article dict | reports listlengths 1 3.97k |
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{
"abstract": "BACKGROUND\nCalcineurin-inhibitor (CNI)-induced nephrotoxicity frequently complicates transplantation. African-Americans are at a greater risk of renal failure than the general population. We investigated whether race was an effect modifier of the relationship between CNI exposure and kidney function after nonrenal solid organ transplantation.\n\n\nMETHODS\nThis is a retrospective cohort study of 1609 patients who underwent initial nonrenal solid organ transplantation between January 2000 and June 2012. A central repository administrative database was queried electronically for demographics, comorbidities, and serial levels of tacrolimus, cyclosporine, and serum creatinine. Predictors of interest were total drug exposure of tacrolimus and cyclosporine (area under the concentration-time curve) and self-reported race. The outcome of interest was cumulative change in estimated glomerular filtration rate (GFR).\n\n\nRESULTS\nThere were 1109 patients treated with tacrolimus (271 African-Americans) and 500 patients treated with cyclosporine (113 African Americans). A decline in GFR over time was seen with total tacrolimus exposure (-1.3 mL/min/1.73 m(2) for every 5 ng/mL·year increase in tacrolimus) and total cyclosporine exposure (-1.1 mL/min/1.73 m(2) for every 50 ng/mL·year increase in cyclosporine). However, total CNI exposure effect on estimated GFR changes did not vary by race (P interaction was 0.9 for tacrolimus and 0.6 for cyclosporine).\n\n\nCONCLUSIONS\nTotal CNI exposure is associated with worsening kidney function among patients with nonrenal solid organ transplantation. However, African-American patients are not more vulnerable to chronic CNI-induced nephrotoxicity when compared to white patients.",
"affiliations": "Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan, United States; Division of Nephrology, Henry Ford Hospital, Detroit, Michigan, United States. Electronic address: lyessay1@hfhs.org.;Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan, United States.;Heart and Vascular Institute, Henry Ford Hospital, Detroit, Michigan, United States.;Heart and Vascular Institute, Henry Ford Hospital, Detroit, Michigan, United States.;Heart and Vascular Institute, Henry Ford Hospital, Detroit, Michigan, United States.;Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan, United States; Heart and Vascular Institute, Henry Ford Hospital, Detroit, Michigan, United States.;Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan, United States; Heart and Vascular Institute, Henry Ford Hospital, Detroit, Michigan, United States; Center for Health Services Research, Henry Ford Hospital, Detroit, Michigan, United States.",
"authors": "Yessayan|L|L|;Shafiq|A|A|;Peterson|E|E|;Wells|K|K|;Hu|Y|Y|;Williams|L K|LK|;Lanfear|D|D|",
"chemical_list": "D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "47(10)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection; D006801:Humans; D015994:Incidence; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D044469:Racial Groups; D051437:Renal Insufficiency; D012189:Retrospective Studies; D015996:Survival Rate; D016559:Tacrolimus; D014481:United States",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2968-72",
"pmc": null,
"pmid": "26707323",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "12490790;12751127;19852526;12819250;12954741;12966368;13680536;14696762;14762861;15041348;15244495;6382005;3702930;3603674;3306096;3291293;3263042;2797067;2687689;2692250;10676738;11805539;23956308;11830194;12141412;12191981;12484345;12490779;2337107;2368696;2064486;2069771;2104260;1508243;7680544;8513650;8356620;8285192;8196296;7763126;9500626;9696431;9825827;15592326;15748097;15888045;16426327;18089354;18089375;19218475",
"title": "Race, Calcineurin Inhibitor Exposure, and Renal Function After Solid Organ Transplantation.",
"title_normalized": "race calcineurin inhibitor exposure and renal function after solid organ transplantation"
} | [
{
"companynumb": "US-ASTELLAS-2016US001369",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "Biotherapies appear as potential drugs for the treatment of inflammatory noninfectious uveitis. In this report, we show that tocilizumab, an anti-IL-6 agent, greatly improved two patients with birdshot chorioretinopathy refractory to conventional immunosuppressive drugs, interferon α2a, and anti-TNFα agents. After a follow-up of 22 months, patients exhibited an improvement of both visual acuity and macular edema. A corticosteroid-sparing effect was achieved in both cases.",
"affiliations": "Normandie Université UNI Rouen, Service de Médecine Interne, CHU Charles Nicolle, 76000, Rouen, France. mat3leclercq@gmail.com.;Normandie Université UNI Rouen U1096, Service de Médecine Interne, CHU Charles Nicolle, 76000, Rouen, France.;Service de Médecine Interne et Maladies Infectieuses, CH Le Havre, 76290, Montivilliers, France.;Normandie Université UNI Rouen, Service de Médecine Interne, CHU Charles Nicolle, 76000, Rouen, France.;Normandie Université UNI Rouen U1096, Service de Médecine Interne, CHU Charles Nicolle, 76000, Rouen, France.;Normandie Université UNI Rouen, Service d'Ophtalmologie, CHU Charles Nicolle, 76000, Rouen, France.;Normandie Université UNI Rouen U1096, Service de Médecine Interne, CHU Charles Nicolle, 76000, Rouen, France.;Normandie Université UNI Rouen, Service d'Ophtalmologie, CHU Charles Nicolle, 76000, Rouen, France.;Normandie Université UNI Rouen, Service d'Ophtalmologie, CHU Charles Nicolle, 76000, Rouen, France.",
"authors": "Leclercq|Mathilde|M|;Le Besnerais|M|M|;Langlois|V|V|;Girszyn|N|N|;Benhamou|Y|Y|;Ngo|C|C|;Levesque|H|H|;Muraine|M|M|;Gueudry|J|J|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D016898:Interferon-alpha; D014409:Tumor Necrosis Factor-alpha; C502936:tocilizumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-018-4007-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "37(3)",
"journal": "Clinical rheumatology",
"keywords": "Birdshot chorioretinopathy; Interferon α2a; Macular edema; Tocilizumab",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D000080365:Birdshot Chorioretinopathy; D002825:Chorioretinitis; D005260:Female; D006801:Humans; D016898:Interferon-alpha; D019233:Retreatment; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D014605:Uveitis",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "849-853",
"pmc": null,
"pmid": "29397459",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "25268663;23374570;21970668;26952547;27010181;24379650;20181409;27602665;27726475;27175923;23893042;28528519;28887113;28315319;23470459;28520640;17050581;25820692;24262929;25204610",
"title": "Tocilizumab for the treatment of birdshot uveitis that failed interferon alpha and anti-tumor necrosis factor-alpha therapy: two cases report and literature review.",
