was a placebo-controlled longitudinal study in patients aged >60 years who sought medical attention in the Urological Department of the 3rd Municipal Hospital (Vladivostok, Russian Federation) from 1 March to 31 December 2012. For this study, 524 patients (347 women, 66.2%, 177 men, 33.8%) who had been diagnosed with a UTI were selected using blinded random sampling. All of them denied the presence of signs of an OAB in their medical history. The study design is shown in Fig. 1. At least 1 month after the end of treatment, and laboratory confirmation of the absence of UTI (positive urine culture, ⩽105 colony-forming units/mL, a physiologically normal number of white and red blood cells in urine, and normal urine density) each patient completed the OAB-Awareness Tool (AT) questionnaire (OAB signs, total 8 points) [25,26], and had a noninvasive examination of urinary function (uroflowmetry) [27–29]. These results were taken as the baseline and determined the percentage of patients with signs of OAB, and the severity of symptoms. All patients with ОAB symptoms were randomly divided into three groups: A (107 patients, mean age 67.2 years), B (99, 65.9 years) and C (102, 65.1 years). Each day the patients in group A took solifenacin 10 mg, and those in group B 5 mg, with group C taking a placebo. The patients were assessed over 2 months, using urinary diaries, and a final assessment with the OAB-AT questionnaire and uroflowmetry. The efficacy of the treatment was assessed clinically by determining the number of urgency episodes (UE), incontinence episodes (IE), and episodes of daytime urination [30–32]. The second endpoint was a comparison of the conditions of the lower urinary tract (LUT) in the patients of each group after the treatment (see Fig. 2).\n\nThe results were analysed statistically by comparing those before and after treatment using the Wilcoxon test, comparing the medians at the three sample times using the Kruskal–Wallis criterion, and analysing the sample contingency using the Spearman index. In all tests, P < 0.05 was considered to indicate significant differences.\n\nResults\nAt 1 month after the end of treatment and the confirmed absence of laboratory signs of UTI, the results of the OAB-AT questionnaire, urinary diaries and uroflowmetry showed that ОAB symptoms were reported in 308 patients (192 women and 116 men, 58.8%). Most patients had symptoms of mild and medium severity (258, 83.8%). Patients complained mostly about an excessive frequency of urination throughout the day and night, and episodes of urgency.\n\nVariables of the LUT before and after solifenacin treatment are shown in Table 1. In group A, all values after the treatment differed significantly from baseline (some at P < 0.01). In group B the variability against the background of treatment was not as obvious, but most variables were significantly different from baseline. The mean (SD) night-time frequency according to both the OAB-AT questionnaire, of 1.7 (1.0) decreasing to 0.5 (0.5) (P > 0.01) and urinary diaries, of 2.3 (1.1) decreasing to 0.9 (0.6) (P > 0.01), were an exception. The variability in the maximum urinary flow rate for this group also increased unreliably, in contrast to the mean flow rate. The results in group C were not significantly different from baseline for all variables.\n\nAfter the end of treatment, the results were similar and there were no statistically significant differences in all variables between groups A and B, but there was a considerable difference between groups A and B and group C. The significant differences between the mean results in A and B and the control group are shown in the last column of Table 1. According to the OAB-AT questionnaire, the differences between final values of UE and IE in groups A and C was significant (P < 0.01). The differences between the final values in patients taking different doses of solifenacin were insignificant (P < 0.05). The differences between these groups and the control group were statistically significant (P < 0.05). For example, according to OAB-AT questionnaire, the daytime frequencies in those taking solifenacin were substantially lower than in group C, at 1.4 (0.8) and 1.4 (0.8) points, vs. 3.7 (1.2) (P < 0.05 in both cases). From the urinary diaries, the mean (SD) number of IE in groups A and B was lower than that in group C, at 0.1 (0.1) and 0.1 (0.1) vs. 0.5 (0.2) (P < 0.05 in both cases). Differences between the mean values of UE in group C and in groups A and B were marginal and statistically insignificant.\n\nThe uroflowmetry results showed a similar change in values. There were no differences between groups A and B, but significant differences in both the average and maximum flow rate between these groups and group C. The most significant (P < 0.01) was for the average flow rate in men (Table 1). The exception was for maximum flow rate in women between groups B and C (P > 0.05).\n\nA plot of the variability of number of UE and IE is shown in Fig. 1. The trend of change in groups A and B shows a synchronous frequency reduction by 3–5 times from the initial values. Changes in the group C over the whole period of monitoring fall within the limits of statistical accuracy.\n\nThe correlation of variability of day-time and nocturnal urinary frequency, urgency and incontinence associated with treatment showed that in groups A and B the correlation of the variability of day-time urinary frequency gave r = 0.83 (P < 0.01). The correlation coefficient between groups A and C, and B and C, was r = 0.43 (P < 0.05) and r = 0.36 (P < 0.05), respectively. The Spearman coefficient for curves of the variability of mean nocturnal urinary frequency between groups A and B was 0.79 (P < 0.05), between groups A and C was 0.45 (P < 0.05), and between groups B and C was 0.39 (P < 0.05). The correlation of urgency frequency was 0.74 (P < 0.05) between groups A and B, 0.56 (P < 0.05) between groups A and C, and 0.51 (P < 0.05) between groups B and C. Finally, the Spearman coefficient between the variability of incontinence in groups A and B was 0.81 (P < 0.01), between groups A and C was 0.61 (P < 0.05), and between groups B and C was 0.52 (P < 0.05). Thus there was a strong direct dependence between changes in the values in groups taking different doses of solifenacin, and the medium and mild severity between these groups and group C.\n\nIn all, 13 patients (4.2%) refused treatment during the study, of whom three refused for reasons unrelated to the study (one in each group), three due to acute exacerbation of chronic diseases of visceral organs (one in group B, two in group C), five because of intolerable side-effects (four in group A, one in group C), and two due to lack of a treatment response (both in group C).\n\nSide-effects were reported by 27 patients during the study, with complaints of dryness of the mouth (21 reported it, 12 in group A, eight in group B, one in group C) being the most numerous. Patients also noted episodes of faintness (two in group A), rash (one each in groups A and C), and diarrhoea (one each in groups B and C). There were no reported episodes of the acute urinary retention during the study.\n\nThus, only five (1.6%) patients refused to participate due to intolerable side-effects. Such effects of various degrees affected 27 others, but these patients found the intensity to be insufficient to justify stopping the treatment. The frequency and intensity of emergent adverse effects thus correlated with data of others who assessed the safety of solifenacin in elderly people.\n\nDiscussion\nDuring the present study, 58.8% of patients aged >60 years had symptoms of an OAB at 1 month after the end of treatment for a UTI and the normalisation of laboratory markers. During the treatment of OAB symptoms with standard and high doses of solifenacin over 8 weeks, most of the variables of the LUT reached normal values or improved. There were significant changes in urodynamic variables in both groups treated with solifenacin. From this we assume that standard dose of solifenacin is sufficient in most cases to manage OAB symptoms typical of elderly patients after a UTI.\n\nAs noted, the pathogenesis of OAB is not sufficiently clear, despite numerous investigations [33,34]. Most potential mechanisms for causing OAB include a decrease in the number of efficient muscarinic receptors in the detrusor, episodic noise or a decrease of coordination of the afferent impulses, detrusor hypoxia, pelvic floor prolapse and others [18,34–36]. We found that more than half of elderly patients have symptoms of an OAB in the month after a UTI (in most cases mild), which are corrected by standard doses of solifenacin. This correlates well with results from others and suggests that the bladder receptors are affected by toxins from pathogenic microorganisms during the inflammatory process [9,37–39]. Muscarinic receptor function might also be influenced by the decreased oxygenation typical of any inflammation. However, in this case the decrease in the activity of receptors is inverse, transient and can be relatively easily treated with antimuscarinic agents, which as a rule stimulate M3 receptors that are not damaged in the ageing bladder.\n\nThe efficacy and safety of solifenacin for treating OAB symptoms in elderly men and women have been confirmed previously [17], but with no correlation to the previous treatment of a UTI as a possible cause of the disease.\n\nThese assumptions undoubtedly need further study and clarification. Another field of study could be analysing the possibilities of decreasing the antimuscarinic drug dose.\n\nIn conclusion, patients aged >60 years who have had a UTI have a high risk of developing symptoms of an OAB. Solifenacin in standard doses is an efficient and safe means of managing OAB symptoms after a UTI. The use of high doses of solifenacin to correct residual OAB symptoms after a UTI is unreasonable.\n\nConflict of interest\nNone.\n\nSource of funding\nNone.\n\nPeer review under responsibility of Arab Association of Urology.\n\nFigure 1 Distribution of the groups, examinations and treatment. UF, uroflowmetry.\n\nFigure 2 Changes in the number of UE (A) and IE (B) after taking solifenacin.\n\nTable 1 Change in OAB questionnaire scores, urinary diary variables and uroflowmetry symptoms before and after treatment (308 patients).\n\n\tGroup (n), solifenacin dose\t\t\t\t\n\tA (107), 10 mg\tB (99) 5 mg\tC (102) placebo\tP after treatment\t\t\t\nMean (SD) variable\tBefore\tAfter\tBefore\tAfter\tBefore\tAfter\tA/B\tA/C\tB/C\t\nOAB-AT (score)\t\nDaytime frequency\t4.1 (1.5)\t1.4 (0.8)∗\t3.8 (1.1)\t1.4 (0.7)∗\t4.0 (0.9)\t3.7 (1.2)\tNS\t∗\t∗\t\nNight-time frequency\t2.1 (0.5)\t0.3 (0.5)∗∗\t1.7 (1.0)\t0.5 (0.5)\t1.5 (0.3)\t1.5 (0.4)\tNS\t∗\tNS\t\nUrgency\t2.5 (0.6)\t0.7 (0.5)∗∗\t2.0 (0.6)\t0.9 (0.5)∗\t2.7 (0.6)\t2.1 (0.6)\tNS\t∗\t∗\t\nUrgency incontinence\t1.4 (0.3)\t0.3 (0.3)∗∗\t1.7 (0.4)\t0.6 (0.4)∗\t1.7 (0.6)\t1.8 (0.5)\tNS\t∗∗\t∗\t\n\n\n\t\nUrinary diary (n episodes/day)\t\nDaytime frequency\t8.9 (1.4)\t5.3 (1.1)∗∗\t7.9 (0.9)\t5.5 (0.9)∗\t8.0 (0.7)\t7.4 (0.8)\tNS\t∗\t∗\t\nNight-time frequency\t2.9 (0.8)\t1.2 (0.5)∗\t2.3 (1.1)\t0.9 (0.6)\t2.8 (0.7)\t2.3 (0.4)\tNS\t∗\t∗\t\nUE\t3.1 (0.7)\t1.2 (1.0)∗\t2.8 (0.7)\t0.7 (0.8)∗∗\t2.5 (0.9)\t2.0 (1.0)\tNS\tNS\tNS\t\nIE\t0.5 (0.3)\t0.1 (0.1)∗\t0.6 (0.3)\t0.1 (0.1)∗\t0.4 (0.1)\t0.5(0.2)\tNS\t∗\t∗\t\n\n\n\t\nUroflowmetry\t\nAverage flow rate, mL/s\t\nMale\t9.9 (2.9)\t20.7 (3.5)∗∗\t9.6 (4.8)\t18.9 (2.9)∗\t8.8 (1.9)\t11.9 (1.5)\tNS\t∗\t∗\t\nFemale\t14.8 (4.1)\t22.0 (1.7)∗\t12.1 (6.1)\t23.0 (4.2)\t9.5 (2.7)\t13.9 (3.1)\tNS\t∗\t∗\t\n\n\n\t\nMax flow rate mL/s\t\nMale\t15.2 (3.0)\t22.9 (4.1)∗\t15.4 (1.7)\t19.6 (3.5)∗\t14.1 (2.3)\t14.7 (4.1)\tNS\t∗\tNS\t\nFemale\t19.8 (2.3)\t27.6 (1.8)∗∗\t18.7 (2.0)\t24.6 (2.1)∗\t18.8 (4.4)\t19.1 (1.3)\tNS\t∗\t∗\t\nNS, P > 0.05; *P < 0.05; **P < 0.01.\n==== Refs\nReferences\n1 Rowe T.A. Juthani-Mehta M. Urinary tract infection in older adults Aging Health 9 5 2013 \n2 Eriksson I. Gustafson Y. Fagerström L. Olofsson B. Do urinary tract infections affect morale among very old women? Health Qual Life Outcomes 8 2010 73 20650004 \n3 Matthews S.J. Lancaster J.W. Urinary tract infections in the elderly population Am J Geriatr Pharmacother 9 2011 286 309 21840265 \n4 Rowe T.A. Juthani-Mehta M. Diagnosis and management of urinary tract infection in older adults Infect Dis Clin North Am 28 2014 75 89 24484576 \n5 Mody L. Juthani-Mehta M. Urinary tract infections in older women: a clinical review JAMA 311 2014 844 854 24570248 \n6 de Ridder D. Roumeguère T. Kaufman L. Overactive bladder symptoms, stress urinary incontinence and associated bother in women aged 40 and above; a Belgian epidemiological survey Int J Clin Pract 67 2013 198 204 23409688 \n7 Kurita N. Yamazaki S. Fukumori N. Overactive bladder symptom severity is associated with falls in community-dwelling adults. The LOHAS Study BMJ Open 3 2013 e002413 \n8 Rodrigues P. Hering F. Campagnari J.C. Involuntary detrusor contraction is a frequent finding in patients with recurrent urinary tract infections Urol Int 93 2014 67 73 25011551 \n9 Moore K.H. Malykhina A.P. What is the role of covert infection in detrusor overactivity, and other LUTD? Neurourol Urodyn 33 2014 606 610 24844724 \n10 Espuña-Pons M. Castro-Díaz D. Díaz-Cuervo H. Pérez M. Impact of overactive bladder treatment on the quality of life of patients over 60 with associated pathologies Arch Esp Urol 66 2013 287 294 23648748 \n11 Patrick D.L. Khalaf K.M. Dmochowski R. Kowalski J.W. Globe D.R. Psychometric performance of the incontinence quality-of-life questionnaire among patients with overactive bladder and urinary incontinence Clin Ther 35 2013 836 845 23747076 \n12 Capo′ J.P. Lucente V. Forero-Schwanhaeuser S. He W. Efficacy and tolerability of solifenacin in patients aged >65 years with overactive bladder: post-hoc analysis of 2 open-label studies Postgrad Med 123 2011 94 104 21293089 \n13 Wagg A. Compion G. Fahey A. Siddiqui E. Persistence with prescribed antimuscarinic therapy for overactive bladder: a UK experience BJU Int 110 2012 1767 1774 22409769 \n14 Mansfield K.J. Liu L. Mitchelson F.J. Moore K.H. Millard R.J. Burcher E. Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radioligand binding and quantitative competitive RT-PCR. changes in ageing Br J Pharmacol 144 2005 1089 1099 15723094 \n15 Ikeda K. Kobayashi S. Suzuki M. Miyata K. Takeuchi M. Yamada T. M(3) receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland Naunyn Schmiedebergs Arch Pharmacol 366 2002 97 103 12122494 \n16 Ohtake A. Ukai M. Hatanaka T. Kobayashi S. Ikeda K. Sato S. In vitro and in vivo tissue selectivity profile of solifenacin succinate (YM905) for urinary bladder over salivary gland in rats Eur J Pharmacol 492 2004 243 250 15178371 \n17 Wagg A. Wyndaele J.J. Sieber P. Efficacy and tolerability of solifenacin in elderly subjects with overactive bladder syndrome: a pooled analysis Am J Geriatr Pharmacother 4 2006 14 24 16730617 \n18 Yoshida M. Miyamae K. Iwashita H. Otani M. Inadome A. Management detrusor dysfunction in the elderly: changes in acetylcholine and adenosine triphosphate release during aging Urology 63 Suppl. 1 2004 17 23 15013648 \n19 Chun J.Y. Song M. Han J.Y. Na S. Hong B. Choo M.S. Clinical factors associated with dose escalation of solifenacin for the treatment of overactive bladder in real life practice Int Neurourol J 18 2014 23 30 24729924 \n20 Natalin R. Lorenzetti F. Dambros M. Management of OAB in those over age 65 Curr Urol Report 14 2013 379 385 \n21 Amend B. Hennenlotter J. Schäfer T. Horstmann M. Stenzl A. Sievert K.-D. Effective treatment of neurogenic detrusor dysfunction by combined high-dosed antimuscarinics without increased side-effects Eur Urol 53 2008 1021 1028 18243516 \n22 Kosilov K.S. Loparev S. Ivanovskaya M. Kosilova L. Management of overactive bladder (OAB) in elderly men and women with combined, high-dose antimuscarinics without increased side effects Urotoday Int J 6 2013 Art 47 \n23 Kosilov K. Loparev S. Ivanovskaya M. Kosilova L. Maintenance of the therapeutic effect of two high-dosage antimuscarinics in the management of overactive bladder in elderly women Int Neurourol J 17 2013 191 196 24466467 \n24 Kosilov K.S. Loparev S. Ivanovskaya M. Kosilova L. Effectiveness of combined high-dosed trospium and solifenacin depending on severity of OAB symptoms in elderly men and women under cyclic therapy Cent Eur J Urol 67 2014 43 48 \n25 Coyne K.S. Zyczynski T. Margolis M.K. Elinoff V. Roberts R.G. Validation of an overactive bladder awareness tool for use in primary care settings Adv Ther 22 2005 381 394 16418145 \n26 Coyne K.S. Margolis M.K. Bavendam T. Roberts R. Elinoff V. Validation of a 3-item OAB awareness tool Int J Clin Pract 65 2011 219 224 21235701 \n27 Singh G. Lucas M. Dolan L. Knight S. Ramage C. Toozs Hobson P. Minimum standards for urodynamic practice in the UK Neurol Urodyn 29 2010 1365 1372 \n28 Schafer W. Abrams P. Liao L. Mattiasson A. Pesce F. Spangberg A. International Continence Society. Good urodynamic practices: uroflowmetry, filling cystometry, and pressure-flow studies Neurol Urodyn 21 2002 261 274 \n29 Gomes C.M. Arap S. Trigo-Rocha F.E. Voiding dysfunction and urodynamic abnormalities in elderly patients Rev Hosp Clín Fac Med S Paulo 59 2004 206 215 15361987 \n30 Parsons M. Amundsen C.L. Cardozo L. Vella M. Webster G.D. Coats A.C. Bladder diary patterns in detrusor overactivity and urodynamic stress incontinence Neurourol Urodyn 26 2007 800 806 17335054 \n31 Amundsen C.L. Parsons M. Cardozo L. Vella M. Webster G.D. Coats A.C. Bladder diary volume per void measurements in detrusor overactivity J Urol 176 2006 2530 2534 17085150 \n32 Okamura K. Nojiri Y. Yamamoto M. Kobayashi M. Okamoto Y. Yasui T. Questionnaire survey on lower urinary tract symptoms (LUTS) for patients attending general practice clinics Nihon Ronen Igakkai Zasshi 43 2006 498 504 16937943 \n33 Heesakkers J.P. Cruz F. Igawa Y. Kocjancic E. Overactive bladder: pathophysiology, diagnostics, and therapies Adv Urol 2011 863504 22761613 \n34 Griebling T.L. Overactive bladder in elderly men: epidemiology, evaluation, clinical effects, and management Curr Urol Report 14 2013 418 425 \n35 Andersson K.E. Antimuscarinics for treatment of overactive bladder Lancet Neurol 2004 46 53 14693111 \n36 Giannitsas K. Athanasopoulos A. Male overactive bladder: pharmacotherapy for the male Curr Opin Urol 23 2013 515 519 23851386 \n37 Hessdoerfer E. Jundt K. Peschers U. Is a dipstick test sufficient to exclude urinary tract infection in women with overactive bladder? Int Urogynecol J 22 2011 229 232 20838986 \n38 Mouttalib S. Khan S. Castel-Lacanal E. Guillotreau J. De Boissezon X. Malavaud B. Risk of urinary tract infection after detrusor botulinum toxin A injections for refractory neurogenic detrusor overactivity in patients with no antibiotic treatment BJU Int 106 2010 1677 1680 20590550 \n39 Antunes-Lopes T. Cruz C.D. Cruz F. Sievert K.D. Biomarkers in lower urinary tract symptoms/overactive bladder: a critical overview Curr Opin Urol 24 2014 352 357 24841379\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2090-598X",
"issue": "13(3)",
"journal": "Arab journal of urology",
"keywords": "Elderly men; IE, incontinence episodes; LUT, lower urinary tract; OAB, overactive bladder; OAB-AT, OAB Awareness Tool (questionnaire); Overactive bladder; Solifenacin; UE, urgency episodes; Urinary tract infection",
"medline_ta": "Arab J Urol",
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"other_id": null,
"pages": "203-8",
"pmc": null,
"pmid": "26413348",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article",
"references": "24391677;21840265;24484576;25011551;16937943;15723094;20590550;11948720;15013648;21293089;22761613;24570248;23645923;24841379;16730617;23747076;17335054;16418145;12122494;15178371;23648748;20650004;24466467;17085150;20838986;14693111;23409688;23851386;20976811;15361987;23913201;18243516;23922134;24844724;22409769;21235701;24982780;24729924",
"title": "The efficacy of different doses of solifenacin in elderly patients after treating a urinary tract infection.",
"title_normalized": "the efficacy of different doses of solifenacin in elderly patients after treating a urinary tract infection"
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"abstract": "Past studies have found an association between cochlear hydrops or early Meniere's disease and acute low-frequency hearing loss (ALHL) without vertigo. However, its mechanism remains unclear in some ALHL cases. This report presents a case of ALHL associated with iron-deficiency anemia (IDA). The patient was a 49-year-old female who had previously been treated with betamethasone for sudden hearing loss in the right ear. Eight months later, the symptoms recurred and cochlear hydrops was diagnosed. Isosorbide and betamethasone were administered orally, and intravenous hydrocortisone tapering was added 1 week later, but these treatments were ineffective. At the same time and subsequently, iron sucrose was intravenously administered for IDA, and the patient's hearing loss gradually resolved within 2 months. In view of the increase in serum hemoglobin levels after iron therapy, this might have been the most effective treatment in this case. The hearing loss could therefore be associated with the patient's IDA.",
"affiliations": "Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan.;Department of Otolaryngology, Akashi City Hospital, Akashi, Hyogo, Japan.;Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan.;Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan.;Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan.",
"authors": "Taki|Masakatsu|M|;Hasegawa|Tatsuhisa|T|;Ninoyu|Yuzuru|Y|;Mohri|Hiroaki|H|;Hirano|Shigeru|S|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5152/iao.2021.9369",
"fulltext": "\n==== Front\nJ Int Adv Otol\nJ Int Adv Otol\nThe Journal of International Advanced Otology\n1308-7649\n2148-3817\nEuropean Academy of Otology and Neurotology and the Politzer Society\n\n34617900\n10.5152/iao.2021.9369\njiao-17-5-465\nCase Report\nLow-Frequency Sensorineural Hearing Loss Associated With Iron-Deficiency Anemia\nTaki Masakatsu 1http://orcid.org/0000-0002-4314-5512\n\nHasegawa Tatsuhisa 2http://orcid.org/0000-0001-7579-953X\n\nNinoyu Yuzuru 1http://orcid.org/0000-0002-9407-4697\n\nMohri Hiroaki 1http://orcid.org/0000-0002-9164-1238\n\nHirano Shigeru 1http://orcid.org/0000-0003-1737-6613\n\n1 Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan\n2 Department of Otolaryngology, Akashi City Hospital, Akashi, Hyogo, Japan\nCorresponding author: Masakatsu Taki, e-mail: taki@koto.kpu-m.ac.jp\nORCID IDs of the authors: M.T. 0000-0002-4314-5512; T.H. 0000-0001-7579-953X; Y.N. 0000-0002-9407-4697; H.M. 0000-0002-9164-1238; S.H. 0000-0003-1737-6613\n\nCite this article as: Taki M, Hasegawa T, Ninoyu Y, Mohri H, Hirano S. Low-frequency sensorineural hearing loss associated with iron-deficiency anemia. J Int Adv Otol. 2021; 17(5): 465-467 .\n\n9 2021\n01 9 2021\n17 5 465467\n18 8 2020\n27 10 2020\n2021 authors\n2021\nauthors\nhttps://creativecommons.org/licenses/by-nc/4.0/ Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.\nPast studies have found an association between cochlear hydrops or early Meniere’s disease and acute low-frequency hearing loss (ALHL) without vertigo. However, its mechanism remains unclear in some ALHL cases. This report presents a case of ALHL associated with iron-deficiency anemia (IDA). The patient was a 49-year-old female who had previously been treated with betamethasone for sudden hearing loss in the right ear. Eight months later, the symptoms recurred and cochlear hydrops was diagnosed. Isosorbide and betamethasone were administered orally, and intravenous hydrocortisone tapering was added 1 week later, but these treatments were ineffective. At the same time and subsequently, iron sucrose was intravenously administered for IDA, and the patient’s hearing loss gradually resolved within 2 months. In view of the increase in serum hemoglobin levels after iron therapy, this might have been the most effective treatment in this case. The hearing loss could therefore be associated with the patient’s IDA.\n\nKeywords:\n\nLow-frequency sensorineural hearing loss\niron\nanemia\nALHL\nThe authors declared that this study has received no financial support.\n==== Body\npmcIntroduction\n\nAcute low-frequency hearing loss (ALHL) without vertigo has been defined as a distinct entity from idiopathic sudden sensorineural hearing loss (ISSNHL) and shows good prognosis.1 Although some studies have found an association with cochlear hydrops or early Meniere’s disease,2,3 its mechanism remains unclear in some ALHL cases. Iron-deficiency anemia (IDA) is common and accounts for approximately half of all anemia cases worldwide. The disease is caused by insufficient dietary intake and/or absorption of iron and/or loss of iron through bleeding of the intestinal, uterine, or urinary tracts.4 Although several studies have shown an association between sensorineural hearing loss (SNHL) and IDA,4-6 there are no existing reports on the relationship between ALHL in particular, and IDA. Here, we report a case of ALHL probably associated with IDA.\n\nCase Presentation\n\nThe patient was a 49-year-old female who visited an ENT clinic for a loss of hearing in her right ear. Pure-tone audiometry (PTA) showed low-frequency SNHL in the right ear. Diagnosed as ISSNHL, oral betamethasone was administered at a daily dose of 6 mg, and the patient’s hearing had improved to normal 2 days later. After 8 months, the patient again experienced hearing loss and fullness in the right ear and visited another ENT clinic. She did not have vertigo, and both ear drums were normal. PTA again showed low-frequency SNHL in the right ear (Figure 1A). The patient was referred to a hospital, where prednisolone was intravenously administered on days 1 to 3 at a daily dose of 60 mg; a subsequent PTA showed no change in condition. Endolymphatic hydrops was suspected because of the recurrent low-frequency SNHL. The patient was treated with 60 mL of 70% isosorbide, an osmotic diuretic, daily, and tapering oral betamethasone with an initial dose of 3 mg decreasing to 1 mg over a period of 6 days. One week later (day 11), PTA showed no improvement. The patient was therefore treated with tapering intravenous hydrocortisone succinate as a higher steroid dose at 300 mg for 2 days, 200 mg for 3 days, and 100 mg for 3 days, but the hearing loss did not completely resolve (Figure 1B). A re-administration of isosorbide from days 25 to 39 was also ineffective, and the hearing level was seen to deteriorate on day 25 (Figure 1C).\n\nThe laboratory examination from day 1 showed microcytic anemia (serum hemoglobin (Hb): 8.3 g/dL; hematocrit: 26.7%; mean corpuscular volume: 75.4 fL). The serum iron level was 28 μg/dL, and the unsaturated iron-binding capacity was 349 μg/dL. These data were compatible with IDA. Considering that the patient had experienced nausea with oral iron tablets, intravenous iron sucrose was administered in 80 mg doses 13 times over 2 months. The total dose of iron sucrose was calculated based on the formula: [target Hb−actual Hb (g/dL)] × 2.4 × body weight (kg) + iron stores (mg)].7 The iron sucrose injections were intermittently administered because of the patient’s schedule. On day 28, the serum Hb level had increased to 11.2 g/dL, near the cut-off value of 12 g/dL in non-pregnant adult women.8 On day 53, PTA showed a significant improvement, despite the cessation of steroid therapy. On day 67, the patient’s hearing level had resolved almost to normal (Figure 1D). Figure 2 illustrates the clinical course including laboratory data, therapies, and mean PTA thresholds at low frequencies (125, 250, and 500 Hz). In view of the increase in serum Hb after iron sucrose administration, iron therapy could be the most effective element in hearing loss management in this case.\n\nDiscussion\n\nThe clinical features of and treatments for ALHL have been discussed in Japan and Korea [1-3,9-11]. A recurrence of hearing loss, and subsequent progression to Meniere’s disease, can suggest a pathophysiology of cochlear endolymphatic hydrops and early-stage Meniere’s.2,3 In terms of ALHL treatment, the efficacy of steroids is controversial. Morita et al.9 showed that recovery rates with a combination of steroids and diuretics were significantly better (91.3%) than those of the control group (66.7%), and of steroids (75.5%) or diuretics (75%) alone. Other studies have also shown significantly high recovery rates of around 80% with combined oral steroid and diuretic treatment.10,11 In the present case, a combination of steroid and diuretic as well as an intravenous steroid were ineffective. However, iron therapy for IDA was possibly effective 2 months later, since neither steroid nor diuretic was administered for a month preceding hearing improvement. The pathophysiology in this case might therefore be a non-hydrops cause. In general, patients with IDA should manifest a response to iron with reticulocytosis in 3 to 7 days, followed by an increase in Hb in 2 to 4 weeks.7 Although the laboratory examinations were not repeated, the increase in Hb to normal level was predicted after the iron sucrose course had been administered.\n\nSome researchers have described the association between ISSNHL and IDA,4,5 with a recent American survey of adults indicating a significant relationship between IDA and SNHL with increased odds of 1.82.6 A vascular mechanism has been proposed to explain the hearing loss due to IDA in that the cochlea is highly susceptible to ischemic damage, since only the labyrinthine artery supplies blood to this area. Another hypothesis is reactive thrombocytosis associated with IDA.6 Our patient presented with fluctuation and recurrence of hearing loss, and therefore it is unlikely that her hearing loss was associated with any stroke-like vascular mechanism. On the other hand, animal studies have shown that iron deficiency can influence cochlear changes by itself, including strial atrophy and a reduction of spiral ganglion cells, which can permanently impact the stereocilia of the inner and outer hair cells.12,13 However, our patient’s hearing loss was not irreversible. Elsewhere, Sun et al.5 reported significant improvements in clinical results using iron therapy in ISSNHL patients, supporting the possible efficacy of iron sucrose treatment in our patient.\n\nNo studies have shown the lesion sides or impaired frequencies in patients with IDA-associated SNHL. However, many studies have shown bilateral and unilateral SNHL at various frequencies in patients with sickle cell anemia (SCA).14 Onakoya et al.15 reported both bilateral (62%) and unilateral (left ear, 18%; right ear, 20%) SNHL in patients with SCA. While high-frequency SNHL was observed in most patients, low-frequency SNHL was observed in some patients, particularly in the right ear (5.6%). Low-frequency SNHL may be caused by diffuse damage to the cochlear organs rather than to the basal turn alone.15 These studies suggest that anemia, including IDA, can cause low-frequency SNHL only unilaterally, similar to Meniere’s disease.\n\nIDA is highly prevalent in women of child-bearing age because of insufficient iron consumption to compensate for blood loss through menstruation.8 ALHL is also significantly prevalent in young female individuals.2 The shared etiology of both conditions supports the possibility that IDA is a key factor in our patient’s ALHL.\n\nConclusion\n\nThe clinical course of this patient suggests a possible association between ALHL and IDA. Serum Hb and iron levels should be examined for this type of SNHL, particularly in premenopausal females.\n\nFigure 1. Pure-tone audiometry from the onset of hearing loss: (A) Day 1; (B) Day 18; (C) Day 39; (D) Day 67.\n\nFigure 2. The clinical course: Circles with continuous lines indicate mean PTA thresholds at 125, 250, and 500 Hz (left-sided ordinate); Triangles with continuous lines indicate serum Hb levels (right-sided ordinate); Arrow with dotted line indicates predictive increase to target Hb; Thick arrows indicate days when iron sucrose was administered intravenously; Thick black bars indicate when isosorbide was administered; Open bars indicate the periods and doses of each steroid therapy (PSL, prednisolone; B, betamethasone; HYD, hydrocortisone succinate).\n\nInformed Consent: Verbal informed consent was obtained from the patient.\n\nPeer Review: Externally peer-reviewed.\n\nAuthor Contributions: Concept – M.T., T.H., Y.N., S.H.; Design – M.T., T.H.; Supervision – M.T.; Resource – M.T., H.M.; Materials – M.T., Y.N., H.M.; Data Collection and/or Processing – M.T., H.M.; Analysis and/or Interpretation – M.T., T.H., S.H.; Literature Search – M.T.; Writing – M.T., T.H.; Critical Reviews – M.T.\n\nConflict of Interest: The authors have no conflict of interest to declare.\n==== Refs\nReferences\n\n1. Abe T Acute sensorineural hearing loss in low-tone frequencies. Otolaryngol Tokyo. 1982;54 :385 3 92.\n2. Sato H Kuwashima S Nishio SY , et al. Epidemiological survey of acute low-tone sensorineural hearing loss. Acta Otolaryngol. 2017;137 (suppl565):S34 S3 7. 10.1080/00016489.2017.1297538) 28366042\n3. Yamasoba T Kikuchi S Sugasawa M Yagi M Harada T . Acute low-tone sensorineural hearing loss without vertigo. Arch Otolaryngol Head Neck Surg. 1994;120 (5):532 53 5. 10.1001/archotol.1994.01880290042007) 8172704\n4. Chung SD Chen PY Lin HC Hung SH . Sudden sensorineural hearing loss associated with iron-deficiency anemia: a population-based study. JAMA Otolaryngol Head Neck Surg. 2014;140 (5):417 4 22. 10.1001/jamaoto.2014.75) 24626300\n5. Sun AH Wang ZM Xiao SZ , et al. Idiopathic sudden hearing loss and disturbance of iron metabolism. A clinical survey of 426 cases. ORL J Otorhinolaryngol Relat Spec. 1992;54 (2):66 70. 10.1159/000276264) 1614687\n6. Schieffer KM Chuang CH Connor J Pawelczyk JA Sekhar DL . Association of iron deficiency anemia with hearing loss in US adults. JAMA Otolaryngol Head Neck Surg. 2017;143 (4):350 35 4. 10.1001/jamaoto.2016.3631) 28033450\n7. Alleyne M Horne MK Miller JL . Individualized treatment for iron-deficiency anemia in adults. Am J Med. 2008;121 (11):943 94 8. 10.1016/j.amjmed.2008.07.012) 18954837\n8. World Health Organization, United Nations Children’s Emergency Fund, United Nations University. Iron Deficiency Anaemia Assessment, Prevention, and Control: a Guide for Programme Managers. Geneva, World Health Organization; 2001.\n9. Morita S Suzuki M Iizuka K . A comparison of the short-term outcome in patients with acute low-tone sensorineural hearing loss. ORL J Otorhinolaryngol Relat Spec. 2010;72 (6):295 29 9. 10.1159/000314695) 20814223\n10. Choi HG Park KH Seo JH , et al. Clinical and audiologic characteristics of acute low-tone sensorineural hearing loss: therapeutic response and prognosis. Korean J Audiol. 2011;15 :8 14.\n11. Im GJ Kim SK Choi J , et al. Analysis of audio-vestibular assessment in acute low-tone hearing loss. Acta Otolaryngol. 2016;136 (7):649 6 54. 10.3109/00016489.2016.1152506) 26963446\n12. Sun AH Xiao SZ Li BS , et al. Iron deficiency and hearing loss. Experimental study in growing rats. ORL J Otorhinolaryngol Relat Spec. 1987;49 (3):118 1 22. 10.1159/000275920) 3614852\n13. Sun AH Wang ZM Xiao SZ , et al. Sudden sensorineural hearing loss induced by experimental iron deficiency in rats. ORL J Otorhinolaryngol Relat Spec. 1992;54 (5):246 2 50. 10.1159/000276307) 1488246\n14. Rissatto-Lago MR Fernandes LDC Alves AAG , et al. Dysfunction of the auditory system in sickle cell anaemia: a systematic review with meta-analysis. Trop Med Int Health. 2019;24 (11):1264 12 76. 10.1111/tmi.13307) 31495037\n15. Onakoya PA Nwaorgu OGB Shokunbi WA . Sensorineural hearing loss in adults with sickle cell anaemia. Afr J Med Sci. 2002;31 (1):21 2 4.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1308-7649",
"issue": "17(5)",
"journal": "The journal of international advanced otology",
"keywords": null,
"medline_ta": "J Int Adv Otol",
"mesh_terms": "D018798:Anemia, Iron-Deficiency; D018159:Endolymphatic Hydrops; D005260:Female; D006319:Hearing Loss, Sensorineural; D003639:Hearing Loss, Sudden; D006801:Humans; D008875:Middle Aged; D014717:Vertigo",
"nlm_unique_id": "101522982",
"other_id": null,
"pages": "465-467",
"pmc": null,
"pmid": "34617900",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Low-Frequency Sensorineural Hearing Loss Associated With Iron-Deficiency Anemia.",
"title_normalized": "low frequency sensorineural hearing loss associated with iron deficiency anemia"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2021-22160",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BETAMETHASONE"
},
"drugadditio... |
{
"abstract": "Block anesthesia for the maxillary division (V2) of the trigeminal nerve is a suitable approach when an entire quadrant of teeth and/or associated structures are involved. The most effective approach to anesthetize the maxillary branch is intraorally via the greater palatine canal. This case report describes the use of a computer-aided design/computer-assisted manufacturing (CAD/CAM) implant surgical template designed with a guide channel to allow for the administration of maxillary nerve block through the greater palatine canal.",
"affiliations": null,
"authors": "Jamjoom|Faris Z|FZ|;Doliveux|Simon|S|;Rousson|Dominique D|DD|;Friedland|Bernard|B|;Hamilton|Adam|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.11607/jomi.7734",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0882-2786",
"issue": "33(5)",
"journal": "The International journal of oral & maxillofacial implants",
"keywords": null,
"medline_ta": "Int J Oral Maxillofac Implants",
"mesh_terms": "D000766:Anesthesia, Dental; D017076:Computer-Aided Design; D006801:Humans; D008437:Maxilla; D008442:Maxillary Nerve; D009407:Nerve Block",
"nlm_unique_id": "8611905",
"other_id": null,
"pages": "1254-1259",
"pmc": null,
"pmid": "31528868",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Modified Implant Surgical Guide for the Administration of Maxillary Nerve Block Anesthesia Intraorally via the Greater Palatine Foramen: Case Report.",
"title_normalized": "a modified implant surgical guide for the administration of maxillary nerve block anesthesia intraorally via the greater palatine foramen case report"
} | [
{
"companynumb": "US-SEPTODONT-201905661",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPINEPHRINE\\LIDOCAINE HYDROCHLORIDE"
},
"drugad... |
{
"abstract": "A recurrence of hepatitis C virus (HCV) after liver transplantation affects survival in human immunodeficiency virus (HIV)/HCV coinfected patients. This study assessed the efficacy and safety of sofosbuvir (SOF)-based regimens in HIV/HCV coinfected patients after liver transplantation.\n\n\n\nTwenty-nine HIV/HCV coinfected transplanted patients receiving tacrolimus-, cyclosporine-, or everolimus-based immunosuppressive therapy were enrolled in the Compassionate Use of Protease Inhibitors in Viral C Liver Transplantation cohort. Their antiviral treatment combined SOF, daclatasvir with or without ribavirin (n = 10/n = 6), or SOF, ledipasvir with or without ribavirin (n = 2/n = 11).\n\n\n\nThe median delay between liver transplantation and treatment initiation was 37.5 months (interquartile range [IQR], 14.4-99.2). The breakdown of HCV genotypes was G1, 22 patients (75.9%); G3, 3 patients (10.3%); and G4, 4 patients (13.8%). The treatment indications were HCV recurrence (≥ F1 n = 23) or fibrosing cholestatic hepatitis (n = 6). Before starting SOF, the HCV viral load and CD4 count were 6.7 log10 IU/mL (IQR, 5.9-7.2) and 342 cells/mm (IQR, 172-483), respectively. At week 4, the HCV viral load was less than 15 IU/mL in 12 (42.9%) patients. The overall sustained virological response 12 was 96.6%. No significant drug-drug interactions were observed.\n\n\n\nSOF-based treatment regimens produced excellent results in HIV/HCV coinfected patients after liver transplantation, suggesting an important change in their prognosis.",
"affiliations": "AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, France.;AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, France.;Rennes 1 University, Pontchaillou University Hospital, Service de Pharmacologie, Rennes, France.;Rennes 1 University, Pontchaillou University Hospital, Service de Pharmacologie, Rennes, France.;Unité de Transplantation, Hôpital Edouard Herriot, Hépatique, Lyon, France.;Clinique Universitaire d'Hépato-Gastroentérologie, Pôle Digidune, CHU de Grenoble, France.;Rennes 1 University, Pontchaillou University Hospital, Service de Pharmacologie, Rennes, France.;Hôpital de la Croix Rousse, Service de Transplantation Hépatique, Lyon, France.;CHU Conception, Service d'Hépato-gastroentérologie, Marseille, France.;Service d'Hépatologie et Réanimation Hépato-Digestive INSERM U773, Université Paris VII, Hôpital Beaujon, Clichy, France.;Université de Rennes 1, Service des Maladies du Foie, INSERM U991, Rennes, France.;Department of Organ Transplantation, CHU Rangueil, Toulouse, France.;CHRU de Lille, Service d'Hépatologie, Hôpital Huriez, Lille, France.;Service de MPU Infectiologie CHD Vendée, La Roche sur Yon, France.;Service d'Hépato-Gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, France.;Unit for Basic and Clinical Research on Viral Hepatitis, ANRS (France REcherche Nord&Sud Sida-HIV Hépatites) Paris, France.;Unit for Basic and Clinical Research on Viral Hepatitis, ANRS (France REcherche Nord&Sud Sida-HIV Hépatites) Paris, France.;DHU Hepatinov, Villejuif, France.;AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, France.;Département d'Hépato-gastroentérologie et de Transplantation Hépatique, CHU Saint-Eloi, Montpellier, France.;AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, France.",
"authors": "Antonini|Teresa Maria|TM|;Coilly|Audrey|A|;Rossignol|Emilie|E|;Fougerou-Leurent|Claire|C|;Dumortier|Jérôme|J|;Leroy|Vincent|V|;Veislinger|Aurélie|A|;Radenne|Sylvie|S|;Botta-Fridlund|Danielle|D|;Durand|François|F|;Houssel-Debry|Pauline|P|;Kamar|Nassim|N|;Canva|Valérie|V|;Perré|Philippe|P|;De Ledinghen|Victor|V|;Rohel|Alexandra|A|;Diallo|Alpha|A|;Taburet|Anne-Marie|AM|;Samuel|Didier|D|;Pageaux|Georges-Philippe|GP|;Duclos-Vallée|Jean-Charles|JC|;|||",
"chemical_list": "D000998:Antiviral Agents; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000001928",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "102(1)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000998:Antiviral Agents; D060085:Coinfection; D005260:Female; D015658:HIV Infections; D006526:Hepatitis C; D006801:Humans; D008099:Liver; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D000069474:Sofosbuvir",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "119-126",
"pmc": null,
"pmid": "28846559",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Sofosbuvir-Based Regimens in HIV/HCV Coinfected Patients After Liver Transplantation: Results From the ANRS CO23 CUPILT Study.",
"title_normalized": "sofosbuvir based regimens in hiv hcv coinfected patients after liver transplantation results from the anrs co23 cupilt study"