"title_normalized": "tocilizumab for the treatment of birdshot uveitis that failed interferon alpha and anti tumor necrosis factor alpha therapy two cases report and literature review"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1048609",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nChronic kidney disease (CKD) is a common complication after liver transplantation (LT). The etiology of CKD is broad and may only be assessed accurately by renal histology. The current study aimed to analyze the safety of renal biopsy in daily clinical practice as well as its usefulness regarding management of CKD after LT.\n\n\nMETHODS\nWe performed a retrospective analysis of clinical data and renal biopsies obtained from patients with severe renal impairment (overt proteinuria, progressive deterioration of renal function) after LT with respect to safety, etiology of renal disease, and therapeutic consequences.\n\n\nRESULTS\nRenal biopsies were obtained from 14 patients at median (minimum-maximum) 3 (0.2-12) years after LT. No major complications associated with renal biopsy were observed. Histomorphological alterations were varied (nephrosclerosis, n = 5; IgA-glomerulonephritis, n = 4; tenofovir-associated nephropathy, membranoproliferative glomerulonephritis type 1, membranous glomerulonephritis, amyloid A amyloidosis, and calcineurin inhibitor nephropathy, n = 1, respectively). The diagnosis of specific renal diseases other than calcineurin-inhibitor nephrotoxicity facilitated specific treaments and avoided unnecessary modification of immunosuppression in the majority of patients.\n\n\nCONCLUSIONS\nRenal biopsy in patients with CKD after LT seems safe and may offer specific therapeutic options. Furthermore, unnecessary changes of immunosuppression can be avoided in a considerable number of patients.",
"affiliations": "Medizinische Klinik I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany. Welker@med.uni-frankfurt.de.;Medizinische Klinik I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.;Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.;Institut für Biostatistik und mathematische Modellierung, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.;Medizinische Klinik III, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.;Medizinische Klinik I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.;Medizinische Klinik I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.;Medizinische Klinik I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.;Abteilung für Nephropathologie, Universitätsklinikum Erlangen, Krankenhausstraße 8-10, 91054, Erlangen, Germany.;Medizinische Klinik III, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.",
"authors": "Welker|Martin-Walter|MW|http://orcid.org/0000-0002-8687-9639;Weiler|Nina|N|;Bechstein|Wolf Otto|WO|;Herrmann|Eva|E|;Betz|Christoph|C|;Schöffauer|Mark|M|;Zeuzem|Stefan|S|;Sarrazin|Christoph|C|;Amann|Kerstin|K|;Jung|Oliver|O|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Italy",
"delete": false,
"doi": "10.1007/s40620-018-0506-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1121-8428",
"issue": "32(1)",
"journal": "Journal of nephrology",
"keywords": "Biopsy; Chronic kidney disease; Etiology; Liver transplantation",
"medline_ta": "J Nephrol",
"mesh_terms": "D000328:Adult; D000368:Aged; D018450:Disease Progression; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011507:Proteinuria; D051436:Renal Insufficiency, Chronic; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9012268",
"other_id": null,
"pages": "129-137",
"pmc": null,
"pmid": "29946864",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": "24713190;20098285;23466637;20824504;23775875;17944734;21931704;16003228;19054383;19541578;26018348;27479161;26303035;10692270;19414839;23171281;29334930;1412766;1499163",
"title": "Key role of renal biopsy in management of progressive chronic kidney disease in liver graft recipients.",
"title_normalized": "key role of renal biopsy in management of progressive chronic kidney disease in liver graft recipients"
} | [
{
"companynumb": "DE-TEVA-2019-DE-1030486",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Fewer than ten biopsy-proven case reports exist on vancomycin-associated interstitial nephritis (VAIN) and vancomycin-associated acute tubular necrosis (VAATN). Among these, several are confounded by the use of other potentially offending drugs. We report a case of isolated VAIN/VAATN in a patient on no other potentially nephrotoxic agents other than vancomycin. The patient received intravenous vancomycin for coagulase-negative staphylococcus bacteremia. Her baseline serum creatinine of 0.9 mg/dL increased to 9.6 mg/dL after 1 week of therapy during which vancomycin levels peaked at 141 μg/mL. Renal biopsy revealed acute interstitial nephritis with lymphocytic and eosinophilic infiltrate and acute tubular necrosis. Upon discontinuation of vancomycin and administration of prednisone complete renal recovery ensued over a period of 4 weeks.",
"affiliations": "Lankenau Medical Center, 100 E Lancaster Ave, Lankenau Medical Office Building West, Suite 130, Wynnewood, PA 19096, USA. nhtike@aol.com",
"authors": "Htike|Naing Lin|NL|;Santoro|Jerome|J|;Gilbert|Brett|B|;Elfenbein|I Bruce|IB|;Teehan|Geoffrey|G|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin; D011241:Prednisone",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10157-011-0559-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1342-1751",
"issue": "16(2)",
"journal": "Clinical and experimental nephrology",
"keywords": null,
"medline_ta": "Clin Exp Nephrol",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D001706:Biopsy; D005260:Female; D006801:Humans; D007668:Kidney; D007683:Kidney Tubular Necrosis, Acute; D008297:Male; D009395:Nephritis, Interstitial; D011241:Prednisone; D014640:Vancomycin",
"nlm_unique_id": "9709923",
"other_id": null,
"pages": "320-4",
"pmc": null,
"pmid": "22086124",
"pubdate": "2012-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9825081;17692725;9645421;16721580;16112787;11601669;20391819;18030187;16323120;15199201;18067058;13542649;19833176;20832269;2596477;6219616;17880374;16236146",
"title": "Biopsy-proven vancomycin-associated interstitial nephritis and acute tubular necrosis.",
"title_normalized": "biopsy proven vancomycin associated interstitial nephritis and acute tubular necrosis"
} | [
{
"companynumb": "CA-PFIZER INC-2013146344",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": "1",
... |
{
"abstract": "A 35-year-old woman presented with a widespread petechial rash and pancytopenia. She underwent simultaneous pancreas and kidney transplantation for type 1 diabetes 8 years previously followed by a renal transplant 1 year prior to presentation, and was taking tacrolimus as long-term immunosuppression. The full blood count showed haemoglobin 97 g/L, platelet count 2×109/L and neutrophil count 0.22×109/L. Peripheral blood film examination confirmed genuine thrombocytopenia in the absence of any haemolytic or malignant features. Serological testing identified autoantibodies against all three blood lineages, consistent with a diagnosis of autoimmune pancytopenia. Treatment with steroids, intravenous immunoglobulins, romiplostim and mycophenolate mofetil achieved only fleeting remissions. Blood counts eventually normalised following the administration of rituximab and a change from tacrolimus to ciclosporin immunosuppression. Cytopenias are a well-recognised complication of post-transplantation care but we believe this to be the first reported case of autoimmune pancytopenia following solid organ transplantation. In this case report, we discuss the approach to investigation of haematological abnormalities post-transplant and the rationale for, and outcome of, the management of this rare case.",
"affiliations": "Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK tombull@nhs.net.;Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.;Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.;Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.",
"authors": "Bull|Tom|T|http://orcid.org/0000-0002-2483-3563;Jolley|Ruth|R|;Martin-Cabrera|Pedro|P|;Thomas|William|W|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-235851",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(9)",
"journal": "BMJ case reports",
"keywords": "haematology (drugs and medicines); haematology (incl blood transfusion); pathology; renal transplantation; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D001327:Autoimmune Diseases; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D016035:Pancreas Transplantation; D010198:Pancytopenia; D011183:Postoperative Complications; D013997:Time Factors",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32900732",
"pubdate": "2020-09-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Autoimmune pancytopenia occurring late after simultaneous pancreas and kidney transplantation.",
"title_normalized": "autoimmune pancytopenia occurring late after simultaneous pancreas and kidney transplantation"
} | [
{
"companynumb": "GB-TEVA-2020-GB-1853807",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": "3",
"d... |
{
"abstract": "The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes.\n\n\n\nTOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50-75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2-3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15-45 mg) or a sulfonylurea (5-15 mg glibenclamide, 2-6 mg glimepiride, or 30-120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856.\n\n\n\nBetween Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74-1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups.\n\n\n\nIn this long-term, pragmatic trial, incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycaemia events.\n\n\n\nItalian Medicines Agency, Diabete Ricerca, and Italian Diabetes Society.",
"affiliations": "Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy. Electronic address: ovaccaro@unina.it.;Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.;Center for Outcomes Research and Clinical Epidemiology (CORESEARCH), Pescara, Italy.;Division of Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy.;Department of Clinical & Experimental Medicine, University of Pisa, Pisa, Italy.;National Association of Hospital Cardiologists (ANMCO) Research Center, Florence, Italy.;Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.;Diabetes Unit, University Hospital Garibaldi-Nesima of Catania, Catania, Italy.;Diabetes Unit, Azienda Sanitaria Locale (ASL) Torino 5, Torino, Italy.;Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Italy.;University Department Laboratory Medicine, Hospital of Desio, Monza, Italy.;Center for Outcomes Research and Clinical Epidemiology (CORESEARCH), Pescara, Italy.;Center for Outcomes Research and Clinical Epidemiology (CORESEARCH), Pescara, Italy.;University Department Laboratory Medicine, Hospital of Desio, Monza, Italy.;University Department Laboratory Medicine, Hospital of Desio, Monza, Italy.;Endocrinology and Metabolism, University of Perugia, Perugia, Italy.;Medical Division, Rimini Hospital, Rimini, Italy.;Dipartimento di Medicina, Università di Padova, Padova, Italy.;Diabetes Unit, Massa Carrara, Azienda Unità Sanitarie Locali (USL) Toscana Nord Ovest, Carrara, Italy.;Section of Endocrinology, Diabetology and Metabolic Diseases, University of Palermo, Palermo, Italy.;Diabetes Unit, ASL 4 Chiavarese, Chiavari, Italy.;Department of Experimental Medicine, Sapienza University, Rome, Italy.;Institute for Research on Population and Social Policies-National Research Council, Penta di Fisciano, Italy.;Diabetes and Metabolism, Livorno Hospital, Livorno, Italy.;Diabetes Unit, Department of Medicine, San Salvatore Hospital, L'Aquila, Italy.;Diabetes Unit, School of Medicine, University of Genova, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Martino Hospital, Genova, Italy.;Endocrinology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Foggia, Italy.;Diabetes Unit, University of Ferrara, Ferrara, Italy.;Endocrinology and Diabetology, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy.;Diabetes and Metabolism Unit, IRCCS Istituto Nazionale Riposo e Cura Anziani, Ancona, Italy.;Diabetes Unit, University of Naples Federico II, Naples, Italy.;Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.;UOC Diabetologia Ospedale Sandro Pertini, Rome, Italy.;Clinical and Experimental Medicine, University of Parma, Parma, Italy.;Diabetes Unit, San Liberatore Hospital, Atri Teramo, Italy.;Endocrinology, Diabetes, Metabolism and Clinical Nutrition Unit, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy.;Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy.;ASST Bergamo Ovest, Treviglio, Italy.;Diabetes Unit, USL 3, Pistoia, Italy.;Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.;Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.;Endocrinology and Diabetes Unit, Azienda Sanitaria Locale di Potenza, Potenza, Italy.;Diabetes Unit, Renzetti Hospital, ASL 2 Abruzzo, Lanciano, Italy.;Diabetes Unit, USL Sud Est, Toscana, Italy.;Department of Emergency and Organ Transplantation, Endocrinology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Apulia, Italy.;Department Endocrinology and Diabetology, Cesena Hospital, Cesena, Italy.;Department of Clinical and Experimental Medicine, Magna Graecia University of Catanzaro, Italy.;Unit of Internal Medicine, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.;Diabetes Unit, Guglielmo da Saliceto Hospital, Piacenza, Italy.;Metabolism Unit, Azienda Ospedaliera di Padova, Padova, Italy.;Department of Medicine and Aging Sciences, and Aging and Translational Medicine Research Center (CeSI-Met), D'Annunzio University, Chieti-Pescara, Italy.;Diabetes Unit, USL Toscana Centro, Prato, Italy.;Diabetes Unit, Ravenna Internal Medicine Department, Romagna Local Health Unit, Ravenna, Italy.;Department of Medical Sciences, University of Turin, Turin, Italy.;Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.",