} | [
{
"companynumb": "FR-ROCHE-2074517",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SOFOSBUVIR"
},
"drugadditional": "3",
"druga... |
{
"abstract": "OBJECTIVE\nImmune checkpoints inhibitors (ICI) represent a new therapy option for the treatment of several advanced tumors. However, this therapy has been linked to a spectrum of ICI related autoimmune (AI) adverse events. Some may be life threatening and their diagnosis is tricky. The aim of our study was to describe various imaging appearances of ICI related secondary hypophysitis and other coincidental AI diseases.\n\n\nMETHODS\nWe included 28 patients (19 females, 9 men, mean aged 58±13 years), who were consecutively treated mostly for advanced stage melanoma by different ICI. All their CT/MRI records and clinical data were reviewed.\n\n\nRESULTS\nWe found 5 (18%) cases of endocrinology proven secondary hypophysitis; 2 cases of panhypopituitarism and 3 cases of central hypocortisolism. Four cases were MRI positive, 1 case was MRI negative. Three cases were accompanied by other AI diseases: 1 by hemorrhagic colitis and mesenterial lymphadenitis, 1 by AI pancreatitis and 1 by pneumonitis. On MRI pituitary gland was swollen in 3 cases, twice enhanced non-homogenously, once homogenously; infundibular enlargement was present in 2 cases. Those 3 cases reacted to glucocorticoid therapy by hypophyseal shrinkage. In 1 case of MRI positive hypophysitis, the pituitary gland was not enlarged, slightly nonhomogeneous with peripheral contour enhancement; no reaction to glucocorticoids was mentioned.\n\n\nCONCLUSIONS\nSecondary hypophysitis is probably more common ICI related adverse event than reported in the literature. Its MRI appearance is variable. Most of our cases were in coincidence with other AI ICI related events that affected their clinical manifestations.",
"affiliations": "Radiology Department, Third Faculty of Medicine, Charles University, Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic.;Radiology Department, Third Faculty of Medicine, Charles University, Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic.;Department of Dermatology, Third Faculty of Medicine, Charles University, Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic.;Department of Dermatology, Third Faculty of Medicine, Charles University, Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic.;Radiology Department, Third Faculty of Medicine, Charles University, Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic.",
"authors": "Malikova|Hana|H|;Holesta|Michal|M|;Fialova|Alena|A|;Arenbergerova|Monika|M|;Weichet|Jiri|J|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000074324:Ipilimumab; C582435:pembrolizumab; D006854:Hydrocortisone",
"country": "Sweden",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-780X",
"issue": "39(3)",
"journal": "Neuro endocrinology letters",
"keywords": null,
"medline_ta": "Neuro Endocrinol Lett",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D001327:Autoimmune Diseases; D000069281:Autoimmune Hypophysitis; D003092:Colitis; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D007018:Hypopituitarism; D000074324:Ipilimumab; D008199:Lymphadenitis; D008279:Magnetic Resonance Imaging; D008297:Male; D008545:Melanoma; D008643:Mesentery; D008875:Middle Aged; D009367:Neoplasm Staging; D010195:Pancreatitis; D010902:Pituitary Gland; D011014:Pneumonia; D012189:Retrospective Studies; D012878:Skin Neoplasms; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8008373",
"other_id": null,
"pages": "196-204",
"pmc": null,
"pmid": "30431741",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hypophysitis and other autoimmune complications related to immune checkpoints inhibitors´ treatment: Spectrum of imaging appearances.",
"title_normalized": "hypophysitis and other autoimmune complications related to immune checkpoints inhibitors treatment spectrum of imaging appearances"
} | [
{
"companynumb": "PHHY2019CZ068928",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND\nTimolol eye-drops are commonly used for the treatment of glaucoma. Despite being topically applied, some systemic absorption occurs with the resulting adverse reactions related to its beta-adrenoreceptor blocking activity\n\n\nMETHODS\nWe report the case of a 68 years old healthy male who was admitted to our department for further workup following two episodes of syncope. Medical history taking revealed that the episodes of syncope occurred soon after beginning treatment with intra-ocular timolol for glaucoma. An electrocardiogram demonstrated a sinus bradycardia rhythm and a prolonged PR interval, consistent with the negative effects of a beta adrenergic receptor antagonist on the heart's electrical generation and conduction system.\n\n\nCONCLUSIONS\nThis case demonstrates the potential for dangerous systemic side effects of a topically-applied medication. It also highlights the importance of thorough medical history taking in the evaluation of syncope, including inquiry regarding the use of all, especially new, medications.\n\n\nCONCLUSIONS\nDetailed medical history taking can help in avoiding the performance of an expensive and unnecessary workup.",
"affiliations": null,
"authors": "Eyal|Allon|A|;Braun|Eyal|E|;Naffaa|Mohammad E|ME|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D013999:Timolol",
"country": "Israel",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-7768",
"issue": "154(11)",
"journal": "Harefuah",
"keywords": null,
"medline_ta": "Harefuah",
"mesh_terms": "D060433:Administration, Ophthalmic; D000319:Adrenergic beta-Antagonists; D000368:Aged; D005901:Glaucoma; D006801:Humans; D008297:Male; D013575:Syncope; D013999:Timolol",
"nlm_unique_id": "0034351",
"other_id": null,
"pages": "701-2, 742",
"pmc": null,
"pmid": "26821501",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "SYNCOPE CAUSED BY INTRA-OCULAR TIMOLOL.",
"title_normalized": "syncope caused by intra ocular timolol"
} | [
{
"companynumb": "IL-BAUSCH-BL-2016-004513",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TIMOLOL"
},
"drugadditional": "1",
"... |
{
"abstract": "To evaluate the risk of nonsteroidal anti-inflammatory drug (NSAID) therapy-associated acute kidney injury (AKI) among neonates diagnosed with patent ductus arteriosus (PDA) who are treated with gentamicin.\n\n\n\nMulticenter retrospective observational study of patients ⩽44 postmenstrual weeks of age diagnosed with PDA who received gentamicin during hospitalization between January 2006 and December 2014. Patients with and without NSAID exposure were matched on covariates associated with AKI and NSAID therapy. The primary end point, AKI, was defined according to Kidney Disease Improving Global Outcomes neonatal criteria.\n\n\n\nThe rate of AKI for the entire cohort (n=594) was 12% (n=71). Among neonates receiving NSAIDS, 14.8% (n=44) experienced an AKI as compared to 9.1% (n=27) for those who were not exposed (relative risk, 1.6; 95% confidence interval, 1.0 to 2.6). Therefore, the attributable risk of NSAID use was 5.7% (95% confidence interval, 0.5 to 11.0).\n\n\n\nAmong neonates with PDA and receiving gentamicin, NSAID therapy increases the risk of AKI by about 6%.",
"affiliations": "Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.;Section of Paediatrics and Child Health, Dunedin School of Medicine, University of Otago, Dunedin, Otago, New Zealand.;Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.;Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.;Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.;Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.;Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.;Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.",
"authors": "Constance|J E|JE|;Reith|D|D|;Ward|R M|RM|;Balch|A|A|;Stockmann|C|C|;Korgenski|E K|EK|;Thorell|E A|EA|;Sherwin|C M T|CMT|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005839:Gentamicins",
"country": "United States",
"delete": false,
"doi": "10.1038/jp.2017.80",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0743-8346",
"issue": "37(10)",
"journal": "Journal of perinatology : official journal of the California Perinatal Association",
"keywords": null,
"medline_ta": "J Perinatol",
"mesh_terms": "D058186:Acute Kidney Injury; D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016022:Case-Control Studies; D004374:Ductus Arteriosus, Patent; D005260:Female; D005839:Gentamicins; D006760:Hospitalization; D006801:Humans; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D007234:Infant, Premature; D008137:Longitudinal Studies; D008297:Male; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "8501884",
"other_id": null,
"pages": "1093-1102",
"pmc": null,
"pmid": "28594394",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "26831913;20614421;18288122;24048379;20494739;10974130;20459609;25114597;10699097;10752764;10586010;24168068;26735892;21809002;19701859;27537855;21947273;26898806;15007713;22572776;25675426;20651693;23055893;25863473;21636639;24839217;24606507;11430325;25766737;21178824;20442340;21071516;18307541;27144699;19067286;26879388;19159727;21427457;7242577;22670489;11889306;21818162;25032825;26400103;9521382;27490643;26796125;24150030;26169430;23224224;20936523;13936192;25088343;25343815;24899060;22284563;20182439;23883698;27338726;25280497;22341541",
"title": "Risk of nonsteroidal anti-inflammatory drug-associated renal dysfunction among neonates diagnosed with patent ductus arteriosus and treated with gentamicin.",
"title_normalized": "risk of nonsteroidal anti inflammatory drug associated renal dysfunction among neonates diagnosed with patent ductus arteriosus and treated with gentamicin"
} | [
{
"companynumb": "US-JNJFOC-20171034598",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
"d... |
{
"abstract": "Sprue-like enteropathy associated with olmesartan is characterized by villous atrophy in the duodenum. We report the case of an 81-year-old woman diagnosed with olmesartan-associated sprue-like enteropathy with no villous atrophy in the duodenum. The patient had been taking olmesartan for 10 years and complained of diarrhea and weight loss. Despite undergoing general treatment for 2 months, her symptoms showed no improvement. Gastrointestinal endoscopy and pathological findings showed no villous atrophy in the duodenum. However, villous atrophy was observed in the small intestine by capsule endoscopy. Pathological biopsy with double balloon endoscopy provided a definitive diagnosis. Diarrhea improved with the discontinuation of olmesartan and weight increased within a week of withdrawal. After the improvement of clinical symptoms, both endoscopic and pathological findings of villous atrophy in small intestine showed improvement.",
"affiliations": "Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu , Gifu, 501-1194, Japan. fiction_may_relieve@yahoo.co.jp.;Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu , Gifu, 501-1194, Japan.;Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu , Gifu, 501-1194, Japan.;Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu , Gifu, 501-1194, Japan.;Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu , Gifu, 501-1194, Japan.;Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu , Gifu, 501-1194, Japan.;Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu , Gifu, 501-1194, Japan.;Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu , Gifu, 501-1194, Japan.;Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu , Gifu, 501-1194, Japan.;Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu , Gifu, 501-1194, Japan.",
"authors": "Taguchi|Daisuke|D|http://orcid.org/0000-0001-6626-7320;Ibuka|Takashi|T|;Arao|Masamichi|M|;Mizutani|Taku|T|;Ozawa|Noritaka|N|;Kubota|Masaya|M|;Shirakami|Yohei|Y|;Shiraki|Makoto|M|;Araki|Hiroshi|H|;Shimizu|Masahito|M|",
"chemical_list": "D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-021-01514-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "14(6)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Capsule endoscopy; Double balloon endoscopy; Olmesartan; Sprue-like enteropathy; Villous atrophy",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000369:Aged, 80 and over; D053704:Capsule Endoscopy; D002446:Celiac Disease; D005260:Female; D006801:Humans; D007093:Imidazoles; D013777:Tetrazoles",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "1649-1654",
"pmc": null,
"pmid": "34480728",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24711933",
"title": "Olmesartan-associated sprue-like enteropathy diagnosed by capsule endoscopy and double balloon endoscopy.",
"title_normalized": "olmesartan associated sprue like enteropathy diagnosed by capsule endoscopy and double balloon endoscopy"
} | [
{
"companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2021-07657",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLMESARTAN"
},
"druga... |
{
"abstract": "The novel available interferon (IFN)-free regimens significantly improved the sustained virological response (SVR) in patients with chronic hepatitis C (CHC), without important side effects and with shorter duration of treatment. In a subset of patients, however, the treatment failure (TF) was due to the presence of resistance-associated substitutions (RAS) that lead to virological breakthrough (BT) or relapse. We analysed in this case series the role of RAS on the TF in cirrhotic patients with genotype (GT)4, treated with a previous IFN-free regimen, and retreated with the combination of sofosbuvir (SOF)/velpatasvir (VEL) for 12 or 24 weeks, without ribavirin (RBV).\n\n\n\nWe included in this analysis all patients with GT4 who failed a previous IFN-free treatment, with the presence of RAS at BT or relapse. All patients were retreated with a fixed combination of SOF/VEL for 12/24 weeks, without RBV. We evaluated the SVR and the MELD score change after the treatment.\n\n\n\nSeven patients were described. All were cirrhotic, Child-Pugh A (n=5), B (n=2); baseline RAS were detected in 4/7 subjects; at post-treatment detection, NS5 RAS were: F28S (n=1), Q30K (n=2), S30G (n=1), NS3 were: S122R (n=1), S122G (n=2), D168V (n=3). All retreated patients gained SVR. MELD score improved in all subjects with a median change of 3 points. No significant side effects or adverse events were reported.\n\n\n\nThe combination SOF/VEL could be considered for the retreatment of cirrhotic GT4 patients who failed a previous IFN-free treatment with the presence of RAS in NS3 or NS5 regions.",
"affiliations": "Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.;Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.;Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.;Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.;Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.",
"authors": "Boglione|Lucio|L|;Pinna|Simone Mornese|SM|;Lupia|Tommaso|T|;Cariti|Giuseppe|G|;Di Perri|Giovanni|G|",
"chemical_list": "D000998:Antiviral Agents; D002219:Carbamates; D006576:Heterocyclic Compounds, 4 or More Rings; C087036:NS-5 protein, hepatitis C virus; C084422:NS3 protein, hepatitis C virus; D017361:Viral Nonstructural Proteins; D007372:Interferons; C000604171:velpatasvir; D000069474:Sofosbuvir",
"country": "England",
"delete": false,
"doi": "10.3851/IMP3226",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1359-6535",
"issue": "23(6)",
"journal": "Antiviral therapy",
"keywords": null,
"medline_ta": "Antivir Ther",
"mesh_terms": "D000998:Antiviral Agents; D002219:Carbamates; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D005260:Female; D015870:Gene Expression; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D007372:Interferons; D008103:Liver Cirrhosis; D008297:Male; D012008:Recurrence; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response; D017361:Viral Nonstructural Proteins",
"nlm_unique_id": "9815705",
"other_id": null,
"pages": "543-547",
"pmc": null,
"pmid": "29442067",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Retreatment with sofosbuvir/velpatasvir in cirrhotic patients with genotype-4 who failed a previous interferon-free regimen: a case series.",
"title_normalized": "retreatment with sofosbuvir velpatasvir in cirrhotic patients with genotype 4 who failed a previous interferon free regimen a case series"
} | [
{
"companynumb": "IT-GILEAD-2018-0327633AA",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SOFOSBUVIR"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo quantitatively evaluate the change in pigment epithelial detachment (PED) morphology on spectral-domain optical coherence tomography (SD-OCT) 18 months after the transition to intravitreal aflibercept in patients with neovascular age-related macular degeneration (AMD) with PED recalcitrant to monthly intravitreal bevacizumab or ranibizumab.\n\n\nMETHODS\nRetrospective case series examining patients with neovascular AMD who had a persistent fibrovascular or serous PED on SD-OCT. PED volume was calculated by manually outlining the PED on individual OCT slices of the raster scan and multiplying by the pixel dimensions.\n\n\nRESULTS\nEleven eyes of 10 patients who had received an average of 25.7 ± 20.1 (range: 6 to 70) prior bevacizumab or ranibizumab injections over a period of 26.6 ± 19.8 months (range: 4 to 63) were included. PED volume decreased with aflibercept from 0.687 ± 0.837 mm(3) to 0.562 ± 0.705 mm(3) (P = .02), a decrease of 19% ± 12.27%.\n\n\nCONCLUSIONS\nAfter 18 months of aflibercept, recalcitrant PED volumes were reduced by 19% while preserving visual acuity in eyes with neovascular AMD.",
"affiliations": null,
"authors": "Kanesa-Thasan|Aditya|A|;Grewal|Dilraj S|DS|;Gill|Manjot K|MK|;Lyon|Alice T|AT|;Mirza|Rukhsana G|RG|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab",
"country": "United States",
"delete": false,
"doi": "10.3928/23258160-20150610-07",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-8160",
"issue": "46(6)",
"journal": "Ophthalmic surgery, lasers & imaging retina",
"keywords": null,
"medline_ta": "Ophthalmic Surg Lasers Imaging Retina",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D004351:Drug Resistance; D057915:Drug Substitution; D005260:Female; D006801:Humans; D058449:Intravitreal Injections; D008268:Macular Degeneration; D008297:Male; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D012163:Retinal Detachment; D015861:Retinal Neovascularization; D055213:Retinal Pigment Epithelium; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity",
"nlm_unique_id": "101599215",
"other_id": null,
"pages": "638-41",
"pmc": null,
"pmid": "26114844",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Quantification of Change in Pigment Epithelial Detachment Volume and Morphology After Transition to Intravitreal Aflibercept in Eyes With Recalcitrant Neovascular AMD: 18-Month Results.",
"title_normalized": "quantification of change in pigment epithelial detachment volume and morphology after transition to intravitreal aflibercept in eyes with recalcitrant neovascular amd 18 month results"
} | [
{
"companynumb": "US-ROCHE-1722747",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Development of a tracheoesophageal fistula (TEF) is a serious complication of treatment for esophageal or lung cancer, especially following radiation therapy. However, development of a TEF as a complication of chemotherapy or tracheal stenting after surgical debulking is quite uncommon. We herein report a rare case involving a patient with advanced adenocarcinoma invading the mediastinum who rapidly developed a TEF after placement of a tracheal stent and administration of nivolumab immunotherapy. A 55-year-old heavy ex-smoker was diagnosed with lung adenocarcinoma with mediastinal invasion. Nine months after first-line therapy (chemotherapy and radiation therapy), he underwent treatment with nivolumab (3 mg/kg) as fourth-line therapy. Two weeks after the first dose, he underwent mechanical debulking of the tumor with tracheal stenting because of the rapid development of paraesophageal lymph node swelling and severe tracheal stenosis. He received a second dose of nivolumab 2 weeks later; however, imaging studies 12 days after this second dose revealed a huge fistula between the upper trachea and esophagus through a metastatic lymph node. Neither an additional stent nor replacement of the stent was considered because of the fistula site expansion and suffocation risk. Despite further treatment, the patient died of his primary disease 2 months later. Our findings will be of great interest to the readers, especially those involved in the clinical treatment of patients with advanced lung cancer treated by immunotherapy. The knowledge of potentially devastating TEF formation in the presence of transmural tracheal metastasis/invasion will allow clinicians to provide the best possible care for their patients.",
"affiliations": "Department of Thoracic Surgery, Osaka City General Hospital, Osaka, Japan.;Department of Thoracic Surgery, Osaka City General Hospital, Osaka, Japan.;Department of Thoracic Surgery, Osaka City General Hospital, Osaka, Japan.;Department of Thoracic Surgery, Osaka City General Hospital, Osaka, Japan.;Department of Thoracic Surgery, Osaka City General Hospital, Osaka, Japan.;Department of Thoracic Surgery, Osaka City General Hospital, Osaka, Japan.",
"authors": "Mizuguchi|Shinjiro|S|;Takahama|Makoto|M|;Nakajima|Ryu|R|;Inoue|Hidetoshi|H|;Ito|Ryuichi|R|;Yamamoto|Ryoji|R|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000501157",
"fulltext": "\n==== Front\nBiomed HubBiomed HubBMHBiomedicine Hub2296-6870S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com 10.1159/000501157bmh-0004-0001Novel Insights from Clinical PracticeRapid Progression of Tracheoesophageal Fistula Caused by Immunotherapy Administered after Tracheal Stent Placement Mizuguchi Shinjiro *Takahama Makoto Nakajima Ryu Inoue Hidetoshi Ito Ryuichi Yamamoto Ryoji Department of Thoracic Surgery, Osaka City General Hospital, Osaka, Japan*Shinjiro Mizuguchi, Department of Thoracic Surgery, Osaka City General Hospital, 2-13-22 Miyakojima-hondori, Miyakojima-ku, Osaka 534-0021 (Japan), E-Mail m1293795@msic.med.osaka-cu.ac.jpMay-Aug 2019 25 7 2019 25 7 2019 4 2 1 5 4 2 2019 23 5 2019 2019 Copyright © 2019 by S. Karger AG, Basel2019This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Development of a tracheoesophageal fistula (TEF) is a serious complication of treatment for esophageal or lung cancer, especially following radiation therapy. However, development of a TEF as a complication of chemotherapy or tracheal stenting after surgical debulking is quite uncommon. We herein report a rare case involving a patient with advanced adenocarcinoma invading the mediastinum who rapidly developed a TEF after placement of a tracheal stent and administration of nivolumab immunotherapy. A 55-year-old heavy ex-smoker was diagnosed with lung adenocarcinoma with mediastinal invasion. Nine months after first-line therapy (chemotherapy and radiation therapy), he underwent treatment with nivolumab (3 mg/kg) as fourth-line therapy. Two weeks after the first dose, he underwent mechanical debulking of the tumor with tracheal stenting because of the rapid development of paraesophageal lymph node swelling and severe tracheal stenosis. He received a second dose of nivolumab 2 weeks later; however, imaging studies 12 days after this second dose revealed a huge fistula between the upper trachea and esophagus through a metastatic lymph node. Neither an additional stent nor replacement of the stent was considered because of the fistula site expansion and suffocation risk. Despite further treatment, the patient died of his primary disease 2 months later. Our findings will be of great interest to the readers, especially those involved in the clinical treatment of patients with advanced lung cancer treated by immunotherapy. The knowledge of potentially devastating TEF formation in the presence of transmural tracheal metastasis/invasion will allow clinicians to provide the best possible care for their patients.\n\nKeywords\nImmunotherapyExtensive invasionTracheoesophageal fistulaLung cancerTracheal stent\n==== Body\nWhat Is It about?\nWe report a rare case involving a patient with advanced lung adenocarcinoma invading the mediastinum who rapidly developed a tracheoesophageal fistula (TEF) after tracheal stent placement and nivolumab immunotherapy. Two weeks after the first dose of immunotherapy, mechanical debulking of the tumor with tracheal stenting was performed because of the rapid severe tracheal stenosis. Two weeks after the second dose, a huge TEF through metastatic lymph node was revealed. Our findings will be of great interest to the readers, especially those involved in the clinical treatment of patients with advanced lung cancer with transmural tracheal invasion treated by immunotherapy.\n\nEstablished Facts\nPseudo-progression, tumor growth from treatment effect rather than true disease progression, has been described in immunotherapy.\n\nThe potential of immunotherapy to mediate dramatic and rapid antitumor effects is well known in several malignant diseases.\n\nNovel Insights\nTo point out a potential safety concern: such anti-tumor effect occurring in patients with transmural metastasis/invasion of the trachea could have grave consequences.\n\nIntroduction\nNivolumab, a monoclonal antibody to the immune-checkpoint protein programmed cell death protein 1, has been approved for the treatment of metastatic non-small cell lung cancer since having conferred a substantial survival benefit in phase III trials [1, 2]. Despite the possibility of an overly vigorous anti-solid tumor response, some reports have stated that only a single dose of nivolumab drastically eradicated the tumor [3, 4]. An acquired tracheoesophageal fistula (TEF) is a life-threatening complication of esophageal or lung cancer. TEF is commonly reported as a complication of radiation therapy and rarely chemotherapy [5]. We herein describe rapid progression of a TEF in a patient with advanced adenocarcinoma invading the mediastinum treated with nivolumab before and after tracheal stent placement.\n\nCase Report\nA 55-year-old man presented for evaluation of dyspnea. He was a heavy ex-smoker (Brinkman index of 1,000). An initial imaging study revealed a lung tumor involving the mediastinum, and a biopsy revealed lung adenocarcinoma with an epidermal growth factor receptor wild-type and anaplastic lymphoma kinase-negative status (c-T4N0M0 stage 3A). The patient received concurrent chemotherapy (cisplatin and titanium silicate-1) and radiation therapy (60 Gy) to the mediastinum as first-line therapy. He was treated with several lines of cytotoxic agents, including carboplatin, nab-paclitaxel and pemetrexed, as well as additional radiation therapy for right supraclavicular and upper mediastinal lymph node metastasis.\n\nNine months after the first-line treatment, he received nivolumab (3 mg/kg) as fourth-line therapy. Two weeks after his first dose of nivolumab, he was referred for dysphagia and severe dyspnea. Imaging examination showed rapid progression of paraesophageal lymph node swelling and severe stenosis of the main trachea (Fig. 1). Because his performance status and Hugh-Jones classification had worsened to 3 and IV, respectively, mechanical debulking of the tumor arising from the membranous trachea was performed, and a silicone stent of 18-mm diameter and 50-mm length (TRACHEOBRONXANETM DUMON® TD; Novatech SA, La Ciotat, France) was placed using rigid bronchoscopy (Fig. 2a–c). Two weeks after stenting, the patient received a second dose of nivolumab. Recurrent aspiration occurred 10 days after this dose, and he was admitted 2 days later. Chest computed tomography and bronchoscopy revealed a huge fistula between the upper trachea and esophagus through a metastatic lymph node, which was 20–30 mm in size (Fig. 2d, e; Fig. 3). The fistula, both the proximal and distal side of the silicone stent (Fig. 2f), had expanded and was clearly visible after 1 week. Neither an additional stent nor replacement of the stent was considered because of the fistula site expansion and suffocation risk. The patient underwent gastrostomy and antibiotic therapy. However, he died of the primary disease 2 months later.\n\nDiscussion\nThe reported incidence of malignant TEF in patients with lung cancer ranges from 0.16 to 0.30% [6, 7]. In one study, the median survival time from diagnosis was only 6 weeks in the absence of appropriate treatment [6]. TEF is commonly reported as a complication of radiation therapy and rarely chemotherapy [5], and various anti-angiogenic agents have been found to increase the risk of fistula formation [8], especially bevacizumab; such agents can cause delayed healing secondary to impaired angiogenesis according to a previous review [9]. TEF formation is rare not only following immunotherapy but also tracheal stenting after tumor debulking of an invasive tracheal tumor.\n\nThe patient in the present report experienced rapid eradiation of a large tumor after two treatments with immunotherapy. Although no histological assessment was performed, the progression of the tumor after the first course of immunotherapy that caused dyspnea and tracheal stenosis might have been “pseudo-progression”; i.e., initial tumor growth followed by tumor regression. A previous review paper showed that approximately 4% of patients with solid tumors who received continued anti-programmed death-ligand 1 treatment after RECIST tumor progression obtained an anti-tumor response [10]. Although our patient underwent mechanical debulking of his rapidly progressing tumor followed by tracheal silicone stenting, it might have been more suitable to use a covered self-expandable metal stent without debulking in view of the risk of TEF following rapid tumor necrosis. The tracheal walls that may have been invaded by the tumor had rapidly necrotized, leading to their collapse and subsequent fistula formation. This rare case highlights that such an anti-tumor effect occurring in patients with transmural metastasis/invasion of the trachea could have grave consequences.\n\nStatement of Ethics\nWritten informed consent was obtained from the patient and his family for publication of this case report and any accompanying images.\n\nDisclosure Statement\nThe authors declare no conflicts of interest.\n\nAcknowledgment\nWe thank Angela Morben, DVM, ELS, from Edanz Group (http://www.edanzediting.com/ac), for editing a draft of the manuscript.\n\nFig. 1 First response of upper thoracic paraesophageal lymph node metastasis to nivolumab. Computed tomography scans showed rapid tumor progression before treatment (a) and 2 weeks after the first treatment (b), raising the possibility of “pseudo-progression.”\n\nFig. 2 Bronchoscopy images before and after tracheal stenting and after one dose of nivolumab. a The bronchoscopy images showed tracheal stenosis and the tumor invading membranous trachea. b Electrocautery and mechanical debulking of the tumor were performed. c A silicone stent was placed after mechanical debulking of the tumor. After the second dose of nivolumab, the stent was migrated to necrotic tissue (d) and a huge fistula between the upper trachea and upper part of esophagus was revealed (e). f The fistula opening was clearly visible and had expanded 3 weeks after the second dose of nivolumab.\n\nFig. 3 Tracheoesophageal fistula through a necrotic paraesophageal lymph node after the second dose of nivolumab. a, d Computed tomography images showed the tracheoesophageal fistula at the proximal side of the placed stent. b, c A 3-cm segment of the membranous trachea had disappeared, and the stent was migrated.\n==== Refs\nReferences\n1 Brahmer J Reckamp KL Baas P Crinò L Eberhardt WE Poddubskaya E Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer N Engl J Med 2015 7 373 (2) 123 35 26028407 \n2 Borghaei H Paz-Ares L Horn L Spigel DR Steins M Ready NE Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer N Engl J Med 2015 10 373 (17) 1627 39 26412456 \n3 Chapman PB D'Angelo SP Wolchok JD Rapid eradication of a bulky melanoma mass with one dose of immunotherapy N Engl J Med 2015 5 372 (21) 2073 4 25891305 \n4 Davar D Socinski MA Dacic S Burns TF Near complete response after single dose of nivolumab in patient with advanced heavily pre-treated KRAS mutant pulmonary adenocarcinoma Exp Hematol Oncol 2015 12 4 (1) 34 26673119 \n5 Perry RR Rosenberg RK Pass HI Tracheoesophageal fistula in the patient with lymphoma: case report and review of the literature Surgery 1989 6 105 (6) 770 7 2471284 \n6 Reed MF Mathisen DJ Tracheoesophageal fistula Chest Surg Clin N Am 2003 5 13 (2) 271 89 12755313 \n7 Martini N Goodner JT D'Angio GJ Beattie EJ Jr Tracheoesophageal fistula due to cancer J Thorac Cardiovasc Surg 1970 3 59 (3) 319 24 4190046 \n8 Goodgame B Veeramachaneni N Patterson A Govindan R Tracheo-esophageal fistula with bevacizumab after mediastinal radiation J Thorac Oncol 2008 9 3 (9) 1080 1 18758321 \n9 Nishie K Yasuo M Kitaguchi Y Kobayashi N Tateishi K Ushiki A Bevacizumab-induced tracheoesophageal fistula in a patient suffering from lung cancer with bulky subcarinal lymph node: a case report Nagoya J Med Sci 2018 2 80 (1) 129 34 29581622 \n10 Chiou VL Burotto M Pseudoprogression and Immune-Related Response in Solid Tumors J Clin Oncol 2015 11 33 (31) 3541 3 26261262\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2296-6870",
"issue": "4(2)",
"journal": "Biomedicine hub",
"keywords": "Extensive invasion; Immunotherapy; Lung cancer; Tracheal stent; Tracheoesophageal fistula",
"medline_ta": "Biomed Hub",
"mesh_terms": null,
"nlm_unique_id": "101692630",
"other_id": null,
"pages": "1-5",
"pmc": null,
"pmid": "31993425",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "26261262;18758321;2471284;26412456;29581622;4190046;26028407;25891305;26673119;12755313",
"title": "Rapid Progression of Tracheoesophageal Fistula Caused by Immunotherapy Administered after Tracheal Stent Placement.",
"title_normalized": "rapid progression of tracheoesophageal fistula caused by immunotherapy administered after tracheal stent placement"
} | [
{
"companynumb": "NVSC2019JP045062",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
"drug... |
{
"abstract": "Novel immunotherapies including antibodies to programmed death ligand 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have become common therapies for neoplasms including metastatic melanoma and non-small cell lung cancer (NSCLC). Dermatologic toxicity is the most common adverse event associated with these immunotherapies. We report a case of bullous pemphogoid (BP) in a patient receiving combination durvalumab and tremelimumab, two newer immunotherapy checkpoint inhibitors under investigation in phase III trials.\nJ Drugs Dermatol. 2019;18(1):103-104.",
"affiliations": null,
"authors": "Fontecilla|Natalia M.|NM|;Khanna|Trisha|T|;Bayan|Claire-Audrey Y.|CY|;Antonov|Nina A.|NA|;Geskin|Larisa J.|LJ|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C000613593:durvalumab; C520704:tremelimumab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-9616",
"issue": "18(1)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D002289:Carcinoma, Non-Small-Cell Lung; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D004890:Erythema; D005121:Extremities; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms; D009367:Neoplasm Staging",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "103-104",
"pmc": null,
"pmid": "30681807",
"pubdate": "2019-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bullous Pemphigoid Associated With a New Combination Checkpoint Inhibitor Immunotherapy",
"title_normalized": "bullous pemphigoid associated with a new combination checkpoint inhibitor immunotherapy"
} | [
{
"companynumb": "US-ASTRAZENECA-2017SE46036",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DURVALUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "Switching from IFX originator to CT-P13 is safe; however, little data on immunogenicity exists.\n\n\n\nConsecutive IBD patients on IFX originator were switched to CT-P13 and followed-up for 12 months. Clinical activity, infliximab trough levels (ITLs), anti-drug antibodies (ATIs), and adverse events were recorded at predefined timepoints (baseline, second CT-P13 infusion, 6 and 12 months). The outcomes investigated were immunogenicity, pharmacokinetics, effectiveness and safety.\n\n\n\n119 patients were switched to CT-P13 after a median time with IFX of 5.8 years. No changes in mean ITLs were observed. ATIs were detected in 30 patients (25.2%): 14 before and 16 after switch. Mean persistent ATIs were significantly higher compared to mean transient ones (109.74 ng/mL ±84.70 vs 18.22 ng/mL ±11.37, p < 0.001), with significantly lower ITLs associated (mean 0.32 µg/mL ±0.6 vs 3.08 µg/mL ±3.22, p < 0.001). A significant decrease of patients in steroid-fee clinical remission was observed after the switch (p = 0.004), with subsequent improvement at 6 months (p = 0.005). Eighteen patients (15.1%) discontinued IFX, only 6 (5%) for loss of response.\n\n\n\nSwitching from infliximab originator to CT-P13 seems safe and effective, without differences in immunogenicity. A temporary reduction of clinical benefit after switching could be potentially explained by a 'nocebo-effect response'.",
"affiliations": "CEMAD - IBD UNIT - Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS , Rome, Italy.;CEMAD - IBD UNIT - Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS , Rome, Italy.;Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore , Rome, Italy.;Department of New Technologies and Translational Research in Medicine and Surgery, University of Pisa , Pisa, Italy.;OU Rheumatology Columbus, Fondazione Policlinico Universitario A. Gemelli IRCCS , Rome, Italy.;CEMAD - IBD UNIT - Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS , Rome, Italy.;Department of New Technologies and Translational Research in Medicine and Surgery, University of Pisa , Pisa, Italy.;OU Rheumatology Columbus, Fondazione Policlinico Universitario A. Gemelli IRCCS , Rome, Italy.;CEMAD - IBD UNIT - Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS , Rome, Italy.;Division of Rheumatology, Università Cattolica del Sacro Cuore , Rome, Italy.;CEMAD - IBD UNIT - Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS , Rome, Italy.;CEMAD - IBD UNIT - Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS , Rome, Italy.;OU Rheumatology Columbus, Fondazione Policlinico Universitario A. Gemelli IRCCS , Rome, Italy.;CEMAD - IBD UNIT - Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS , Rome, Italy.;Department of General Surgery and Gastroenterology, IBD Unit, Pisa University Hospital , Pisa, Italy.;CEMAD - IBD UNIT - Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS , Rome, Italy.",
"authors": "Pugliese|Daniela|D|0000-0001-7930-5402;Guidi|Luisa|L|;Privitera|Giuseppe|G|;Bertani|Lorenzo|L|;Tolusso|Barbara|B|;Papparella|Luigi Giovanni|LG|;Maltinti|Simona|S|;Di Mario|Clara|C|;Onali|Sara|S|;Ceccarelli|Linda|L|;Rapaccini|Gian Lodovico|GL|;Scaldaferri|Franco|F|;Gremese|Elisa|E|;Gasbarrini|Antonio|A|0000-0002-6230-1779;Costa|Francesco|F|;Armuzzi|Alessandro|A|",
"chemical_list": "D000911:Antibodies, Monoclonal; D059451:Biosimilar Pharmaceuticals; C000591237:CT-P13; D005765:Gastrointestinal Agents; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1080/14712598.2020.1839045",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1471-2598",
"issue": "21(1)",
"journal": "Expert opinion on biological therapy",
"keywords": "CT-P13; Inflammatory bowel disease; immunogenicity; infliximab; pharmacokinetics; trough levels",
"medline_ta": "Expert Opin Biol Ther",
"mesh_terms": "D000911:Antibodies, Monoclonal; D059451:Biosimilar Pharmaceuticals; D057915:Drug Substitution; D005765:Gastrointestinal Agents; D006801:Humans; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D011446:Prospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101125414",
"other_id": null,
"pages": "97-104",
"pmc": null,
"pmid": "33074723",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Switching from IFX originator to biosimilar CT-P13 does not impact effectiveness,safety and immunogenicity in a large cohort of IBD patients.",
"title_normalized": "switching from ifx originator to biosimilar ct p13 does not impact effectiveness safety and immunogenicity in a large cohort of ibd patients"
} | [
{
"companynumb": "IT-CELLTRION INC.-2020IT035204",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHigh dose buprenorphine (HDB), commonly known as Subutex(®), is nowadays largely prescribed as a replacement therapy for major opiate dependence. Its sublingual administration allows a decrease in the withdrawal syndrome accompanying opiate abuse cessation. Over the past few decades, epidemiological data on people on replacement therapy have emphasized an increase in the misuse of Subutex(®) and more specifically intravenous injections of HDB. These growing practices pave the way to major physical consequences or even death. Several studies have highlighted the infectious, vascular, venous and arterial (pseudo-aneurysm) complications stemming from this habit. Among the possible vascular complications, we can notice the presence of abscess, venous thrombosis, phlegmons, skin necrosis, cellulite, and profound and superficial thrombophlebitis at injection sites. These can evolve into chronic edemas of the tips and subcutaneous nodules. The Popeye syndrome is one of the possible complications of this misuse. This syndrome is characterized by the swelling of both sides of the forearms and hands. These edemas tend to become persistent and to be paired with tissue changes such as skin thickening. Besides, the increase in the hands volume can occur bilaterally or sometimes in an asymmetrical way, accentuated on the hand of the non-dominant limb. This syndrome does not decrease, or just a little, after the stoppage of injections. It can have a psychological, social, psychopathological and esthetic impact.\n\n\nOBJECTIVE\nIn this article, we will focus on the clinical case of a 43-year-old man, who is hospitalized in an addictology unit for massive injections of HDB. This patient suffers from a Popeye syndrome as well as from an alcoholic dependence.\n\n\nMETHODS\nFollowing the description of psychopathological disorders, our analysis will originate from a clarification relative to the specificities of the practice of intravenous HDB injection to better sharpen the understanding of these misuses in their psychopathological and clinical aspects. We will discuss some proposals for interventions aiming at taking better care of the people suffering from a drug addiction characterized by the injection of HDB replacement therapy.\n\n\nRESULTS\nAdam requested an admission in an addictology ward for treatment of a self-medication by Subutex started 4 years ago. A certain awkwardness can be perceived when he lays his highly damaged and marked hands on the desk. His upper limbs, thus on display, have tripled in volume: this indicates the presence of a Popeye syndrome, consequence of repeated Subutex injections. These observations lead us to question the function and the sense of this injection behavior in the mental economy, as this repeated behavior engages the body specifically. This bruised body, marked with repeated injection holes has become a place of inscription, of representation that shows the impossibility to access other ways of expression. In this sense, taking action is becoming an act of speech. Within this speech, we can notice the existence of a profound state of uneasiness. To put up with the painful feeling of inner emptiness that is calling for a necessary filling, aiming at re-establishing a frail balance, Adam appeals to repeated injections. However, when the tortured body signifies its incapacity to receive an ultimate injection, thus showing its limits and the destruction it is undergoing, it is no longer possible to resort to Subutex injections. As a consequence, Adam came up with the idea of quitting. The withdrawal was initiated by himself and not coupled with medical care. It has led him to feel a gap, beyond the physical uneasiness. Adam has tried to fill in this unbearable feeling of empty body with tobacco, alcohol and food. The body, highly mobilized, translates the presence of a physical conflict where a massive mental anxiety is expressed in a hidden way. During the interview, Adam also addressed the repetitive familial pattern and the transgeneration effects. He seems to be fully aware of these.\n\n\nCONCLUSIONS\nSeveral perspectives can be addressed as part of Adam's treatment and especially cognitive-behavioral therapies as they could prove to be of a certain interest. The aim of this therapy would thus be to assess the motivation for change in order to begin a psychotherapeutic work based on personal adherence to the cessation of this misuse. This could be set up in parallel with an anxiety management work.\n\n\nCONCLUSIONS\nA better understanding and an extensive knowledge of the possible complications linked to the misuse of HDB seems necessary to sensitize and better inform people who suffer from high-risk behaviors and also to enable a more adapted care.",