"authors": "Vaccaro|Olga|O|;Masulli|Maria|M|;Nicolucci|Antonio|A|;Bonora|Enzo|E|;Del Prato|Stefano|S|;Maggioni|Aldo P|AP|;Rivellese|Angela A|AA|;Squatrito|Sebastiano|S|;Giorda|Carlo B|CB|;Sesti|Giorgio|G|;Mocarelli|Paolo|P|;Lucisano|Giuseppe|G|;Sacco|Michele|M|;Signorini|Stefano|S|;Cappellini|Fabrizio|F|;Perriello|Gabriele|G|;Babini|Anna Carla|AC|;Lapolla|Annunziata|A|;Gregori|Giovanna|G|;Giordano|Carla|C|;Corsi|Laura|L|;Buzzetti|Raffaella|R|;Clemente|Gennaro|G|;Di Cianni|Graziano|G|;Iannarelli|Rossella|R|;Cordera|Renzo|R|;La Macchia|Olga|O|;Zamboni|Chiara|C|;Scaranna|Cristiana|C|;Boemi|Massimo|M|;Iovine|Ciro|C|;Lauro|Davide|D|;Leotta|Sergio|S|;Dall'Aglio|Elisabetta|E|;Cannarsa|Emanuela|E|;Tonutti|Laura|L|;Pugliese|Giuseppe|G|;Bossi|Antonio C|AC|;Anichini|Roberto|R|;Dotta|Francesco|F|;Di Benedetto|Antonino|A|;Citro|Giuseppe|G|;Antenucci|Daniela|D|;Ricci|Lucia|L|;Giorgino|Francesco|F|;Santini|Costanza|C|;Gnasso|Agostino|A|;De Cosmo|Salvatore|S|;Zavaroni|Donatella|D|;Vedovato|Monica|M|;Consoli|Agostino|A|;Calabrese|Maria|M|;di Bartolo|Paolo|P|;Fornengo|Paolo|P|;Riccardi|Gabriele|G|;|||;|||",
"chemical_list": "D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D008687:Metformin; D000077205:Pioglitazone",
"country": "England",
"delete": false,
"doi": "10.1016/S2213-8587(17)30317-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2213-8587",
"issue": "5(11)",
"journal": "The lancet. Diabetes & endocrinology",
"keywords": null,
"medline_ta": "Lancet Diabetes Endocrinol",
"mesh_terms": "D000368:Aged; D002318:Cardiovascular Diseases; D003924:Diabetes Mellitus, Type 2; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D015994:Incidence; D008297:Male; D008687:Metformin; D008875:Middle Aged; D000077205:Pioglitazone; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D016896:Treatment Outcome",
"nlm_unique_id": "101618821",
"other_id": null,
"pages": "887-897",
"pmc": null,
"pmid": "28917544",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial.",
"title_normalized": "effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin tosca it a randomised multicentre trial"
} | [
{
"companynumb": "IT-CIPLA LTD.-2017IT21638",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Chemoradiotherapy for the unresectable pancreatic cancer and biliary cancer has been used for improving survival. In this study, we examined its safety and efficacy in cases with the local recurrence of pancreatic or biliary cancer after primary resection. Seven consecutive patients with recurrence of carcinoma of pancreas (n=3) and biliary system (n =4) were treated chemoradiotherapy. Local recurrence occurred around the portal vein in 6 patients and remnant pancreas in one patient respectively. Disease free survival after primary surgery was 22 months (range: 5-84). All patients received 50 Gy of conformal three-dimensional radiotherapy with concurrent 5-FU, Gemcitabine or S-1. Grade 3 of anorexia and elevation of transaminase level occurred in one patient respectively. Local tumor response was observed in two patients of pancreatic and biliary cancer respectively. Median survival calculated from the start of the chemoradiotherapy was 14.5 months (range: 6.4-23.9) in pancreatic cancer and 13.5 months (range: 10.8-19.8)in biliary cancer. Our data suggest that chemoradiotherapy is feasible and effective treatment option in patients who present local recurrence after primary surgery in pancreatic or biliary cancer.",
"affiliations": "Dept. of Surgical Oncology and Digestive Surgery, Field of Oncology Kagoshima University Graduate School of Medical and Dental Sciences.",
"authors": "Maemura|Kosei|K|;Shinchi|Hiroyuki|H|;Noma|Hidetoshi|H|;Mataki|Yukou|Y|;Kurahara|Hiroshi|H|;Maeda|Shinichi|S|;Natsugoe|Shoji|S|;Takao|Sonshin|S|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "36(2)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001661:Biliary Tract Neoplasms; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D012008:Recurrence; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "265-8",
"pmc": null,
"pmid": "19223743",
"pubdate": "2009-02",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Chemoradiotherapy for locally recurrence after primary resection of biliary-pancreatic cancer.",
"title_normalized": "chemoradiotherapy for locally recurrence after primary resection of biliary pancreatic cancer"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1014630",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "Remote monitoring has become an essential component of the care of patients with a cardiac implantable electronic device, including those undergoing cardiac resynchronization therapy-defibrillator implantations. It allows for earlier detection of battery- and lead-related issue, atrial and ventricular arrhythmias, and may facilitate early identification of patients at risk for developing an exacerbation of heart failure. The data for the clinical utility of remote monitoring have been mixed. Additional studies are ongoing to determine how best to detect heart failure in these patients and how best to manage these patients based on the information.",
"affiliations": "Electrophysiology Laboratory, The Valley Hospital, Valley Health System, Snyder Center for Comprehensive Atrial Fibrillation, 223 North Van Dien Avenue, Ridgewood, NJ 07450, USA. Electronic address: mittsu@valleyhealth.com.",
"authors": "Mittal|Suneet|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ccep.2018.11.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1877-9182",
"issue": "11(1)",
"journal": "Cardiac electrophysiology clinics",
"keywords": "Cardiac resynchronization therapy; Outcomes; Remote monitoring",
"medline_ta": "Card Electrophysiol Clin",
"mesh_terms": "D058406:Cardiac Resynchronization Therapy; D058409:Cardiac Resynchronization Therapy Devices; D006801:Humans; D017216:Telemedicine; D013686:Telemetry; D016896:Treatment Outcome",
"nlm_unique_id": "101549998",
"other_id": null,
"pages": "123-130",
"pmc": null,
"pmid": "30717844",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Increasing Role of Remote Monitoring of Cardiac Resynchronization Therapy Devices in Improving Outcomes.",
"title_normalized": "increasing role of remote monitoring of cardiac resynchronization therapy devices in improving outcomes"
} | [
{
"companynumb": "US-009507513-1902USA005964",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
"drugadditional": "3",
... |
{
"abstract": "Waldenström's macroglobulinemia (WM) is a neoplasm of lymphoplasmacytic cells that produces monoclonal IgM protein. Although hyperviscosity syndrome is a common feature of WM, central nervous system (CNS) involvement in WM is rare and is known as Bing-Neel syndrome. A 60-year-old woman was referred to our hospital with bed-bound polyneuropathy, edema, splenomegaly, IgM-λ-type monoclonal protein and CD20-positive lymphocyte infiltration in the bone marrow. She was diagnosed with WM accompanying POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) and was treated with rituximab and thalidomide. She achieved partial remission of WM, and thalidomide was continued for POEMS syndrome. She visited our outpatient clinic 6 years later with sudden onset of vertigo and nausea. Magnetic resonance imaging (MRI) revealed a low-density area 4 cm in diameter in her right cerebrum and right mid-brain and she was referred to our hospital. Pathological analysis of brain biopsy samples revealed diffuse large B-cell lymphoma (DLBCL) in the CNS. Nucleic acid sequence analysis of the VDJ region using DNA obtained from the original WM tumor cells and brain tissue revealed that the DLBCL cells were derived from the original WM malignant lymphoma cells. She received five cycles of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy and 23.4 Gy of whole-brain irradiation followed by two cycles of high-dose cytarabine, which resolved her neurological symptoms in association with reduction of IgM levels to 367 mg/dL. MRI and computed tomography of the brain demonstrated complete remission of her CNS lymphoma.",
"affiliations": "Departments of Hematology, Rheumatology, and Infectious Diseases, KumamotoUniversity Graduate School of Medicine.",
"authors": "Kikukawa|Yoshitaka|Y|;Yamamura-Fujimoto|Ayako|A|;Endo|Shinya|S|;Miyagawa|Eiko|E|;Kawano|Yawara|Y|;Ueno|Shikiko|S|;Mitsuya|Hiroaki|H|;Hata|Hiroyuki|H|;Okuno|Yutaka|Y|",
"chemical_list": "D011344:Procarbazine; D000069283:Rituximab; D014750:Vincristine; D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.3960/jslrt.55.113",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1346-4280",
"issue": "55(2)",
"journal": "Journal of clinical and experimental hematopathology : JCEH",
"keywords": null,
"medline_ta": "J Clin Exp Hematop",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008279:Magnetic Resonance Imaging; D008727:Methotrexate; D008875:Middle Aged; D016878:POEMS Syndrome; D011344:Procarbazine; D011859:Radiography; D000069283:Rituximab; D014750:Vincristine; D008258:Waldenstrom Macroglobulinemia",
"nlm_unique_id": "101141257",
"other_id": null,
"pages": "113-9",
"pmc": null,
"pmid": "26490525",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of Bing-Neel Syndrome Accompanying Waldenström's Macroglobulinemia with R-MPV: A Case Report.",
"title_normalized": "successful treatment of bing neel syndrome accompanying waldenstr m s macroglobulinemia with r mpv a case report"
} | [
{
"companynumb": "JP-TEVA-686893ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Hereditary haemorrhagic telangiectasia is a genetic condition which results in arteriovenous malformations involving the skin, mucous membranes, lung, brain, gastrointestinal tract, liver and spinal canal. The shunting of blood through arteriovenous malformations, especially in the liver,; leads to maldistribution of cardiac output. In order to supply blood to vital organs, cardiac output is increased through vasodilation, elevated stroke volume and elevated heart rate. Pregnancy can worsen the effects of the arteriovenous malformations. We present the peripartum management of a woman with hereditary haemorrhagic telangiectasia predominantly involving the liver that resulted in high output cardiac failure during two consecutive pregnancies.",
"affiliations": "Department of Anaesthesia, Austin Health, Heidelberg, Victoria, Australia. chungfeilai@gmail.com",
"authors": "Lai|C F|CF|;Dennis|A|A|;Graham|J|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0310057X1003800224",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0310-057X",
"issue": "38(2)",
"journal": "Anaesthesia and intensive care",
"keywords": null,
"medline_ta": "Anaesth Intensive Care",
"mesh_terms": "D000328:Adult; D016534:Cardiac Output, High; D017548:Echocardiography, Transesophageal; D005260:Female; D006333:Heart Failure; D006801:Humans; D011247:Pregnancy; D013683:Telangiectasia, Hereditary Hemorrhagic",
"nlm_unique_id": "0342017",
"other_id": null,
"pages": "381-6",
"pmc": null,
"pmid": "20369778",
"pubdate": "2010-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "High output cardiac failure in a parturient with hereditary haemorrhagic telangiectasia.",
"title_normalized": "high output cardiac failure in a parturient with hereditary haemorrhagic telangiectasia"
} | [
{
"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-270765",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugad... |
{
"abstract": "OBJECTIVE\nThe case of a schizoaffective patient with a neurotoxic encephalopathy related to lithium-risperidon combination treatment is explored.\n\n\nMETHODS\nA case report and the relevant theoretical and clinical deliberations are described.\n\n\nCONCLUSIONS\nNeurotoxicity related to lithium-risperidon combination treatment is the result of an interaction of different ethiopathogenetic mechanisms. The EEG is the most important diagnostic parameter.",
"affiliations": "Psychiatrische Universitätsklinik Zürich, Zürich, Switzerland. boeker@bli.unizh.ch",
"authors": "Böker|Heinz|H|;Brandenberger|Mathias|M|;Schopper|Christian|C|",
"chemical_list": "D018692:Antimanic Agents; D014150:Antipsychotic Agents; D018967:Risperidone",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-2005-915352",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-4259",
"issue": "34(1)",
"journal": "Psychiatrische Praxis",
"keywords": null,
"medline_ta": "Psychiatr Prax",
"mesh_terms": "D018692:Antimanic Agents; D014150:Antipsychotic Agents; D003072:Cognition Disorders; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced; D004569:Electroencephalography; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome; D009460:Neurologic Examination; D020258:Neurotoxicity Syndromes; D011618:Psychotic Disorders; D018967:Risperidone",
"nlm_unique_id": "0423204",
"other_id": null,
"pages": "38-41",
"pmc": null,
"pmid": "17106843",
"pubdate": "2007-01",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Neurotoxicity related to lithium-risperidon combination treatment in a patient with schizoaffective disorder.",
"title_normalized": "neurotoxicity related to lithium risperidon combination treatment in a patient with schizoaffective disorder"
} | [
{
"companynumb": "DE-DRREDDYS-GER/GER/20/0127171",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": "3",
... |
{
"abstract": "Gabapentin is an anticonvulsant medication that reduces synaptic transmission by decreasing presynaptic voltage-gated Ca2+ and Na+ channels. It is approved to treat focal seizures but also used to treat post-herpetic and neuropathic pain. Although uncommon, there have been three reported cases of myasthenia gravis exacerbation associated with gabapentin in the literature. We present a patient with uncontrolled recurrent myasthenia gravis exacerbations secondary to chronic gabapentin use and provide a review for the three published cases.",
"affiliations": "Department of Medicine, Medstar Harbor Hospital, Baltimore, MD, USA.;Department of Medicine, Medstar Harbor Hospital, Baltimore, MD, USA.;Department of Medicine, Medstar Harbor Hospital, Baltimore, MD, USA.",
"authors": "Chien|Jason L|JL|;Baez|Valentina|V|;Mody|Harshad R|HR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/20009666.2019.1643220",