"affiliations": "Service d'addictologie, hôpital maritime de Zuydcoote, boulevard Vancauwenberghe, 59123 Zuydcoote, France. Electronic address: jessica.bekaert@hotmail.fr.;Laboratoire Psitec, domaine universitaire du Pont-de-Bois, université Lille Nord de France, UL3, BP 60149, 59653 Villeneuve d'Ascq cedex, France.",
"authors": "Békaert|J|J|;Podevin|G|G|",
"chemical_list": "D002047:Buprenorphine",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-7006",
"issue": "41(3)",
"journal": "L'Encephale",
"keywords": "Addiction; Injection intraveineuse; Intravenous injection; Popeye syndrome; Subutex(®); Syndrome de Popeye",
"medline_ta": "Encephale",
"mesh_terms": "D000328:Adult; D000437:Alcoholism; D002047:Buprenorphine; D002908:Chronic Disease; D015928:Cognitive Behavioral Therapy; D015897:Comorbidity; D003220:Conflict, Psychological; D003430:Cross-Sectional Studies; D003674:Defense Mechanisms; D004305:Dose-Response Relationship, Drug; D004487:Edema; D005542:Forearm; D005602:France; D006227:Hand Deformities, Acquired; D006801:Humans; D008297:Male; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D063487:Prescription Drug Misuse; D011599:Psychopathology; D012008:Recurrence; D012871:Skin Diseases; D015819:Substance Abuse, Intravenous; D013577:Syndrome",
"nlm_unique_id": "7505643",
"other_id": null,
"pages": "229-37",
"pmc": null,
"pmid": "25212472",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Psychopathology of the misuse of Subutex®: The Popeye syndrome.",
"title_normalized": "psychopathology of the misuse of subutex the popeye syndrome"
} | [
{
"companynumb": "FR-RECKITT BENCKISER PHARMACEUTICAL, INC-RB-71960-2014",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALCOHOL"
},
"dru... |
{
"abstract": "Primary liver tumor, especially hepatocellular carcinoma (HCC), is a common cause of cancer death worldwide. The incidence is generally higher in Asian countries than in western countries. Carcinogenesis of HCC is often associated with hepatitis viral infections. Current standard treatment of HCC is surgical resection or transplantation in patients with early stage disease. However, the patient with advanced stage disease, surgical resection is often limited. Sorafenib or other treatment modalities are not so effective as well. We report a case of unusual radiation super-sensitivity in advanced stage HCC, and review the literature.",
"affiliations": "Department of Radiation Oncology, Pusan National University Yangsan Hospital, Yangsan, Korea.;Department of Radiation Oncology, Pusan National University Yangsan Hospital, Yangsan, Korea.;Department of Radiation Oncology, Pusan National University Yangsan Hospital, Yangsan, Korea.;Department of Radiation Oncology, Pusan National University Yangsan Hospital, Yangsan, Korea.;Department of Radiation Oncology, Pusan National University Yangsan Hospital, Yangsan, Korea.;Department of Radiation Oncology, Pusan National University Yangsan Hospital, Yangsan, Korea.",
"authors": "Lee|Jayoung|J|;Lee|Ju Hye|JH|;Yoon|Hanbin|H|;Lee|Ho Jeong|HJ|;Jeon|Hosang|H|;Nam|Jiho|J|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.3857/roj.2017.00262",
"fulltext": "\n==== Front\nRadiat Oncol JRadiat Oncol JROJRadiation Oncology Journal2234-19002234-3164The Korean Society for Radiation Oncology 2871228110.3857/roj.2017.00262roj-2017-00262Case ReportExtraordinary radiation super-sensitivity accompanying with sorafenib combination therapy: what lies beneath? Lee Jayoung MDPhDLee Ju Hye MDYoon Hanbin PhDLee Ho Jeong MSJeon Hosang PhDNam Jiho MD\nDepartment of Radiation Oncology, Pusan National University Yangsan Hospital, Yangsan, KoreaCorrespondence: Jiho Nam, MD, Department of Radiation Oncology, Pusan National University Yangsan Hospital, 20 Geumoro, Mulgeum-eup, Yangsan 50612, Korea. Tel: +82-55-360-3453, Fax: +82-55-360-3449, E-mail: jihonam@hanmail.net6 2017 30 6 2017 35 2 185 188 19 5 2017 24 5 2017 31 5 2017 Copyright © 2017. The Korean Society for Radiation Oncology2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Primary liver tumor, especially hepatocellular carcinoma (HCC), is a common cause of cancer death worldwide. The incidence is generally higher in Asian countries than in western countries. Carcinogenesis of HCC is often associated with hepatitis viral infections. Current standard treatment of HCC is surgical resection or transplantation in patients with early stage disease. However, the patient with advanced stage disease, surgical resection is often limited. Sorafenib or other treatment modalities are not so effective as well. We report a case of unusual radiation super-sensitivity in advanced stage HCC, and review the literature.\n\nHepatocellular carcinomaRadiotherapySorafenib\n==== Body\nIntroduction\nHepatocellular carcinoma (HCC) is the most common type of primary liver malignancy [1]. Treatment of HCC is quite challenging for their poor baseline liver function, and combined medical illness. For early stage tumors, surgical resection is the first choice of curative treatment. However, not so many patients are suitable for surgery. Recently, advanced HCC is often treated with sorafenib, however its treatment results are not satisfactory yet [2].\n\nOld data regarding radiotherapy (RT) to the primary liver tumor was not good because of normal liver toxicity. With advanced RT techniques, increasing number of patients receiving RT for either curative or palliative intent. When the patient has advanced liver disease, the utility of RT is still limited due to their poor treatment response [3].\n\nHere we have reported a case of unusual and unexplained super-sensitivity to combined sorafenib and RT.\n\nCase Report\nA 63-year-old woman was admitted to our cancer center in 2015, complaining of right upper abdominal pain. Otherwise she was healthy with good general condition. From radiologic evaluations in other hospital, she was diagnosed with primary HCC associated with hepatitis B virus and liver cirrhosis. Additional computed tomography (CT) and magnetic resonance (MR) imaging for staging workup showed that over 16 cm mass at the right hepatic lobe with tumor thrombus in the right portal and main portal vein (Fig. 1). Right hepatic vein and suprahepatic inferior vena cava were also involved. Multiple portocaval and para-aortic lymph nodes were enlarged. At the time of initial visit, her alpha fetoprotein (AFP) level was >4,340 ng/mL (normal range [NR], 0.1 to 9.0 ng/mL), and the results of liver function tests are aspartate transaminase (AST) 298 IU/L (NR, 0 to 35 IU/L), alanine transaminase (ALT) 31 IU/L (NR, 0 to 35 IU/L), alkaline phosphatase 299 IU/L (NR, 30 to 120 IU/L), and total bilirubin 1.1 mg/dL (NR, 0.3 to 1.2 mg/dL), respectively.\n\nShe was recommended for the treatment with either trans-arterial chemoembolization (TACE) or sorafenib. She refused TACE for concerning the toxicity. Her initial treatment began with sorafenib for palliative aim. Following CT scan showed that the disease was slightly progressed. Because her abdominal pain was also persisted, sorafenib alone appeared to be not enough to control her disease, then we decided to combine RT to liver expecting additional local control and symptom palliation.\n\nConsidering the tumor size and limited normal liver volume, her RT was given with intensity-modulated radiotherapy (IMRT) technique using conventional fractionated schedule. Almost entire liver was included in the planning target volume due to the huge right lobe tumor and tumor thrombus.\n\nDuring the course of RT, abdominal CT scan was repeated for measuring tumor response. Her liver tumor was markedly reduced even after 3 weeks of RT. Because the tumor volume change was so prominent, hepatic tumor rupture was initially suspected rather than the tumor response. However, there were no symptom and clinical and radiologic finding of tumor rupture. Laboratory test results also did not significantly change from the initial test results. Her abdominal pain was even subsided during the course.\n\nBecause the tumor volume change was so significant, RT plan modification was necessary to adequately cover tumor mass and to spare surrounding normal organs.\n\nAfter completion of RT with a total dose of 50 Gy in 5 weeks, serum levels of AFP decreased to 180 ng/mL. Her blood tests for the liver function was also slightly improved compared to the initial values. Sorafenib was given continuously.\n\nSix months later, her abdominal CT scan showed remarkable hepatic tumor regression (Fig. 2).\n\nHowever, she had cough and mild dyspnea and upper abdominal distension with slight general weakness. Thoracic CT scan showed radiation pneumonitis (Fig. 3), and gastric ulcer was diagnosed on endoscopic exam. Hospitalization and supportive care was required.\n\nNine months later, following radiologic studies revealed no progression of liver disease, however, new appearance of peritoneal seeding was found on abdominal CT scan.\n\nShe was discharged for hospice care.\n\nDiscussion\nPrimary liver cancer is one of the main cause of cancer death worldwide. Most of primary liver cancer is HCC. It is reportedly more common in the regions of Asia and Africa. The incidence of HCC is 0.01%–0.02% per year, and gradually increasing in many countries, especially in Europe and America [1].\n\nHCC are generally associated with various risk factors, i.e., hepatitis viruses, liver cirrhosis, aflatoxin, alcohol consumption, etc. More than two-thirds of virus related HCCs are caused by the hepatitis B virus infection. Nationwide hepatitis B virus vaccination program has greatly contributed in reducing the risk of HCC development. HCC surveillance is also known to be effective for decreasing cancer mortality [4].\n\nCurrent treatment options for HCC are primarily surgical resection, transplantation, TACE, targeted agents, and so on [2]. Tumor stage and baseline liver function are important factors to select best treatment modality for the patient.\n\nFor the early stage HCC, curative resection alone is successful for long-term survival. However, for the patient with advanced stage disease, surgery is not usually feasible. Systemic targeted agents, such as sorafenib, is recommended for the treatment of the advanced disease.\n\nRole of RT for the treatment of liver cancer is unclear. Although there are many published literature regarding the use of RT for the selected patient groups might be effective, the clinical significance has been still debating.\n\nHistorically, curative RT for HCC was not feasible for their lower efficacy and severe toxicity. Liver RT has been performed in limited patients group for symptom palliation for liver pain or symptoms associated metastatic disease. However, recent advanced RT techniques may offer promising results. Emerging stereotactic ablative RT technique can safely deliver higher dose to liver tumor with relatively lower surrounding normal organ dose. Local control rates from published reports are approximately 90% at 2–3 years [3]. Even though the number of patients were small and not randomized prospectively, most of the studies consistently reported excellent tumor control rates. It is not easy to combine those results as they have used the various treatment schedules, such as 24 Gy to 60 Gy in 3 to 5 fractions.\n\nThere are some studies reported using chemotherapy agents as a radiation sensitizer for the treatment of HCC. Cisplatin was used as a classic radiosensitizer in other cancer for more than 30 years. And doxorubicin and 5-fluorouracil are also available. Their results were somewhat mixed, so additional clinical investigation may be required [3]. Newer molecular targeted agents are not often used as a radiosensitizer yet. In other cancers, sorafenib has been reported promising results when combined with RT.\n\nSeveral clinical trials testing the efficacy of the combined sorafenib and RT in advanced HCC patients are ongoing [5,6]. Treatment responses in the available reports appeared to be somewhat superior, but overcoming treatment toxicities might be challenging.\n\nIn our case, the treatment response was unexpectedly prominent comparing with the ordinary responses of each treatment modality. We have tried to reduce the treatment associated toxicities with modern RT techniques, but the tumor volume shrinkage was too fast to catch up with. Dose volume histogram analysis of initial RT plan with adaptive simulation CT image results are shown in Fig. 4. Current sophisticated RT techniques do not provide any practical methods for daily tumor volume change adaptation yet. We have changed her RT plan three times during the course to avoid excess radiation dose/volume to normal organs. Nevertheless, she had more severe complications than expected as usual.\n\nIn conclusion, treatment of advanced HCCs has been challenging for several decades. Multimodal treatments may be helpful to improve treatment outcomes. Although the role of RT in the treatment of HCC needs to be determined with further clinical trials, like our case, appropriate combination of multimodal treatment options may contribute in successful treatment even in patients with advanced disease.\n\nConflict of Interest\n\nNo potential conflict of interest relevant to this article was reported.\n\nFig. 1. Huge right lobe hepatocellular carcinoma with portal vein thrombosis was found on pre-treatment computed tomography image. The tumor was occupying almost entire right lobe of the liver. Initially measured tumor volume was around 3,500 mL.\n\nFig. 2. Liver tumor had markedly reduced on follow-up abdomen computed tomography image.\n\nFig. 3. Follow-up chest computed tomography scan revealed the radiation pneumonitis on the right lower lung.\n\nFig. 4. Patient's re-planning computed tomography (CT) image (A) and the dose volume histogram (DVH) comparison of initial radiotherapy plan (B) with the new adaptive CT simulation image (C) were presented. There were significant right shifts in DVH curves of normal organs due to the liver tumor volume change. GTV, gross tumor volume.\n==== Refs\nReferences\n1 Mittal S El-Serag HB Epidemiology of hepatocellular carcinoma: consider the population J Clin Gastroenterol 2013 47 Suppl S2 6 23632345 \n2 Raza A Sood GK Hepatocellular carcinoma review: current treatment, and evidence-based medicine World J Gastroenterol 2014 20 4115 27 24764650 \n3 Ohri N Dawson LA Krishnan S Radiotherapy for hepatocellular carcinoma: new indications and directions for future study J Natl Cancer Inst 2016 108 djw133 27377923 \n4 McGlynn KA London WT The global epidemiology of hepatocellular carcinoma: present and future Clin Liver Dis 2011 15 223 43 vii-x 21689610 \n5 Brade AM Ng S Brierley J Phase 1 Trial of sorafenib and stereotactic body radiation therapy for hepatocellular carcinoma Int J Radiat Oncol Biol Phys 2016 94 580 7 26867886 \n6 Chen SW Lin LC Kuo YC Liang JA Kuo CC Chiou JF Phase 2 study of combined sorafenib and radiation therapy in patients with advanced hepatocellular carcinoma Int J Radiat Oncol Biol Phys 2014 88 1041 7 24661657\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2234-1900",
"issue": "35(2)",
"journal": "Radiation oncology journal",
"keywords": "Hepatocellular carcinoma; Radiotherapy; Sorafenib",
"medline_ta": "Radiat Oncol J",
"mesh_terms": null,
"nlm_unique_id": "101577577",
"other_id": null,
"pages": "185-188",
"pmc": null,
"pmid": "28712281",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
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"title": "Extraordinary radiation super-sensitivity accompanying with sorafenib combination therapy: what lies beneath?",
"title_normalized": "extraordinary radiation super sensitivity accompanying with sorafenib combination therapy what lies beneath"
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"abstract": "Cross-sectional studies show a lower health-related quality of life (HRQoL) in individuals with narcolepsy. We aimed to describe changes in HRQoL after two years of multidisciplinary follow-up in a cohort of mainly post-H1N1 vaccination narcolepsy type-1 (NT1) patients in Norway.\n\n\n\nProspective-cohort study. Narcolepsy diagnosis was based on the International Classification of Sleep Disorders (third edition). Psychiatric comorbidity was assessed using the Achenbach System of Empirically Based Assessment (ASEBA). HRQoL was evaluated with the Pediatric Quality of Life Inventory (PedsQL™ Generic Core Scales 4.0) at baseline and follow-up. Mean follow-up time was 20.7 (2.7) months.\n\n\n\nThirty one patients (18 females) with NT1, mean age 14.6 (SD = 4.8) years answered questionnaires at baseline and follow-up. On a group level, the PedsQL Total Health Summary score significantly improved by a mean of 5.9 (95%CI = 0.4, 11.9), p = 0.038; this was mainly driven by improvements in the Physical Health Summary score by 9.8 (3.0, 16.5) points, p = 0.006 and the School Functioning Scale score by 7.5 (1.0, 13.9) points p = 0.025. The Total ASEBA score was correlated with PedsQL Total Health Summary score at baseline, but not with changes in HRQoL. Sodium oxybate (Xyrem®) treatment at follow up was positively associated with changes in PedsQL Total Health Summary score, after adjusting for age and gender, p = 0.027.\n\n\n\nHRQoL in NT1 patients improved after two years of follow-up. The use of sodium oxybate (Xyrem®) at follow-up was associated with increases in HRQoL. Psychiatric comorbidity was correlated with HRQoL at baseline but did not predict changes in HRQoL at follow-up.",
"affiliations": "Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias, Department of Rare Disorders, Oslo University Hospital, Norway; Faculty of Medicine, University of Oslo, Norway. Electronic address: sebnor@ous-hf.no.;Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias, Department of Rare Disorders, Oslo University Hospital, Norway; Faculty of Medicine, University of Oslo, Norway; Division of Mental Health Akershus University Hospital, Lorenskog, Norway.;National Health Quality Registries, Oslo University Hospital, Norway.;Department of Neuromedicine and movement science, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, Section for Clinical Neurophysiology, Oslo University Hospital, Ullevål, Norway.;Faculty of Medicine, University of Oslo, Norway; Department of Paediatrics, Oslo University Hospital, Norway.;Faculty of Health and Sports Sciences, University of Agder, Norway.;Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias, Department of Rare Disorders, Oslo University Hospital, Norway.",
"authors": "Nordstrand|Sebjørg Hesla|SH|;Hansen|Berit Hjelde|BH|;Kamaleri|Yusman|Y|;Nilsen|Kristian Bernhard|KB|;Rootwelt|Terje|T|;Karlsen|Tor-Ivar|TI|;Knudsen|Stine|S|",
"chemical_list": "D000759:Adjuvants, Anesthesia; D012978:Sodium Oxybate",
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"journal": "Sleep medicine",
"keywords": "H1N1; Narcolepsy; Pediatric; Pediatrics comorbidity; Quality of life",
"medline_ta": "Sleep Med",
"mesh_terms": "D000759:Adjuvants, Anesthesia; D000293:Adolescent; D002648:Child; D015897:Comorbidity; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D017589:Immunization Programs; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human; D008297:Male; D009290:Narcolepsy; D009664:Norway; D011446:Prospective Studies; D011788:Quality of Life; D012720:Severity of Illness Index; D012978:Sodium Oxybate; D014611:Vaccination; D055815:Young Adult",
"nlm_unique_id": "100898759",
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"pages": "175-180",
"pmc": null,
"pmid": "30075393",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Changes in quality of life in individuals with narcolepsy type 1 after the H1N1-influenza epidemic and vaccination campaign in Norway: a two-year prospective cohort study.",
"title_normalized": "changes in quality of life in individuals with narcolepsy type 1 after the h1n1 influenza epidemic and vaccination campaign in norway a two year prospective cohort study"
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"abstract": "Glyphosate-containing herbicides are less toxic than paraquat and are one of the most widely used herbicides today.\n\n\n\nWe report a case of ingestion of a pesticide containing glyphosate in a suicide attempt. The patient was admitted to the psychiatric department because of persistent suicidal thoughts. He suffered from short-term memory impairment on day 3. Magnetic resonance imaging (MRI) showed swelling in the bilateral medial temporal lobes and hippocampi and high signal on T2-weighted images. Gradually, the patient's cognitive impairments improved, and he was discharged on day 33.\n\n\n\nA physician should examine the patient with the possibility of glyphosate encephalopathy in mind.",
"affiliations": "Department of Psychiatry, Dokkyo Medical University, School of Medicine, Shimotsuga, Japan.;Department of Psychiatry, Dokkyo Medical University, School of Medicine, Shimotsuga, Japan.;Department of Psychiatry, Dokkyo Medical University, School of Medicine, Shimotsuga, Japan.;Department of Psychiatry, Dokkyo Medical University, School of Medicine, Shimotsuga, Japan.;Department of Psychiatry, Dokkyo Medical University, School of Medicine, Shimotsuga, Japan.;Department of Neurology, Dokkyo Medical University, School of Medicine, Shimotsuga, Japan.;Department of Neurology, Dokkyo Medical University, School of Medicine, Shimotsuga, Japan.;Department of Psychiatry, Dokkyo Medical University, School of Medicine, Shimotsuga, Japan.;Department of Psychiatry, Dokkyo Medical University, School of Medicine, Shimotsuga, Japan.",
"authors": "Yokoyama|Saaya|S|;Sugisaki|Tomomi|T|;Ryota|Yoshida|Y|;Yoshiteru|Sato|S|;Okayasu|Hiroaki|H|0000-0003-4206-307X;Shioda|Mukuto|M|;Suzuki|Keisuke|K|;Yasui-Furukori|Norio|N|0000-0002-4414-3770;Shimoda|Kazutaka|K|",
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"doi": "10.1002/npr2.12201",
"fulltext": "\n==== Front\nNeuropsychopharmacol Rep\nNeuropsychopharmacol Rep\n10.1002/(ISSN)2574-173X\nNPR2\nNeuropsychopharmacology Reports\n2574-173X\nJohn Wiley and Sons Inc. Hoboken\n\n34357684\n10.1002/npr2.12201\nNPR212201\nCase Report\nCase Reports\nTransient glyphosate encephalopathy due to a suicide attempt\nYOKOYAMA et al.\nYokoyama Saaya 1\nSugisaki Tomomi 1 2\nRyota Yoshida 1\nYoshiteru Sato 1\nOkayasu Hiroaki https://orcid.org/0000-0003-4206-307X\n1\nShioda Mukuto 3\nSuzuki Keisuke 3\nYasui‐Furukori Norio https://orcid.org/0000-0002-4414-3770\n1 furukori@dokkyomed.ac.jp\n\nShimoda Kazutaka 1\n1 Department of Psychiatry Dokkyo Medical University School of Medicine Shimotsuga Japan\n2 Department of Clinical Training Center Dokkyo Medical University School of Medicine Shimotsuga Japan\n3 Department of Neurology Dokkyo Medical University School of Medicine Shimotsuga Japan\n* Correspondence\nNorio Yasui‐Furukori, Department of Psychiatry, Dokkoyo Medical University, School of Medicine, Mibu, 321‐0293 Shimotsuga, Tochigi, Japan.\nEmail: furukori@dokkyomed.ac.jp\n\n06 8 2021\n9 2021\n41 3 10.1111/npr2.v41.3 444447\n13 7 2021\n19 6 2021\n18 7 2021\n© 2021 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nAim\n\nGlyphosate‐containing herbicides are less toxic than paraquat and are one of the most widely used herbicides today.\n\nCase presentation\n\nWe report a case of ingestion of a pesticide containing glyphosate in a suicide attempt. The patient was admitted to the psychiatric department because of persistent suicidal thoughts. He suffered from short‐term memory impairment on day 3. Magnetic resonance imaging (MRI) showed swelling in the bilateral medial temporal lobes and hippocampi and high signal on T2‐weighted images. Gradually, the patient's cognitive impairments improved, and he was discharged on day 33.\n\nConclusion\n\nA physician should examine the patient with the possibility of glyphosate encephalopathy in mind.\n\nThe patient presented with delayed and transient short‐term memory impairment due to glyphosate medication. MRI showed bilateral medial temporal lobe and hippocampal swelling and high signal on T2‐weighted images, high signal in the right predominant insular cortex on diffusion‐weighted images, and high signal in the hippocampus and insular cortex on T2FLAIR.\n\nencephalopathy\nglyphosate\nMRI\nsuicide attempt\nsource-schema-version-number2.0\ncover-dateSeptember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.6 mode:remove_FC converted:02.09.2021\nYokoyamaS, SugisakiT, RyotaY, YoshiteruS, OkayasuH, ShiodaM, et al. Transient glyphosate encephalopathy due to a suicide attempt. Neuropsychopharmacol Rep. 2021;41 :444–447. 10.1002/npr2.12201\n==== Body\npmc1 BACKGROUND\n\nGlyphosate‐containing herbicides are less toxic than paraquat and are one of the most widely used classes of herbicides today. Glyphosate‐containing preparations are marketed at home improvement stores as safe herbicides. Therefore, with the increasing quantity of herbicides shipped, increasingly, many poisoning cases have occurred due to large doses of these compounds, and deaths have been reported. Gastrointestinal symptoms were the main symptoms of glyphosate poisoning. In severe cases, shock, acute renal failure, and disturbance of consciousness are observed.1, 2 Because of the ready availability of glyphosate‐containing herbicides, serious acute poisoning with these herbicides due to suicide attempts is a frequent occurrence, especially in developing countries and rural areas.\n\nWe report a case of transient encephalopathy after poisoning with a pesticide containing glyphosate as a suicide attempt. Written consent for publication was obtained from the patient.\n\n2 CASE PRESENTATION\n\nA 71‐year‐old man with no history of episodes suggesting mental illness was brought to us after a suicide attempt. Forty days earlier, he had undergone cataract surgery, and during the operation, the artificial lens fell inside the lens, resulting in a decrease in visual function compared with before the illness. Thereafter, he tended to have insomnia due to stress caused by the difficulty he faced in returning to his work and hobbies. He gradually developed depression, along with anxiety related to physical ailments such as discomfort in his right eye, back pain, and complaints of right knee pain. The depressive mood continued to worsen, and the patient complained that \"I'm finished\" and \"I want to die\"; he then ingested an herbicide (glyphosate) and was rushed to the emergency room. After gastric lavage, there was no physical abnormality, but as the patient's suicidal thoughts continued, the need for psychiatric treatment was recognized, and he was admitted to the psychiatric department the next day.\n\nThe patient had been experiencing insomnia, depressed mood, weight loss of 5 kg in 1 month due to loss of appetite, poor concentration, low energy, feelings of worthlessness, loss of interest, and hopelessness for more than 2 weeks, triggered by the loss of vision caused by the surgery, which had made it difficult for him to lead his daily life without getting help from his family. Therefore, we diagnosed the patient with major depressive disorder and started him on mirtazapine (15 mg/day). On the seventh day, mirtazapine was discontinued due to suspected mirtazapine‐induced delirium. Although his anxiety and agitation improved slightly, the patient scored 23/30 points on the Hasegawa Dementia Scale‐Revised (HDS‐R), with some disorientation and short‐term memory impairment. The patient did not remember his suicide attempt or cataract surgery and had both anterograde and retrograde amnesia; on that basis, we suspected some organic cause. EEG showed some slow waves at 6‐7 Hz on the 12th day (Figure 1). MRI showed bilateral swelling of the medial temporal lobes and hippocampi and high signal on T2‐weighted imaging; diffusion‐weighted imaging showed high signal predominantly in the right insular cortex, and T2‐weighted fluid‐attenuated inversion recovery (T2‐FLAIR) also showed high signal predominantly in the right insular cortex (Figure 2). In addition to the insular cortex, T2‐FLAIR also showed a high signal in the hippocampus (Figure 2). On the 13th day, involuntary movements of the left face, tongue biting, and weakness of the right side of the body were observed with no impairment of consciousness; these movements were judged to be a simple partial seizure. On the same day, the patient was placed in the ICU for general management. There were no abnormal findings on a CT scan of the head. The patient was given 1000 mg of levetiracetam. On the following day, he was free of convulsions and hemiplegia and was able to communicate well; therefore, he returned to the psychiatric ward that day. On the 14th day, the patient returned to the psychiatric ward. An electroencephalogram (EEG) showed spikes in the right frontal lobe (F4), suggesting epilepsy originating in this region, and levetiracetam 1000 mg was continued. A lumbar puncture performed on the same day showed no increase in cerebrospinal fluid cell count, and cultures were negative, suggesting encephalopathy rather than infectious or autoimmune encephalitis. Gradually, in addition to the original disorientation, the patient became agitated, had difficulty maintaining attention, and was unable to receive rest instructions. For this reason, we considered him to be in a state of delirium and started physical restraint on the same day. At night, the patient became emotionally unstable, shouting, \"I'm going to the office,\" yelling, and suddenly bursting into tears. In addition, from the 15th to the 16th day, 11 bouts of involuntary movements occurred on the left side of the face, lasting a few minutes each. The dose of levetiracetam was increased to 2000 mg/day on the 16th day, and simple partial epileptic seizures did not occur from then on. Risperidone (0.5 mg/day) was added before bedtime on the 17th day, and although there were some fluctuations in affect and disorientation after that, the patient was able to sleep at night and received rest instructions on the 19th day. Risperidone was discontinued. Gradually, the patient recovered from his cognitive impairments, including disorientation, and the HDS‐R on the 26th day showed a score of 23/30, with improvement only in the recall item. An EEG on the 27th day showed no slow waves or spikes, and an MRI scan on the 28th day showed a slight improvement in the high signal and swelling of the hippocampus and insular cortex on T2‐weighted, T2‐FLAIR, and diffusion‐weighted imaging; on this basis, the patient was discharged on the 33rd day.\n\nFIGURE 1 Electroencephalography (EEG) of the patient. EEG showed some 6‐7 Hz slow waves on the 12th day\n\nFIGURE 2 Diffusion‐weighted (left), T2 (middle), and T2‐FLAIR (right) MRI. MRI showed bilateral swelling of the medial temporal lobes and hippocampi and high signal on T2‐weighted imaging; diffusion‐weighted imaging showed high signal predominantly in the right insular cortex; and T2‐FLAIR also showed high signal predominantly in the right insular cortex. In addition to the insular cortex, T2‐FLAIR also showed a high signal in the hippocampus\n\n3 DISCUSSION AND CONCLUSION\n\nWe reported a case of encephalopathy caused by glyphosate. In general, glyphosate poisoning is known to cause gastrointestinal symptoms and hepatic and renal dysfunction, and severe cases require ventilator management and hemodialysis. Consistent with the limited number of case reports, the following findings were noted: (a) delayed onset of short‐term memory impairment 2 days after oral administration; (b) high signal and swelling of the hippocampus on T2 MRI, T2‐FLAIR, and diffusion‐weighted imaging; and (c) high levels of protein in the cerebrospinal fluid, which supported the usefulness of these findings for the diagnosis of glyphosate encephalopathy.3, 4\n\nCattani et al reported that glyphosate may cause glutamate excitotoxicity and oxidative stress‐induced cell death in the rat hippocampus.5 According to Sedlaczek et al, the CA1 region, located in the perfusion zone of the posterior cerebral artery, has been identified as the most vulnerable hippocampal region to ischemia and is associated with transient global amnesia‐like memory impairment. In addition, they reported that hippocampal blood flow reduction due to stress, vasoconstriction, migraine, venous congestion, etc, is a factor in transient global amnesia.6 In addition, Yamana et al reported that left posterior aortic infarction with left medial temporal lobe lesion is associated with amnesia syndrome, and medial temporal lobe lesion is associated with pure dyslexia or dyslexia with dyscalculia.7 Powell et al noted that memory, unlike language function, is not dominant; one hemisphere or the other is sufficient, and in the case of unilateral lesions, the other side of the limbic system compensates, indicating that the lesions are transient and capable for the improvement.8\n\nIn the present case, the sudden onset of disorientation and \"severe confusion, repeatedly asking the same questions about the date and the surrounding environment\" closely resembled the symptoms of transient global amnesia, except that it was irreversible. Single‐photon emission computed tomography (SPECT) showed decreased blood flow in the dominant hemisphere (the patient was right‐handed), including the left frontal lobe, temporal lobe, bilateral parietal lobes, and left occipital lobe; the decreased blood flow in the left parietal lobe was particularly noticeable.\n\nOne limitation is that, although the patient's HDS‐R score improved, several components of his recovery—including the improvement of depression triggered by the onset of encephalopathy, the control of symptomatic epilepsy, and the improvement of cognition—could have contributed; it is difficult to distinguish the causal relationships of these variables. In addition, we cannot rule out the possibility that the decrease in cerebral blood flow shown by SPECT was due to a chronic decrease in blood flow caused by hypertension, alcohol consumption, and smoking. However, at least in this case, the patient had been working as a truck driver and an office worker until 1 month before the suicide attempt, and he had shown no loss of short‐term memory or of his ability to write or perform arithmetic.\n\nIn this case, the glutamate excitotoxicity and oxidative stress caused by glyphosate may have caused a decrease in blood flow not only to the posterior cerebral artery, which is the dominant artery supplying the hippocampus, but also to the middle cerebral artery, which perfuses the parietal lobe. In addition, in this case, the left hemisphere, which is the dominant hemisphere, was predominantly hypoperfused, and there was a gradual tendency toward memory impairment, although verbal learning remained intact. This suggests that SPECT may be effective in predicting the prognosis of memory impairment by evaluating whether the blood flow decrease is unilateral or bilateral. Assuming that the causative pathology is vascular, risk factors for glyphosate encephalopathy include advanced age, hypertension, hyperlipidemia, diabetes mellitus, and a history of drinking or smoking. Three of the four reported cases of memory impairment with glyphosate poisoning, including hippocampal infarction, were in patients over 60 years old.3, 5, 9 The present patient was 71 years old, had smoked 25 cigarettes/day for more than 20 years, had been drinking 3 cups of sake/day for the past month, and had controlled hypertension.\n\nGlyphosate is not known to cause encephalopathy, and asymptomatic or mild cases may not prompt MRIs or other imaging studies; such cases may be diagnosed only as part of the symptoms of depression or delirium or may be misdiagnosed as a dissociative disorder. Therefore, when we encounter an emergency case of glyphosate poisoning, we should examine the patient with the possibility of glyphosate encephalopathy in mind, which may guide future treatment and help to further elucidate the pathogenesis of glyphosate encephalopathy.\n\nCONFLICT OF INTEREST\n\nThe authors declare that they have no competing interests.\n\nAUTHOR CONTRIBUTIONS\n\nSY, ST, RY, and MS treated the patient and acquired data. NYF wrote the manuscript and analyzed image data. SY drafted the work, analyzed image data. HO, KS, and KS supervised the work and substantively revised it. All authors read and approved the final manuscript.\n\nAPPROVAL OF THE RESEARCH PROTOCOL BY AN INSTITUTIONAL REVIEWER BOARD\n\nThe ethics committee is not required to review case reports.\n\nINFORMED CONSENT\n\nThe patient has consented in a written form to the submission of the case report for submission to the journal.\n\nDATA AVAILABILITY STATEMENT\n\nThe data are not publicly available due to privacy restrictions.\n==== Refs\nREFERENCES\n\n1 MesnageR, DefargeN, Spiroux de VendômoisJ, SéraliniGE. Potential toxic effects of glyphosate and its commercial formulations below regulatory limits. Food Chem Toxicol. 2015;84 :133–53.26282372\n2 RobertsDM, BuckleyNA, MohamedF, EddlestonM, GoldsteinDA, MehrsheikhA, et al. A prospective observational study of the clinical toxicology of glyphosate‐containing herbicides in adults with acute self‐poisoning. Clin Toxicol (Phila). 2010;48 :129–36.20136481\n3 PlancheV, VergnetS, AuzouN, BonnetM, TourdiasT, TisonF. Acute toxic limbic encephalopathy following glyphosate intoxication. Neurology. 2019;92 :534–6.30737339\n4 LeeHK, ParkHS, OhJH, LeeJS. Glyphosate‐induced encephalopathy: a case report. J Clin Neurol. 2019;15 :132–3.30618226\n5 CattaniD, de Liz Oliveira CavalliVL, Heinz RiegCE, DominguesJT, Dal‐CimT, TascaCI, et al. Mechanisms underlying the neurotoxicity induced by glyphosate‐based herbicide in immature rat hippocampus: involvement of glutamate excitotoxicity. Toxicology. 2014;320 :34–45.24636977\n6 NishiyoriY, NishidaM, ShiodaK, SudaS, KatoS. Unilateral hippocampal infarction associated with an attempted suicide: a case report. J Med Case Rep. 2014;8 :219.24957787\n7 YamanaT, ItoE, IkedaT, OkudaS, YoshidaM. Amnesic syndrome due to ischemic lesions in the posterior cerebral artery territory. Stroke. 1991;13 :257–64. (In Japanses).\n8 PowellGE, PolkeyCE, CanavanAG. Lateralisation of memory functions in epileptic patients by use of the sodium amytal (Wada) technique. J Neurol Neurosurg Psychiatry. 1987;50 :665–72.3612147\n9 MalhotraRC, GhiaDK, CordatoDJ, BeranRG. Glyphosate‐surfactant herbicide‐induced reversible encephalopathy. J Clin Neurosci. 2010;17 :1472–3.20655231\n\n",
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"title": "Transient glyphosate encephalopathy due to a suicide attempt.",
"title_normalized": "transient glyphosate encephalopathy due to a suicide attempt"
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"abstract": "Patients with autism spectrum disorders (ASDs) are at an increased risk for many diseases. However, little has been published about the dental health of patients with ASDs. Here, we describe the clinical presentations in a 28-year-old woman with autistic disorder. The most striking finding was the severe dental problems which had been neglected for several years. Our patient exhibited a combination of several factors that may have increased the risk of development of severe dental problem. The early recognition is still challenging to managing this unusual condition in patients with ASDs. From the experience of caring for this patient, a team of parents or caregivers, psychiatrist and dentist should be involved in maintaining oral health care of such patients with early intervention and long-term follow-up. Evidence-based behavioral management approaches for patients with ASD need to be developed to improve compliance with oral care procedures.",
"affiliations": "Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan.",
"authors": "Lu|Yuan-Yuan|YY|;Wei|I-Hua|IH|;Huang|Chih-Chia|CC|",
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"keywords": null,
"medline_ta": "Gen Hosp Psychiatry",
"mesh_terms": "D000328:Adult; D001321:Autistic Disorder; D003731:Dental Caries; D003951:Diagnostic Errors; D005260:Female; D006801:Humans; D009909:Oral Health; D012559:Schizophrenia",
"nlm_unique_id": "7905527",
"other_id": null,
"pages": "214.e1-3",
"pmc": null,
"pmid": "22819155",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dental health - a challenging problem for a patient with autism spectrum disorder.",
"title_normalized": "dental health a challenging problem for a patient with autism spectrum disorder"
} | [
{
"companynumb": "TW-MYLANLABS-2015M1002135",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Resistance to 1st or 2nd generation epidermal growth factor receptor (EGFR) - tyrosine kinases (TKIs) develops predominantly due to an acquired mutation, EGFR T790M. Third-generation EGFR-TKIs have demonstrated potent activity against TKI resistance mediated by EGFR T790M. Thus, it become critical to identify T790M mutation on disease progression. Analysis of tumor tissue biopsy material is considered as gold standard for mutation detection. However, lung re-biopsy in a progressed patient involves several challenges - access to tumor, patient's willingness, safety, cost. Minimally invasive plasma circulating tumor DNA (ctDNA) evolved as an alternative for detection of EGFR T790M mutation when tumor genotyping is not feasible. Although a positive T790M result from ctDNA analysis is actionable, caution should be exercised in interpreting negative plasma results. A negative result may imply the absence of a mutation or merely that a patient's tumor is not shedding ctDNA at detectable levels, thus necessitating a confirmatory tissue biopsy to rule out a false negative plasma result. In this case report, we described a 78-year-old female who underwent a reflexed tumor biopsy and tissue based testing upon negative plasma genotyping. Our case report exhibited the importance to follow proposed T790M plasma testing algorithm to screen eligible patients for 3rd generation TKI therapy.",
"affiliations": "Director-Oncology & Consultant Surgical Oncology, Surgical Oncology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Four Bungalows, Andheri West, Mumbai, Maharashtra, India.;Senior Clinical Associate, Surgical Oncology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Four Bungalows, Andheri West, Mumbai, Maharashtra, India.",
"authors": "Mistry|R|R|;Patil|A|A|",
"chemical_list": "D000074141:Circulating Tumor DNA; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "India",
"delete": false,
"doi": "10.4103/ijc.IJC_545_17",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0019-509X",
"issue": "54(Supplement)",
"journal": "Indian journal of cancer",
"keywords": "Anaplastic lymphoma kinase gene rearrangement; epidermal growth factor receptor mutation; exon 19; plasma (ctDNA) genotyping",
"medline_ta": "Indian J Cancer",
"mesh_terms": "D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D000074141:Circulating Tumor DNA; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D005260:Female; D005838:Genotype; D006801:Humans; D009154:Mutation; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "0112040",
"other_id": null,
"pages": "S65-S66",
"pmc": null,
"pmid": "29292710",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Importance of repeat tissue biopsy and tissue-based epidermal growth factor receptor T790M testing in progressed nonsmall cell lung carcinoma patients upon negative plasma genotyping for selection of third-generation tyrosine kinase inhibitor therapy: A case study.",
"title_normalized": "importance of repeat tissue biopsy and tissue based epidermal growth factor receptor t790m testing in progressed nonsmall cell lung carcinoma patients upon negative plasma genotyping for selection of third generation tyrosine kinase inhibitor therapy a case study"
} | [
{
"companynumb": "IN-MYLANLABS-2018M1064226",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ERLOTINIB"
},
"drugadditional": null,
... |
{
"abstract": "Ameloblastoma is a rare low-grade odontogenic tumor of epithelial origin. The World Health Organization (WHO) has defined malignant ameloblastoma (MA) as a histologically benign-appearing ameloblastoma that has metastasized. Treatment of the primary ameloblastoma usually consists of radical excision of the tumor and adjuvant radiotherapy. Chemotherapy should be used to treat metastases due to its indolent clinical course. Presented here is the case of a 43-year-old woman who was admitted to a hospital in 2006 with a large mass involving the neck and left mandible. The mass had formed over years and had been neglected. The woman was diagnosed with a primary ameloblastoma of the mandible. Surgical resection was performed, followed by adjuvant radiotherapy. In September 2016, she was admitted again, and the findings were consistent with metastases of the previously identified ameloblastoma to the lungs. The patient was evaluated for further chemotherapy with 6 cycles of cisplatin at a dose of 100 mg/m2 on day 1, 5-FU at a dose of 1000 mg/m2/day on day 1-4 (3 wk), and pegylated filgrastim. The current case represents the classical course of a rare disease, which in this instance involved the common presentation of MA. This case is a valid incidence of MA based on the typical histology, findings from a lung biopsy, the immunohistochemical profile of the tumor, the typical clinical features, and a history of a previous primary disease.",
"affiliations": "Clinic of Medical Oncology, UMHAT \"St. Marina\", Varna, Bulgaria.;Clinic of Medical Oncology, UMHAT \"St. Marina\", Varna, Bulgaria.;Centre of Clinical Pathology, UMHAT \"St. Marina\", Varna, Bulgaria.;Clinic of Medical Oncology, UMHAT \"St. Marina\", Varna, Bulgaria.",
"authors": "Valkadinov|Ivan|I|;Conev|Nikolay|N|;Dzhenkov|Dian|D|;Donev|Ivan|I|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.5582/irdr.2017.01032",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2186-3644",
"issue": "6(3)",
"journal": "Intractable & rare diseases research",
"keywords": "Ameloblastoma; ameloblastic carcinoma; metastases",
"medline_ta": "Intractable Rare Dis Res",
"mesh_terms": null,
"nlm_unique_id": "101586847",
"other_id": null,
"pages": "211-214",
"pmc": null,
"pmid": "28944145",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports",
"references": "20970910;1221327;11948077;17156974;2207999;25298718;2663133;11762824;23837011;26015700;25409846;21968082;25926124;21459020;10468461;25692490;26205138;12152164",
"title": "Rare case of ameloblastoma with pulmonary metastases.",
"title_normalized": "rare case of ameloblastoma with pulmonary metastases"
} | [
{
"companynumb": "BG-ACCORD-059202",
"fulfillexpeditecriteria": "1",
"occurcountry": "BG",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"dr... |
{
"abstract": "This is the first study in which the carfilzomib, lenalidomide and dexamethasone (KRd) regimen was evaluated in heavily pretreated multiple myeloma. This study is a multicenter, open-label phase 1 study of KRd in Japanese patients with relapsed or refractory multiple myeloma (RRMM) patients. The objectives were to evaluate the safety, tolerability, efficacy and pharmacokinetics of the regimen. Carfilzomib was administrated intravenously over 10 min on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. In cycle 1, the dosage for days 1 and 2 was 20 mg/m2 , followed by 27 mg/m2 . Lenalidomide and dexamethasone were administered at 25 mg (days 1-21) and 40 mg (days 1, 8, 15 and 22), respectively. Twenty-six patients were enrolled. Patients had received a median of four prior regimens and 88.5% and 61.5% received previous bortezomib and lenalidomide, respectively. High-risk cytogenetics were seen in 53.8% of patients. The overall response rate was 88.5%. A higher rate of hyperglycemia was observed than in a previous carfilzomib monotherapy study, but this was attributed to dexamethasone. Carfilzomib pharmacokinetics were not affected by lenalidomide and dexamethasone. The KRd regimen was well tolerated and showed efficacy in Japanese RRMM patients.",
"affiliations": "Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan.;Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.;Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan.;Division of Hematology and Oncology, Toyohashi Municipal Hospital, Toyohashi.;Department of Hematology, National Hospital Organization Disaster Medical Center, Tachikawa, Japan.;Department of Hematology, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan.;Department of Hematology, Tochigi Cancer Center, Utsunomiya, Japan.;Department of Hematology, Tokushima Prefectural Central Hospital, Tokushima, Japan.;Department of Oncology Clinical Development Planning, Ono Pharmaceutical, Osaka, Japan.;Department of Oncology Clinical Development Planning, Ono Pharmaceutical, Osaka, Japan.;Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.",
"authors": "Suzuki|Kenshi|K|;Ri|Masaki|M|;Chou|Takaaki|T|;Sugiura|Isamu|I|;Takezako|Naoki|N|;Sunami|Kazutaka|K|;Ishida|Tadao|T|;Izumi|Tohru|T|;Ozaki|Shuji|S|;Shumiya|Yoshihisa|Y|;Ota|Kenji|K|;Iida|Shinsuke|S|",
"chemical_list": "D000970:Antineoplastic Agents; D009842:Oligopeptides; D013792:Thalidomide; C524865:carfilzomib; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "England",
"delete": false,
"doi": "10.1111/cas.13166",
"fulltext": "\n==== Front\nCancer SciCancer Sci10.1111/(ISSN)1349-7006CASCancer Science1347-90321349-7006John Wiley and Sons Inc. Hoboken 10.1111/cas.13166CAS13166Original ArticleOriginal ArticlesClinical ResearchCarfilzomib, lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma: A phase 1 study in Japan Suzuki et al.Suzuki Kenshi ken-suzuki@mtb.biglobe.ne.jp \n1\nRi Masaki \n2\nChou Takaaki \n3\nSugiura Isamu \n4\nTakezako Naoki \n5\nSunami Kazutaka \n6\nIshida Tadao \n1\n\n7\nIzumi Tohru \n8\nOzaki Shuji \n9\nShumiya Yoshihisa \n10\nOta Kenji \n10\nIida Shinsuke \n2\n1 Department of HematologyJapanese Red Cross Medical CenterTokyoJapan2 Department of Hematology and OncologyNagoya City University Graduate School of Medical SciencesNagoyaJapan3 Department of Internal MedicineNiigata Cancer Center HospitalNiigataJapan4 Division of Hematology and OncologyToyohashi Municipal HospitalToyohashi5 Department of HematologyNational Hospital Organization Disaster Medical CenterTachikawaJapan6 Department of HematologyNational Hospital Organization Okayama Medical CenterOkayamaJapan7 Department of Gastroenterology, Rheumatology and Clinical ImmunologySapporo Medical University School of MedicineSapporoJapan8 Department of HematologyTochigi Cancer CenterUtsunomiyaJapan9 Department of HematologyTokushima Prefectural Central HospitalTokushimaJapan10 Department of Oncology Clinical Development PlanningOno PharmaceuticalOsakaJapan* Correspondence\n\nKenshi Suzuki, Japanese Red Cross Medical Center, 4‐1‐22 Hiroo, Shibuya‐ku, Tokyo, Japan.\n\nTel: +81‐3‐3400‐1311; Fax: +81‐3‐3409‐1604;\n\nE‐mail: ken-suzuki@mtb.biglobe.ne.jp\n03 4 2017 3 2017 108 3 10.1111/cas.2017.108.issue-3461 468 12 10 2016 27 12 2016 06 1 2017 © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.This is the first study in which the carfilzomib, lenalidomide and dexamethasone (KRd) regimen was evaluated in heavily pretreated multiple myeloma. This study is a multicenter, open‐label phase 1 study of KRd in Japanese patients with relapsed or refractory multiple myeloma (RRMM) patients. The objectives were to evaluate the safety, tolerability, efficacy and pharmacokinetics of the regimen. Carfilzomib was administrated intravenously over 10 min on days 1, 2, 8, 9, 15 and 16 of a 28‐day cycle. In cycle 1, the dosage for days 1 and 2 was 20 mg/m2, followed by 27 mg/m2. Lenalidomide and dexamethasone were administered at 25 mg (days 1–21) and 40 mg (days 1, 8, 15 and 22), respectively. Twenty‐six patients were enrolled. Patients had received a median of four prior regimens and 88.5% and 61.5% received previous bortezomib and lenalidomide, respectively. High‐risk cytogenetics were seen in 53.8% of patients. The overall response rate was 88.5%. A higher rate of hyperglycemia was observed than in a previous carfilzomib monotherapy study, but this was attributed to dexamethasone. Carfilzomib pharmacokinetics were not affected by lenalidomide and dexamethasone. The KRd regimen was well tolerated and showed efficacy in Japanese RRMM patients.\n\ncarfilzomibdexamethasoneJapanlenalidomidemultiple myelomaOno PharmaceuticalCelgene K.K source-schema-version-number2.0component-idcas13166cover-dateMarch 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.0.9 mode:remove_FC converted:03.04.2017\n\nCancer Sci \n108 (2017 ) 461 –468 \n\n\n\n\nFunding Information\n\n\nT. Chou received honoraria from Ono Pharmaceutical and Celgene K.K. T. Ishida received personal fees from Celgene K.K. T. Izumi, M. Ri, I. Sugiura, K. Sunami, K. Suzuki and S. Ozaki received research funding from Ono Pharmaceutical K. Sunami received research funding from Celgene K.K. S. Iida received honoraria from Ono Pharmaceutical and Celgene K.K. The study was funded by Ono Pharmaceutical. Carfilzomib was provided by Ono Pharmaceutical.\n\nClinical trial registration: Japic CTI 142677\n==== Body\nSurvival rates for patients with multiple myeloma have improved, but relapse remains common,1, 2 indicating that there is an ongoing need for novel therapeutic approaches. Having demonstrated improved progression‐free survival (PFS) compared with dexamethasone alone, dexamethasone in combination with the immunomodulatory agent lenalidomide is now considered a standard therapy for newly diagnosed and relapsed multiple myeloma.3\n\n\nCarfilzomib is a next‐generation proteasome inhibitor that binds selectively and irreversibly to the constitutive proteasome and immunoproteasome, leading to sustained inhibition.4 The ASPIRE study was a pivotal phase 3 study investigating the use of carfilzomib in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma who had received one to three prior treatments.5 Overall, 792 patients were randomized to receive either carfilzomib with lenalidomide and dexamethasone or lenalidomide and dexamethasone alone. At the interim analysis, it was shown that the addition of carfilzomib resulted in significantly improved PFS.\n\nOn the basis of the ASPIRE study, carfilzomib in combination with lenalidomide and dexamethasone has recently been approved for use in Europe and the USA in patients with relapsed multiple myeloma.\n\nThe recent ENDEAVOR study compared carfilzomib plus dexamethasone with bortezomib plus dexamethasone in a head‐to‐head randomized trial in relapsed or refractory multiple myeloma (RRMM) patients.6 Patients receiving carfilzomib and dexamethasone demonstrated longer PFS compared with those receiving bortezomib and dexamethasone, supporting evidence for the role of carfilzomib regimens in RRMM treatment.\n\nA recently published study investigated carfilzomib monotherapy in Japanese patients with RRMM.7 This phase 1/2 study investigated the safety, pharmacokinetics/pharmacodynamics and overall response rate (ORR) at a dose of 20/27 mg/m2. It demonstrated efficacy and tolerability, although the authors indicated that control of hypertension may be necessary with carfilzomib use.\n\nThe objectives of the present study were to evaluate the safety, tolerability, efficacy and pharmacokinetics of carfilzomib in combination with lenalidomide and dexamethasone in Japanese patients with RRMM, and to explore the efficacy of this combination regimen and the pharmacokinetic profile of carfilzomib.\n\nPatients and Methods\nStudy design and setting\nThis was a multicenter, open‐label phase 1 study in Japanese patients with RRMM. The study was conducted in nine centers in Japan. Patients were enrolled between November 2014 and March 2015 and the date of data cut‐off was 8 July 2015.\n\nParticipants\nThe study enrolled male and female patients aged ≥20 years with RRMM and an Eastern Cooperative Oncology Group performance status of 0–2, and those who had received at least one prior treatment. Patients previously treated with lenalidomide and dexamethasone were eligible if they demonstrated tolerability to the therapy. Patients had to have adequate cardiovascular, hepatic, hematological and renal function (measured as creatinine clearance ≥50 mL/min) at screening. Those with grade 3 or 4 peripheral neuropathy (or grade 2 with pain) or New York Heart Association class III or IV heart failure at screening were excluded from the study. Pregnant or lactating females were excluded from participating. Furthermore, women of childbearing potential and men had to agree to use two forms of contraception from the start of the study until at least 3 months after the last dose of any of the three drugs used in the study.\n\nInterventions\nTreatment comprised a maximum of 18 cycles, with each cycle lasting 28 days. During cycles 1–12, carfilzomib was administered as a 10‐min intravenous infusion on days 1, 2, 8, 9, 15 and 16. Patients received a starting dosage of 20 mg/m2 carfilzomib on days 1 and 2 of the first cycle, and a target dose of 27 mg/m2 thereafter. During cycles 13–18, carfilzomib was administered on days 1, 2, 15 and 16. The study drug was not administered beyond 18 cycles. The dosage regimen was selected based on the ASPIRE study.5 Lenalidomide 25 mg was given orally on days 1–21 during cycles 1–18. The dose of lenalidomide was reduced if creatinine clearance was <50 mL/min. Dexamethasone 40 mg was given orally or intravenously on days 1, 8, 15 and 22 during cycles 1–18. If dexamethasone administration overlapped with carfilzomib, it was administered from 4 h to 30 min prior to carfilzomib administration. Patients received pre‐treatment and post‐treatment intravenous hydration (250–500 mL) during the first treatment cycle. Patients were also treated with antiviral and antithrombotic prophylaxis.\n\nEndpoints\nThe transition rate to the extended treatment period (cycle 2 and thereafter) and adverse events (AE) meeting the criteria for evaluation of tolerability were assessed for the first six patients. The criteria for evaluation of tolerability were defined as any of the following AE in cycle 1 that were at least possibly related to carfilzomib, lenalidomide or dexamethasone: grade 3 or 4 peripheral neuropathy or grade 2 peripheral neuropathy with pain; grade ≥3 non‐hematological toxicities; grade ≥3 nausea, vomiting or diarrhea that was uncontrolled after an adequate administration of anti‐emetic or anti‐diarrheal medications; grade ≥4 fatigue persisting for >7 days; grade 4 neutropenia persisting for >8 days; febrile neutropenia; grade 4 thrombocytopenia that required platelet transfusion or was accompanied by bleeding; and AE that required a dosing delay for >21 days.\n\nSafety endpoints were assessed as AE, drug‐related AE, general laboratory tests, vital signs and 12‐lead electrocardiography. AE were classified using the Medical Dictionary for Regulatory Activities (MedDRA) version 18 (Japanese version), and tabulated by system organ class and preferred term (PT). Severity of AE was graded using the Common Terminology Criteria for Adverse Events (CTCAE).\n\nEfficacy was assessed as ORR (partial response or better), overall survival (OS), PFS, time‐to‐progression (TTP), duration of response (DOR), best overall response, clinical benefit rate and disease control rate. Treatment responses and disease progression were assessed by investigators based on the central laboratory results. The efficacy and safety evaluation committee reviewed the investigator assessments.\n\nDisease assessments were made with the use of the International Myeloma Working Group Uniform Response Criteria,8, 9 with minimal response defined according to European Society for Blood and Marrow Transplantation criteria.10, 11\n\n\nBone marrow specimens for chromosome analysis were collected during screening. Chromosome analysis was performed using G‐banding and fluorescence in situ hybridization, which was used to detect t(4;14), t(14;16) and t(11;14) translocations, and deletion of the short arm of chromosome 17 in ≥20% of screened plasma cells.\n\nPlasma samples were collected on days 1 and 16 of cycle 1 at the following time points: pre‐dose, 5 and 15 min after the start of infusion, the end of infusion, and 5, 15, 30, 60, 120 and 240 min post‐infusion. Samples were processed by solid phase extraction using Oasis HLB 10‐mg cartridges (Waters Corporation, Milford, MA, USA) followed by LC–MS/MS analysis to measure the plasma concentration of carfilzomib. A deuterated analog (d10‐carfilzomib) was used as the internal standard for quantification, with a calibration range of 0.100–200 ng/mL. Chromatographic separation was achieved on a Gemini‐NX C18 column (2.0 × 100 mm, 3‐μm particle size; [Phenomenex, Torrance, USA]) and a linear gradient solvent system consisting of a methanol/water/25% ammonia solution. PK assessments included an estimation of the maximum plasma concentration (C\nmax), time to maximum plasma concentration, area under the plasma concentration‐time curve (AUC), elimination half‐life (T\n1/2), systemic clearance (CL) and volume of distribution at steady state (V\nss).\n\nSample size\nThe sample size was determined as the number of subjects required for the evaluation of ORR, which was the efficacy endpoint. In the ASPIRE study,5 the ORR was 87.1% (95% confidence interval [CI; Clopper–Pearson method] 83.4–90.3) in the carfilzomib, lenalidomide and dexamethasone group, and 66.7% (95% CI 61.8–71.3) in the lenalidomide and dexamethasone group. Under the expected ORR of 87.1%, the number of subjects required to reject the null hypothesis of 66.7% with at least 70% power based on a one‐sided exact test with a significance level of 5.0% was calculated to be 25. Allowing for an estimated 4% of unevaluable subjects including dropouts, the target number of subjects for the study was determined as 26. The number of subjects for the evaluation of tolerability was determined as six, in line with the Guidelines for Clinical Evaluation Methods of Antimalignant Tumor Drugs.12\n\n\nEthical considerations\nThe study was performed according to the Declaration of Helsinki (as revised in Fortaleza, Brazil, October 2013) and was approved by the Institutional Review Board of each participating site. All participants provided written informed consent. The study was conducted in accordance with Japanese Good Clinical Practice Guidelines.\n\nStatistical methods\nSafety\nSafety endpoints were analyzed in the safety analysis set. The numbers of patients with AE and drug‐related AE, CTCAE grade ≥3 AE or drug‐related AE, serious AE or drug‐related AE, or those resulting in discontinuation were tabulated.\n\nEfficacy\nEfficacy endpoints were analyzed in the full analysis set. ORR and its 90% CI using the Clopper–Pearson method were calculated. Distributions of OS, PFS, TTP and DOR were presented using Kaplan–Meier curves.\n\nPharmacokinetics\nPharmacokinetic parameters were analyzed in the pharmacokinetic analysis set. Pharmacokinetic parameters were analyzed using summary statistics, and non‐compartmental analysis was performed using Phoenix WinNonlin version 6.2.1 (Certara L.P., Princeton, NJ, USA).\n\nAll statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC, USA).\n\nResults\nTwenty‐six Japanese patients with RRMM were enrolled in the study. All 26 were included in the safety and efficacy analyses. The median number of cycles administered was four (range, 1–8 cycles). Patient baseline characteristics are summarized in Table 1. The median age was 64 years (range, 38–81 years), and the study included 13 women and 13 men. The median number of previous regimens received by study subjects was four (range, 1–10). Overall, 88.5% had received prior bortezomib therapy and 61.5% had received prior lenalidomide therapy. A total of 53.8% of patients had high‐risk abnormal cytogenetics, defined as t(4;14), t(14;16), del(17p) in ≥20% of screened plasma cells, or hypodiploidy.\n\nTable 1 Patient demographics and baseline characteristics\n\nParameter\tCategory\tKRd†\n\t\nNumber of subjects\t\t26\t\nSex\tMale\t13\t(50.0)\t\nFemale\t13\t(50.0)\t\nAge (years)\tMedian\t64.0\t\nMin–Max\t38–81\t\nECOG performance status\t0\t16\t(61.5)\t\n1\t9\t(34.6)\t\n2\t1\t(3.8)\t\nSubtype\tIgGκ\t17\t(65.4)\t\nIgGλ\t2\t(7.7)\t\nIgAκ\t4\t(15.4)\t\nBJPκ\t3\t(11.5)\t\nStage (ISS)\t1\t11\t(42.3)\t\n2\t10\t(38.5)\t\n3\t5\t(19.2)\t\nPeripheral neuropathy‡\n\tGrade 0\t13\t(50.0)\t\nGrade 1\t10\t(38.5)\t\nGrade 2\t2\t(7.7)\t\nMissing\t1\t(3.8)\t\nNumber of prior regimens by subject\t1\t5\t(19.2)\t\n2\t4\t(15.4)\t\n3\t3\t(11.5)\t\n≥4\t14\t(53.8)\t\nMedian\t4.0\t\nMin–Max\t1–10\t\nNumber of prior bortezomib treatments\t0\t3\t(11.5)\t\n1\t12\t(46.2)\t\n≥2\t11\t(42.3)\t\nPrior lenalidomide treatment\tYes\t16\t(61.5)\t\nNo\t10\t(38.5)\t\nPrior thalidomide treatment\tYes\t8\t(30.8)\t\nNo\t18\t(69.2)\t\nPrior corticosteroid treatment\tYes\t26\t(100.0)\t\nNo\t0\t\t\nHigh‐risk cytogenetics§\n\tYes\t14\t(53.8)\t\nNo\t12\t(46.2)\t\nt(4;14)\tNegative\t18\t(69.2)\t\nPositive\t8\t(30.8)\t\nt(14;16)\tNegative\t24\t(92.3)\t\nPositive\t2\t(7.7)\t\ndel(17p)\tNegative\t24\t(92.3)\t\nPositive\t2\t(7.7)\t\nG‐band method (hypodiploidy)\tNormal\t23\t(88.5)\t\nAbnormal\t3\t(11.5)\t\nCreatinine clearance (mL/min)\t<50\t4\t(15.4)\t\n50 to <80\t9\t(34.6)\t\n≥80\t13\t(50.0)\t\nMean ± SD\t81.109 ± 29.028\t\n†Figures in parentheses indicate percentages. ‡In cases of multiple neuropathy, the highest grade is used. §High‐risk cytogenetics are defined as positive t(4;14), t(14;16) or del(17p) in ≥20% of screened plasma cells, or hypodiploidy with the G‐band method. BJP, Bence Jones protein; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; KRd, carfilzomib + lenalidomide + dexamethasone regimen; SD, standard deviation.\n\nJohn Wiley & Sons, LtdSafety findings\nOne patient out of six evaluated for tolerability experienced grade 3 upper respiratory tract infection, which met the definition of AE for the evaluation of tolerability. No other subjects experienced AE for the evaluation of tolerability. All patients experienced at least one AE, and 73.1% had at least one AE of CTCAE grade ≥3. AE are summarized in Tables 2 and 3. The most common AE (summarized by MedDRA PT) included decreased lymphocyte count (53.8%), decreased platelet count (53.8%), hyperglycemia (38.5%), hypophosphatemia (38.5%), constipation (30.8%), decreased white blood cell count (30.8%) and rash (30.8%; Table 2).\n\nTable 2 All grade AE and drug‐related AE occurring in ≥20% of subjects\n\n\tKRd\t\nAE (SOC・PT)†\n\tAE [n (%)]\tDrug‐related AE [n (%)]\t\nNumber of subjects\t26\t26\t\nAll\t26\t(100.0)\t26\t(100.0)\t\nGastrointestinal disorders\t14\t(53.8)\t12\t(46.2)\t\n Constipation\t8\t(30.8)\t6\t(23.1)\t\nInvestigations\t24\t(92.3)\t24\t(92.3)\t\n Alanine aminotransferase increased\t7\t(26.9)\t7\t(26.9)\t\n Lymphocyte count decreased\t14\t(53.8)\t11\t(42.3)\t\n Neutrophil count decreased\t7\t(26.9)\t4\t(15.4)\t\n Platelet count decreased\t14\t(53.8)\t12\t(46.2)\t\n White blood cell count decreased\t8\t(30.8)\t4\t(15.4)\t\nMetabolism and nutrition disorders\t19\t(73.1)\t18\t(69.2)\t\n Hyperglycemia\t10\t(38.5)\t10\t(38.5)\t\n Hypophosphatemia\t10\t(38.5)\t5\t(19.2)\t\nMusculoskeletal and connective tissue disorders\t7\t(26.9)\t6\t(23.1)\t\n Muscle spasms\t6\t(23.1)\t6\t(23.1)\t\nSkin and subcutaneous tissue disorders\t11\t(42.3)\t9\t(34.6)\t\n Rash\t8\t(30.8)\t7\t(26.9)\t\n†Medical Dictionary for Regulatory Activities Version 18.0 (Japanese version). AE, adverse events; KRd, carfilzomib + lenalidomide + dexamethasone regimen; PT, preferred term; SOC, system organ class.\n\nJohn Wiley & Sons, LtdTable 3 Grade ≥3 AE and drug‐related AE occurring during the study\n\n\tKRd\t\nAE (SOC・PT)†\n\tAE [n (%)]\tDrug‐related AE [n (%)]\t\nNumber of subjects\t26\t26\t\nAll\t19\t(73.1)\t17\t(65.4)\t\nBlood and lymphatic system disorders\t3\t(11.5)\t1\t(3.8)\t\n Anemia\t3\t(11.5)\t1\t(3.8)\t\nCardiac disorders\t1\t(3.8)\t0\t\t\n Prinzmetal angina\t1\t(3.8)\t0\t\t\nEye disorders\t1\t(3.8)\t0\t\t\n Age‐related macular degeneration\t1\t(3.8)\t0\t\t\nHepatobiliary disorders\t1\t(3.8)\t1\t(3.8)\t\n Hepatic function abnormal\t1\t(3.8)\t1\t(3.8)\t\nInfections and infestations\t2\t(7.7)\t2\t(7.7)\t\n Pneumonia\t2\t(7.7)\t2\t(7.7)\t\n Upper respiratory tract infection\t1\t(3.8)\t1\t(3.8)\t\n Respiratory tract infection\t1\t(3.8)\t1\t(3.8)\t\nInvestigations\t14\t(53.8)\t11\t(42.3)\t\n Alanine aminotransferase increased\t2\t(7.7)\t2\t(7.7)\t\n Aspartate aminotransferase increased\t1\t(3.8)\t1\t(3.8)\t\n Hemoglobin decreased\t1\t(3.8)\t1\t(3.8)\t\n Lymphocyte count decreased\t11\t(42.3)\t8\t(30.8)\t\n Neutrophil count decreased\t3\t(11.5)\t3\t(11.5)\t\n Platelet count decreased\t6\t(23.1)\t4\t(15.4)\t\n White blood cell count decreased\t3\t(11.5)\t1\t(3.8)\t\nMetabolism and nutrition disorders\t9\t(34.6)\t7\t(26.9)\t\n Hyperglycemia\t3\t(11.5)\t3\t(11.5)\t\n Hypermagnesemia\t1\t(3.8)\t0\t\t\n Hypokalemia\t1\t(3.8)\t1\t(3.8)\t\n Hypophosphatemia\t5\t(19.2)\t3\t(11.5)\t\nPsychiatric disorders\t1\t(3.8)\t1\t(3.8)\t\n Delirium\t1\t(3.8)\t1\t(3.8)\t\nSkin and subcutaneous tissue disorders\t2\t(7.7)\t1\t(3.8)\t\n Drug eruption\t1\t(3.8)\t0\t\t\n Rash\t1\t(3.8)\t1\t(3.8)\t\n†Medical Dictionary for Regulatory Activities Version 18.0 (Japanese version). AE, adverse events; KRd, carfilzomib + lenalidomide + dexamethasone regimen; PT, preferred term; SOC, system organ class.\n\nJohn Wiley & Sons, LtdThe most common grade ≥3 AE were decreased lymphocyte count (42.3%), decreased platelet count (23.1%), hypophosphatemia (19.2%), anemia (11.5%), neutrophil count decreased (11.5%), decreased white blood cell count (11.5%) and hyperglycemia (11.5%; Table 3). Peripheral neuropathy was observed in 15.4% of patients, but no grade ≥3 peripheral neuropathy or peripheral neuropathy associated with pain was reported. Regarding cardiac disorders, 1 patient experienced grade 2 congestive cardiac failure, which led to dose interruption of carfilzomib. One patient experienced grade 3 Prinzmetal angina, but this was not considered to be related to carfilzomib because the patient had a medical history of Prinzmetal angina and did not receive treatment for Prinzmetal angina when the event occurred. No interstitial lung disease was observed during the study, and no patients died during the treatment period or within 30 days after the last dose of any of the three drugs.\n\nRegarding serious AE, grade 4 pneumonia and grade 3 respiratory tract infection developed in one patient, who recovered following treatment. A causal relationship with any of the three drugs could not be ruled out. One patient developed delirium, which led to treatment discontinuation. The investigator considered the event of delirium to be related to dexamethasone. There were no other AE that led to treatment discontinuation. AE that led to interruption or dose reduction of carfilzomib occurred in 46.2% of patients, with events occurring in two or more patients including pneumonia (11.5%), upper respiratory tract inflammation (11.5%), pharyngitis (7.7%) and hypophosphatemia (7.7%).\n\nEfficacy findings\nThe ORR during the study was 88.5% (90% CI 72.8–96.8). The lower end of this CI rejected the null hypothesis of 66.7%. Tumor response is shown in Table 4, and the maximum percentage change in the amount of M‐protein, and the change in M‐protein level stratified by Bence Jones protein (BJP) and non‐BJP subtype for each patient are shown in Figures 1 and 2, respectively. The rate of very good partial response or better was 23.1%. The ORR benefit of KRd was consistently observed in all subgroups (Fig. 3). Overall, 7/8 (87.5%), 2/2 (100%), 1/2 (50.0%) and 2/3 (66.7%) patients with t(4:14), t(14;16), del(17p) or hypodiploid cytogenetics, respectively, demonstrated good ORR (Table 5). The median time to best response was 63 days (range, 28–168 days; n = 23 responders). The median PFS, OS, TTP and DOR could not be estimated because of the short follow‐up period of the study.\n\nTable 4 Best anti‐tumor effect (International Myeloma Working Group Uniform Response Criteria)\n\nResponse\t\nN (%)\t\nNumber of subjects\t26\t\nStringent complete response\t0\t\nComplete response\t1 (3.8)\t\nVery good partial response\t5 (19.2)\t\nPartial response\t17 (65.4)\t\nMinimal response\t1 (3.8)\t\nStable disease†\n\t2 (7.7)\t\nProgressive disease\t0\t\nNot evaluable\t0\t\n†Patients who were assessed as having stable disease according to the International Myeloma Working Group. Of these, patients who were assessed as having minimal response in accordance with the European Society for Blood and Marrow Transplantation were excluded.\n\nJohn Wiley & Sons, LtdFigure 1 Waterfall plot showing the maximum percentage change in the amount of M‐protein for each patient. Data are not shown for one patient because of a limited number of time points where M‐protein was measurable.\n\nFigure 2 Change in M‐protein over time for each patient. Data are not shown for 1 patient because of a limited number of time points where M‐protein was measurable. aUrine M‐protein. BJP, Bence Jones protein; KRd, carfilzomib + lenalidomide + dexamethasone regimen; PR, partial response.\n\nFigure 3 Subgroup analysis for overall response rate. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; KRd, carfilzomib + lenalidomide + dexamethasone regimen.\n\nTable 5 Best response of individual patients included in the study\n\nPatient\tBest response\tSubtype\tNumber of prior regimens\tNumber of Completed cycles\tChromosomal abnormalities\tRisk\t\n1\tCR\tBJPκ\t1\t4\tt(11;14)\t—\t\n2\tVGPR\tIgAκ\t9\t7\tt(4;14)\tHigh\t\n3\tVGPR\tIgGκ\t7\t4\tHypodiploid\tHigh\t\n4\tVGPR\tIgGκ\t5\t5\tt(14;16)\tHigh\t\n5\tVGPR\tIgGκ\t4\t5\tHyperdiploid\t—\t\n6\tVGPR\tIgAκ\t4\t3\tt(4;14)\tHigh\t\n7\tPR\tIgAκ\t10\t4\tt(4;14), Hyperdiploid\tHigh\t\n8\tPR\tIgGκ\t8\t7\tt(11;14)\t—\t\n9\tPR\tIgGκ\t7\t6\t—\t—\t\n10\tPR\tIgGκ\t6\t5\t—\t—\t\n11\tPR\tIgAκ\t4\t4\t—\t—\t\n12\tPR\tIgGκ\t4\t4\tt(4;14), Hypodiploid\tHigh\t\n13\tPR\tIgGκ\t3\t8\tt(4;14), Hyperdiploid\tHigh\t\n14\tPR\tIgGκ\t3\t3\tdel(17p)\tHigh\t\n15\tPR\tBJPκ\t3\t3\tt(11;14)\t—\t\n16\tPR\tIgGκ\t2\t5\t—\t—\t\n17\tPR\tIgGλ\t2\t4\tt(4;14)\tHigh\t\n18\tPR\tBJPκ\t2\t4\t—\t—\t\n19\tPR\tIgGκ\t2\t1\tt(11;14)\t—\t\n20\tPR\tIgGκ\t1\t6\t—\t—\t\n21\tPR\tIgGκ\t1\t6\tt(14;16)\tHigh\t\n22\tPR\tIgGκ\t1\t4\tt(4;14)\tHigh\t\n23\tPR\tIgGκ\t1\t3\t—\t—\t\n24\tSD\tIgGλ\t10\t7\tdel(17p)\tHigh\t\n25\tSD\tIgGκ\t5\t3\tt(11;14), Hypodiploid\tHigh\t\n26\tSD\tIgGκ\t4\t3\tt(4;14), Non‐hyperdiploid\tHigh\t\nBJP, Bence Jones protein; CR, complete response; PR, partial response; SD, stable disease; VGPR, very good partial response.\n\nJohn Wiley & Sons, LtdPharmacokinetic findings\nEleven patients were included in the pharmacokinetic analysis set. The pharmacokinetic parameters of carfilzomib on days 1 and 16 of the first cycle are summarized in Table 6. The carfilzomib plasma concentration declined quickly at both doses following intravenous administration (Fig. 4). T\n1/2 ranged from 0.58 to 0.74 h. C\nmax and AUCINF increased dose‐dependently, whereas CL and V\nss were comparable at both doses.\n\nTable 6 Pharmacokinetic parameters of carfilzomib on days 1 and 16 of the first cycle\n\n\tPlasma carfilzomib†\n\t\nParameter\t20 mg/m2 (day 1)\t27 mg/m2 (day 16)\t\nNumber of patients\t11\t9\t\n\nC\nmax (ng/mL)\t1540 ± 391\t2030 ± 282\t\n\nT\nmax (h)‡\n\t0.150 (0.083–0.167)\t0.150 (0.133–0.183)\t\nAUCLAST (ng*h/mL)\t326 ± 73.5\t444 ± 56.0\t\nAUCINF (ng*h/mL)\t326 ± 73.5\t445 ± 55.7\t\n\nT\n1/2 (h)\t0.580 ± 0.260\t0.740 ± 0.272\t\nCL (L/h)\t102 ± 27.3\t98.8 ± 16.1\t\n\nV\nss (L)\t10.9 ± 4.39\t11.7 ± 5.40\t\n†All values are mean ± standard deviation unless stated otherwise. ‡Median (min–max). AUC, area under the plasma concentration‐time curve; CL, systemic clearance; C\nmax, maximum plasma concentration; T\nmax, time to maximum plasma concentration; T\n1/2, elimination half‐life; V\nss, volume of distribution at steady‐state.\n\nJohn Wiley & Sons, LtdFigure 4 Carfilzomib plasma concentration‐time profile following a 10‐min intravenous infusion of carfilzomib (mean + standard deviation; first cycle).\n\nDiscussion\nThis is the first study to investigate the use of the carfilzomib, lenalidomide and dexamethasone regimen in heavily pretreated RRMM patients, with patients having received a median of four prior regimens. The regimen was well tolerated and demonstrated early indications of efficacy in this group of Japanese RRMM patients.\n\nThe phase 3 ASPIRE study also examined the use of carfilzomib in combination with lenalidomide and dexamethasone.5 The ORR was similar between the current study and the ASPIRE study (88.5% and 87.1%, respectively), while the current study enrolled patients at a later stage, with a median of four prior regimens having been used compared with a median of two in ASPIRE. However, the rate of very good partial response or better was lower in this study compared with ASPIRE (23.1% and 69.9%, respectively). This may have been a result of the lower number of cycles administered (median of four in the current study versus 18 in ASPIRE). The current study showed a ≥15% higher incidence of decreased lymphocyte count (53.8% and <20%, respectively), decreased platelet count (53.8% and <20%, respectively), hyperglycemia (38.5% and <20%, respectively) and hypophosphatemia (38.5% and <20%, respectively) compared with the ASPIRE study.\n\nIxazomib, elotuzumab and daratumumab have also been recently approved for use in multiple myeloma. Similar to the current study, Moreau et al.13 compared the use of the proteasome inhibitor ixazomib in combination with lenalidomide plus dexamethasone with placebo and lenalidomide plus dexamethasone. ORR was 78.3% in the ixazomib group, which is lower than that reported in the current study, although a cross‐study comparison is difficult. The monoclonal antibody elotuzumab was also examined in a similar regimen (elotuzumab plus lenalidomide and dexamethasone compared with lenalidomide and dexamethasone alone).14 The elotuzumab regimen also showed a slightly lower ORR (79%) than the current study, providing further support for the use of the carfilzomib plus lenalidomide and dexamethasone regimen. Interim data from a phase 3 study by Dimopoulos et al.15 showed a comparable ORR for the daratumumab plus lenalidomide and dexamethasone regimen (93%) to that observed in the current study.\n\nWatanabe et al.7 recently conducted a phase 1/2 study of carfilzomib monotherapy in Japanese RRMM patients. The ORR of 88.5% in the current study was significantly higher than that observed in the monotherapy study (22.5%). Regarding AE, a higher rate of hyperglycemia was observed in the current study compared with the monotherapy study, but this is thought to be attributable to the addition of dexamethasone. No other clinically important differences in safety profile were observed with the carfilzomib, lenalidomide and dexamethasone regimen compared with carfilzomib monotherapy. One patient out of six evaluated for tolerability experienced grade 3 upper respiratory tract infection, supporting early evidence of the tolerability of the regimen in this cohort of Japanese patients. The pharmacokinetic profile of carfilzomib did not appear to be affected by the addition of lenalidomide and dexamethasone.\n\nA potential weakness of the current study is that PFS and OS could not be determined because of the short follow‐up period. However, the study is ongoing and further survival data, including PFS and OS, are to be reported in the near future. A strength of the study is that a relatively high percentage of patients with abnormal cytogenetics were enrolled (53.8% compared with 12.1% in the ASPIRE study), with the combination regimen showing efficacy in this high‐risk population.\n\nIn conclusion, in this cohort of Japanese RRMM patients, the addition of carfilzomib to lenalidomide and dexamethasone resulted in improved ORR, and the benefit–risk profile appeared to be favorable. These findings indicate that the use of the carfilzomib, lenalidomide and dexamethasone regimen in RRMM patients is promising in this population, consistent with earlier results from the ASPIRE study.\n\nDisclosure Statement\nT. Chou received honoraria from Ono Pharmaceutical and Celgene K.K. T. Ishida received personal fees from Celgene K.K. T. Izumi, M. Ri, I. Sugiura, K. Sunami, K. Suzuki and S. Ozaki received research funding from Ono Pharmaceutical K. Sunami received research funding from Celgene K.K. K. Ota and Y. Shumiya are employees of Ono Pharmaceutical. S. Iida received honoraria from Ono Pharmaceutical and Celgene K.K. N. Takezako has no conflicts of interest to declare. The study was designed under the responsibility of Ono Pharmaceutical. The study was funded by Ono Pharmaceutical. Carfilzomib was provided by Ono Pharmaceutical. Ono Pharmaceutical collected and analyzed the data and contributed to the interpretation of the study. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication.\n\nAcknowledgments\nWe thank all study participants and their families, and all investigators, physicians, nurses, and clinical research coordinators who assisted with the study. We would also like to thank the medical consultant, Dr Hirokazu Murakami (Gunma University Graduate School of Health Science, Maebashi), and Dr Chihiro Shimazaki (Japan Community Health Care Organization Kyoto‐Kuramaguchi Medical Center, Kyoto), Dr Masahiro Kizaki (Saitama Medical Center, Saitama Medical University, Saitama), Dr Takao Katoh (International University of Health and Welfare, Mita Hospital, Tokyo), Dr Masahiro Endo (Shizuoka Cancer Center, Nagaizumi) and Dr Terufumi Kato (Kanagawa Cancer Center, Yokohama) for their review of the clinical data as members of the Efficacy and Safety Evaluation Committee. We also acknowledge the statistical support of Naokazu Gion (Ono Pharmaceutical, Osaka) and critical review of the manuscript by Mike Kelsh, Sanjay Aggarwal, Sunhee Ro and Ying Ou (Amgen, Thousand Oaks). Medical writing support was provided by Helen Roberton and Dr Sarah Williams.\n==== Refs\nReferences\n1 \n\nKumar \nSK \n, \nRajkumar \nSV \n, \nDispenzieri \nA \n, et al\nImproved survival in multiple myeloma and the impact of novel therapies . Blood \n2008 ; 111 : 2516 –20 .17975015 \n2 \n\nMohty \nB \n, \nEl‐Cheikh \nJ \n, \nYakoub‐Agha \nI \n, \nAvet‐Loiseau \nH \n, \nMoreau \nP \n, \nMohty \nM \n. Treatment strategies in relapsed and refractory multiple myeloma: a focus on drug sequencing and ‘retreatment’ approaches in the era of novel agents . Leukemia \n2012 ; 26 : 73 –85 .22024721 \n3 \n\nBenboubker \nL \n, \nDimopoulos \nMA \n, \nDispenzieri \nA \n, et al\nLenalidomide and dexamethasone in transplant‐ineligible patients with myeloma . N Engl J Med \n2014 ; 371 : 906 –17 .25184863 \n4 \n\nSiegel \nDS \n, \nMartin \nT \n, \nWang \nM \n, et al\nA phase 2 study of single‐agent carfilzomib (PX‐171‐003‐A1) in patients with relapsed and refractory multiple myeloma . Blood \n2012 ; 120 : 2817 –25 .22833546 \n5 \n\nStewart \nAK \n, \nRajkumar \nSV \n, \nDimopoulos \nMA \n, et al\nCarfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma . N Engl J Med \n2015 ; 372 : 142 –52 .25482145 \n6 \n\nDimopoulos \nMA \n, \nMoreau \nP \n, \nPalumbo \nA \n, et al\nCarfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open‐label, multicentre study . Lancet Oncol \n2016 ; 17 : 27 –38 .26671818 \n7 \n\nWatanabe \nT \n, \nTobinai \nK \n, \nMatsumoto \nM \n, et al\nA phase 1/2 study of carfilzomib in Japanese patients with relapsed and/or refractory multiple myeloma . Br J Haematol \n2016 ; 172 : 745 –56 .26732066 \n8 \n\nDurie \nBG \n, \nHarousseau \nJL \n, \nMiguel \nJS \n, et al\nInternational uniform response criteria for multiple myeloma . Leukemia \n2006 ; 20 : 1467 –73 .16855634 \n9 \n\nRajkumar \nSV \n, \nHarousseau \nJL \n, \nDurie \nB \n, et al\nConsensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1 . Blood \n2011 ; 117 : 4691 –5 .21292775 \n10 \n\nBladé \nJ \n, \nSamson \nD \n, \nReece \nD \n, et al\nCriteria for evaluating disease response and progression in patients with multiple myeloma treated by high‐dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant . Br J Haematol \n1998 ; 102 : 1115 –23 .9753033 \n11 \n\nKyle \nRA \n, \nRajkumar \nSV \n. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma . Leukemia \n2009 ; 23 : 3 –9 .18971951 \n12 \nMinistry of Health, Labour and Welfare, Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau \n. Guidelines for Clinical Evaluation Methods of Antimalignant Tumor Drugs . Notification No. 1101001. 2005. [cited 2 June 2016] Available from URL: https://www.pmda.go.jp/files/000206740.pdf. In Japanese.\n13 \n\nMoreau \nP \n, \nMasszi \nT \n, \nGrzasko \nN \n, et al\nOral ixazomib, lenalidomide, and dexamethasone for multiple myeloma . N Engl J Med \n2016 ; 374 : 1621 –34 .27119237 \n14 \n\nLonial \nS \n, \nDimopoulos \nM \n, \nPalumbo \nA \n, et al\nElotuzumab therapy for relapsed or refractory multiple myeloma . N Engl J Med \n2015 ; 373 : 621 –31 .26035255 \n15 \n\nDimopoulos \nMA \n, \nOriol \nA \n, \nNahi \nH \n, et al\nAn open‐label, randomised phase 3 study of daratumumab, lenalidomide, and dexamethasone (DRD) versus lenalidomide and dexamethasone (RD) in relapsed or refractory multiple myeloma (RRMM): POLLUX . Haematologica \n2016 ; 101 (Suppl 1 ): S342 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1347-9032",