"fulltext": "\n==== Front\nJ Community Hosp Intern Med PerspectJ Community Hosp Intern Med PerspectZJCHzjch20Journal of Community Hospital Internal Medicine Perspectives2000-9666Taylor & Francis 164322010.1080/20009666.2019.1643220Case ReportUncontrolled recurrent myasthenia gravis exacerbations secondary to chronic gabapentin use J. L. CHIEN ET AL.JOURNAL OF COMMUNITY HOSPITAL INTERNAL MEDICINE PERSPECTIVESChien Jason L. Baez Valentina Mody Harshad R. Department of Medicine, Medstar Harbor Hospital, Baltimore, MD, USACONTACT Jason L. Chien chienjl831@gmail.comDepartment of Medicine, Medstar Harbor Hospital, 3001 S Hanover St, Baltimore, MD 212252019 5 9 2019 9 4 371 372 23 5 2019 05 7 2019 © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Greater Baltimore Medical Center.2019The Author(s)This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 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.ABSTRACT\nGabapentin is an anticonvulsant medication that reduces synaptic transmission by decreasing presynaptic voltage-gated Ca2+ and Na+ channels. It is approved to treat focal seizures but also used to treat post-herpetic and neuropathic pain. Although uncommon, there have been three reported cases of myasthenia gravis exacerbation associated with gabapentin in the literature. We present a patient with uncontrolled recurrent myasthenia gravis exacerbations secondary to chronic gabapentin use and provide a review for the three published cases.\n\nKEYWORDS\nGabapentinmyasthenia gravis\n==== Body\n1. To the editor\nGabapentin is an anticonvulsant medication that reduces synaptic transmission by decreasing presynaptic voltage-gated Ca2+ and Na+ channels. It is approved to treat focal seizures but also used to treat post-herpetic and neuropathic pain[1]. Although uncommon, there have been three reported cases of MG exacerbation associated with gabapentin in the literature [2–4]. We present a patient with uncontrolled recurrent MG exacerbations secondary to chronic gabapentin use.\n\n2. Case report\nA 77-year-old man with medical history of MG diagnosed 1 year ago with multiple MG exacerbations for the past year returned for neck weakness, dysphagia, intermittent diplopia, and arm weakness consistent with his usual symptoms of MG exacerbations. He has had frequent MG exacerbations while treated with pyridostigmine, with the most recent exacerbation earlier the same month, another episode 2 months prior, and multiple exacerbations almost monthly during the past year. Prior hospitalizations for his MG exacerbations resolved with combinations of intravenous methylprednisolone, plasmapheresis, and intravenous immunoglobulin.\n\nOn admission, he was found to have decreased strength in all extremities, diplopia, and dysphagia. ACHr binding antibody was elevated to 3.9 nmol/L (positive>0.5 nmol/L). Computed tomography of the chest was negative for thymoma. During the hospital course, he developed worsened respiratory distress consistent with MG crisis requiring intubation. He was treated with intravenous methylprednisolone, mycophenolic acid, an increased dose of pyridostigmine, and five rounds of plasmapheresis, which resolved his acute MG crisis. A review of home medications revealed patient had been taking gabapentin for the past year for neuropathic pain. He did not have risk factors known to trigger MG crisis such as infection, stress, or recent surgery. The recurrent MG exacerbations were speculated to be secondary to his gabapentin use. His gabapentin was discontinued given reports [2–4] of MG exacerbations associated with gabapentin. At discharge, no dose changes to his original home medication pyridostigmine were made. Symptoms of MG exacerbations were monitored. At the six months follow-up, no further exacerbations were reported.\n\n3. Discussion\nWe report a case of recurrent MG exacerbation in a patient with chronic gabapentin use. The patient’s uncontrolled recurrent MG exacerbations while taking gabapentin coupled with the resolution of MG exacerbations after discontinuing gabapentin led us to believe that gabapentin contributed to this patient’s uncontrolled MG exacerbations. Other medications with the potential to exacerbate weakness include certain local anesthetics, beta-blockers, calcium channel blockers, antiepileptics (phenytoin and gabapentin), phenothiazines, diuretics, procainamide, magnesium, and opioids. In normal patients, these effects are usually of no consequence, but in patients with MG, they may exacerbate muscle weakness presenting as respiratory or bulbar weakness. This can be especially deleterious in the presence of residual anesthetic agents[5].\n\nTo our knowledge, this case represents the 4th case in the literature reporting gabapentin’s deleterious effects on MG. In 2000, gabapentin unmasking of MG was first reported in a patient without previous neuromuscular symptoms (Table 1)[2]. The same findings were reproduced in a rat model suffering from experimental autoimmune MG[2]. Subsequently, a report described a patient with antibody-positive MG complicated by herpetic neuralgia treated with gabapentin with worsened weakness that resolved with discontinuing gabapentin (Table)[3]. Recently, Sheen et al. reported a patient who was diagnosed with MG after treated with gabapentin for dysarthria, dysphagia, paresthesia, and muscle weakness in arms and legs (Table)[4]. In summary, while gabapentin exacerbation of MG is exceedingly rare, providers should consider it as a possible side effect of gabapentin.10.1080/20009666.2019.1643220-T0001Table 1. Cases of myasthenia gravis exacerbation associated with gabapentin.\n\nCase Number; Authors; Published year\tAge\tGender\tIndication for Gabapentin\tOnset of MG exacerbation after starting Gabapentin\tClinical Symptoms\tTreatment\t\n1; Boneva et al; 2000\t67\tFemale\tSevere calf cramps\t2 month\tSlurring of speech, dry mouth, ptosis, chewing and fatigue in speech\tDiscontinuing gabapentin and received pyridostigmine\t\n2; Scheschonka et al; 2002\t64\tFemale\tPost-herpetic neuralgia\t1 week\tIncreased weakness\tDiscontinuing gabapentin\t\n3; Sheen et al;2010\t65\tMale\tNumbness in hands and thighs\t1 week\tDysphagia and vomiting, trouble talking, impaired tongue movement, chest tightness on swallowing\tDiscontinuing gabapentin and received pyridostigmine and methylprednisolone\t\n4; Chien et al; 2019\t77\tMale\tNeuropathic pain\tUnknown as patient had recurrent MG exacerbation for 1 year while on gabapentin\tNeck weakness, dysphagia, intermittent diplopia, arm weakness, difficulty breathing\tDiscontinuing gabapentin and received\nintravenous methylprednisolone, mycophenolic acid, increased dose of pyridostigmine, and 5 rounds of plasmapheresis\t\nMG: Myasthenia Gravis.\n\n\n\n\nAuthorship\nAll authors had full access to data during design and drafting of this manuscript. All authors were responsible for conception and design. JLC drafted the manuscript, VB revised the article, and HRM gave final approval of the manuscript.\n\nDisclosure statement\nNo potential conflict of interest was reported by the authors.\n==== Refs\nReferences\n[1] Nicholson B. \nGabapentin use in neuropathic pain syndromes . Acta Neurol Scand . 2000 ;101 :359 –371 .10877151 \n[2] Boneva N , Brenner T , Argov Z \nGabapentin may be hazardous in myasthenia gravis . Muscle Nerve . 2000 ;23 :1204 –1208 .10918256 \n[3] Scheschonka A , Beuche W \nTreatment of post-herpetic pain in myasthenia gravis: exacerbation of weakness due to gabapentin . Pain . 2003 ;104 :423 –424 .12855353 \n[4] Sheen VL , Ohaegbulam C , Rencus T , et al \nGabapentin-induced exacerbation of myasthenia gravis . Muscle Nerve . 2010 ;42 :149 .20583123 \n[5] Gritti P , Sgarzi M , Carrara B , et al \nA standardized protocol for the perioperative management of myasthenia gravis patients. Experience with 110 patients . Acta Anaesthesiol Scand . 2012 ;56 :66 .22092037\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2000-9666",