"issue": "108(3)",
"journal": "Cancer science",
"keywords": "Japan; carfilzomib; dexamethasone; lenalidomide; multiple myeloma",
"medline_ta": "Cancer Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D003907:Dexamethasone; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D006943:Hyperglycemia; D007564:Japan; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009842:Oligopeptides; D013792:Thalidomide",
"nlm_unique_id": "101168776",
"other_id": null,
"pages": "461-468",
"pmc": null,
"pmid": "28092421",
"pubdate": "2017-03",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study",
"references": "9753033;26732066;17975015;18971951;27119237;28092421;26671818;26035255;22024721;25482145;25184863;22833546;16855634;21292775",
"title": "Carfilzomib, lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma: A phase 1 study in Japan.",
"title_normalized": "carfilzomib lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma a phase 1 study in japan"
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"abstract": "Disseminated Intravascular Coagulation (DIC) is a disorder of coagulation which is commonly seen as a complication of infections, traumas, obstetric diseases, and cancers especially hematological and rarely solid cancers. DIC may rarely be the presenting feature of an undiagnosed malignancy. It may present in the form of different phenotypes which makes its diagnosis difficult and leads to high mortality. The treatment comprises supportive, symptomatic treatment and removal of the underlying source. Here, we present a patient with history of being on warfarin for atrial fibrillation and other comorbidities who presented with elevated INR of 6.3 and increasing dyspnea on exertion. Over the course of her stay, her platelet counts started dropping with a concurrent decrease in fibrinogen levels. She eventually developed pulmonary embolism, followed by stroke and limb ischemia, which was indicative of the thrombotic phenotype of DIC. Her pleural fluid analysis showed huge burden of malignant cells in glandular pattern suggestive of adenocarcinoma and was started on heparin drip. However, the patient had cardiac arrest and expired on the same day of diagnosis.",
"affiliations": "Department of Internal Medicine, AMITA Health Saint Francis Hospital, 355 Ridge Avenue, Evanston, IL 60202, USA.;Department of Internal Medicine, AMITA Health Saint Francis Hospital, 355 Ridge Avenue, Evanston, IL 60202, USA.;Department of Internal Medicine, AMITA Health Saint Francis Hospital, 355 Ridge Avenue, Evanston, IL 60202, USA.;Department of Internal Medicine, AMITA Health Saint Francis Hospital, 355 Ridge Avenue, Evanston, IL 60202, USA.;Department of Internal Medicine, AMITA Health Saint Francis Hospital, 355 Ridge Avenue, Evanston, IL 60202, USA.",
"authors": "Sohal|Sumit|S|https://orcid.org/0000-0002-0176-258X;Thakur|Akhilesh|A|;Zia|Aleena|A|https://orcid.org/0000-0001-9609-0677;Sous|Mina|M|;Trelles|Daniela|D|",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 3197610310.1155/2020/9147105Case ReportDisseminated Intravascular Coagulation and Malignancy: A Case Report and Literature Review https://orcid.org/0000-0002-0176-258XSohal Sumit sumit.sohal@amitahealth.orgThakur Akhilesh https://orcid.org/0000-0001-9609-0677Zia Aleena Sous Mina Trelles Daniela Department of Internal Medicine, AMITA Health Saint Francis Hospital, 355 Ridge Avenue, Evanston, IL 60202, USAAcademic Editor: Jose I. Mayordomo\n\n2020 2 1 2020 2020 91471056 7 2019 18 12 2019 Copyright © 2020 Sumit Sohal 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.Disseminated Intravascular Coagulation (DIC) is a disorder of coagulation which is commonly seen as a complication of infections, traumas, obstetric diseases, and cancers especially hematological and rarely solid cancers. DIC may rarely be the presenting feature of an undiagnosed malignancy. It may present in the form of different phenotypes which makes its diagnosis difficult and leads to high mortality. The treatment comprises supportive, symptomatic treatment and removal of the underlying source. Here, we present a patient with history of being on warfarin for atrial fibrillation and other comorbidities who presented with elevated INR of 6.3 and increasing dyspnea on exertion. Over the course of her stay, her platelet counts started dropping with a concurrent decrease in fibrinogen levels. She eventually developed pulmonary embolism, followed by stroke and limb ischemia, which was indicative of the thrombotic phenotype of DIC. Her pleural fluid analysis showed huge burden of malignant cells in glandular pattern suggestive of adenocarcinoma and was started on heparin drip. However, the patient had cardiac arrest and expired on the same day of diagnosis.\n==== Body\n1. Introduction\nDisseminated Intravascular Coagulation (DIC) is a condition characterized by systemic activation of coagulation, potentially leading to thrombotic obstruction of small and midsize vessels, thereby contributing to organ dysfunction [1]. It may result as a complication of infection, solid cancers, hematological malignancies, obstetric diseases, trauma, aneurysms, liver diseases, etc. [2]. DIC reportedly develops in 10% to 15% of patients with cancer where it may exhibit a chronic phenotype or present as an acute phenomenon [3]. We present a case of a patient who was admitted with unrelated complaints and developed DIC during her hospital course, with her workup revealing an underlying malignancy.\n\n2. Case Presentation\nAn 81-year-old female with a past medical history of hypertension, hyperlipidemia, orthostatic hypotension, atrial fibrillation, and bioprosthetic mitral valve replacement on warfarin presented at clinic after the International Normalized Ratio (INR) was reported as 6.3, without any signs or symptoms of bleeding. On review of systems, the patient endorsed increased dyspnea on exertion over the last few weeks. She did not endorse a change in dose or diet and no new medications except for methylprednisolone (Medrol) dose pack about a week prior to admission.\n\nPhysical exam on presentation was significant for a temperature of 97.4°F, blood pressure of 130/70, heart rate of 83 beats per minute (bpm), and an oxygen saturation of 96% on room air. She had decreased breath sounds at lung bases and superficial scratches on bilateral upper extremities with no overt signs of bleeding. Laboratory findings were significant for white blood count of 13.5 k/mm cu (ref range: 4.0-11.0 k/mm cu), hemoglobin 10.8 g/dl (ref range: 12-15.3 g/dl), and platelet count 285 k/cu mm (ref range: 150-450 k/cu mm). Chest X-ray showed minimal increased opacity at the left lung base, a nodular opacity in the right midlung unchanged from the prior study, and slight blunting of the costophrenic angles bilaterally. CT chest without contrast was done and showed chronic diffuse emphysema, minimal bilateral pleural effusion, and a reidentified spiculated left upper lobe mass that measured 0.7 × 0.6 cm which had slightly increased in conspicuity (previously 0.4 × 0.5 cm). Warfarin was held and IV Vitamin K 5 mg was given. INR dropped to 1.4 the next day, and the patient was started on low-dose warfarin. She was also started on empiric antibiotics (vancomycin and piperacillin/tazobactam) as she showed worsening respiratory status.\n\nHer platelets on the 3rd day of admission dropped by >50% to 127. She had no exposure to heparin or its products, and her warfarin was held. A peripheral blood film showed no schistocytes. Her hemoglobin dropped to 7 g/dl. Her fibrinogen was 147 mg/dl (ref range: 163-463 mg/dl), INR 1.3, haptoglobin 86 mg/dl (ref range: 44-215 mg/dl), LDH 593 IU/l (ref range: 140-271 IU/l), and total bilirubin 0.4 mg/dl (ref range: 0.0-1.0 mg/dl). Hematology was consulted, and various other tests to exclude multiple diagnoses were initiated. Transthoracic echocardiography was done and showed an ejection fraction of 59% and ruled out any vegetation on valves. Her blood cultures and urine cultures remained negative. Her platelets continued to drop. On the 8th day of admission, her respiratory status continued to worsen, and hence, CT angiogram of the chest was done which revealed multiple subsegmental pulmonary emboli (SSPE) (Figures 1(a) and 1(b)) and significant pleural effusion (no anticoagulation given as SSPE and platelet level 22 k/cu mm). On the next day, interventional radiology- (IR-) guided thoracentesis was done (after platelet transfusion) and drained 920 cc of sanguineous fluid. This was complicated by pneumothorax, followed by chest tube placement. Later on the same day, her mental status declined, as she appeared confused with slurring of speech and had rightward gaze preference. CT head was done followed by CT angiogram of the head and neck which demonstrated right MCA, M1 occlusion (Figures 2(a) and 2(b)), but she was not a candidate for tissue plasminogen (tPA) due to low platelet count and thrombectomy was not pursued due to her multiple comorbidities. She was then conservatively managed in the ICU.\n\nOn the 10th day, her lung fluid cytology revealed multiple malignant cells arranged in a well-defined glandular pattern consistent with adenocarcinoma (Figure 3), and simultaneously, it was reported that her left lower extremity turned blue concerning for acute limb ischemia. Her laboratory values of fibrinogen and INR also worsened (87 mg/dl and 1.7, respectively), and she was started on heparin drip for the diagnosis of DIC with multiple thrombotic events secondary to occult malignancy. Unfortunately, the patient had a cardiac arrest and expired that day. The tumor cells came back positive for TTF-1 and negative for Napsin, GATA-3, Calretinin, and CK 5/6, consistent with metastatic adenocarcinoma of lung primary.\n\n3. Discussion\nDIC can be defined as a widespread hypercoagulable state that can lead to both microvascular and macrovascular clotting and compromised blood flow, ultimately resulting in multiple organ dysfunction syndrome (MODS) [4]. At the same time, the use and subsequent depletion of platelets and coagulation proteins resulting from the ongoing coagulation may induce severe bleeding [5]. In addition to coagulation activation, fibrinolytic activation occurs and the degree of activation of this system leads to the classification of the two major types of symptoms in DIC, i.e., bleeding symptoms and organ symptoms (dysfunction) [6]. When dealing with patients with cancer-related DIC, it is useful to consider the different pathogenic mechanisms that can lead to the abovementioned different clinical manifestations [7].\n\n3.1. Diagnosis of DIC\nThe active members of the subcommittee for DIC of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH) attempted to harmonize the three guidelines for DIC that have been published in the literature from the British Committee for Standards in Haematology (BCSH), the Japanese Society of Thrombosis and Hemostasis (JSTH), and the Italian Society for Thrombosis and Hemostasis (SISET). Though DIC does not have any gold standard test, ISTH favors the use of scoring systems to diagnose DIC [8–11].\n\nThree different diagnostic scoring systems have been devised by the ISTH/SSC [12], Japanese Ministry Health, Labour and Welfare (JMHLW) [13], and Japanese Association of Acute Medicine (JAAM) [14]. A prospective study in Japan reported no significant differences in the odds ratio for predicting DIC outcomes among these three diagnostic criteria [15]. The bleeding type of DIC can be easily diagnosed using the ISTH overt-DIC and JMHLW criteria, while the organ failure type of DIC is diagnosed according to the JAAM diagnostic criteria [2].\n\nOur patient was positive for DIC as per these criteria as her platelet count (26 k/cu mm), fibrinogen level (87 mg/dl), and INR (1.7) were conclusive for DIC.\n\n3.2. DIC and Cancer\nProfessor Trousseau in 1865 first described an association between recurrent migratory thrombophlebitis and cancer, and since then, several studies have proven a tight relationship between thrombosis and malignant disease. However, the thrombotic complications of cancer are not limited to venous thromboembolism and may appear as DIC [16, 17].\n\nCancer-related DIC may present in one of these 3 forms: firstly, the “procoagulant” form, where excess thrombin generated causes thrombosis in microvascular and macrovascular fields and thus clinically manifest as DIC with thrombotic features; secondly, the “hyperfibrinolytic” form, where activation of the fibrinolytic system dominates the picture and thus clinically presents as bleeding; and last but not the least, the “subclinical” form, where the amounts of thrombin and plasmin generated do not cause obvious clinical manifestations but can be reflected in laboratory markers of coagulation or fibrinolysis activation. While most of the solid tumors come under the umbrella of subclinical DIC, pancreatic and lung adenocarcinomas are procoagulant whereas acute promyelocytic leukemia and metastatic prostate cancer are likely to be in the hyperfibrinolytic form [7]. Though the association between solid cancers and DIC is well-known and has been described in almost all histologic types [18], the mortality rate from DIC is higher in patients with lung cancer than in non-lung cancer patients and prevalence of DIC varies among the pathologic types of lung cancer [19]. Many studies have shown that patients with adenocarcinoma are at a very high risk of DIC [7] especially in lung adenocarcinoma [20] due to the procoagulant mucin in the cancer cells [21]; however, one recent study has refuted this claim [19].\n\nOur patient with evidence of pulmonary embolism, stroke, and acute limb ischemia presented with thrombotic features of DIC. There was no biopsy performed; however, the malignant cells found on the pleural fluid analysis were consistent with metastatic adenocarcinoma of lung primary.\n\n3.3. Treatment of Cancer-Related DIC\nThe cornerstone of DIC treatment is providing treatment for the underlying disorders, such as the administration of antibiotics or surgical drainage in patients with infectious diseases and anticancer drugs or surgery in patients with malignant diseases [2]. However, patients with DIC resulting from sepsis, hematologic malignancy, or obstetric disease can be successfully treated for DIC, whereas DIC associated with solid cancers may not respond to standard treatments [11].\n\n3.3.1. In Patients with Procoagulant Form of DIC Which Is Characterized by Evidence of Venous or Arterial Thromboembolism with No Evidence of Bleeding\nFeinstein [22] recommended to initiate anticoagulant therapy with unfractionated heparin and maintain fibrinogen levels at ≥100 mg/l and platelet counts >50,000/μl via appropriate transfusions of cryoprecipitate and platelets [22]. Wada et al. also recommended therapeutic doses of heparin in cases of DIC where thrombosis predominates [11].\n\n3.3.2. In Patients with Bleeding Form of DIC Which Is Characterized by Severe Bleeding\nWada et al. [11] recommend transfusion of platelets if platelet count < 50 × 109 L−1 or in those with a high risk of bleeding and a platelet count of <20 × 109 L−1, administration of Fresh Frozen Plasma (FFP) for either prolonged prothrombin time/activated partial thromboplastin time (>1.5 times normal) or decreased fibrinogen (<1.5 g dL−1) and fibrinogen concentrate or cryoprecipitate in actively bleeding patients with persisting severe hypofibrinogenemia (<1.5 g L−1) despite FFP replacement. Thachil et al. also supported these recommendations [7].\n\n3.3.3. Role of Chemotherapy\nThe patients with DIC should be started on chemotherapy as soon as clinical problems associated with DIC are under control [22]. No Randomized Control Trials (RCTs) have ever been done for solid tumors; however, several case reports suggest the role of chemotherapy in these patients. Targeted chemotherapies have been used in some case reports with good outcomes [3].\n\nOur patient was on warfarin prior to presentation, and when warfarin was stopped, her platelets started to drop and she initially developed a picture of subclinical DIC, followed by procoagulant form of DIC leading to thrombosis of various organ systems. This happened when her diagnosis was unclear, and eventually when the diagnosis was made, she was well beyond recovery.\n\n4. Conclusion\nEarly diagnosis and identification of underlying condition is the key to reduce mortality in these patients with DIC. It can often be challenging to establish the underlying cause, especially if the patient is on anticoagulants or has other risk factors for bleeding/thrombosis. Malignancy should always be considered in laboratory findings of subclinical DIC, especially without overt cause and with risk factors for lung cancer.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 (a, b) A CT angiogram of the chest shows filling defects in the subsegmental arteries (arrows).\n\nFigure 2 (a, b) CT angiogram of the head shows abrupt occlusion of the branch of the middle cerebral artery (arrows).\n\nFigure 3 (a, b) Microscopic picture of pleural fluid analysis (200x/400x). Numerous tumor cells arranged in well-differentiated glandular pattern consistent with metastatic adenocarcinoma.\n==== Refs\n1 Levi M. Scully M. How I treat disseminated intravascular coagulation Blood 2018 131 8 845 854 10.1182/blood-2017-10-804096 2-s2.0-85042447844 29255070 \n2 Wada H. Matsumoto T. Yamashita Y. Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines Journal of Intensive Care 2014 2 1 p. 15 10.1186/2052-0492-2-15 2-s2.0-84988723393 25520831 \n3 Kim J. S. Ryu J. S. Jeon S. H. Dramatic response of acute disseminated intravascular coagulation to erlotinib in a patient with lung adenocarcinoma with activating EGFR mutation The Journal of International Medical Research 2018 46 1 533 537 10.1177/0300060517720099 2-s2.0-85041428920 28730909 \n4 Costello R. A. Nehring S. M. Disseminated Intravascular Coagulation (DIC). Stat Pearls 2018 Treasure Island, FL, USA Stat Pearls Publishing Stat Pearls Publishing LLC \n5 Levi M. Ten Cate H. Disseminated intravascular coagulation The New England Journal of Medicine 1999 341 8 586 592 10.1056/NEJM199908193410807 2-s2.0-0033584457 10451465 \n6 Asakura H. Classifying types of disseminated intravascular coagulation: clinical and animal models Journal of Intensive Care 2014 2 1 p. 20 10.1186/2052-0492-2-20 2-s2.0-84988732046 25520834 \n7 Thachil J. Falanga A. Levi M. Liebman H. Di Nisio M. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH Journal of Thrombosis and Haemostasis. 2015 13 4 671 675 10.1111/jth.12838 2-s2.0-84926134907 25556711 \n8 Levi M. Toh C. H. Thachil J. Watson H. G. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology British Journal of Haematology 2009 145 1 24 33 10.1111/j.1365-2141.2009.07600.x 2-s2.0-61849136778 19222477 \n9 Wada H. Asakura H. Okamoto K. Expert consensus for the treatment of disseminated intravascular coagulation in Japan Thrombosis Research 2010 125 1 6 11 10.1016/j.thromres.2009.08.017 2-s2.0-76449097783 19782389 \n10 Di Nisio M. Baudo F. Cosmi B. Diagnosis and treatment of disseminated intravascular coagulation: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET) Thrombosis Research 2012 129 5 e177 e184 10.1016/j.thromres.2011.08.028 2-s2.0-84860453810 21930293 \n11 Wada H. Thachil J. di Nisio M. Guidance for diagnosis and treatment of disseminated intravascular coagulation from harmonization of the recommendations from three guidelines Journal of Thrombosis and Haemostasis 2013 11 4 761 767 10.1111/jth.12155 2-s2.0-84876183270 \n12 Taylor F. B. Jr. Toh C. H. Hoots W. K. Wada H. Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation Thrombosis and Haemostasis 2001 86 11 1327 1330 10.1055/s-0037-1616068 11816725 \n13 Kobayashi N. Maekawa T. Takada M. Tanaka H. Gonmori H. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the Research Committee on DIC in Japan Bibliotheca Haematologica 1983 49 265 275 10.1159/000408467 \n14 Gando S. Iba T. Eguchi Y. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria Critical Care Medicine 2006 34 3 625 631 10.1097/01.ccm.0000202209.42491.38 2-s2.0-33644589346 16521260 \n15 Takemitsu T. Wada H. Hatada T. Prospective evaluation of three different diagnostic criteria for disseminated intravascular coagulation Thrombosis and Haemostasis 2011 105 1 40 44 10.1160/TH10-05-0293 2-s2.0-78651102024 20941463 \n16 Donati M. B. Thrombosis and cancer: trousseau syndrome revisited Best Practice & Research Clinical Haematology 2009 22 1 3 8 10.1016/j.beha.2009.01.005 2-s2.0-61649128786 19285268 \n17 Levi M. Disseminated intravascular coagulation in cancer patients Best Practice & Research Clinical Haematology 2009 22 1 129 136 10.1016/j.beha.2008.12.005 2-s2.0-61649083524 19285279 \n18 Sallah S. Wan J. Y. Nguyen N. P. Hanrahan L. R. Sigounas G. Disseminated intravascular coagulation in solid tumors: clinical and pathologic study Thrombosis and Haemostasis 2001 86 3 828 833 11583315 \n19 Nakano K. Sugiyama K. Satoh H. Risk factors for disseminated intravascular coagulation in patients with lung cancer Thoracic Cancer 2018 9 8 931 938 10.1111/1759-7714.12766 2-s2.0-85047814083 29851300 \n20 Blom J. W. Osanto S. Rosendaal F. R. The risk of a venous thrombotic event in lung cancer patients: higher risk for adenocarcinoma than squamous cell carcinoma Journal of Thrombosis and Haemostasis 2004 2 10 1760 1765 10.1111/j.1538-7836.2004.00928.x 2-s2.0-13244250995 15456487 \n21 Pineo G. F. Regoeczi E. Hatton M. W. Brain M. C. The activation of coagulation by extracts of mucus: a possible pathway of intravascular coagulation accompanying adenocarcinomas The Journal of Laboratory and Clinical Medicine 1973 82 2 255 266 4352814 \n22 Feinstein D. I. Disseminated intravascular coagulation in patients with solid tumors Oncology 2015 29 2 96 102 25683828\n\n",
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"title": "Disseminated Intravascular Coagulation and Malignancy: A Case Report and Literature Review.",
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"abstract": "We evaluated the safety and clinical outcome of autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) in patients with severe Crohn disease (CD) defined as a Crohn Disease Activity Index (CDAI) greater than 250, and/or Crohn Severity Index greater than 16 despite anti-tumor necrosis factor therapy. Stem cells were mobilized from the peripheral blood using cyclophosphamide (2.0 g/m(2)) and G-CSF (10 μg/kg/day), enriched ex vivo by CD34(+) selection, and reinfused after immune suppressive conditioning with cyclophosphamide (200 mg/kg) and either equine antithymocyte globulin (ATG, 90 mg/kg) or rabbit ATG (6 mg/kg). Eighteen of 24 patients are 5 or more years after transplantation. All patients went into remission with a CDAI less than 150. The percentage of clinical relapse-free survival defined as the percent free of restarting CD medical therapy after transplantation is 91% at 1 year, 63% at 2 years, 57% at 3 years, 39% at 4 years, and 19% at 5 years. The percentage of patients in remission (CDAI < 150), steroid-free, or medication-free at any posttransplantation evaluation interval more than 5 years after transplantation has remained at or greater than 70%, 80%, and 60%, respectively. This trial was registered at www.clinicaltrials.gov as NCT0027853.",
"affiliations": "Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. rburt@northwestern.edu",
"authors": "Burt|Richard K|RK|;Craig|Robert M|RM|;Milanetti|Francesca|F|;Quigley|Kathleen|K|;Gozdziak|Paula|P|;Bucha|Jurate|J|;Testori|Alessandro|A|;Halverson|Amy|A|;Verda|Larissa|L|;de Villiers|Willem J S|WJ|;Jovanovic|Borko|B|;Oyama|Yu|Y|",
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"abstract": "Although Enhanced Recovery after Surgery (ERAS) pathways are becoming the standard of care in microvascular breast reconstruction, evidence supporting their use is limited or based on small sample sizes. We hypothesized that improvements in postoperative outcomes would persist when examining the largest cohort of patients undergoing abdominal-based microvascular breast reconstruction, to date.\n\n\n\nData were retrospectively reviewed for 276 consecutive patients who underwent abdominal-based free flap breast reconstruction before and after ERAS implementation (pre-ERAS, n = 138 patients; post-ERAS, n = 138 patients). Primary outcomes were postoperative opioid use measured in oral morphine equivalents (OMEs), median hospital length of stay (LOS) in days, and incidence of postoperative complications.\n\n\n\nPostoperative opioid requirements were significantly lower in the post-ERAS cohort compared with the pre-ERAS cohort (57.3 OME, [interquartile range 20.0-115.5] versus 297.3 OME [interquartile range 138.6-437.7], P < 0.0001). There was no significant difference in hospital LOS when controlling for variables that differed between the groups. In addition, there were no differences in the rate of postoperative complications, return to operating room, or readmission after ERAS pathway implementation.\n\n\n\nERAS improves specific aspects of recovery for patients undergoing microvascular breast reconstruction, most notably postoperative opioid use. Patient selection and a shift toward less invasive procedures may explain a nonsignificant impact on hospital LOS.",
"affiliations": "Duke University School of Medicine, Durham, North Carolina.;Duke University School of Medicine, Durham, North Carolina.;Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.;Division of Plastic and Reconstructive Surgery, Duke University Medical Center, Durham, North Carolina.;Division of Plastic and Reconstructive Surgery, Duke University Medical Center, Durham, North Carolina. Electronic address: Scott.hollenbeck@duke.edu.",
"authors": "Sharif-Askary|Banafsheh|B|;Hompe|Eliza|E|;Broadwater|Gloria|G|;Anolik|Rachel|R|;Hollenbeck|Scott T|ST|",
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"medline_ta": "J Surg Res",
"mesh_terms": "D034861:Abdominal Wall; D000328:Adult; D019091:Critical Pathways; D000080482:Enhanced Recovery After Surgery; D005260:Female; D058752:Free Tissue Flaps; D006284:Health Plan Implementation; D006801:Humans; D015994:Incidence; D007902:Length of Stay; D016462:Mammaplasty; D008875:Middle Aged; D010359:Patient Readmission; D011183:Postoperative Complications; D015397:Program Evaluation; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome",
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"title": "The Effect of Enhanced Recovery after Surgery Pathway Implementation on Abdominal-Based Microvascular Breast Reconstruction.",
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"abstract": "BACKGROUND\nHodgkin lymphoma (HL) is the most common hematological malignancy during pregnancy. The first-line treatment for HL in pregnancy is the standard ABVD regimen without any drug and/or dose adjustment. However, data on chemotherapy during twin pregnancies are sparse, and a better understanding of the mechanisms involved in exposure to and the toxic effects of anticancer drugs in the fetuses is needed.\n\n\nMETHODS\nA 41-year-old dichorionic diamniotic pregnant patient was given ABVD treatment for HL at a gestational age of 28 weeks and 3 days. The patient received 2 cycles of chemotherapy with a 15-day therapeutic window including an actual 25 mg/m2 dose of doxorubicin per cycle. Unlike the female twin, the male twin presented four days after birth a left cardiac dysfunction. Doxorubicin cardiotoxicity in the male newborn was also supported by high blood levels of troponin. At one month of age, echocardiography findings were normal. We investigated literature data on physiological aspects of pregnancy that may influence doxorubicin pharmacokinetics, and pharmacodynamic and pharmacokinetic data on the use of doxorubicin in pregnancy. We detailed the role of the transporters in doxorubicin placenta distribution, and tried to understand why only one fetus was affected.\n\n\nCONCLUSIONS\nFetal safety depends at least on maternal doxorubicin pharmacokinetics.Because of drug interactions (i.e. drug metabolism and drug transport), care should always be taken to avoid maternal pharmacokinetic variability. The toxic effects were discrepant between the dizygotic twins, suggesting additional fetus-specific pharmacokinetic/pharmacodynamic factors in doxorubicin toxicity.",
"affiliations": "Hôpital universitaire Necker - Enfants malades, Pharmacie, F-75015, Paris, France.;Hôpital universitaire Necker - Enfants malades, Pharmacie, F-75015, Paris, France.;Hôpital universitaire Necker - Enfants malades, Hématologie adultes, F-75015, Paris, France.;Hôpital universitaire Necker - Enfants malades, gynécologie-obstétrique, F-75015, Paris, France.;Hôpital universitaire Necker - Enfants malades, Pharmacie, F-75015, Paris, France.;Hôpital universitaire Necker - Enfants malades, Pharmacie, F-75015, Paris, France. joel.schlatter@aphp.fr.",
"authors": "Cotteret|Camille|C|;Pham|Yen-Vi|YV|;Marcais|Ambroise|A|;Driessen|Marine|M|;Cisternino|Salvatore|S|;Schlatter|Joël|J|",
"chemical_list": "D001761:Bleomycin; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin",
"country": "England",
"delete": false,
"doi": "10.1186/s12884-020-02928-6",
"fulltext": "\n==== Front\nBMC Pregnancy Childbirth\nBMC Pregnancy Childbirth\nBMC Pregnancy and Childbirth\n1471-2393 BioMed Central London \n\n2928\n10.1186/s12884-020-02928-6\nCase Report\nMaternal ABVD chemotherapy for Hodgkin lymphoma in a dichorionic diamniotic pregnancy: a case report\nCotteret Camille camille.cotteret@aphp.fr 1 Pham Yen-Vi yen-vi.pham@aphp.fr 1 Marcais Ambroise ambroise.marcais@aphp.fr 2 Driessen Marine marine.driessen@aphp.fr 3 Cisternino Salvatore salvatore.cisternino@aphp.fr 14 Schlatter Joël joel.schlatter@aphp.fr 1 1 grid.412134.10000 0004 0593 9113Hôpital universitaire Necker - Enfants malades, Pharmacie, F-75015 Paris, France \n2 grid.412134.10000 0004 0593 9113Hôpital universitaire Necker - Enfants malades, Hématologie adultes, F-75015 Paris, France \n3 grid.412134.10000 0004 0593 9113Hôpital universitaire Necker - Enfants malades, gynécologie-obstétrique, F-75015 Paris, France \n4 grid.10992.330000 0001 2188 0914Inserm UMR-S 1144, Team “Blood-brain barrier in brain pathophysiology and therapy”, Université Paris Descartes, F-75006 Paris, France \n19 4 2020 \n19 4 2020 \n2020 \n20 23117 8 2019 7 4 2020 © The Author(s) 2020Open 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.Background\nHodgkin lymphoma (HL) is the most common hematological malignancy during pregnancy. The first-line treatment for HL in pregnancy is the standard ABVD regimen without any drug and/or dose adjustment. However, data on chemotherapy during twin pregnancies are sparse, and a better understanding of the mechanisms involved in exposure to and the toxic effects of anticancer drugs in the fetuses is needed.\n\nCase presentation\nA 41-year-old dichorionic diamniotic pregnant patient was given ABVD treatment for HL at a gestational age of 28 weeks and 3 days. The patient received 2 cycles of chemotherapy with a 15-day therapeutic window including an actual 25 mg/m2 dose of doxorubicin per cycle. Unlike the female twin, the male twin presented four days after birth a left cardiac dysfunction. Doxorubicin cardiotoxicity in the male newborn was also supported by high blood levels of troponin. At one month of age, echocardiography findings were normal. We investigated literature data on physiological aspects of pregnancy that may influence doxorubicin pharmacokinetics, and pharmacodynamic and pharmacokinetic data on the use of doxorubicin in pregnancy. We detailed the role of the transporters in doxorubicin placenta distribution, and tried to understand why only one fetus was affected.\n\nConclusions\nFetal safety depends at least on maternal doxorubicin pharmacokinetics.Because of drug interactions (i.e. drug metabolism and drug transport), care should always be taken to avoid maternal pharmacokinetic variability. The toxic effects were discrepant between the dizygotic twins, suggesting additional fetus-specific pharmacokinetic/pharmacodynamic factors in doxorubicin toxicity.\n\nKeywords\nTwin dizygotic pregnancyHodgkin lymphomaDoxorubicinCardiotoxicityFetusissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nWhile the simultaneous occurrence of cancer and pregnancy is a rare medical event, hematological malignancies such as Hodgkin lymphoma (HL) occur in about 1/6000 pregnancies, which represent 3% of all HL patients [1–7]. In France, the number of new HL cases was estimated to be around 2000 per year, with 45% of them affecting women [8]. Staging the disease helps to determine the appropriate treatment. To treat advanced stages (IIB, III and IV) during pregnancy, the ABVD regimen (doxorubicin, bleomycin, vinblastine and dacarbazine) is considered to be the best therapeutic choice, providing good overall survival and low toxicity for the fetus [9–12]. No consensus has been proposed to treat stage IA and IIA HL during pregnancy, but recommendation is to delay chemotherapy until delivery [11, 12]. Therapeutic decision also depends on gestational age and fetal development. The management of ABVD toxicity requires consideration of physiological changes in pregnancy which affects drug pharmacokinetics. However, based on the limited clinical data about adaptation of chemotherapy during pregnancy, the standard ABVD protocol remains the current treatment for HL in pregnancy in North America and Europe [13, 14]. Small case series and retrospective studies in pregnancies treated for HL reported that doxorubicin was safe for the fetal heart when administered during the second and third trimester [9, 12, 15–17]. But they reported that doxorubicin in pregnancy could reduce the thickness of the left ventricular wall without causing heart defects or functional disorders [15].\n\nIn this article, we report a case of HL-complicated a twin dizygotic pregnancy in which ABVD administration was associated with reversible cardiac dysfunction in only one of the twins.\n\nCase presentation\nA 41-year-old woman pregnant with twins was admitted to our hematology department at a gestational age of 27 weeks for stage IIA HL. The disease history started with a vena cava syndrome associated with a right supra-clavicular adenopathy up to 3 cm. A thoracic-abdominal-pelvic scan showed a compressive anterior mediastinal mass of 16 cm in diameter, and a lymph node biopsy confirmed the diagnosis of classic HL. The CRAT (French reference center about teratogenic agents) states that if the examination is necessary to ensure the best diagnostic/treatment of the patient, it can be performed with protective measures in a specialized department. Radiation levels were lower than the maximum recommended during pregnancy [18]. A course of corticosteroid (prednisone 80 mg/d and then 40 mg/d) was started at the time of diagnosis. Maternal transthoracic echocardiography and electrocardiogram were normal. Fetuses’ transabdominal echography at gestational ages of 18 weeks and 4 days, and 22 weeks and 3 days revealed normal morphologic examination. The heart was in normal position and there were four equilibrated cardiac cavities for each of twin. The intersection of the big vessels was normal. No abnormal cardiac rhythm was detectable. Cytological, urinary and hemostasis results were within the normal range at patient admission. A multidisciplinary team (hematologists and obstetricians) decided to start a chemotherapy regimen based on the ABVD protocol at a gestational age of 28 weeks and 3 days. The patient received 2 chemotherapy cycles on a 15-day outpatient basis (Table 1). During each outpatient hematology session, doxorubicin 25 mg/m2, bleomycin 10 mg/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2 (ABVD), and dexamethasone 10 mg were given. The patient received medications such as ondansetron (8 mg twice a day), prednisone (40 mg per day from the diagnosis until 1 week after the first ABVD), enoxaparin (4000 UI twice a day), lansoprazole (30 mg once a day), and valaciclovir (500 mg once a day). Preterm premature rupture of membranes (PPROM) occurred on the same day as the completion of the second cycle of ABVD, corresponding to a gestational age of 32 weeks and 4 days. She was admitted in the maternity unit for surveillance and was given antibiotics by amoxicillin and steroids for fetal lung maturity. No sign of chorioamnionitis was found at that time (no contractions, no inflammatory sign in blood sample, no fetal tachycardia). She spontaneously went into labor at 33 weeks, and a cesarean section was performed given the prematurity and twin pregnancy. The latency period, from the PPROM to the delivery, seems to be shorter in twins compared with singleton pregnancies. Most studies report a median latency of less than 24 h [19].\nTable 1 ABVD protocol administered to twin pregnant women\n\nPatient: 41 years old\tWeight (kg): 85\nSize (cm): 173\nBody surface area (m2): 1,99\nCreatinine (μmol/L): 58\nClearance(mL/min, Cockroft Gault): 151\tUnit: Hematology\nCycle 1 J1 = November 08, 2017\nCycle duration: 28 days\t\t\nDrug\tDose of protocol\tTotal dose\tVehicle\tMedical device\tRoute\tDuration\tTiming\t\nDoxorubicin\t25 mg/m2\t50 mg\tGlucose 5% 20 mL\tSyringe\tIntravenous\t5 min\tJ1 and J15\t\nBleomycin\t10 mg/m2\t19.8 mg\tSodium chloride 0.9% 20 mL\tSyringe\tIntravenous\t5 min\tJ1 and J15\t\nVinblastine\t5 mg/m2\t10 mg\tSodium chloride 0.9% 20 mL\tBag\tIntravenous\t5 min\tJ1 and J15\t\nDacarbazine\t375 mg/m2\t750 mg\tGlucose 5% 250 mL\tBag\tInfusion\t45 min\tJ1 and J15\t\nOndansetron\t8 mg\t8 mg\tNo dilution\t\tIntravenous\t1 min\tJ1 and J15\t\nDexamethasone\t10 mg\t10 mg\tNo dilution\t\tIntravenous\t5 min\tJ1 and J15\t\nMonitoring: hemogram, C-reactive protein (CRP), creatininemia, liver checkup\n\n\n\nThe first twin born was a boy weighing 2030 g (50th percentile) and measuring 48 cm. Head circumference was 31.5 cm, Apgar score was 9/10/10 and umbilical cord pH was 7.32. The neonate presented normal respiration (45 breaths/min) and heart rate was 150 beats/min. Blood count was normal with hemoglobin at 18 g/dL and platelets at 328,000/mm3. To avoid premature apnea, an intravenous loading and maintenance dose of caffeine (5 mg/kg/day) was given. The neonate breathed spontaneously with no apnea or bradycardia. Four days after delivery, an echocardiographic control examination showed a minor left cardiac dysfunction with preserved ejection fraction (HFpEF) at 48%, associated with a high concentration of troponin (Tn1: 103 ng/L; reference: < 26 ng/L). Cardiological advice was given and no therapy was initiated, but medical monitoring was started. When he was one-month-old, echocardiography findings were normal with a borderline LVEF at 50% without pulmonary arterial hypertension. No troponin measurement was further performed. Following exclusive parenteral nutrition for 4 days, oral nutrition was progressively introduced with complete autonomy on day 17. Neurological investigation was normal.\n\nThe second twin was a girl weighing 1785 g (25th percentile) and measuring 42 cm at birth. Head circumference was 32 cm; Apgar score was 9/10/10 and umbilical cord pH was 7.32.Blood count was normal with hemoglobin at 19.2 g/dL and platelets at 310,000/mm3. At birth, echocardiography results were normal, with a LVEF > 55%. Neurological investigation was normal.\n\nFor the mother, 18F-FDG PET and TDM scans were performed 20 days later and revealed complete metabolic remission. She was treated with 6 further ABVD cycles for consolidation.\n\nDiscussion and conclusions\nWe report here a case of a twin dizygotic pregnancy complicated by HL. A preterm rupture of membranes was diagnosed at 32 weeks and 4 days. ABVD administration was associated with reversible cardiac dysfunction in only one of the twins. Maggen and al. reported in a multicenter cohort study that 3% of 123 children born from mothers diagnosed with HL had a major congenital abnormality (syndactyly, atrial septal defect) at birth and 3% with minor abnormalities. They also reported that mothers who received prenatal chemotherapy experienced more obstetric complications (preterm contractions, preterm ruptures of membranes) [20]. In pregnancy, drug pharmacokinetics may be altered by maternal physiological changes. Thus, maternal drug distribution and/or elimination may be affected. Indeed, maternal serum albumin concentrations decrease from the pre-pregnancy value of 45.8 g/L (7.6%), to 37.6 g/L (10%) at 34 weeks and 31.5 g/L (17%) at 40 weeks of gestation [21, 22]. The increase in intravascular and extravascular fluid partly explains the hypoalbuminemia observed during pregnancy, with a significant increase in the total body water [23]. Hypoalbuminemia can increase the free plasma fraction of drugs and alter their distribution in tissues. However, the low serum protein binding of doxorubicin (~ 75%) limits such variations in doxorubicin distribution.\n\nThe CYP2D6 and CYP3A4 activities increase up to 35% during the second and third trimesters [24]. The clearance of doxorubicin (CYP3A4 and CYP2D6 substrate) mainly involves liver metabolization and excretion via the bile duct [21]. However, some reports on doxorubicin clearance during pregnancy provide conflicting results about the effect of pregnancy on doxorubicin metabolism and variations in biliary excretion [22, 25–27]. Doxorubicin, a low molecular weight (544 g/mol) amphiphilic drug is also known as a substrate of the carbonyl reductases CBR1 and CBR3, which convert doxorubicin to doxorubicinol, an active and toxic metabolite, and other enzymes that produce some inactive metabolites (e.g. aglycones, glucuronides, and sulfates) [28–30]. Doxorubicinol is more powerful than doxorubicin to compromise both systolic and diastolic cardiac functions [31]. Cardiotoxicity is reduced by decreasing circulating levels of doxorubicinol through the inhibition of CBR1 [32]. Doxorubicinol formation is under control of AKR1C3, CBR1, and CBR3 expressions [33]. To our knowledge, no data exist about impact of changes in their expression or activity during pregnancy. However, doxorubicinol quantity expressed as a ratio of its plasma concentrations, represented as an area-under-the-curve (AUC) (AUCdoxorubicinol/AUCdoxorubicin: 0.45 ± 0.10; range: 0.33–0.61) was not significantly different from that in non-pregnant women. It suggests that pregnancy does not affect metabolic pathway involved in the doxorubicinol formation [22]. Moreover, these studies also suggest that distribution volume and elimination (half-life) of doxorubicin are not statistically different in pregnant than in non-pregnant women [22, 27–29]. Placental capacity to transfer doxorubicin or pegylated liposomal doxorubicin from maternal blood to the fetal circulation was studied ex vivo with the human placental perfusion model [34]. This study showed a rapid decrease in doxorubicin concentration, with 30% doxorubicin remaining in the maternal circulation after 4 h, and 12% doxorubicin in the fetal circulation. On the contrary, doxorubicin was not detected in the fetal circulation at any time point over 4 h of ex vivo placental perfusion with pegylated liposomal doxorubicin. These results suggest that pegylated liposomal doxorubicin did not cross the blood-placental barrier. While these reported data suggested that the maternal doxorubicin pharmacokinetic did not appear to differ during pregnancy, placental function and fetal factors were also possible sources of variability in the fetal exposure to doxorubicin or in its pharmacokinetics.\n\nTo further explain the low risk of fetal doxorubicin cardiotoxicity, the critical role of placental drug efflux transporters of the ABC superfamily in effectively controlling and limiting fetal drug/substrate exposure has been suggested [35, 36]. Some studies demonstrated that ABCB1, also known as P-glycoprotein (P-gp), is critical for fetal protection by limiting exposure to substrates from the maternal circulation and removing them from the fetal circulation to the maternal circulation [37–39]. Table 2 summarizes the localization of selected doxorubicin carrier-mediated systems of the ABC superfamily, known to limit, at least at the human placenta, doxorubicin access to the fetal blood compartment. There are also known to affect the pharmacokinetics of doxorubicin through their polymorphisms. Therefore, the function of these drug transporters may be critical for fetal protection. P-gp and ABCG2 (BCRP) are expressed at the placenta and doxorubicin is well known as a dual P-gp and BCRP substrate. Detected in the syncytiotrophoblast microvilli bordering the maternal side of the human placenta, mean P-gp expression decreases from the 14th to the 40th weeks of gestation, suggesting a gradual decrease in fetal efficacy and protection [35, 36]. Although its clinical consequences are still poorly known, lowered P-gp expression/function at the placenta might increase the distribution of the drug substrate to the fetus, possibly intensifying its effects [37]. P-gp function could also be decreased by drug interactions with inhibitors such as amiodarone, cyclosporine or quinidine [44].\nTable 2 ABC transporter gene polymorphisms of doxorubicin involved in human placenta [40–43]\n\nTransporter\tSyncytiotrophoblast localization\tVariant\tModulation on disposition of doxorubicin\tModulation on cardiotoxicity of doxorubicin\t\nABCB1 (P-gp)\tApical\t1236C > T\tHigher maximum plasma concentration, higher AUC in T carriers\tNo data\t\nHaplotype 1236TT 2677TT 3435TT\tHigher plasma concentrations in TT carriers\tNo data\t\nABCG2\tApical\t421C > A\tNo significant impact on doxorubicin pharmacokinetics\tNo data\t\nABCC1 (MRP1)\tApical\t2012G > T\tNo data\tHigher acute cardiotoxicity in T carriers\t\nABCC2\tApical\t3563 T > A 4544G > A\tNo data\tHigher acute cardiotoxicity in A carriers\t\nABCC5\tBasolateral\t1679 T > A\tHigher doxorubicinol exposure in TT carriers\tNo data\t\n\n\nIntravenous ondansetron to prevent nausea and vomiting was prescribed off-label in our case report. Side effects including potential QT prolongation and torsade de pointes have been reported in the literature [45–47]. In the study conducted by Danielsson et al., data were analyzed from the Swedish medical birth register to identify 1349 infants born from women who had taken ondansetron in early pregnancy. There was a statistically increased risk for cardiovascular defects [48]. The authors hypothesized that potential QT interval prolongation by ondansetron could cause embryonic arrhythmias, suggesting that the drug should not be used off-label in early pregnancy. A recent study conducted by Fejzo et al. analyzed fetal outcome in pregnancies exposed to ondansetron in the United States. The results were similar with these findings [49].\n\nDrug-drug interactions involving doxorubicin metabolism and/or transport should always be considered prior to initiation of doxorubicin treatment. The predictive role of P-gp polymorphism in doxorubicin fetal toxicity requires further clinical studies. Such genetic tests were not performed in our case.\n\nIn this case report, the maternal age of 41 years was a risk factor that should be considered. Advanced maternal age can contribute to multiple pregnancy complications such as spontaneous abortion, preeclampsia, gestational diabetes, fetal growth restriction, and stillbirth [50, 51]. Some studies have also reported an increased risk of septal defects in women who become pregnant at an advanced age [52, 53]. Conversely, some studies have not found evidence of an association between maternal age and congenital heart disease [54–56].\n\nOne specificity of this case report is that twins reacted differently to the exposure. Even though the twins share the same uterus, the presence of two separate placentas brings a particular environmental influence for each twin [57, 58]. The delivery of compounds, toxic or not, depends on the vascular system devoted to the individual twin [57]. In their study, Igbal and al. suggested that different expressions in the twins-genetic variation in the genes that encode for these drug transporters can significantly alter transporter function and may play a significant role in determining fetal sensitivity to maternal drugs [43]. In 2017, Hermel reported a case in which only one of the twins, born to a mother treated with dasatinib for chronic myeloid leukemia, had cardiac defects [59]. Hence, hypothesis could be placental discrepancy in doxorubicin distribution with a higher blood transfusion for the male twin.\n\nThe treatment of HL diagnosed during pregnancy is a major challenge for medical staff, who must propose the best treatment options while avoiding fetal toxicity. We report one case of HL treated with an ABVD regimen during a dizygotic twin pregnancy, complicated by premature rupture of membranes and cardiotoxicity in one of the twins.\n\nEven if no molecular mechanism could be hypothesized in our study, this case highlights the role of specific fetal factors that could confer variability in the pharmacokinetics and/or pharmaco/toxico-dynamics of doxorubicin.\n\nAbbreviations\nABVDAdriamycin/doxorubicin, bleomycin, vincristine, dacarbazine\n\nABCATP-binding cassette\n\nAUCArea under the curve\n\nBCRPBreast cancer resistance protein; ABCG2\n\nHLHodgkin lymphoma\n\nLVEFLeft ventricular ejection fraction\n\nP-gpP-glycoprotein; ABCB1\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe thank Rasika Sowmyalakshmi for editing the English text.\n\nAuthors’ contributions\nAM and MD analyzed and interpreted the patient data regarding the hematological disease and twins data regarding clinical evaluation. CC, YVP, SC and JS analyzed and discussed safety of doxorubicin treatment. CC, SC and JS were major contributor in writing manuscript. All authors read, revised and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nAll data analyzed during this study are included in this published article.\n\nEthics approval and consent to participate\nNot applicable. The local ethics committee ruled that no formal ethics approval was required in this particular case.\n\nConsent for publication\nThe patient has given written consent for the publication of images and/or clinical details, on behalf of themselves and their children. A copy of the consent form is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Haas JF. Pregnancy in association with a newly diagnosed cancer: a population-based epidemiologic assessment. 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Maggen C, Dierickx D, Lugtenburg P, Laenen A, Cardonick E, Smakov R, Bellido M, Cabrera-Garcia A, Gziri MM, Halaska MJ, Ottevanger PB, Van Calsteren K, O'Laughlin A, Polushkina E, Van Dam L, Avivi I, Vandenberghe P, Woei-A-Jin FJSH, Amant F. International Network on Cancer, Infertility and Pregnancy. Obstetric and maternal outcomes in patients diagnosed with Hodgkin lymphoma during pregnancy: a multicentre, retrospective, cohort study. Lancet Haematol 2019;6(11):e551-e561. https://doi.org/10.1016/S2352-3026(19)30195-4.\n21. Abduljalil K, Furness P, Johnson TN, Rostami-Hodjegan A, Soltani H. Anatomical, physiological and metabolic changes with gestational age during normal pregnancy: a database for parameters required in physiologically based pharmacokinetic modelling. Clin Pharmacokinet 2012;51(6):365–396. https://doi.org/10.2165/11597440-000000000-00000.\n22. Ryu RJ, Eyal S, Kaplan HG, Akbarzadeh A, Hays K, Puhl K, Easterling TR, Berg SL, Scorsone KA, Feldman EM, Umans JG, Miodovnik M, Hebert MF. Pharmacokinetics of doxorubicin in pregnant women. Cancer Chemother Pharmacol 2014;73(4):789–797. https://doi.org/10.1007/s00280-014-2406-z.\n23. Lukaski H, Skiers W, Nielsen E, Hall C. Total body water in pregnancy: assessment by using bioelectrical impedance. Am J Clin Nutr 1994;59:578–585. https://doi.org/10.1093/ajcn/59.3.578.\n24. Tracy TS, Venkataramanan R, Glover DD, Caritis SN, National Institute for child health and human development network of maternal-fetal-medicine units. Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A activity) during pregnancy. Am J Obstet Gynecol 2005;192(2):633–639. https://doi.org/10.1016/j.ajog.2004.08.030.\n25. Piscitelli SC, Rodvold KA, Rushing DA, Tewksbury DA. Pharmacokinetics and pharmacodynamics of doxorubicin in patients with small cell lung cancer. Clin Pharmacol Ther 1993;53:555–561. https://doi.org/10.1038/clpt.1993.69.\n26. Rodvold KA, Rushing DA, Tewksbury DA. Doxorubicin clearance in the obese. J Clin Oncol 1988 ;6:1321–1327. DOI: 10.1200/JCO.1988.6.8.1321.\n27. Jacquet JM, Bressolle F, Galtier M, et al. Doxorubicin and doxorubicinol: intra and inter-individual variations of pharmacokinetic parameters. Cancer Chemother Pharmacol 1990;39:507. https://doi.org/10.1007/BF00685716.\n28. Bains OS, Karkling MJ, Grigliatti TA, Reid RE, Riggs KW. Two nonsynonymous single nucleotide polymorphisms of human carbonyl reductase 1 demonstrate reduced in vitro metabolism of daunorubicin and doxorubicin. Drug Metab Dispos 2009;37(5):1107–1114. https://doi.org/10.1124/dmd.108.024711.\n29. Bains OS, Karkling MJ, Lubieniecka JM, Grigliatti TA, Reid RE, Riggs KW. Naturally occurring variants of human CBR3 alter anthracycline in vitro metabolism. J Pharmacol Exp Ther 2010;332(3):755–763. https://doi.org/10.1124/jpet.109.160614.\n30. Kassner N, Huse K, Martin HJ, Gödtel-Armbrust U, Metzger A, Meineke I, Brockmöller J, Klein K, Zanger UM, Maser E, Wojnowski L. Carbonyl reductase 1 is a predominant doxorubicin reductase in the human liver. Drug Metab Dispos 2008;36(10):2113–2120. https://doi.org/10.1124/dmd.108.022251.\n31. Forrest GL Gonzalez B Tseng W Li X Mann J Human carbonyl reductase overexpression in the heart advances the development of doxorubicin-induced cardiotoxicity in transgenic mice Cancer Res 2000 60 18 5158 5164 11016643 \n32. Olson LE Bedja D Alvey SJ Cardounel AJ Gabrielson KL Reeves RH Protection from doxorubicin-induced cardiac toxicity in mice with a null allele of carbonyl reductase 1 Cancer Res 2003 63 20 6602 6606 14583452 \n33. Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, Altman RB. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics 2011;21(7):440–446. DOI: 10.1097/FPC.0b013e32833ffb56.\n34. Soininen SK, Repo JK, Karttunen V, Auriola S, Vähäkangas KH, Ruponen M. Human placental cell and tissue uptake of doxorubicin and its liposomal formulations. Toxicol Lett 2015;239(2):108–114. https://doi.org/10.1016/j.toxlet.2015.09.011.\n35. MacFarland A, Abramovich DR, Ewen SW, Pearson CK. Stage-specific distribution of P-glycoprotein in first-trimester and full-term human placenta. Histochem J 1994;26(5):417–423. https://doi.org/10.1007/BF00160054.\n36. Gil S, Saura R, Forestier F, Farinotti R. P-glycoprotein expression of the human placenta during pregnancy. Placenta 2005;26(2–3):268–270. https://doi.org/10.1016/j.placenta.2004.05.013.\n37. Ceckova-Novotna M, Pavek P, Staud F. P-glycoprotein in the placenta: expression, localization, regulation and function. Reprod Toxicol 2006;22(3):400–410. https://doi.org/10.1016/j.reprotox.2006.01.007.\n38. Nanayakkara AK, Follit CA, Chen G, Williams NS, Vogel PD, Wise JG. Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells. Sci Rep 2018;8(1):967. https://doi.org/10.1038/s41598-018-19325-x.\n39. Pavek P, Staud F, Fendrich Z, Slenarova H, Libra A, Novotna M, et al. Examination of the functional activity of P-glycoprotein in the rat placental barrier using rhodamine 123. J Pharmacol Exp Ther 2003;305(3):1239–1250. https://doi.org/10.1124/jpet.102.048470.\n40. Walker N, Filis P, Soffientini U, Bellingham M, O'Shaughnessy PJ, Fowler PA. Placental transporter localization and expression in the human: the importance of species, sex, and gestational age differences. Biol Reprod 2017;96(4):733–742. https://doi.org/10.1093/biolre/iox012.\n41. Joshi AA, Vaidya SS, St-Pierre MV, Mikheev AM, Desino KE, Nyandege AN, Audus KL, Unadkat JD, Gerk PM. Placental ABC transporters: biological impact and pharmaceutical significance. Pharm Res 2016;33(12):2847–2878. https://doi.org/10.1007/s11095-016-2028-8.\n42. Staud F, Cerveny L, Ceckova M. Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure. J Drug Target 2012;20(9):736–763. https://doi.org/10.3109/1061186X.2012.716847.\n43. Iqbal M, Audette MC, Petropoulos S, Gibb W, Matthews SG. Placental drug transporters and their role in fetal protection. Placenta 2012;33(3):137–142. https://doi.org/10.1016/j.placenta.2012.01.008.\n44. Pavek P, Fendrich Z, Staud F, Malakova J, Brozmanova H, Laznicek M, et al. Influence of P-glycoprotein on the transplacental passage of cyclosporine. J Pharm Sci 2001;90(10):1583–1592. https://doi.org/10.1002/jps.1108.\n45. Koren G. Scary science: Ondansetron safety in pregnancy-two opposing results from the same Danish registry. Ther Drug Monit 2014;36: 1–2. doi: 10.1097/FTD.0000000000000020.\n46. Li K, Vo K, Lee BK, Addo N, Coralic Z. Effect of a single dose of i.v. ondansetron on QTc interval in emergency department patients. Am J Health Syst Pharm 2018;75(5):276–282. https://doi.org/10.2146/ajhp161070.\n47. Lee DY, Trinh T, Roy SK. Torsades de Pointes after Ondansetron Infusion in 2 Patients. Tex Heart Inst J 2017;44(5):366–369. https://doi.org/10.14503/THIJ-16-6040.\n48. Danielsson B, Wikner BN, Källén B. Use of ondansetron during pregnancy and congenital malformations in the infant. Reprod Toxicol 2014;50:134–137. https://doi.org/10.1016/j.reprotox.2014.10.017.\n49. Fejzo MS, MacGibbon KW, Mullin PM. Ondansetron in pregnancy and risk of adverse fetal outcomes in the United States. Reprod Toxicol 2016;62:87–91. https://doi.org/10.1016/j.reprotox.2016.04.027.\n50. Salem Yaniv S, Levy A, Wiznitzer A, Holcberg G, Mazor M, Sheiner E. A significant linear association exists between advanced maternal age and adverse perinatal outcome. Arch Gynecol Obstet 2011;283(4):755–759. https://doi.org/10.1007/s00404-010-1459-4.\n51. Laopaiboon M, Lumbiganon P, Intarut N, Mori R, Ganchimeg T, Vogel JP, Souza JP, Gülmezoglu AM. WHO Multicountry Survey on Maternal Newborn Health Research Network. Advanced maternal age and pregnancy outcomes: a multicountry assessment. BJOG 2014;121 Suppl 1:49–56. https://doi.org/10.1111/1471-0528.12659.\n52. Miller A, Riehle-Colarusso T, Siffel C, Frías JL, Correa A. Maternal age and prevalence of isolated congenital heart defects in an urban area of the United States. Am J Med Genet A 2011;155A(9):2137–2145. https://doi.org/10.1002/ajmg.a.34130.\n53. Forrester MB, Merz RD. Descriptive epidemiology of selected congenital heart defects, Hawaii, 1986-1999. Paediatr Perinat Epidemiol 2004;18(6):415–424. https://doi.org/10.1111/j.1365-3016.2004.00594.x.\n54. Cedergren MI, Selbing AJ, Källén BA. Risk factors for cardiovascular malformation--a study based on prospectively collected data. Scand J Work Environ Health 2002;28(1):12–17. doi:10.5271/sjweh.641.\n55. Long J, Ramadhani T, Mitchell LE. Epidemiology of nonsyndromic conotruncal heart defects in Texas, 1999-2004. Birth Defects Res A Clin Mol Teratol 2010;88(11):971–979. https://doi.org/10.1002/bdra.20724.\n56. Best KE, Rankin J. Is advanced maternal age a risk factor for congenital heart disease? Birth Defects Res A Clin Mol Teratol 2016;106(6):461–467. https://doi.org/10.1002/bdra.23507.\n57. Marceau K, McMaster MT, Smith TF, Daams JG, van Beijsterveldt CE, Boomsma DI, Knopik VS. The prenatal environment in twin studies: a review on Chorionicity. Behav Genet 2016;46(3):286–303. https://doi.org/10.1007/s10519-016-9782-6.\n58. Weiner E, Barber E, Feldstein O, Dekalo A, Schreiber L, Bar J, Kovo M. Placental histopathology differences and neonatal outcome in Dichorionic-Diamniotic as compared to Monochorionic-Diamniotic twin pregnancies. Reprod Sci 2018;25(7):1067–1072. https://doi.org/10.1177%2F1933719117732163.\n59. Hermel DJ, Chiu V, Hermel MH, Tulpule A, Akhtari M. Cardiac birth defects in a twin infant born to a woman with chronic myeloid leukemia on dasatinib. J Oncol Pharm Pract 2019;25(3):699–702. https://doi.org/10.1177/1078155217745710.\n\n",
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"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D003606:Dacarbazine; D004317:Doxorubicin; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D059285:Pregnancy, Twin; D014747:Vinblastine",
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"title": "Maternal ABVD chemotherapy for Hodgkin lymphoma in a dichorionic diamniotic pregnancy: a case report.",
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"abstract": "Leishmaniasis is a vector borne disease transmitted by phlebotomine sandflies. Cutaneous leishmaniasis (CL) predominantly causes skin ulcers but may disseminate. CL may present a therapeutic challenge. The present study reports the case of a 15-year old boy with CL consisting of a single, ulcer on the leg, resistant to pentavalent antimony, oral fluconazole and topical ketoconazole therapy. Repeated photodynamic therapy using aminolevulinic acid resulted in complete healing of the ulcer, suggesting utility of this approach in resistant cases of CL.",
"affiliations": "Department of Dermatology, Zealand University Hospital, Roskilde, Denmark.;Department of Dermatology, Zealand University Hospital, Roskilde, Denmark.;Department of Dermatology, Zealand University Hospital, Roskilde, Denmark.",
"authors": "Johansen|Mila Broby|MB|0000-0002-7624-5018;Jemec|Gregor B E|GBE|;Fabricius|Susanne|S|",
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"mesh_terms": "D000293:Adolescent; D000622:Aminolevulinic Acid; D005500:Follow-Up Studies; D006801:Humans; D016773:Leishmaniasis, Cutaneous; D008297:Male; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D012867:Skin",
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"title": "Effective treatment with photodynamic therapy of cutaneous leishmaniasis: A case report.",
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"abstract": "Emergency liver transplantation (LT) for acute liver failure (ALF) is a life-saving treatment. Occurrence of this situation in the same patient twice is very rare. Herein, we describe a patient who underwent two emergency LTs for ALF, both from living donors. When she was 26 years old, she underwent a right lobe living donor LT (LDLT) from her sister for ALF due to use of herbal weight loss medications. The next 3 years were uneventful but another ALF developed during a terminal stage pregnancy (37th week). Despite medical treatment, her liver functions worsened, and the baby was delivered by caesarean section. The second time, her brother was the donor and she recovered after the emergency right lobe re-LDLT. Both patient and baby were well at the 2-month follow-up. As far as we know, there is no reported similar case, and we concluded that LDLT is a paramount treatment option for both primary and secondary ALFs.",
"affiliations": "Inonu University, Liver Transplantation Institute, Department of General Surgery, Turkey.;Inonu University, Liver Transplantation Institute, Department of General Surgery, Turkey.;Inonu University, Liver Transplantation Institute, Department of General Surgery, Turkey.;Inonu University, Liver Transplantation Institute, Department of General Surgery, Turkey.;Inonu University, Liver Transplantation Institute, Department of General Surgery, Turkey.;Inonu University, Liver Transplantation Institute, Department of Anesthesiology, Turkey.;Inonu University, Liver Transplantation Institute, Department of General Surgery, Turkey.;Inonu University, Liver Transplantation Institute, Department of General Surgery, Turkey.;Inonu University, Liver Transplantation Institute, Department of General Surgery, Turkey.",
"authors": "Ince|V|V|;Kayaalp|C|C|;Otan|E|E|;Ozdemir|F|F|;Dirican|A|A|;Toprak|H I|HI|;Aydin|C|C|;Ara|C|C|;Yilmaz|S|S|",
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"fulltext": "\n==== Front\nInt J Organ Transplant MedInt J Organ Transplant MedIjotmInternational Journal of Organ Transplantation Medicine2008-64822008-6490Avicenna Organ Transplantation Institute Shiraz, Iran ijotm-9-050Case ReportLiving Donor Re-transplantation for Repeated Acute Liver Failure Ince V. 1*Kayaalp C. 1Otan E. 1Ozdemir F. 1Dirican A. 1Toprak H. I. 2Aydin C. 1Ara C. 1Yilmaz S. 1\n1 Inonu University, Liver Transplantation Institute, Department of General Surgery, Turkey\n2 Inonu University, Liver Transplantation Institute, Department of Anesthesiology, Turkey* Correspondence: Volkan Ince, Inonu University, Liver Transplantation Institute, Department of General Surgery, Turkey ,E-mail: volkanince@outlook.com2018 1 2 2018 9 1 50 52 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Emergency liver transplantation (LT) for acute liver failure (ALF) is a life-saving treatment. Occurrence of this situation in the same patient twice is very rare. Herein, we describe a patient who underwent two emergency LTs for ALF, both from living donors. When she was 26 years old, she underwent a right lobe living donor LT (LDLT) from her sister for ALF due to use of herbal weight loss medications. The next 3 years were uneventful but another ALF developed during a terminal stage pregnancy (37th week). Despite medical treatment, her liver functions worsened, and the baby was delivered by caesarean section. The second time, her brother was the donor and she recovered after the emergency right lobe re-LDLT. Both patient and baby were well at the 2-month follow-up. As far as we know, there is no reported similar case, and we concluded that LDLT is a paramount treatment option for both primary and secondary ALFs.\n\nKey Words\nLiver failureacuteLiving donorsTransplantation\n==== Body\nINTRODUCTION\nAcute liver failure (ALF) is a clinically serious condition with a high risk of mortality. Etiologies vary from pediatric to adult patients and from developing countries to industrial societies [1]. Emergency liver transplantation (LT) is a unique treatment for those in the irreversible phase of liver failure, regardless of its etiology and patient age. Under this circumstance, living donor LT (LDLT) presents an advantage to shorten the organ waiting period compared with that of cadaveric LT [2]. Although drug-related ALF has been reported among patients who underwent LT, no record of repeated ALF in a patient with a previous history of LT due to ALF exists in the English medical literature [3]. Herein, we initially present a patient with a previous history of LDLT due to ALF who underwent a second LDLT due to repeated ALF.\n\nCASE REPORT\nA 29-year-old woman underwent LDLT due to ALF induced by consumption of herbal tea. The donor was her brother. The post-operative period was uneventful, and the patient became pregnant after getting married. The early course of the pregnancy was stable with single tacrolimus immunosuppressive treatment (blood level of 2.5–10.5 ng/mL). However, her serum transaminase levels increased during the gestational week 37. She underwent a caesarian section and delivered a healthy boy weighing 2900 g. She was admitted to the LT ward post-operatively. Her physical examinations were normal in a conscious state. She had a platelet count of 207×103/mm3, international normalized ratio of 2.0, aspartate transaminase of 1441 U/L, alanine transaminase of 1351 U/L, total bilirubin of 11.6 mg/dL, ammonia level of 224 (normal range: 0–109) µg/dL, and serum lactate level of 20 (normal range: 4.5–19.8) mmol/L. Doppler ultrasonography and multislice abdominal computed tomography revealed normal anatomical and vascular structures. Magnetic resonance cholangiography was also normal. The blood tacrolimus level was 9.7 ng/mL; no clinical or laboratory signs of infection were apparent. She was admitted to the intensive care unit (ICU) following stage I-II hepatic encephalopathy that developed and progressed to stage III. Her emergency was reported to the National Organ Sharing Association for Cadaveric Liver Procurement. Her brother was evaluated as a donor. She was treated with two sessions of a molecular adsorbent recirculating system and three sessions of plasmapheresis as a bridging procedure to LT. No significant improvement was observed. She developed tonic-clonic contractions resembling a seizure and underwent LDLT in which her brother was the donor. During the intra-operative exploration, adherent tissues were removed and the graft was observed to be pale and stiff on palpation. Following removal of the transplanted graft, retransplantation with the new right-lobe liver graft was performed successfully (no blood products were administered intra-operatively). The patient was taken to the ICU and extubated on post-operative day 1. She was transferred to the liver transplant patients’ ward on post-operative day four and was discharged on postoperative day 19 following an uneventful course. Zone 3 necrosis and inflammation was diagnosed by pathological examination of the removed graft. The patient and her baby were living uneventfully two months post-operatively.\n\nDISCUSSION\nIn Turkey, the most common etiologies for ALF among the adult population are viral (40%) (mainly hepatitis B virus), drug toxicity (20%), and intoxication (11%). The survival rate of patients treated with LT is significantly higher than that of patients treated conservatively (65% vs. 36%, p<0.001) [1, 4-6]. The timing for LT in a patient with ALF remains controversial. King’s College criteria are still used for this purpose. However, brain death is common among these patients following LT and patients are lost with a functioning liver graft [7]. Following progression of encephalopathy to grade III, our emergency case was reported to the National Organ Sharing Association for Cadaveric Liver Procurement. However, seizures led to the decision of a re-LDLT, which minimized time loss and provided a definitive treatment for the rapidly progressing condition. Similarly, this patient’s state of emergency was declared before her initial LT. However, LDLT was performed for lack of a suitable cadaveric graft. LDLT reduces the waiting period for the graft and improves survival.\n\nSeveral drug-related liver failures following LT cases have been reported, most of which were resolved with medical treatment but one case underwent re-transplantation [3, 8]. All of these cases had an initial diagnosis other than ALF, which makes our case unique.\n\nALF during the course of pregnancy is not rare. Fatty liver disease in pregnancy, viral hepatitis (especially, hepatitis E virus), and HELLP syndrome (Hemolysis, Elevated Liver Enzymes, and Low Platelet Count) are well-known conditions related to ALF. None of these conditions in which pre-eclampsia co-exists were diagnosed in our case. After rejection was clinically ruled out, conservative treatment was initiated, but it did not resolve the condition and led to an emergency report to the National Organ Sharing Association. In a study of 18 cases from our center presenting risks and results of pregnancy after LT, no pregnancy-related liver failure was observed. The rate of natural childbirth was 65.4% and the most frequent maternal complication was hypertension with a rate of 16.6% [9]. No similar study reporting on pregnancy following LT has reported ALF.\n\nAs a result, no other person in the world is so unlucky and so lucky. A patient with ALF may be treated with LDLT. However, undergoing a second LDLT due for lack of a cadaveric graft is an extremely rare condition. Our case is the first individual report of this condition.\n==== Refs\nReferences\n1 Kayaalp C Ersan V Yılmaz S Acute liver failure in Turkey: a systematic review Turk J Gastroenterol 2014 25 35 40 24918128 \n2 Ates M Hatipoglu S Dirican A Right-lobe living-donor liver transplantation in adult patients with acute liver failure Transplant Proc 2013 45 1948 52 23769080 \n3 Sembera S Lammert C Talwalkar JA Frequency, clinical presentation, and outcomes of drug-induced liver injury after liver transplantation Liver Transpl 2012 18 803 10 22389256 \n4 Ates M Dirican A Ozgor D Living donor liver transplantation for acute liver failure in pediatric patients caused by the ingestion of fireworks containing yellow phosphorus Liver Transpl 2011 17 1286 91 21761550 \n5 Çakır T Ara C Soyer HV Koc S Successful living donor liver transplantation of fulminant liver failure due to isoniazid prophylaxis BMJ Case Rep 2015 23 2015 doi: 10.1136/bcr-2015-209448 \n6 Hatipoglu S Bulbuloglu E Ates M Liver transplantation following blunt liver trauma Transplant Proc 2012 44 1720 1 22841253 \n7 Sarici KB Karakas S Otan E Can Patients Who Develop Cerebral Death in Fulminant Liver Failure Despite Liver Transplantation Be Previously Forseen? Transplant Proc 2017 49 571 4 28340835 \n8 Polard E Camus C Abault AY Retransplantation for acute liver failure due to combined antiviral agents in an HIV-HCV coinfected liver transplant recipient Transplantation 2005 80 1136 8 16278602 \n9 Baskiran A Karakas S Ince V Pregnancy after liver transplantation: Risks and outcomes Transplant Proc 2017 49 1875 1878 28923640\n\n",
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"issue": "9(1)",
"journal": "International journal of organ transplantation medicine",
"keywords": "Liver failure; Living donors; Transplantation; acute",
"medline_ta": "Int J Organ Transplant Med",
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"title": "Living Donor Re-transplantation for Repeated Acute Liver Failure.",
"title_normalized": "living donor re transplantation for repeated acute liver failure"
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"abstract": "The pathophysiology of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) may include platelet activation and microthrombi formation. Antiplatelet therapy may reduce the incidence of DCI and improve clinical outcomes after aSAH. This study compared outcomes among aSAH patients receiving aspirin monotherapy versus dual antiplatelet therapy (DAPT).\n\n\n\nAneurysmal subarachnoid hemorrhage patients treated at a single institution between November 2011 and December 2017 were divided according to whether they received aspirin monotherapy or DAPT after endovascular treatment. Baseline characteristics and outcomes of the groups were compared, including incidences of delayed cerebral ischemia, bleeding complications, symptomatic vasospasm, in-hospital mortality, and functional status 6 months after discharge.\n\n\n\nDuring the study period, 142 patients met study inclusion criteria, of which 123 were treated with aspirin monotherapy (87 %) and 19 were treated with DAPT (13 %). There was no statistically significant difference between the aspirin monotherapy and DAPT groups with respect to incidences of delayed cerebral ischemia (4.9 vs 10.5 %; p = 0.32), symptomatic vasospasm (13.0 vs 15.8 %; p = 0.74), or good clinical outcome at 6-month follow up (73.3 vs 66.7 %; p = 0.56). The DAPT group experienced a higher incidence of in-hospital mortality (21 vs 5.7 %; p = 0.02), but DAPT did not remain independently predictive of this outcome on regression analysis. There was a trend toward a higher bleeding complication rate in the DAPT group (0.8 vs 5.3 %; p = 0.13).\n\n\n\nDAPT does not reduce the incidence of DCI or improve outcomes in aSAH patients, and may increase the risk of clinically significant bleeding complications.",
"affiliations": "Division of Neurointerventional Surgery, Ascension Columbia St. Mary's Hospital, Milwaukee, WI, USA; University of Iowa, Department of Radiology, Iowa City, IA, USA. Electronic address: adam.wallace1@ascension.org.;Division of Neurointerventional Radiology, Neuroscience Institute, Abbott Northwestern Hospital, Minneapolis, MN, USA.;Division of Neurointerventional Radiology, Neuroscience Institute, Abbott Northwestern Hospital, Minneapolis, MN, USA.;Department of Critical Care, Abbott Northwestern Hospital, Minneapolis, MN, USA.;Division of Neurointerventional Radiology, Neuroscience Institute, Abbott Northwestern Hospital, Minneapolis, MN, USA.;Division of Neurointerventional Radiology, Neuroscience Institute, Abbott Northwestern Hospital, Minneapolis, MN, USA.;Neuroscience Institute, Abbott Northwestern Hospital, Minneapolis, MN, USA.;Neuroscience Institute, Abbott Northwestern Hospital, Minneapolis, MN, USA.;Neuroscience Institute, Abbott Northwestern Hospital, Minneapolis, MN, USA.",
"authors": "Wallace|Adam N|AN|;Kayan|Yasha|Y|;Almandoz|Josser E Delgado|JED|;Mulder|Maximilian|M|;Milner|Anna A|AA|;Scholz|Jill M|JM|;Stiernagle|Kayla|K|;Contestabile|Emma|E|;Tipps|Megan E|ME|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D001241:Aspirin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.clineuro.2020.106038",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-8467",
"issue": "195()",
"journal": "Clinical neurology and neurosurgery",
"keywords": "Aneurysm; Antiplatelet therapy; Delayed cerebral ischemia; Subarachnoid haemorrhage; Vasospasm",
"medline_ta": "Clin Neurol Neurosurg",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001241:Aspirin; D000080903:Dual Anti-Platelet Therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D013345:Subarachnoid Hemorrhage; D016896:Treatment Outcome; D020301:Vasospasm, Intracranial; D055815:Young Adult",
"nlm_unique_id": "7502039",
"other_id": null,
"pages": "106038",
"pmc": null,
"pmid": "32650208",
"pubdate": "2020-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Dual antiplatelet therapy does not improve outcomes after aneurysmal subarachnoid hemorrhage compared with aspirin monotherapy.",
"title_normalized": "dual antiplatelet therapy does not improve outcomes after aneurysmal subarachnoid hemorrhage compared with aspirin monotherapy"
} | [
{
"companynumb": "US-SA-2020SA189396",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TICAGRELOR"
},
"drugadditional": null,
"dr... |
{
"abstract": "Prophylactic warfarin with an International Normalized Ratio (INR) goal of 1.5 to 2.0 is one antithrombotic therapy utilized in children after cardiothoracic surgery (CTS); published sources suggest a dose of 0.1 mg/kg per day to achieve this goal. However, few studies have evaluated dosing in this population. The purpose of this study was to evaluate dosing and safety outcomes in children receiving warfarin after CTS.\n\n\n\nA descriptive, retrospective review was conducted to evaluate warfarin dosing and INR outcomes in patients 18 years of age or younger who underwent CTS and received prophylactic warfarin with an INR goal of 1.5 to 2.0 from January 2014 through December 2018. The primary objective was to determine the median initial warfarin dose. Secondary objectives included identifying the percentage of documented INR values that were outside the therapeutic range, the percentage of patients with therapeutic INRs at discharge, and the 30-day readmission rate.\n\n\n\nTwenty-six patients were included in the review. The median initial warfarin dosage was 0.07 mg/kg/d (interquartile range [IQR], 0.05-0.10 mg/kg/d). Of the total of 177 INR values collected during the entire study period, 67 (37.9%) were therapeutic, 64 (36.2%) were subtherapeutic, and 46 (26.0%) were supratherapeutic. Eighteen patients (69.2%) had at least 1 supratherapeutic INR at any point during the study period, most frequently on days 2 through 4 of therapy. At discharge, 11 patients (42.3%) had therapeutic INRs. Four patients (15.4%) were readmitted within 30 days, with bleeding documented in 2 patients during their readmission.\n\n\n\nThe majority of patients received an initial warfarin dose less than that specified in published recommendations but still had a supratherapeutic INR at least once during the study period. When initiating warfarin after CTS, a dosage of <0.1 mg/kg per day and frequent monitoring may be needed to achieve an INR goal of 1.5 to 2.0.",
"affiliations": "Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, Oklahoma City, OK.;Department of Pharmacy Services, Ascension: The Children's Hospital at Sacred Heart, Pensacola, FL.;Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, Oklahoma City, OK.;Department of Pharmacy, Children's Hospital at OU Medical Center, Oklahoma City, OK.;Department of Pharmaceutical Care, University of Iowa Hospitals & Clinic, Iowa City, IA.;Pharmacy Department, Primary Children's Hospital, Salt Lake City, UT.;Department of Pharmacy, Children's Hospital at OU Medical Center, Oklahoma City, OK.;Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK.;Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, Oklahoma City, OK.",
"authors": "Harkin|Maura|M|;Shaddix|Brittany Powers|BP|;Neely|Stephen B|SB|;Peek|Leigh A|LA|;Stephens|Katy|K|;Barker|Philip|P|;McMullan|Lauren|L|;Gormley|Andrew|A|;Johnson|Peter N|PN|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "England",
"delete": false,
"doi": "10.1093/ajhp/zxaa111",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "77(13)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": "Fontan procedure; pediatrics; thoracic surgery; warfarin",
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000293:Adolescent; D000925:Anticoagulants; D006348:Cardiac Surgical Procedures; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D018729:Fontan Procedure; D006801:Humans; D007223:Infant; D019934:International Normalized Ratio; D008297:Male; D056990:Post-Exposure Prophylaxis; D011182:Postoperative Care; D012189:Retrospective Studies; D016896:Treatment Outcome; D014859:Warfarin",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1018-1025",
"pmc": null,
"pmid": "32470108",
"pubdate": "2020-06-23",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of dosing and safety outcomes of low-dose prophylactic warfarin in children after cardiothoracic surgery.",
"title_normalized": "evaluation of dosing and safety outcomes of low dose prophylactic warfarin in children after cardiothoracic surgery"
} | [
{
"companynumb": "US-TEVA-2021-US-1915086",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "3",
"... |
{
"abstract": "Papillary renal cell carcinoma (pRCC) represents the second most common histologic subtype of renal cell carcinoma and comprises 2 subtypes. Prognosis for type 2 is associated with poor clinical outcome. Current guidelines are based on phase II trials, phase III trials in patients with clear cell histology, or retrospective data.\nTo our knowledge, we describe for the first time a case of a patient with heavily pretreated metastatic pRCC who benefited from the combination of lenvatinib plus everolimus for more than 2 years.\nAccording to immunohistologic and biological findings in our patient both on primary tumor and liver metastasis, we hypothesize that selected patients with metastatic pRCC, progressed to standard/available treatments (including angiogenic drugs, mTOR inhibitors, and immunotherapy) and dissociated response to everolimus, could benefit from adding lenvatinib to everolimus.",
"affiliations": "Medical Oncology Unit, University Hospital of Parma, Parma, Italy.;Department of Medicine and Surgery, Pathology Unit, University Hospital of Parma, Parma, Italy.;Medical Oncology Unit, University Hospital of Parma, Parma, Italy.",
"authors": "Zielli|Teresa|T|;Gnetti|Letizia|L|;Buti|Sebastiano|S|https://orcid.org/0000-0003-0876-0226",
"chemical_list": "D010671:Phenylurea Compounds; D011804:Quinolines; D000068338:Everolimus; C531958:lenvatinib",
"country": "United States",
"delete": false,
"doi": "10.1177/0300891620924472",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8916",
"issue": "106(6)",
"journal": "Tumori",
"keywords": "Metastatic papillary renal cell carcinoma; combination; everolimus; lenvatinib; pRCC",
"medline_ta": "Tumori",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D002292:Carcinoma, Renal Cell; D000068338:Everolimus; D006801:Humans; D007680:Kidney Neoplasms; D008297:Male; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010671:Phenylurea Compounds; D011804:Quinolines; D019233:Retreatment; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "0111356",
"other_id": null,
"pages": "NP79-NP83",
"pmc": null,
"pmid": "32458743",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Activity of lenvatinib plus everolimus combination in a heavily pretreated patient with papillary renal cell carcinoma: a case report.",
"title_normalized": "activity of lenvatinib plus everolimus combination in a heavily pretreated patient with papillary renal cell carcinoma a case report"
} | [
{
"companynumb": "IT-BAYER-2021-033171",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CABOZANTINIB"
},
"drugadditional": null,
... |
{
"abstract": "Cytomegalovirus (CMV) infection of the gastrointestinal (GI) tract has been reported in both immunocompetent and, more frequently, in immunocompromised patients. We describe a case of a 19-year-old male who developed CMV infection of the terminal ileum while receiving immunosuppression for lupus nephritis. This was a distinctly unusual site of infection which clinically mimicked Crohn's ileitis. We note that reports of terminal ileal CMV infection have been infrequent. Despite a complicated hospital course, ganciclovir therapy was effective in resolving his symptoms and normalizing his ileal mucosa. This report highlights the importance of accurate histological diagnosis and clinical follow-up of lupus patients with GI symptoms undergoing intense immunosuppression.",
"affiliations": "Department of Nephrology, Westchester Medical Center, Valhalla, NY 10595, USA.",