"issue": "9(4)",
"journal": "Journal of community hospital internal medicine perspectives",
"keywords": "Gabapentin; myasthenia gravis",
"medline_ta": "J Community Hosp Intern Med Perspect",
"mesh_terms": null,
"nlm_unique_id": "101601396",
"other_id": null,
"pages": "371-372",
"pmc": null,
"pmid": "31528296",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10877151;10918256;12855353;20583123;22092037",
"title": "Uncontrolled recurrent myasthenia gravis exacerbations secondary to chronic gabapentin use.",
"title_normalized": "uncontrolled recurrent myasthenia gravis exacerbations secondary to chronic gabapentin use"
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{
"companynumb": "US-ASSERTIO THERAPEUTICS, INC.-US-2019DEP001068",
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"abstract": "Monoclonal antibodies (mABs) against calcitonin gene-related peptide (CGRP) or its receptor have emerged as effective and well-tolerated preventive medications for migraine. The key role played by CGRP has been recently demonstrated also in the pathophysiology of cluster headache (CH), paving the way for studies aimed to investigate the effectiveness of mABs targeting CGRP also in CH. However, no trials have been conducted so far to test the efficacy and tolerability of erenumab as CH preventive treatment.\n\n\n\nWe describe the cases of 5 patients with both migraines and CH with previous failures of preventive treatments. All patients were treated with monthly erenumab (70 or 140 mg) showing good results not only on migraine but also on CH attacks frequency and intensity. Improvements of both intensity and frequency of CH attacks occurred only after at least 3 months of treatment, with monthly erenumab 140 mg, suggesting that longer treatment and higher doses are needed in CH in comparison to migraine.\n\n\n\nOur findings support the efficacy and tolerability of monthly erenumab 140 mg as a preventive treatment in patients suffering from both migraines without aura and CH. We speculate that erenumab could represent a low-risk alternative for CH patients (with or without comorbid migraine) who did not tolerate common CH preventatives therapies or for whom the therapies were not successful. Certainly, randomized trials are needed to confirm these observations and we hope that our data, showing a delayed therapeutic effect only with the highest dose of erenumab (140 mg/month), can be taken into account in designing future trials.",
"affiliations": "Headache Center, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Headache Center, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Headache Center, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Headache Center, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Headache Center, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania \"Luigi Vanvitelli\", Naples, Italy.",
"authors": "Silvestro|Marcello|M|;Tessitore|Alessandro|A|;Scotto di Clemente|Fabrizio|F|;Tedeschi|Gioacchino|G|;Russo|Antonio|A|0000-0002-0601-0475",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; C000605816:erenumab",
"country": "United States",
"delete": false,
"doi": "10.1111/head.13832",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-8748",
"issue": "60(6)",
"journal": "Headache",
"keywords": "calcitonin gene-related peptide; cluster headache; erenumab; migraine; real-world",
"medline_ta": "Headache",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D003027:Cluster Headache; D015897:Comorbidity; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders; D020326:Migraine without Aura; D016896:Treatment Outcome",
"nlm_unique_id": "2985091R",
"other_id": null,
"pages": "1187-1195",
"pmc": null,
"pmid": "32359106",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Erenumab Efficacy on Comorbid Cluster Headache in Patients With Migraine: A Real-World Case Series.",
"title_normalized": "erenumab efficacy on comorbid cluster headache in patients with migraine a real world case series"
} | [
{
"companynumb": "IT-JNJFOC-20200631280",
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"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
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"abstract": "Cryptococcus neoformans and Cryptococcus gattii are environmental fungi that can cause fever, cough, pneumonia, meningoencephalitis, dissemination, and death. C. gattii causes cryptococcomas more frequently than does C. neoformans and may require prolonged antifungal treatment. We present a rare case of C. gattii pneumonia in a renal transplant patient. A 44-year-old man, living in a rural area endemic for C. gattii and who had received a kidney transplant, was admitted to the hospital with fever, vomiting, weight loss, and diarrhea. A chest computed tomography revealed 2 alveolar, nodular, subpleural infiltrates in the periphery of the lungs. Differential diagnoses included infectious infiltrates, granulomatosis, embolization, and hemorrhage. C. gattii, molecular type VGI, was confirmed on day 28. Treatment consisted of amphotericin B at 1 mg/kg/day or fluconazole at 800 mg/day for first 6 weeks, followed by fluconazole at 400 mg/day for the subsequent 12 months. Response to the therapy has been slow. Because of the occurrence of outbreaks and its high morbidity and mortality rates, physicians must be aware of this complication in transplant recipients to avoid delays in diagnosis and to provide prompt management.",
"affiliations": "Renal Transplantation, Hospital de Alta Complejidad Pte JD Perón, Formosa, Argentina.;Renal Transplantation, Hospital de Alta Complejidad Pte JD Perón, Formosa, Argentina.;Renal Transplantation, Hospital de Alta Complejidad Pte JD Perón, Formosa, Argentina.;Foundation for Research and Assistance in Kidney Disease - FINAER, Buenos Aires, Argentina.",
"authors": "Cicora|F|F|;Petroni|J|J|;Formosa|P|P|;Roberti|J|J|",
"chemical_list": "D000935:Antifungal Agents; D015725:Fluconazole",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12371",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "17(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Cryptococcus gattii; cryptococcosis; kidney transplantation; mycosis; pneumonia",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D003453:Cryptococcosis; D056285:Cryptococcus gattii; D015725:Fluconazole; D006801:Humans; D016030:Kidney Transplantation; D008168:Lung; D008297:Male; D011014:Pneumonia",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "463-6",
"pmc": null,
"pmid": "25689604",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A rare case of Cryptococcus gattii pneumonia in a renal transplant patient.",