"authors": "Khan|Faisal Nazir|FN|;Prasad|Vinod|V|;Klein|Michael David|MD|",
"chemical_list": "D000998:Antiviral Agents; D015774:Ganciclovir",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.15.4327",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "15(34)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000998:Antiviral Agents; D003424:Crohn Disease; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D015774:Ganciclovir; D006801:Humans; D007079:Ileitis; D007082:Ileum; D008181:Lupus Nephritis; D008297:Male; D055815:Young Adult",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "4327-30",
"pmc": null,
"pmid": "19750578",
"pubdate": "2009-09-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19011502;15229955;16937514;10875475;18371229;9863901;3020973;9593246;7481970;14749990;8776773;3986009;10614168;18627655;12209517;17041367;10472478",
"title": "Cytomegalovirus enteritis mimicking Crohn's disease in a lupus nephritis patient: a case report.",
"title_normalized": "cytomegalovirus enteritis mimicking crohn s disease in a lupus nephritis patient a case report"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK202103731",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": ... |
{
"abstract": "COVID-19 is novel infectious disease with an evolving understanding of its epidemiology and clinical manifestations. Immunocompromised patients often present atypical presentations of viral diseases. Herein we report a case of a COVID-19 infection in a solid organ transplant recipient, in which the first clinical symptoms were of gastrointestinal viral disease and fever, which further progressed to respiratory symptoms in 48 hours. In these high risk populations, protocols for screening for SARS-Cov2 may be needed to be re-evaluated.",
"affiliations": "Department of Nephrology and Kidney Transplantation, Hospital Clinic Barcelona, Barcelona, Spain.;Department of Nephrology and Kidney Transplantation, Hospital Clinic Barcelona, Barcelona, Spain.;Department of Nephrology and Kidney Transplantation, Hospital Clinic Barcelona, Barcelona, Spain.;Department of Nephrology and Kidney Transplantation, Hospital Clinic Barcelona, Barcelona, Spain.;Department of Infectious Diseases, Hospital Clinic Barcelona, Barcelona, Spain.;Department of Infectious Diseases, Hospital Clinic Barcelona, Barcelona, Spain.;Department of Nephrology and Kidney Transplantation, Hospital Clinic Barcelona, Barcelona, Spain.;Department of Nephrology and Kidney Transplantation, Hospital Clinic Barcelona, Barcelona, Spain.;Department of Nephrology and Kidney Transplantation, Hospital Clinic Barcelona, Barcelona, Spain.",
"authors": "Guillen|Elena|E|;Pineiro|Gaston J|GJ|;Revuelta|Ignacio|I|;Rodriguez|Diana|D|;Bodro|Marta|M|;Moreno|Asunción|A|;Campistol|Josep M|JM|;Diekmann|Fritz|F|https://orcid.org/0000-0001-6199-3016;Ventura-Aguiar|Pedro|P|https://orcid.org/0000-0003-3381-7503",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15874",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "20(7)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": null,
"medline_ta": "Am J Transplant",
"mesh_terms": "D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D005922:Glomerulonephritis, IGA; D006801:Humans; D007108:Immune Tolerance; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D012121:Respiration, Artificial; D012307:Risk Factors; D000086402:SARS-CoV-2",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "1875-1878",
"pmc": null,
"pmid": "32198834",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports",
"references": "32109013;1503334;32091533;32296069;32096567;31986264;32198834;26667069;32061333;32096611;32362394",
"title": "Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation?",
"title_normalized": "case report of covid 19 in a kidney transplant recipient does immunosuppression alter the clinical presentation"
} | [
{
"companynumb": "ES-TEVA-2020-ES-1809843",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1-4 (EGR1-4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.",
"affiliations": "Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.;Department of Psychiatry, University of California, San Francisco, San Franciso, CA, USA.;Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.;Department of Psychiatry, University of California, San Francisco, San Franciso, CA, USA.;Department of Psychiatry, University of California, San Francisco, San Franciso, CA, USA.;Department of Psychiatry, University of California, San Francisco, San Franciso, CA, USA.;Department of Psychiatry, University of California, San Francisco, San Franciso, CA, USA.;Department of Psychiatry, University of California, San Francisco, San Franciso, CA, USA.;GeneNews Ltd., Richmond Hill, ON, Canada.;GeneNews Ltd., Richmond Hill, ON, Canada.;Department of Medicine, Hematology-Oncology, University of California, School of Medicine, Los Angeles, Los Angeles, CA, USA.",
"authors": "Mellon|S H|SH|;Wolkowitz|O M|OM|;Schonemann|M D|MD|;Epel|E S|ES|;Rosser|R|R|;Burke|H B|HB|;Mahan|L|L|;Reus|V I|VI|;Stamatiou|D|D|;Liew|C-C|CC|;Cole|S W|SW|",
"chemical_list": "D000928:Antidepressive Agents; C497325:EGR1 protein, human; C497326:EGR2 protein, human; C079945:EGR3 protein, human; C111028:EGR4 protein, human; D051766:Early Growth Response Protein 1; D051767:Early Growth Response Protein 2; D051765:Early Growth Response Transcription Factors; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D051776:Early Growth Response Protein 3",
"country": "United States",
"delete": false,
"doi": "10.1038/tp.2016.79",
"fulltext": "\n==== Front\nTransl PsychiatryTransl PsychiatryTranslational Psychiatry2158-3188Nature Publishing Group tp20167910.1038/tp.2016.7927219347Original ArticleAlterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment Alterations in leukocyte transcriptional control pathway activity in MDDMellon S H 1*Wolkowitz O M 2Schonemann M D 1Epel E S 2Rosser R 2Burke H B 2Mahan L 2Reus V I 2Stamatiou D 3Liew C -C 3Cole S W 41 Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA2 Department of Psychiatry, University of California, San Francisco, San Franciso, CA, USA3 GeneNews Ltd., Richmond Hill, ON, Canada4 Department of Medicine, Hematology-Oncology, University of California, School of Medicine, Los Angeles, Los Angeles, CA, USA* Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. E-mail: sindy.mellon@ucsf.edu05 2016 24 05 2016 1 5 2016 6 5 e821 25 03 2014 23 03 2016 31 03 2016 Copyright © 2016 Macmillan Publishers Limited2016Macmillan Publishers LimitedThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1–4 (EGR1–4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.\n==== Body\nIntroduction\nMajor depressive disorder (MDD) is a pressing public health problem, with up to 16% of the US population experiencing at least one episode in their lives.1, 2 It is the leading cause of disability in North America and is projected to become the second leading cause of disability worldwide by 2020.3, 4, 5, 6, 7 Identifying circulating biomarkers that parallel disease progression and effective treatment might help illuminate the pathophysiology of MDD and identify distinct subtypes amenable to specific therapies.8, 9, 10, 11, 12, 13 Several studies have investigated whether specific profiles of gene expression in circulating leukocytes might provide peripheral diagnostic biomarkers of MDD that could be ascertained easily.14, 15, 16, 17, 18, 19, 20 Despite considerable evidence that vulnerability to MDD is partially heritable, to date, leukocyte transcriptome analysis has not shown replicable differences as a function of MDD or its treatment.14, 15, 16, 17, 18, 19, 21, 22, 23, 24 However, several studies have linked MDD to activation of upstream gene regulatory pathways that modulate broad patterns of gene expression in immune cells. These pathways include the cAMP response element-binding/activating transcription factor (CREB/ATF) family of transcription factors (TFs),18, 22 the glucocorticoid receptor (GR)25, 26, 27, 28, 29, 30 and early growth response (EGR) family TFs.31, 32, 33, 34 Other studies have linked MDD to altered activity of circulating mediators that regulate TF activity, including glucocorticoids,35, 36, 37, 38 pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6 and tumor necrosis factor-α,36, 37, 39, 40 Type I interferons37, 41, 42, 43 and oxidative stress.40, 44, 45, 46\n\nFor both biological and statistical reasons, variations in the activity of signal transduction pathways, rather than small variations in expression of individual downstream gene targets, might show more reliable associations with MDD. We hypothesize that even if correlations between depression and transcriptionally activated pathways exist, it may be difficult to identify significant changes in the expression of individual genes activated through those pathways because of the additional effects of individual differences in genetic background, early developmental influences (for example, epigenetic imprinting) and current physiologic conditions (for example, individual variation in the activity of other hormones or TFs that jointly influence transcription). Statistically, reliability in measurements will increase when levels of expression of individual genes are aggregated into a single measure of common signaling pathway activity. The activity of transcriptional control pathways may also help clarify the biological mechanisms by which gene expression in immune cells correlates with MDD. Regulatory pathway analysis, rather than individual gene analysis, may thus be a more reliable biomarker of MDD and its sequelae.\n\nIn the present study, we applied a promoter-based bioinformatic strategy to assess transcriptional control pathway activity via its functional impact on genome-wide transcriptional profiles, to test several emerging theories regarding immune system and oxidative stress involvement in MDD pathophysiology and its remediation by antidepressant treatment. In this bioinformatics approach, differentially expressed genes are first identified, and the promoter DNA sequence of each differentially expressed gene is then scanned to identify the prevalence of TF-binding motifs (TFBMs) that are hypothesized to be activated in association with the condition under study (for example, MDD-associated activation of CREB/ATF TFs, which mediate signaling by many neurotransmitter systems including catecholamines from the sympathetic nervous system). The identification of such 'promoter TFBM enrichment' within a set of differentially expressed genes has been shown in several previous validation studies to provide a generally accurate indication of whether a given TF contributes to the observed difference in gene expression profiles.47, 48, 49 The conceptual logic of the analysis is as follows: if a TF is activated, it will only modulate the expression of those genes that bear the specific TFBM to which that TF binds. Thus, the subset of upregulated genes will show a relative enrichment of promoter TFBMs for the activated TF (for example, CREB) relative to that observed in a control set of genes (for example, the basal prevalence across all genes in a genome, or TFBM prevalence in a parallel derived set of downregulated genes, which better controls for the fact that about half of the genome is not expressible in any given cell type because of intrinsic variations in the transcriptional basis for cell development and differentiation). In the present study, we conducted such promoter TFBM enrichment analyses to test a series of a priori theories regarding the transcription control pathways that may be activated in the context of MDD, including the CREB/ATF family,18, 22 the GR,25, 26, 27, 28, 29, 30, 50, 51, 52 EGR family TFs,31, 32, 33, 34 the nuclear factor kappa-B cell (NF-κB)/Rel family of TFs that mediate signaling by many pro-inflammatory cytokines,36, 37, 39, 40 interferon regulatory factor (IRF) family TFs that mediate signaling by Type I interferons37, 41, 42, 43, 53 and the nuclear factor erythroid-derived 2-like 2 (NRF2) TF that mediates transcriptional responses to oxidative stress.40, 44, 45, 46\n\nMaterials and methods\nSubjects\nWe recruited 20 subjects with MDD, diagnosed with the Structured Clinical Interview for DSM-IV-TR (SCID),54 and 20 healthy controls matched by sex, ethnicity and age (±3 years; Table 1). These subjects are from the same sample as described previously.55, 56 Subjects gave informed consent to participate in this study, which was approved by the University of California, San Francisco Committee on Human Research. The subjects were recruited by fliers, bulletin board notices, Craigslist postings (http://sfbay.craigslist.org), newspaper ads and through clinical referrals. Subjects were seen in an outpatient setting, and were paid for their participation. SCID diagnostic interviews were conducted by an experienced clinical psychologist and were clinically verified by a separate psychiatric interview with a board-certified psychiatrist. Depressed subjects with psychosis, bipolar histories and post-traumatic stress disorder were excluded from participation in the study; other comorbid anxiety disorders were allowed when the depressive diagnosis was considered to be the primary diagnosis. MDD subjects were required to have a rating of 17 or greater on the 17-item Hamilton Depression Rating Scale (HDRS).57 Healthy control subjects were also screened with the SCID, and were required to have no present or past history of any DSM-IV Axis I diagnosis. Potential subjects were also excluded if they met SCID criteria for alcohol or substance abuse within 6 months of entering the study. Subjects in both groups were medically healthy (assessed by physical examination, review of systems and screening laboratory tests), had no acute illnesses or infections and had not had any vaccinations within 6 weeks of entering the study. Depressed and control subjects were free of any psychotropic medications, including antidepressants, antipsychotics and mood stabilizers, hormone supplements, steroid-containing birth control or other medications (for example, statins) or vitamin supplements above the US Recommended Daily Allowances (for example, vitamin C, 90 mg per day) for a minimum of 6 weeks before entry into the study; use of short-acting sedative hypnotics was allowed as needed, up to a maximum of three times per week, but none within 1 week before testing.\n\nProcedure\nSubjects were admitted as outpatients to the University of California, San Francisco Clinical and Translational Science Institute’s Clinical Research Center at 0800 hours, having fasted (except water) since 2200 hours the night before. Subjects were required to test negative on a urine toxicology screen (measuring the presence of abused drugs) and, in women of child-bearing capacity, a urine pregnancy test. While subjects sat or reclined in a resting position, blood samples were obtained for leukocyte RNA preparation.\n\nTreatment\nFollowing the baseline evaluation and blood draw, depressed subjects were treated for 8 weeks, in an open-label manner, with sertraline, dosed according to the clinicians’ judgment, based on efficacy and tolerability, beginning with 50 mg per day, increasing to a maximum of 200 mg per day. In two cases, the beginning dose was lowered to 25 mg per day because of transient side effects. Medication compliance was monitored by pill counts and by plasma levels at weeks 4 and 8 of treatment. The mean plasma concentration of sertraline+N-desmethylsertraline at week 4 was 46±23 ng ml−1; range: 10–97 ng ml−1 and at week 8 was 67±37 ng ml−1; range: 10–146 ng ml−1. All individuals had plasma concentrations within the range of published steady-state concentrations for sertraline at therapeutic doses,59 indicating good compliance with medication treatment. One depressed subject prematurely dropped out of the study because of clinical worsening while on sertraline, and two were excluded because of developing exclusionary criteria unrelated to sertraline (medical illness) during the 8-week follow-up period, leaving 17 treated MDD subjects.\n\nGene expression profiling and transcription control bioinformatics\nGenome-wide transcriptional profiling was carried out on peripheral blood mononuclear cells (PBMCs) obtained from 20 individuals meeting diagnostic criteria for MDD (HDRS>17) and 20 age- sex- and ethnicity-matched non-depressed controls. All participants were unmedicated at baseline, and 17 MDD subjects subsequently initiated antidepressant treatment and were assessed again for changes in PBMC gene expression profile after 8 weeks of treatment. Blood was collected into vacutainer tubes containing EDTA. RNA was extracted from 10 ml whole blood, after red cell lysis in a hypotonic buffer (150 mm ammonium chloride, 10 mm potassium bicarbonate and 1 mm EDTA) and was incubated on ice for 15 min. Samples were centrifuged at 500 g for 10 min at 4 oC, the supernatant was discarded, 1 ml of lysis buffer was added to the pellet and the leukocytes were resuspended by vortexing. The leukocyte suspension was centrifuged, the supernatant was removed, the leukocyte pellet was resuspended in TRIzol Reagent (Invitrogen, Grand Island, NY, USA), extracted with chloroform and RNA was precipitated with isopropanol at −20 oC, followed by centrifugation. The RNA pellet was resuspended in 10 mm Tris-Cl pH 7.5/1 mm EDTA; total RNA was tested for quantity (Nanodrop ND1000, Thermo Scientific, Wilmington, DE, USA), integrity and purity (Agilent Bioanalyzer, Santa Clara, CA, USA). All samples met quality criteria: RIN⩾7.0 ('RIN' is RNA integrity number, a software tool designed to estimate RNA integrity; Agilent Technologies, Santa Clara, CA, USA); 28 S:18 S rRNA ratio⩾1.0. Subsequently, 5 μg of total RNA per sample were used for genome-wide transcriptional profiling using Affymetrix U133 Plus 2 high-density oligonucleotide arrays, following the manufacturer’s protocol (Affymetrix, Santa Clara, CA, USA). Low-level gene expression data were normalized by robust multi-array averaging60, 61 and were log2-transformed for analysis. Differentially expressed genes were identified by >15% difference in average expression level across groups (that is, a low-stringency screening as recommended for the development of optimally replicable gene lists62, 63, 64, 65, 66, 67). Functional characteristics of differentially expressed genes were identified by enrichment analysis of Gene Ontology annotations and Entrez-Gene/RefSeq annotations.68 To test the hypothesis that differential gene expression was mediated in part by altered activity of specific TFs, TELiS bioinformatics analysis47, 62 analyzed the promoters of differentially expressed genes for over-representation of TFBMs targeted by CREB/ATF factors (TRANSFAC V$CREB_01 position-specific weight matrix)69 the GR (V$GR_Q6), NF-κB/Rel factors (V$CREL_01), EGR1–4 (V$EGR1_01, V$EGR2_01, V$EGR3_01, V$NGFIC_01), interferon-responsive TFs (V$ISRE_01) and the oxidative-stress-responsive TF NRF2 (V$NRF2_01). TFBM prevalence was ascertained within the promoters of genes selectively upregulated in association with MDD, and separately within the promoters of genes selectively downregulated in association with MDD (that is, relatively upregulated in controls), and the magnitude of differential TF activity was estimated by the ratio of TFBM prevalence in promoters from upregulated genes versus downregulated genes. This approach ensures that all genes analyzed are potentially expressible within the PBMC pool (that is, are expressed at differentially detectable levels in either MDD or controls), and thereby eliminates potential biases that may stem from using the genome-wide prevalence of promoter TFBMs as a reference point (given that approximately half of the human genome is not materially expressible in PBMC at all because of intrinsic transcriptome biases associated with cell development and differentiation). TFBM ratios were calculated in analyses using nine alternative TFBM scan parameters involving varying signal detection stringency (mat_sim=0.80, 0.90, 0.95)70 and promoter length (−300, −600, −1000 to +200 bp relative to the RefSeq-annotated gene transcription start site),71 and log-transformed ratios were averaged to estimate TFBM prevalence ratios robust to methodological variations. Average relative prevalence ratios significantly exceeding the null hypothesis of 1.0 indicate greater TFBM prevalence among genes upregulated in association with MDD (that is, relative TF activation in MDD), and average TFBM ratios significantly less than the null hypothesis value of 1.0 indicate lower TFBM prevalence among genes upregulated in association with MDD (that is, relative TF de-activation in MDD, or equivalently, relative TF activation in controls). These bioinformatics indications have been found to provide accurate inferences of TF activity as assessed by direct assays of TF binding (for example, electrophoretic mobility shift assays or nuclear protein enzyme-linked immunosorbent assays) and experimental manipulation of TF activity.47, 48, 49, 72 To assess the generality of the present findings, we also repeated TF bioinformatics analyses on data from two archival studies that compared peripheral blood cell RNA samples from MDD patients versus controls (GSE38206) and cancer patients with low versus high levels of depressive symptoms (GSE36957).\n\nQuantitative PCR analysis of subject RNA\nTotal RNA was isolated from human samples using Qiagen RNeasy (Qiagen, Valencia, CA, USA) following the recommended protocol supplied with the kit. Lysis buffer was added to solubilize the sample and added to the nucleic acid-binding columns supplied with the kit. RNA bound to the column was washed and eluted, and the concentration of the RNA was measured with a Nanodrop Spectrophotometer (Thermo Scientific, Wilmington, DE, USA).\n\nInvitrogen Superscript III (Life Technologies, Grand Island, NY, USA) was used to generate complementary DNA (cDNA), using the manufacturer’s protocols. Samples with yields close to 4–5 μg of total RNA were used to synthesize cDNA. cDNA reactions containing RNA and random primers were annealed at 50 oC and combined with dNTPs, reaction buffer and Superscript III to synthesize cDNA at 42 oC.\n\nPrimers used for quantitative PCR (qPCR; Supplementary Table S1) gave single bands of the appropriate size using agarose gel electrophoresis. For qPCR reactions, the cDNA concentration was normalized to 25 ng per reaction. The iQ SYBR Green Supermix (Bio-Rad Laboratories, Hercules, CA, USA) was used in the qPCR reactions and was monitored using MyiQ iCycler qPCR (Bio-Rad Laboratories). The quality of the PCR reactions was monitored for their Ct values to ensure that data obtained occurred before the reagents were exhausted. To confirm the quality of the data and to ensure that single DNA fragments were generated, PCR amplification products were analyzed using agarose gel electrophoresis at the end of the runs. qPCR reactions were performed in duplicate. The Ct value of the reference gene (GAPDH) was monitored as an internal control. Gene expression differences were estimated using the 'Comparative Ct method' of relative quantification, normalizing the Ct values relative to the reference gene. This was performed by calculating ΔCtsample=Cttargetgene−Ctreferencegene. The relative fold change was represented as 2-ΔΔCt, where ΔΔCt=mean ΔCtsamples−mean ΔCtcontrolsamples. The amplification efficiencies (close to 100%) of the genes of interest and the housekeeping genes were similar (within 5–10%).\n\nResults\nGene expression in MDD versus control\nThere were no significant differences in the mean age of the depressed versus control subjects, their sex distribution, ethnicity or body mass index (Table 1). The groups also did not differ in current and past alcohol and nicotine consumption, marital status, highest educational level attained, although both self-rated socioeconomic status58 and the mean household income were significantly lower in the depressed subjects (P<0.04 socioeconomic status; P<0.01 household income). Average activity/exercise levels per month, as measured by the Yale Physical Activity Survey,73 were not different between groups. The mean 17-item HDRS57 rating in the depressed subjects at baseline was 18.71±3.22 and after 8 weeks of antidepressant treatment was 10.24±6.32, P<0.001, and the mean chronicity of depression (that is, lifetime years of depression) was 14.02±11.75 years (range 0.77–35 years), corresponding to a mean ratio of lifetime depression to chronological age of 0.36±0.27 (range 0.02–0.88).\n\nIn comparisons of depressed individuals with controls, microarray gene expression analysis identified 346 distinct transcripts showing >15% difference in the average expression level across groups (Supplementary Table S2). The 157 transcripts relatively overexpressed in leukocytes from subjects with MDD included multiple genes involved in Type I interferon responses (IFI44, IFI44L, IFIT1, IFI6, MX1, OAS3, OASL and RNASE2), antimicrobial responses/tissue remodeling (APOBEC3B, DEFA1, FCER1G, FCGR2B/CD32, MMP8, NOD2 and PI3), cytokine and chemokine signaling (CCL3, CCR3, IL-5RA and IL-18), immunoglobulin production (IGJ and IGH@), cellular activation and proliferation (HLA-DR, HLA-DQ, IGF1R, PTEN and EGR3), skewing of macrophage responses toward M2 profiles (ARG1) and cellular responses to oxidative stress (GSTM4). Prominent among the 189 downregulated transcripts in subjects with MDD were genes involved in cAMP/PKA signaling (PRKACB, PRKAR2B and PDE3B), genes encoding antibody immunoglobulin heavy chains (IGHD and IGHM) and antibody receptors (FCRL1, FCRL3, FCRL5/CD307 and FCRLA), the T-cell receptor alpha gene (TRA@), chemokine receptors (CCR7 and CXCR6), multiple leukocyte cell surface antigens (CD6, CD7, CD22, CD79A and LY9/CD229) and EGR1. The prominent differential expression of leukocyte cell type-specific transcripts suggested potential alterations in subset distribution within the leukocyte pool in MDD versus control subjects. However, we found no significant difference in the leukocyte pool level of mRNA for any canonical leukocyte subset marker (CD14, CD19, CD16/FCGR3A CD56/NCAM1, CD3, CD4 and CD8; all average differences <15%, all P>0.10).\n\nTranscription control pathways in MDD versus control\nPromoter-based bioinformatics analyses (Table 2) showed significant over-representation of response elements for CREB/ATF factors and the master antioxidant TF NRF2 in the promoters of genes upregulated in association with MDD. Results also indicated nominally significant and unanticipated under-representations of NF-κB and EGR2 response elements in promoters of genes upregulated in association with MDD, although these latter two findings would not attain significance under Bonferroni correction for multiple testing across the nine TFBMs analyzed. Primary analyses showed no significant indication of GR, EGR1, EGR3 or EGR4 activation in MDD versus control subjects. Ancillary analyses adjusting gene expression data for age, sex, body mass index and the fractional distribution of lymphocytes, monocytes and eosinophils in the assayed leukocyte pool (Table 2) continued to indicate over-representation of CREB/ATF and NRF2 response elements in promoters of genes upregulated in association with MDD. Several additional TFBM signals also reached significance in the adjusted analyses, including under-representation of EGR2, EGR3 and interferon-simulated response element TFBMs, and over-representation of EGR1 motifs (although the latter two results would not reach significance under Bonferroni correction).\n\nGene expression changes with MDD treatment\nAfter 8 weeks of antidepressant therapy, average HDRS depression scores were reduced significantly from baseline levels in MDD subjects (baseline: 18.71±3.22; week 8: 10.24± 6.32, P<0.001). Transcriptional profiling of leukocytes collected after 8-week treatment identified 183 transcripts showing >15% upregulation relative to baseline and 101 showing >15% downregulation (Supplementary Table S3). Prominent among upregulated transcripts were gene products involved in Type I interferon response, including several that were upregulated in the MDD versus control baseline comparison (marked with *); these were IFI27, IFI44*, IFI44L*, IFI6*, IFIT1, IRF7, ISG15, OAS1, OAS2, OAS3* and OASL*. Multiple transcripts associated with the myeloid lineage of immune cells were also upregulated, including CD36, LY6E and the macrophage-associated TF MAFB. However, transcripts associated with macrophage activation also numbered among the downregulated transcripts, including several that were upregulated in leukocytes from MDD versus control subjects at baseline (for example, APOBEC3B*, ARG1*, IL-1R1, MMP8, PI3* and XIST*). Downregulated transcripts also included the oxidative stress response gene SOD2.\n\nTranscription control pathways in MDD after treatment\nPromoters of genes that were downregulated following antidepressant treatment (Table 2) showed significant over-representation of NRF2 TFBMs, whereas those that were upregulated following antidepressant treatment showed over-representation of interferon-related TFBMs. Analyses also linked treatment-related changes in gene expression to TFBM prevalence patterns indicative of increased NF-κB activity and decreased EGR2 and EGR3 activity (although these latter three counter-hypothetical findings would not reach statistical significance under Bonferroni correction). Primary analyses showed no significant indications of CREB, GR, EGR1 or EGR4 involvement in treatment-related changes in gene expression. Ancillary analyses adjusting for age, sex and leukocyte subset distribution in the leukocyte pool showed similar results, with the notable difference that CREB/ATF, EGR1, EGR2 and EGR3 TFBMs also become significantly over-represented among upregulated promoters (Table 2).\n\nConfirmatory studies\nThe microarray data showing differences between RNA abundance in leukocytes from healthy control and MDD subjects were confirmed by direct amplification and quantitation with quantitative reverse transcriptase PCR (RT-PCR) analysis (primers shown in Supplementary Table S1). Among the 11 transcripts re-tested with RT-PCR, nine showed significant differences in expression that matched those indicated by microarray results (Supplementary Table S4).\n\nTo assess the generality of the TF bioinformatics findings from this sample, we compared results from contrasting MDD patients versus controls with results from parallel analyses of peripheral blood cell RNA in an archival data set comparing MDD versus controls in another population (GSE38206) and cancer patients with high versus low levels of depressive symptoms (GSE36957). Results (Table 3) showed good concordance for the primary positive results reported above for CREB/ATF and NRF2. Genes upregulated in archival comparison of MDD versus controls also showed significant over-representation of CREB and NRF2 TFBMs, and genes upregulated in cancer patients with high levels of depressive symptoms showed significant over-representation of CREB/ATF TFBMs and marginally significant (P=0.059) over-representation of NRF2 TFBMs. Results from these two archival data sets were also consistent among themselves in indicating elevated prevalence of NF-κB and interferon-responsive TFBMs (results not identified in analyses of the present sample). Analysis of the archival MDD versus control comparison also indicated highly significant signals for all of the other pathways analyzed; however, these indications were not corroborated in the cancer/depressive symptoms' sample.\n\nDiscussion\nThe present analyses utilize a transcriptome-driven bioinformatic strategy to evaluate the activity of several transcriptional control pathways that have been hypothesized to be activated in association with MDD. Results comparing unmedicated MDD subjects versus control subjects support previously proposed roles for CREB and the oxidative stress response factor NRF2. However, only NRF2 showed a significant reduction in activity following 8 weeks of antidepressant therapy. Indices of CREB-mediated gene transcription were not reversed by antidepressant therapy, and continued to trend upward after 8 weeks of sertraline treatment. Thus, the NRF2 transcriptional pathway is distinct from the other candidate transcriptional control pathways evaluated here, as it tracked with both disease (MDD) and effective antidepressant treatment.\n\nThese analyses do not support a role for activation of the master pro-inflammatory TF NF-κB, interferon regulatory factors, the GR or the EGR family of TFs in the basic pathogenesis of MDD. Significant associations did emerge for EGR family factors in analyses adjusting for age, sex and leukocyte subset distributions; however, these effects trended in the opposite direction of previous hypotheses (that is, under-representation in MDD-associated and treatment-responsive promoters). Because our sample size is small, and thus has limited statistical power to detect small effects, we cannot conclude that our results definitively refute roles for NF-κB, interferons or the GR in the pathophysiology of depression. Indeed, altered hypothalamic pituitary axis activity may be restricted mainly to the subset of MDD cases associated with trauma.74 However, our failure to see positive signals for NFκB and GR activation, when other transcription control pathways such as CREB/ATF and NRF2 show detectable differences in activity, suggests that NF-κB and GR do not constitute the most sensitive or clinically useful TF pathway biomarkers of MDD.\n\nOur results have significant implications for five published hypotheses regarding peripheral immune system function in the genetic basis of MDD. First, it has been proposed75, 76, 77, 78, 79 that MDD is associated with reductions in tonic CREB activity, possibly secondary to reduced activity of neurotrophic factors (for example, brain-derived neurotrophic factor) and/or neurotransmitters (for example, adrenergic signaling from catecholamines). Alterations in CREB activity in the central nervous system (CNS) in animal models of depression77, 78, 80, 81, 82, 83, 84, 85 and findings from clinical studies linking increased leukocyte CREB activity to successful behavioral or antidepressant therapy22, 75, 76, 86, 87, 88, 89 support this view. However, our results find no tonic inhibition of CREB/ATF-mediated gene expression in leukocytes from untreated MDD patients versus control subjects, but rather indicate upregulation of CREB/ATF activity at baseline before treatment. Moreover, comparisons of CREB/ATF-associated gene expression before and after antidepressant treatment are consistent with previous observations that successful MDD treatment is associated with increased CREB phosphorylation in leukocytes.79, 90, 91 Thus, although the pathophysiologic role of leukocyte CREB activity remains uncertain, our results are consistent with previous studies, suggesting that increasing leukocyte CREB activity levels may potentially serve as a biomarker of treatment response. Our data are also consistent with studies, suggesting that the mRNAs for ATF3 TFs are increased in MDD compared with healthy controls.31\n\nA second hypothesis suggests that dysregulated activity of innate immune response signaling pathways may activate CNS 'sickness behavior' systems that trigger motivational deficits and affective alterations characteristic of MDD.41, 42, 43 Administration of Type I interferons induces symptoms of major depression, suggesting that some cases of depression may stem from brain responses to subclinical viral infections or other physiologic dynamics that elicit systemic Type I interferon signaling (for example, reviewed in Raison and Miller9 and Loftis et al.92). Our results are partially consistent with this hypothesis, as they show increased expression of several individual interferon-responsive genes in untreated MDD subjects, including genes involved in the interferon-mediated 'antiviral state'. However, TFBM analyses found no evidence of an aggregate-level elevation in interferon-responsive TF activity in unmedicated MDD patients relative to healthy controls. Moreover, genes that were downregulated in association with antidepressant treatment showed a significant under-representation of interferon-related TFBMs, and individual interferon target transcripts continued to show an upward trend during treatment. This treatment-associated upregulation of interferon signaling activity is consistent with previous observations of increased activation of the interferon response factor 7 TF following citalopram treatment.93 These data suggest that if subclinical infectious dynamics or other immunoregulatory disturbances underlie the aberrant interferon signaling associated with some cases of MDD, antidepressants may potentially block the downstream neurobiological consequences of interferon activity, but they are not likely to have an impact on the underlying infectious/physiologic elicitors of interferon activity. This interpretation would be consistent with studies showing that antidepressant prophylaxis can block the emergence of depressive symptoms and sickness behavior following pharmacologic interferon treatment.41, 42, 43, 94, 95, 96, 97, 98, 99, 100, 101\n\nThird, the 'macrophage theory of depression' suggests that upregulated monocyte/macrophage production of pro-inflammatory cytokines such as IL-1β, tumor necrosis factor-α and IL-6 activates CNS sickness behavior functions in a manner analogous to that hypothesized for Type I interferons.102, 103, 104 This hypothesis would predict that MDD should be linked to TFs involved in monocyte/macrophage activation such as NF-κB and EGR family factors. Although our study replicated previous observations of increased EGR3 mRNA in leukocytes from MDD patients, analyses of NF-κB and EGR TFBM distributions provide no evidence that EGR3, other EGR family members or NF-κB/Rel family members show increased transcriptional activity in MDD. By contrast, we found modest indications of baseline reductions in NF-κB- and EGR3-mediated gene expression in leukocytes from MDD patients. These results are not likely to differ from previous findings because of differences in the cell types examined (leukocytes versus isolated monocytes in previous studies) because our adjusted analyses controlled for the relative prevalence of monocytes in the assayed leukocyte pool and because our present study replicated previous indications of increased EGR3 mRNA. Nevertheless, our results suggest reduced functional activity of that pathway. The differing conclusions likely stem from our study’s focus on TF activity, whereas previous studies only focused on EGR3 mRNA abundances. This distinction is consistent with data in other systems showing that TF mRNA abundances do not correlate perfectly with functional TF activity, which can also be substantially regulated by post-translational modifications of TFs.105\n\nA fourth hypothesis is that peripheral oxidative stress signals to the CNS to evoke symptoms of depression.55, 100, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122 Our results are highly consistent with that hypothesis. We found baseline indications of increased activity for the oxidative stress response TF NRF2 in MDD, and reduced NRF2 transcriptional activity following antidepressant treatment. The mRNA abundance of SOD2, a redox-sensitive enzyme, also declined following antidepressant treatment. Those effects could not be attributed to differences in body mass index, age or other demographic variables. The implication of NRF2 and SOD2 in altered leukocyte transcription in MDD subjects suggests a potential leukocyte gene transcriptional biomarker in MDD, a potential target for therapeutic intervention, and a potential biomarker of effective treatment. Given that NRF2 emerged as the only TF in our analysis that directly tracked both depression under basal conditions and the effects of antidepressant therapy, identification of the etiology of peripheral reactive oxygen species in MDD and its relationship to other immune-related transcriptional dynamics (for example, type I interferon signaling, NF-κB activity, CREB activity and so on) may provide deeper insights into the biological basis for depression.\n\nA fifth hypothesis that is not supported by our study suggests that chronically high cortisol levels, and consequent alterations in glucocorticoid-responsive transcription contribute to the pathogenesis of MDD.8, 29, 36, 37, 52, 86, 103, 123, 124, 125, 126, 127, 128, 129, 130 We found no significant alterations in GR-mediated gene expression in control versus untreated MDD subjects, either before or after 8 weeks of antidepressant treatment. Because the GR hypothesis primarily concerns glucocorticoid activity in the CNS, our data from circulating leukocytes cannot be taken as a direct contradiction of this hypothesis. However, our results suggest that leukocyte GR activity may not be a useful proxy biomarker of alterations in glucocorticoid response in the CNS.\n\nOur data provide new insights into the potential immunobiological and oxidative processes that might contribute to, or serve as biomarkers of, the neurobiological substrates of MDD. However, our study has several limitations, especially small sample size. Replication with larger samples will be needed to resolve small effects that might remain undetected in the present study. Indeed, such power limitations may explain why some significant TFBM patterns that emerged in analyses of the archival data sets were not confirmed in the present sample (for example, linking MDD to activation of NF-κB and interferon signaling pathways). However, this study’s primary findings regarding CREB/ATF and NRF TFs did prove replicable in the two independent archival data sets. Our target gene mRNA read-out provides a genome-wide functional framework for assessing TF activity. However, we inferred TF activity from promoter sequence analyses; future studies may use more direct assays of TF activity, such as chromatin immunoprecipitation or nuclear protein assays.49, 72 Our bioinformatic findings can suggest targets for such analyses, but do not provide direct indications of TF functional activity (for example, DNA binding or transcriptional induction). Our study is also not powered to discover statistically significant associations between individual gene transcripts and MDD versus control status or sertraline treatment. The results in Supplementary Tables S2 and S3 are not tested for statistical significance at the level of specific individual transcript–phenotype associations. Our use of leukocytes as the target cell pool is a strength, in that these cells are readily available, but leukocytes constitute a heterogeneous mix of cells, so that future studies will need to isolate specific leukocyte subtypes to define the specific cell type(s) mediating the observed effects. However, most of the genes that were differentially expressed were from the myeloid lineage, such as monocytes and dendritic cells, which have been implicated in other studies of MDD-associated transcriptional alteration29, 43 as well as in studies of socioenvironmental conditions that can precipitate depression.49, 131, 132, 133, 134\n\nOur results provide valuable new insights into the pathobiology of MDD by confirming that cells of the immune system show coherent and highly focal transcriptional alterations in association with MDD and effective antidepressant treatment. These results add to a burgeoning literature implicating immune system dynamics in MDD, and they provide information that helps to discriminate among several of the most prominent current theories of MDD. Future studies should address the roles of oxidative stress and CREB/ATF signaling in crosstalk between the peripheral immune system and CNS biology in the context of MDD.\n\nThis research was supported by the O’Shaughnessy Family Foundation, The Tinberg Family and NIH grants from the National Institute of Mental Health (MH083784), the National Institute of Aging (P30-AG107265), the National Cancer Institute (R01-CA116778) and the National Center for Advancing Translational Sciences (through UCSF-CTSI Grant Number UL1 TR000004).\n\nDisclaimer\n\nThe contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.\n\nSupplementary Information accompanies the paper on the Translational Psychiatry website (http://www.nature.com/tp)\n\nDS is an employee of GeneNews and C-CL co-founded GeneNews, is its Chief Scientist and serves as the Chairman of the Scientific Advisory Board. DS, C-CL and GeneNews have no financial interest in this study. GeneNews prepared RNA from the subjects’ blood, and performed the microarray assays. The remaining authors declare no conflicts of interest.\n\nSupplementary Material\nSupplementary Table 1 Click here for additional data file.\n\n Supplementary Table 2 Click here for additional data file.\n\n Supplementary Table 3 Click here for additional data file.\n\n Supplementary Table 4 Click here for additional data file.\n\n Table 1 Characteristics of depressed and control subjects\n \tControls (n=20)\tDepressed (n=20)\tP\t\nAge (years)\t36.6±11.8\t37.0±10.8\tns\t\nSex (% female)\t65%\t65%\tns\t\nEthnicity (% Caucasian, African-American, Asian, other or mixed)\t75%, 15%, 5%, 5%\t70%, 10%, 15%, 5%\tns\t\nBody mass index\t24.7±3.7\t24.8±4.3\tns\t\nNo tobacco ever (%)\t55%\t50%\tns\t\nCurrent tobacco use (%)\t20%\t35%\tns\t\nSubjective socioeconomic statusa\t6.6±1.0\t5.4±1.8\t<0.04\t\nYears of education\t14.8±2.2\t14.7±2.0\tns\t\nHousehold income ($)\t$59 400±$46 500\t$28 450±$24 600\t<0.02\t\na Subjective socioeconomic status was measured using a 10-rung ladder version of the MacArthur Scale of Subjective Social Status.58\n\nTable 2 Promoter transcription factor-binding motif distributions for candidate transcription control pathways\n \tMDD versus Control\tMDD baseline versus antidepressant Tx\t\n \tObserved\tAdjusteda\tObserved\tAdjusteda\t\nCREB\t2.66±0.20, P=0.0007b\t2.40±0.17, P=0.0005b\t1.04±0.10, P=0.6872\t2.63±0.12, P=0.0001b\t\nISRE\t1.46±0.39, P=0.3091\t0.64±0.17, P=0.0482\t3.14±0.20, P=0.0003b\t4.17±0.36, P=0.0098\t\nNRF2\t2.11±0.18, P=0.0019b\t1.72±0.09, P=0.0003b\t0.61±0.08, P=0.0002b\t0.48±0.14, P=0.0005b\t\nNF-κB\t0.92±0.03, P=0.0480\t0.96±0.04, P=0.3067\t1.43±0.12, P=0.0115\t0.81±0.06, P=0.0078\t\nGR\t1.05±0.06, P=0.4198\t1.01±0.06, P=0.9164\t0.91±0.10, P=0.3437\t0.82±0.14, P=0.1747\t\nEGR1\t1.10±0.10, P=0.4216\t1.34±0.09, P=0.0230\t0.83±0.08, P=0.0685\t2.59±0.21, P=0.0042b\t\nEGR2\t0.42±0.23, P=0.0140\t0.70±0.08, P=0.0017b\t0.82±0.09, P=0.0483\t1.67±0.13, P=0.0025b\t\nEGR3\t0.41±0.43, P=0.0665\t0.58±0.65, P=0.0016b\t0.69±0.13, P=0.0139\t2.86±0.12, P=0.0001b\t\nEGR4/NGFIC\t0.53±0.36, P=0.1113\t0.82±0.16, P=0.2233\t0.89±0.09, P=0.2128\t2.47±0.25, P=0.0101\t\nAbbreviations: CREB, cAMP response element-binding; EGR, early growth response; GR, glucocorticoid receptor; ISRE, interferon-stimulated response element; MDD, major depressive disorder; NF-κB, nuclear factor kappa-B; NRF2, nuclear factor erythroid-derived 2-like 2; PBMC, peripheral blood mononuclear cell; TFBM, transcription factor-binding motif.\n\nValues represent the mean fold difference in promoter TFBM distribution±s.e., and two-tailed P-value testing null hypothesis 1.0-fold\n\n.\n\na Analyses controlling for age, sex and PBMC % lymphocytes, monocytes and eosinophils.\n\nb Statistically significant under Bonferroni correction for simultaneous testing of nine pathways (individual P<0.0056).\n\nTable 3 Relationship of present findings to analyses of archival data sets\n \tMDD versus control\t\n \tObserved\tGSE38206\tGSE36957\tRelationshipa\t\nCREB\t2.66±0.20, P=0.0007b\t1.23±0.03, P<0.0001b\t1.55±0.08, P<0.0001b\tConsistent\t\nISRE\t1.46±0.39, P=0.3091\t1.81±0.17, P=0.0003b\t1.46±0.23, P=0.0030b\tAdditional\t\nNRF2\t2.11±0.18, P=0.0019b\t1.42±0.05, P<0.0001b\t1.06±0.04, P=0.0593\tPartially consistent\t\nNF-κB\t0.92±0.03, P=0.0480\t1.06±0.03, P=0.0016b\t1.29±0.09, P<0.0001b\tAdditional\t\nGR\t1.05±0.06, P=0.4198\t0.84±0.07, P=0.0033b\t0.83±0.10, P=0.0657\tNull\t\nEGR1\t1.10±0.10, P=0.4216\t1.59±0.13, P=0.0010b\t1.07±0.03, P=0.2893\tNull\t\nEGR2\t0.42±0.23, P=0.0140\t1.96±0.24, P=0.0004b\t0.98±0.05, P=0.6717\tNull\t\nEGR3\t0.41±0.43, P=0.0665\t1.75±0.14, P=0.0002b\t1.04±0.09, P=0.4854\tNull\t\nEGR4/NGFIC\t0.53±0.36, P=0.1113\t1.78±0.18, P=0.0008b\t1.21±0.23, P=0.0629\tNull\t\nAbbreviations: CREB, cAMP response element-binding; EGR, early growth response; GR, glucocorticoid receptor; ISRE, interferon-stimulated response element; MDD, major depressive disorder; NF-κB, nuclear factor kappa-B; NRF2, nuclear factor erythroid-derived 2-like 2; TFBM, transcription factor-binding motif.\n\nValues represent the mean fold difference in promoter TFBM distribution±s.e., and two-tailed P-value testing null hypothesis 1.0-fold.\n\na Consistent, archival studies are consistent and are in concordance with results of present MDD versus control comparison; Additional, archival studies are consistent, but relationship is not detected in present sample; Partially consistent, archival studies are inconsistent, but one is in concordance with present MDD versus Control comparison; Null, archival studies are inconsistent.\n\nb Statistically significant under Bonferroni correction for simultaneous testing of nine pathways (individual P<0.0056).\n==== Refs\nHasin DS, Goodwin RD, Stinson FS, Grant BF. 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"mesh_terms": "D000328:Adult; D000928:Antidepressive Agents; D003865:Depressive Disorder, Major; D051766:Early Growth Response Protein 1; D051767:Early Growth Response Protein 2; D051776:Early Growth Response Protein 3; D051765:Early Growth Response Transcription Factors; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007962:Leukocytes; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors",
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"title": "Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment.",
"title_normalized": "alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment"
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"abstract": "OBJECTIVE\nTo investigate the efficacy and safety of repeated botulinum toxin type-A (BTX-A) injections for patients with drug-refractory nonneurogenic overactive bladder (NNOAB) and explore factors predictive of outcome.\n\n\nMETHODS\nData were collected from all patients receiving repeated BTX-A injections for drug-refractory NNOAB between 2004 and 2012. Trigone-sparing injections were administered under sedation with antibiotic prophylaxis. Patient characteristics including age, sex, preoperative urodynamics, injection number, BTX-A dose, complications, and patient global impression of improvement (PGI-I) scores were collected. Correlations between patient factors and outcomes were assessed by using Pearson's chi-square tests.\n\n\nRESULTS\nFifty-two patients with a mean age of 67.4 years (range, 26-93 years) received 140 BTX-A injections in total; 33 (64%), 15 (29%), and 4 patients (7%) received 2, 3 to 4, and 5 to 8 injections, respectively. Mean follow-up time was 49 months (range, 9-101 months). Nine patients developed urinary tract infection; additionally, 3 patients experienced transient urinary retention. Median PGI-I score was 2 out of 7 (interquartile range [IQR], 2). For 46 patients, the PGI-I score remained stable with the administration of each injection. Pearson chi-square tests revealed that male patients or reduced bladder compliance was associated with a higher (worse) PGI-I score. Median PGI-I scores for men and women were 3 (IQR, 1) and 2 (IQR, 1), respectively; additionally, median PGI-I scores for those with normal bladder compliance and those with reduced bladder compliance were 2 (IQR, 2) and 4.5 (IQR, 1), respectively. Median PGI-I scores and complication rates were the same in the older patient (≥70 years) and younger (<70 years) patient cohorts.\n\n\nCONCLUSIONS\nEfficacy is maintained with repeated BTX-A injections. Patients including the elderly show a good degree of tolerability with a low complication rate. Male patients or reduced bladder compliance is associated with poorer outcomes.",
"affiliations": "Department of Urology, Concord Repatriation General Hospital, Sydney, Australia.;Department of Urology, Concord Repatriation General Hospital, Sydney, Australia.;Department of Urology, Concord Repatriation General Hospital, Sydney, Australia.;Department of Urology, Concord Repatriation General Hospital, Sydney, Australia.;Department of Urology, Concord Repatriation General Hospital, Sydney, Australia.;Department of Urology, Concord Repatriation General Hospital, Sydney, Australia.",
"authors": "Kim|Shannon Hk|SH|0000-0003-3203-5120;Habashy|David|D|0000-0003-4790-363X;Pathan|Sana|S|;Tse|Vincent|V|0000-0002-0993-2176;Collins|Ruth|R|0000-0002-7513-2038;Chan|Lewis|L|0000-0001-7876-6768",
"chemical_list": null,
"country": "Korea (South)",
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"doi": "10.5213/inj.1630450.225",
"fulltext": "\n==== Front\nInt Neurourol JInt Neurourol JINJInternational Neurourology Journal2093-47772093-6931Korean Continence Society 2703255610.5213/inj.1630450.225inj-1630450-225Original ArticleClinical InvestigationEight-Year Experience With Botulinum Toxin Type-A Injections for the Treatment of Nonneurogenic Overactive Bladder: Are Repeated Injections Worthwhile? http://orcid.org/0000-0003-3203-5120Kim Shannon HK 1http://orcid.org/0000-0003-4790-363XHabashy David 1Pathan Sana 1http://orcid.org/0000-0002-0993-2176Tse Vincent 12http://orcid.org/0000-0002-7513-2038Collins Ruth 12http://orcid.org/0000-0001-7876-6768Chan Lewis 121 Department of Urology, Concord Repatriation General Hospital, Sydney, Australia2 Department of Surgery, University of Sydney, Sydney, AustraliaCorresponding author: David Habashy http://orcid.org/0000-0003-4790-363X Department of Urology, Concord Repatriation General Hospital, Hospital Road, Concord, Sydney, NSW 2137, Australia E-mail: david_habashy@hotmail.com / Tel: +61-2-9767-5000 / Fax: +61-2-9767-50803 2016 16 3 2016 20 1 40 46 24 9 2015 8 11 2015 Copyright © 2016 Korean Continence Society2016This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose:\nTo investigate the efficacy and safety of repeated botulinum toxin type-A (BTX-A) injections for patients with drug-refractory nonneurogenic overactive bladder (NNOAB) and explore factors predictive of outcome.\n\nMethods:\nData were collected from all patients receiving repeated BTX-A injections for drug-refractory NNOAB between 2004 and 2012. Trigone-sparing injections were administered under sedation with antibiotic prophylaxis. Patient characteristics including age, sex, preoperative urodynamics, injection number, BTX-A dose, complications, and patient global impression of improvement (PGI-I) scores were collected. Correlations between patient factors and outcomes were assessed by using Pearson’s chi-square tests.\n\nResults:\nFifty-two patients with a mean age of 67.4 years (range, 26–93 years) received 140 BTX-A injections in total; 33 (64%), 15 (29%), and 4 patients (7%) received 2, 3 to 4, and 5 to 8 injections, respectively. Mean follow-up time was 49 months (range, 9–101 months). Nine patients developed urinary tract infection; additionally, 3 patients experienced transient urinary retention. Median PGI-I score was 2 out of 7 (interquartile range [IQR], 2). For 46 patients, the PGI-I score remained stable with the administration of each injection. Pearson chi-square tests revealed that male patients or reduced bladder compliance was associated with a higher (worse) PGI-I score. Median PGI-I scores for men and women were 3 (IQR, 1) and 2 (IQR, 1), respectively; additionally, median PGI-I scores for those with normal bladder compliance and those with reduced bladder compliance were 2 (IQR, 2) and 4.5 (IQR, 1), respectively. Median PGI-I scores and complication rates were the same in the older patient (≥70 years) and younger (<70 years) patient cohorts.\n\nConclusions:\nEfficacy is maintained with repeated BTX-A injections. Patients including the elderly show a good degree of tolerability with a low complication rate. Male patients or reduced bladder compliance is associated with poorer outcomes.\n\nBotulinum ToxinsUrinary Bladder, OveractiveUrodynamicsTreatment Outcome\n==== Body\nINTRODUCTION\nOveractive bladder (OAB) is defined as the presence of urinary urgency, frequency, and nocturia; with or without urge incontinence; and in the absence of urinary tract infection (UTI) or other obvious pathology. OAB may be related to neurological disorders, or it may be idiopathic [1].\n\nWhile some patients respond to conservative therapies such as bladder retraining and pelvic floor exercises, a significant number of patients proceed to pharmacologic treatment, which typically involves the use of antimuscarinic agents. Many patients discontinue the use of the antimuscarinic agents because of inadequate efficacy and/or intolerable side effects [2,3]. Second-line treatment options for patients with OAB that do not benefit from oral drug therapy include intradetrusor injections of botulinum toxin type-A (BTX-A), sacral neuromodulation, percutaneous tibial nerve stimulation, long-term catheterization, and the more invasive third-line surgical treatments of bladder augmentation or urinary diversion [4,5]. With the various modalities available for treatment of drug-refractory OAB, an open discussion with the patient about the risks and benefits of each option is important. BTX-A is emerging as the preferred second-line option [6].\n\nThe short-term efficacy of a single injection of BTX-A in nonneurogenic overactive bladder (NNOAB) has been well established; however, there are limited data on longer-term follow-up and effectiveness of repeated injections [7-11]. Studies examining repeated BTX-A injections have shown that BTX-A remains efficacious with good tolerability and in most patients, interinjection intervals are of 9–19 months [12-16]. The schedule of the repeated injection administration is patient-driven (though not before 3 months); the patients are presented again when the last injection’s effect is wearing off [17,18]. The reasons for a longer interinjection interval than the expected one and the reasons for discontinuation of repeated injections are less well elucidated and are more likely to be multifactorial in nature. The studies exploring these aspects have shown that lack of efficacy, dislike for clean intermittent self-catheterization, and loss to follow-up are the three main reasons for discontinuation of administration of further injections in patients [15,16]. Questions that remain unanswered include the influence of age, sex, and preoperative urodynamics (apart from detrusor overactivity [DO]) on the efficacy and safety of repeated BTX-A injections. The majority of efficacy studies include a study population that mostly or wholly comprises of women with no information about the possible differences between male and female patients.\n\nIn this study, we report the safety and efficacy of the first Australian series of patients receiving up to eight repeated BTX-A injections for NNOAB with an average follow-up period of greater than 4 years. Additionally, we report the influence of age, sex, and preoperative urodynamic factors on the efficacy of BTX-A.\n\nMATERIALS AND METHODS\nData were collected from all the patients who received two or more injections of BTX-A for NNOAB at Concord Hospital from 2004 to 2012. All the patients had failed a trial of at least two oral anticholinergic medications. Preoperatively, all the patients underwent urodynamic assessment according to the International Continence Society standards [1]. Prior hospital drug committee approval was obtained for the use of BTX-A for patients with NNOAB. Additionally, informed consents of the patients were obtained by the treating urologist prior to each injection’s administration. Further, all the patients received a prophylactic dose of intravenous antibiotic during the procedure (gentamicin was not used because of its inhibitory synergistic effects with BTX-A). Three consultant urologists and fellows (under the direct supervision of a urologist) administered the injections. Injections were administered cystoscopically (at a concentration of 10 U/mL) to the base of the bladder using a template technique sparing the trigone [17,18]. This was done under sedation/light general anesthesia. Efficacy was measured using the patient global impression of improvement (PGI-I) scoring system. PGI-I scores were obtained at follow-ups of 6–8 weeks post injections. When patients felt that the effect of their BTX-A injection was wearing off, they were presented again and the next injection was scheduled. Urodynamic tests were not routinely performed between each injection’s administrations. Information regarding patient’s sex, age, preoperative urodynamics, injection number, BTX-A injection dose, PGI-I scores post injection, and complications were collected. Statistical analysis was performed using IBM SPSS Statistics ver. 21.0 (IBM Co., Armonk, NY, USA), and categorical variables were compared using Pearson chi-square test. Median PGI-I scores for subgroup analyses were compared using a nonparametric Pearson chi-square test. This study was performed in accordance with the Helsinki declaration.\n\nRESULTS\nFifty-two patients (37 women and 15 men) with a mean age of 67.4 years (range, 26–93 years) received two or more injections. This accounted for a total of 140 BTX-A injections. Of the 52 patients, 33 (64%) received 2 injections, 15 (29%) received 3 to 4 injections, and 4 (7%) received 5 to 8 injections.\n\nOn performing urodynamics, 45 patients (87%) had DO, 4 patients (8%) had reduced bladder compliance, and 3 patients (6%) had increased bladder sensation during the filling phase. The average maximum fill volume was 317 mL (range, 84–500 mL). Twenty-one patients (40%) were incontinent at the time of urodynamics. Table 1 shows a comparison of patients who received only 2 injections and those who received 3 or more injections.\n\nAverage time between injections was 14.9 months. Mean follow-up time was 49 months (range, 9–101 months). The doses administered by 19 (14%), 26 (18%), 84 (60%), 2 (1%), 8 (6%), and 1 BTX-A injection (1%) were of 100, 150, 200, 250, 300, and 400 units, respectively. During the study, the number of patients receiving repeated injections increased, and the average dose of BTX-A administered gradually decreased (Table 2).\n\nDuring the follow-ups, 3 patients died because of unrelated causes and 5 patients developed neurological conditions (2 cerebrovascular accidents, 2 Parkinson disease, and 1 multiple sclerosis). Of the 52 patients, 8 (15%) were recommenced oral anticholinergic medications with BTX-A injection administration. Nine patients (7% of all injections – I mean 7 of the 140 injections included in this study) developed UTI (Clavien-Dindo classification II); additionally, 3 of them experienced transient urinary retention (1% of all injections) requiring catheterization of less than 2 weeks (Clavien-Dindo classification III). Of these 9 complications, 6 occurred in the patients who received 200 units of BTX-A; the remaining three events occurred in patients receiving either 150 or 200 units of BTX-A. There were no episodes of urosepsis.\n\nMedian PGI-I score was 2.0 out of 7.0 (interquartile range [IQR], 2). For 46 of the 52 patients, the PGI-I scores remained stable with the administration of each injection. PGI-I scores improved and worsened by one point in two and four patients, respectively.\n\nPearson chi-square tests were performed to assess the correlation between PGI-I scores and several variables including patient age, sex, presence of reduced bladder compliance, presence of incontinence at the time of performing urodynamics, and absence of DO. A significant relationship was found between PGI-I scores and patient’s sex and presence of reduced bladder compliance. Male patients or reduced bladder compliance was associated with a higher (worse) PGI-I score.\n\nWhen the results are analyzed by sex, the median PGI-I scores for women and men were 2 (IQR, 1) and 3 (IQR, 1), respectively. Baseline characteristics between both the groups are similar (Table 3). A statistically significant difference in PGI-I scores between male and female patients is present at the first and second injection administration; however, no difference is seen at the third injection administration; P=0.005 for the first injection, P=0.01 for the second injection, and P=0.1 for the third injection (Fig. 1).\n\nThere were 4 patients, that is, 2 men and 2 women, with reduced bladder compliance. The median PGI-I score for patients with reduced bladder compliance was 4.5 (IQR, 1) and for those with normal bladder compliance was 2 (IQR, 2). A statistically significant difference in PGI-I scores between those with reduced bladder compliance and those with normal bladder compliance is present at the first and second injection administration; P=0.013 for the first injection, and P=0.013 for the second injection (Fig. 2). No patients with reduced bladder compliance received a third injection.\n\nOf the 52 patients, 28 (54%) were 70 years or older in age, and 80 of the 140 injections (57%) were administered to patients that were 70 years or older in age. Median PGI-I scores in the younger and the older groups were 2 (IQR, 1) and 2 (IQR, 3), respectively. There was no statistically significant difference at any time point between the 2 groups; P=0.3 for the first injection, P=0.4 for the second injection, and P=0.8 for the third injection. Complication rates were also similar. Table 4 shows a comparison of baseline characteristics, outcomes, and complication rates of younger versus older patients.\n\nDISCUSSION\nDrug-refractory NNOAB represents a common clinical problem, and its frequency is expected to increase in an ageing population. BTX-A is being increasingly used for this indication. Given that each BTX-A injection is expected to provide temporary relief, repeated injections are used increasingly for the management of OAB. Therefore, ensuring safety and efficacy of repeated injections is important.\n\nWith a median PGI-I score of 2.0, our study shows that in patients with drug refractory NNOAB, repeated BTX-A injections provide an effective therapeutic option. Overall, for each patient, the PGI-I score remained stable with the administration of each injection; it only worsened by one point in 4 patients and in 4 of the 140 injections administered. The PGI-I score stability with each repeated injection suggests that efficacy is maintained, and patients’ initial response to BTX-A is likely to be a good predictor of their response to future injections. These findings are consistent with that of the other published data exploring this question [12-15]. In this patient cohort, the time between injections is also comparable to that of the other published studies [15,16].\n\nOur study showed that there was no significant relationship between patient age and efficacy based on PGI-I scores. Additionally, there was no increase in complications in the older patient cohort (≥70 years of age) compared to that in the younger patient cohort (<70 years of age). This is of particular relevance given that the older patients are more likely to have overactive bladder and are more likely to be intolerant to the side effects of oral anticholinergic medications. In our cohort, almost two-thirds of all the injections were administered to patients aged ≥70 years. This is likely to reflect our local patient demographics, given the fact that Concord Hospital was previously a repatriation hospital. Our findings support not only the efficacy but also the safety of repeated BTX-A injections in the elderly; additionally, advanced age should not necessarily be a factor for exclusion from repeated BTX-A injection administration. Only one other study, to our knowledge, focuses on this patient population. The study included 21 elderly patients aged 75–92 years and showed good short-term efficacy and tolerability after a single injection of BTX-A was administered [19].\n\nMale patients or reduced bladder compliance was associated with a higher (worse) PGI-I score. While this study does not give an explanation as to why this may be the case, it is the first to make this observation.\n\nOne of the limitations of this study stems from the study population. As the aim of the study was to assess safety and efficacy of repeated injections, only those patients who had received some degree of benefit (even if small) from the first injection would have been considered for a repeated injection, that is, this cohort assesses those who were likely to be responders to BTX-A rather than the nonresponders. In spite of this selection bias, there were no patients with reduced bladder compliance that received a third injection; additionally, median PGI-I score of 4 (no difference) was observed because of the lack of efficacy and these patients did not receive further injections.\n\nAdditionally, male patients were associated with a higher PGI-I score. The authors propose that the higher PGI-I scores in the male patients as opposed to those in the female patients may be because of the added complexity of the prostate pathology. The enlarged prostate would result in bladder outlet obstruction. While preoperative urodynamics should detect bladder outlet obstruction, occult obstruction under the artificial circumstances of a urodynamic assessment may not detect the minor yet chronic degrees of obstruction.\n\nIn response to stretch induced by bladder outlet obstruction, the bladder epithelial and smooth muscle cells undergo changes in gene expression and protein synthesis. These processes lead to many ultrastructural changes [20,21]. In an informative study by Mirone et al. [21] using light and electron microscopy, the morphology of the normal bladder was compared to that of the ageing bladder and that of the obstructed bladder. In contrast to the normal bladder where the smooth muscle cells were closely packed together with very little intervening connective tissue, the obstructed bladder showed decreased nervous innervation, more widely displaced muscle cells with large increases in connective tissue mass, and contractile function loss of the myocytes. Interestingly, the ageing unobstructed bladder did not demonstrate any of these changes; it had the same appearance as that of the normal bladder [22]. In addition, several studies have also shown a direct relationship between reduced bladder compliance and increased passive urethral resistance and bladder outlet obstruction [23,24]. Given the histologic changes associated with bladder outlet obstruction, one would not expect the obstructed bladder to respond in the same way to BTX-A as the histologically normal bladder would. These findings are in accordance with our clinical observations that male patients or reduced bladder compliance results in a less favorable response to BTX-A. A recently published study assessing the efficacy of BTX-A in male patients with NNOAB also demonstrated a poor response to BTX-A in those with a history of bladder outlet obstruction requiring transurethral resection of the prostate [25].\n\nNo significant difference between the male and female patients from the third injection onwards is most likely explained by selection bias: only those patients who did benefit from the second would have gone on to have a third injection whilst those who did not benefit from the third injection would have been ‘excluded’ from going on to have a third injection. This is reflected in the fact that the ratio of men to women was lower in those receiving three or more injections than in those receiving 2 injections (Table 1).\n\nFurther limitations of our study include the retrospective nature of the study, relatively small patient number, and that efficacy was based on a subjective measure (PGI-I score). To our knowledge, there are only two other published studies that have assessed repeated BTX-A injections in NNOAB with a larger patient population [16,26]; additionally, a study by Sahai et al. [13] showed improvements in the urodynamic parameters with up to three repeated injections. The remaining identified studies used a subjective measure of efficacy [13-16,26]. Given that OAB is a symptom complex rather than a urodynamic diagnosis, using improvement in symptoms (rather than a change in urodynamic parameters) as a measure of outcome is felt to be appropriate. A further limitation is that while a multivariate analysis would have been ideal, owing to the small patient numbers, only univariate analyses were performed.\n\nThis study demonstrated a low occurrence of complications, that is, a UTI rate of 6.4% and urinary retention rate of 2% with a good degree of tolerability and acceptance in the elderly.\n\nIn conclusion, while repeated intradetrusor BTX-A injections in patients with drug-refractory NNOAB were safe and effective, male patients or reduced bladder compliance might not respond as favorably. Patients including the elderly showed a good degree of tolerability, and complications including UTI and urinary retention were uncommon. Patients showed that global improvement in symptoms and efficacy was maintained with repeated BTX-A injections.\n\nResearch Ethics\n\nThe study was performed in accordance with the Helsinki declaration.\n\nConflict of Interest\n\nNo potential conflict of interest relevant to this article was reported.\n\nThe authors acknowledge the assistance of Professor Jennifer Peat with the statistical analysis.\n\nFig. 1. Median patient global impression of improvement (PGI-I) scores by sex and injection number.\n\nFig. 2. Median patient global impression of improvement (PGI-I) scores by bladder compliance and injection number.\n\nTable 1. Comparison of patients who received 2 injections with those who received three or more injections (n=52)\n\nVariable\t2 Injections\t≥3 Injections\t\nNo. of patients\t33\t19\t\nNo. of injections\t66\t74\t\nDose of BTX-A (unit), mean±SD\t174±43\t196±52.8\t\nSex\t\t\t\n Men:women (ratio)\t10:23 (0.43)\t5:14 (0.36)\t\nAge (yr), mean (range)\t64 (26–85)\t73 (47–96)\t\nReduced bladder compliance\t4\t0\t\nAbsent DO\t4\t0\t\nPGI-I score, median (IQR)\t2 (2)\t1 (1)\t\nBTX-A, botulinum toxin type-A; SD, standard deviation; DO, detrusor overactivity; PGI-I, patient global impression of improvement; IQR, interquartile range.\n\nTable 2. Number and dose of BTX-A injections by year\n\nYear\tNo. of BTX-A injections\tAverage dose (unit)\t\n100 Units\t150–200 Units\t>200 Units\t\n2004\t0\t3\t0\t200\t\n2005\t1\t2\t1\t200\t\n2006\t0\t9\t0\t194\t\n2007\t0\t6\t1\t214\t\n2008\t0\t15\t1\t200\t\n2009\t2\t17\t2\t188\t\n2010\t6\t25\t1\t173\t\n2011\t1\t18\t2\t192\t\n2012\t8\t14\t4\t169\t\nBTX-A, botulinum toxin type-A.\n\nTable 3. Comparison of male and female subgroups (n=52)\n\nVariable\tWomen (n=37)\tMen (n=15)\t\nNo. of injections\t100\t40\t\nMean dose of BTX-A (unit)\t174±45\t212±50\t\nMean age (yr)\t67.6±14.6\t67.3±17.0\t\nDetrusor overactivity\t35 (95)\t12 (80)\t\nReduced compliance\t2 (5)\t2 (13)\t\nMean max fill volume (mL)\t304±125\t372±173\t\nIncontinence at urodynamics\t9 (24)\t2 (13)\t\nPGI-I score, median (IQR)\t2 (1)\t3 (1)\t\nComplications, No. of injections (%)\t\t\t\n UTI\t5/100 (5)\t1/40 (3)\t\n UTI + retention\t1/100 (1)\t2/40 (5)\t\nValues are presented as mean±standard deviation or number (%) unless otherwise indicated.\n\nBTX-A, botulinum toxin type-A; PGI-I, patient global impression of improvement; IQR, interquartile range; UTI, urinary tract infection.\n\nTable 4. Comparison of younger (<70 years) and older patients (≥70 years) (n=52)\n\nVariable\t<70 yr (n=24)\t≥70 yr (n=28)\t\nSex\t\t\t\n Men:women\t9:15 (0.6)\t7:21 (0.3)\t\nNo. of injections\t60\t80\t\nMean dose of BTX-A (unit)\t184\t182\t\nMean time between injections (mo)\t14.8\t15.8\t\nDetrusor overactivity, n (%)\t19 (79)\t27 (96)\t\nReduced compliance, n (%)\t2 (8)\t2 (7)\t\nMean maximum fill volume (mL)\t380\t277\t\nIncontinence at urodynamics, n (%)\t1 (4)\t10 (36)\t\nPGI-I score, median (IQR)\t2 (1)\t2 (3)\t\nComplications, No. of injections (%)\t\t\t\n UTI\t2/60 (3)\t4/80 (5)\t\n UTI+retention\t1/60 (2)\t2/80 (3)\t\nBTX-A, botulinum toxin type-A; PGI-I, patient global impression of improvement; IQR, interquartile range; UTI, urinary tract infection.\n==== Refs\nREFERENCES\n1 Abrams P Cardozo L Fall M Griffiths D Rosier P Ulmsten U The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society Neurourol Urodyn 2002 21 167 78 11857671 \n2 Chapple CR Khullar V Gabriel Z Muston D Bitoun CE Weinstein D The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis Eur Urol 2008 54 543 62 18599186 \n3 Brostrom S Hallas J Persistence of antimuscarinic drug use Eur J Clin Pharmacol 2009 65 309 14 19107469 \n4 Gormley EA Lightner DJ Burgio KL Chai TC Clemens JQ Culkin DJ Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline J Urol 2012 188 6 Suppl 2455 63 23098785 \n5 Allahdin S Oo N An overview of treatment of overactive bladder syndrome in women J Obstet Gynaecol 2012 32 217 21 22369391 \n6 Balchandra P Rogerson L Women’s perspective: intra-detrusor botox versus sacral neuromodulation for overactive bladder symptoms after unsuccessful anticholinergic treatment Int Urogynecol J 2014 25 1059 64 24633067 \n7 Sahai A Dowson C Khan MS Dasgupta P Improvement in quality of life after botulinum toxin-A injections for idiopathic detrusor overactivity: results from a randomized double-blind placebo-controlled trial BJU Int 2009 103 1509 15 19389019 \n8 Rovner E Kennelly M Schulte-Baukloh H Zhou J Haag-Molkenteller C Dasgupta P Urodynamic results and clinical outcomes with intradetrusor injections of onabotulinumtoxinA in a randomized, placebo-controlled dose-finding study in idiopathic overactive bladder Neurourol Urodyn 2011 30 556 62 21351127 \n9 Tincello DG Kenyon S Abrams KR Mayne C Toozs-Hobson P Taylor D Botulinum toxin a versus placebo for refractory detrusor overactivity in women: a randomised blinded placebo-controlled trial of 240 women (the RELAX study) Eur Urol 2012 62 507 14 22236796 \n10 Denys P Le Normand L Ghout I Costa P Chartier-Kastler E Grise P Efficacy and safety of low doses of onabotulinumtoxinA for the treatment of refractory idiopathic overactive bladder: a multicentre, double-blind, randomised, placebo-controlled dose-ranging study Eur Urol 2012 61 520 9 22036776 \n11 Sahai A Khan MS Dasgupta P Efficacy of botulinum toxin-A for treating idiopathic detrusor overactivity: results from a single center, randomized, double-blind, placebo controlled trial J Urol 2007 177 2231 6 17509328 \n12 Reitz A Denys P Fermanian C Schurch B Comperat E Chartier-Kastler E Do repeat intradetrusor botulinum toxin type a injections yield valuable results? Clinical and urodynamic results after five injections in patients with neurogenic detrusor overactivity Eur Urol 2007 52 1729 35 17884281 \n13 Sahai A Dowson C Khan MS Dasgupta P GKT Botulinum Study Group Repeated injections of botulinum toxin-A for idiopathic detrusor overactivity Urology 2010 75 552 8 20035984 \n14 Abeywickrama L Arunkalaivanan A Quinlan M Repeated botulinum toxin type A (Dysport) injections for women with intractable detrusor overactivity: a prospective outcome study Int Urogynecol J 2014 25 601 5 24132493 \n15 Dowson C Watkins J Khan MS Dasgupta P Sahai A Repeated botulinum toxin type A injections for refractory overactive bladder: medium-term outcomes, safety profile, and discontinuation rates Eur Urol 2012 61 834 9 22204745 \n16 Veeratterapillay R Harding C Teo L Vasdev N Abroaf A Dorkin TJ Discontinuation rates and inter-injection interval for repeated intravesical botulinum toxin typeA injections for detrusor overactivity Int J Urol 2014 21 175 8 23819724 \n17 The American College of Obstetricians and Gynecologists OnabotulinumtoxinA and the bladder. Committee Opinion No. 604 Obstet Gynecol 2014 123 1408 11 24848923 \n18 Apostolidis A Dasgupta P Denys P Elneil S Fowler CJ Giannantoni A Recommendations on the use of botulinum toxin in the treatment of lower urinary tract disorders and pelvic floor dysfunctions: a European consensus report Eur Urol 2009 55 100 19 18823697 \n19 White WM Pickens RB Doggweiler R Klein FA Short-term efficacy of botulinum toxin a for refractory overactive bladder in the elderly population J Urol 2008 180 2522 6 18930481 \n20 Brierly RD Hindley RG McLarty E Harding DM Thomas PJ A prospective evaluation of detrusor ultrastructural changes in bladder outlet obstruction BJU Int 2003 91 360 4 12603415 \n21 Mirone V Imbimbo C Longo N Fusco F The detrusor muscle: an innocent victim of bladder outlet obstruction Eur Urol 2007 51 57 66 16979287 \n22 Gosling JA Modification of bladder structure in response to out-flow obstruction and ageing Eur Urol 1997 32 Suppl 1 9 14 9218937 \n23 Liao LM Schaefer W Cross-sectional and longitudinal studies on interaction between bladder compliance and outflow obstruction in men with benign prostatic hyperplasia Asian J Androl 2007 9 51 6 16888684 \n24 Madersbacher S Pycha A Klingler CH Mian C Djavan B Stulnig T Interrelationships of bladder compliance with age, detrusor instability, and obstruction in elderly men with lower urinary tract symptoms Neurourol Urodyn 1999 18 3 15 10090122 \n25 Habashy D Losco G Tse V Collins R Chan L Botulinum toxin (OnabotulinumtoxinA) in the male non-neurogenic overactive bladder: clinical and quality of life outcomes BJU Int 2015 116 Suppl 3 61 5 26176660 \n26 Mohee A Khan A Harris N Eardley I Long-term outcome of the use of intravesical botulinum toxin for the treatment of overactive bladder (OAB) BJU Int 2013 111 106 13 22672569\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2093-4777",
"issue": "20(1)",
"journal": "International neurourology journal",
"keywords": "Botulinum Toxins; Treatment Outcome; Urinary Bladder, Overactive; Urodynamics",
"medline_ta": "Int Neurourol J",
"mesh_terms": null,
"nlm_unique_id": "101534513",
"other_id": null,
"pages": "40-6",
"pmc": null,
"pmid": "27032556",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article",
"references": "22672569;21351127;22236796;19389019;24132493;11857671;18930481;10090122;19107469;20035984;22204745;12603415;24633067;9218937;17509328;18599186;23819724;16888684;18823697;22369391;24848923;22036776;23098785;17884281;26176660;16979287",
"title": "Eight-Year Experience With Botulinum Toxin Type-A Injections for the Treatment of Nonneurogenic Overactive Bladder: Are Repeated Injections Worthwhile?",
"title_normalized": "eight year experience with botulinum toxin type a injections for the treatment of nonneurogenic overactive bladder are repeated injections worthwhile"
} | [
{
"companynumb": "AU-IPSEN BIOPHARMACEUTICALS, INC.-2016-03001",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BOTULINUM TOXIN TYPE A"
},
... |
{
"abstract": "Interstitial Lung Disease (ILD) is a common finding of Systemic Sclerosis (SSc) mainly presenting in the form of Nonspecific Interstitial Pneumonia (NSIP) and deeply affecting patients' prognosis. Beside NSIP, other types of ILD have been reported. The most recently described pattern is the so-called Combined-pulmonary emphysema and lung fibrosis, characterized by the coexistence of both upper lobes centrilobular and paraseptal emphysema and lower lobes ILD. We presented three cases of patients with SSc, in which High Resolution Computed Tomography examinations showed emphysema with atypical distribution and radiological presentation, without or with mild signs of fibrosing lung disease, that stabilized after immunosuppressive treatment.",
"affiliations": "Department of Radiology, University and IRCCS Policlinico S. Matteo Foundation, 27100, Pavia, Italy. Electronic address: afrancon88@gmail.com.;Division of Rheumatology, University and IRCCS Policlinico S. Matteo Foundation, 27100, Pavia, Italy.;Radiology Unit, Isituti Clinici Città di Pavia, 27100, Pavia, Italy.;Division of Rheumatology, University and IRCCS Policlinico S. Matteo Foundation, 27100, Pavia, Italy; Rheumatology Dept, Hopital Cochin, Paris, France.;Department of Radiology, University and IRCCS Policlinico S. Matteo Foundation, 27100, Pavia, Italy.;Centre for Inherited Cardiovascular Diseases, Transplant Research Area - IRCCS Foundation Policlinico San Matteo Pavia, Italy.;Division of Pneumology, University and IRCCS Policlinico S. Matteo Foundation, 27100, Pavia, Italy.;Division of Rheumatology, University and IRCCS Policlinico S. Matteo Foundation, 27100, Pavia, Italy.;Division of Rheumatology, University and IRCCS Policlinico S. Matteo Foundation, 27100, Pavia, Italy.;Department of Radiology, University and IRCCS Policlinico S. Matteo Foundation, 27100, Pavia, Italy.;Division of Rheumatology, University and IRCCS Policlinico S. Matteo Foundation, 27100, Pavia, Italy.",
"authors": "Franconeri|Andrea|A|;Marasco|Emiliano|E|;Dore|Roberto|R|;Codullo|Veronica|V|;Calliada|Fabrizio|F|;Disabella|Eliana|E|;Meloni|Federica|F|;Zanframundo|Giovanni|G|;Montecucco|Carlomaurizio|C|;Valentini|Adele|A|;Cavagna|Lorenzo|L|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1016/j.rmed.2019.105816",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6111",
"issue": "160()",
"journal": "Respiratory medicine",
"keywords": "Emphysema; High Resolution Computed Tomography; Interstitial lung disease; Systemic Sclerosis",
"medline_ta": "Respir Med",
"mesh_terms": "D006801:Humans; D054988:Idiopathic Interstitial Pneumonias; D007166:Immunosuppressive Agents; D011656:Pulmonary Emphysema; D011658:Pulmonary Fibrosis; D012595:Scleroderma, Systemic; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8908438",
"other_id": null,
"pages": "105816",
"pmc": null,
"pmid": "31739247",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pulmonary emphysema not combined with lung fibrosis in systemic sclerosis.",
"title_normalized": "pulmonary emphysema not combined with lung fibrosis in systemic sclerosis"
} | [
{
"companynumb": "NVSC2019IT061228",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
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