"title_normalized": "a rare case of cryptococcus gattii pneumonia in a renal transplant patient"
} | [
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"companynumb": "PHHY2015AR081384",
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"occurcountry": "AR",
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"activesubstancename": "TACROLIMUS"
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"abstract": "OBJECTIVE\nTo summarize the characteristics of and therapeutic options for cancer patients whose treatments may be vasotoxic and cause intracranial arterial stenotic disease and stroke.\n\n\nMETHODS\nWe describe 3 patients with symptomatic cerebrovascular pathology that were being actively treated for cancer.\n\n\nRESULTS\nTwo of the patients were being treated with tyrosine kinase inhibitors (TKIs); and the third was being treated with 2 monoclonal antibodies, one of which was targeting an endothelial growth factor. These agents have been associated with vascular adverse events. Surgical revascularization was done in the first 2 patients, as they were suffering from cerebral ischemia. The third patient had suffered a significant brain hemorrhage, and therapeutic options were limited. In the first 2 patients, treatments also included antiplatelet agents and stopping/changing the TKI. In one of these patients we demonstrated regression of arterial stenosis after changing the TKI.\n\n\nCONCLUSIONS\nPossibilities for treatment in this population, beyond the usual medical and surgical administrations, may include stopping or changing cancer drugs that may be related to the development of arterial pathology. Collaboration with oncologists is essential in this subset of patients. While aware of the potential for vascular toxicity, oncologists are often not fully appreciative of the fact that their therapeutic agents can cause stroke.",
"affiliations": "Departments of Neurosurgery and Radiology, Huntington Memorial Hospital, Pasadena, CA. Electronic address: ianrossmd@gmail.com.;Departments of Neurosurgery and Radiology, Huntington Memorial Hospital, Pasadena, CA. Electronic address: angeloskonstas@yahoo.com.",
"authors": "Ross|Ian B|IB|;Konstas|Angelos A|AA|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D010975:Platelet Aggregation Inhibitors; D047428:Protein Kinase Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2019.04.005",
"fulltext": null,
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"issn_linking": "1052-3057",
"issue": "28(7)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Stroke; cancer; immunotherapy; moyamoya; targeted therapy",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D001157:Arterial Occlusive Diseases; D002533:Cerebral Angiography; D002539:Cerebral Arterial Diseases; D002536:Cerebral Arteries; D002548:Cerebral Revascularization; D002560:Cerebrovascular Circulation; D000072226:Computed Tomography Angiography; D000072700:Conservative Treatment; D003251:Constriction, Pathologic; D057915:Drug Substitution; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055420:Perfusion Imaging; D010975:Platelet Aggregation Inhibitors; D047428:Protein Kinase Inhibitors; D016896:Treatment Outcome; D014654:Vascular Patency",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "1886-1890",
"pmc": null,
"pmid": "31078387",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of Intracranial Stenotic Disease in Cancer Patients Treated With Vasotoxic Agents.",
"title_normalized": "management of intracranial stenotic disease in cancer patients treated with vasotoxic agents"
} | [
{
"companynumb": "US-PFIZER INC-2019272735",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "1",
... |
{
"abstract": "In patients with primary sclerosing cholangitis (PSC), ursodeoxycholic acid (UDCA) treatment improves serum liver tests and surrogate markers of prognosis but has no proven effect on survival. Additional therapies are obviously needed. Fibrates, PPAR agonists with anti-cholestatic properties, have a beneficial effect in primary biliary cholangitis. The aim of this study was to evaluate the safety and efficacy of fibrates in PSC patients.\n\n\n\nRetrospectively, we investigated PSC patients treated with fibrates (fenofibrate 200mg/day or bezafibrate 400mg/day) for at least 6 months in addition to UDCA, after an incomplete biochemical response (alkaline phosphatase [ALP] ≥1.5×upper limit of normal) to UDCA. Changes in biochemical parameters and clinical features were assessed.\n\n\n\nTwenty patients were included (fourteen from Paris and six from Barcelona): median age 43.8 years, median liver stiffness 11kPa (≥F3). Upon treatment with fibrates (median duration of 1.56 years), liver tests significantly improved, including a reduction of ALP levels by 41% and pruritus significantly decreased. No serious adverse event attributable to fibrates occurred. Discontinuation of fibrates was followed by a clear rebound of ALP. Despite biochemical improvement, liver stiffness significantly increased.\n\n\n\nCombining UDCA with fibrates results in a significant biochemical improvement and pruritus decrease in PSC patients with incomplete response to UDCA. These results provide a rationale for larger and prospectively designed studies to establish the efficacy and safety of fibrates in PSC.",
"affiliations": "Hepatology department, reference center for inflammatory biliary diseases and autoimmune hepatitis, Saint-Antoine Hospital, Assistance publique-Hôpitaux de Paris, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France; INSERM, Sorbonne université, centre de recherche Saint-Antoine (CRSA), faculté de médecine, site Saint-Antoine, 27, rue de Chaligny, 75012 Paris, France. Electronic address: sara_lemoinne@yahoo.fr.;IDIBAPS, CIBERehd, Liver Unit, Hospital Clínic, Univesity of Barcelona, Carrer de Villarroel, 170, 08036 Barcelona, Spain. Electronic address: apares@clinic.cat.;IDIBAPS, CIBERehd, Liver Unit, Hospital Clínic, Univesity of Barcelona, Carrer de Villarroel, 170, 08036 Barcelona, Spain. Electronic address: anna.rg86@gmail.com.;Hepatology department, reference center for inflammatory biliary diseases and autoimmune hepatitis, Saint-Antoine Hospital, Assistance publique-Hôpitaux de Paris, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France; INSERM, Sorbonne université, centre de recherche Saint-Antoine (CRSA), faculté de médecine, site Saint-Antoine, 27, rue de Chaligny, 75012 Paris, France. Electronic address: karima.benbelkacem@aphp.fr.;Hepatology department, reference center for inflammatory biliary diseases and autoimmune hepatitis, Saint-Antoine Hospital, Assistance publique-Hôpitaux de Paris, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France; INSERM, Sorbonne université, centre de recherche Saint-Antoine (CRSA), faculté de médecine, site Saint-Antoine, 27, rue de Chaligny, 75012 Paris, France. Electronic address: kastriddonald@yahoo.fr.;Hepatology department, reference center for inflammatory biliary diseases and autoimmune hepatitis, Saint-Antoine Hospital, Assistance publique-Hôpitaux de Paris, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France. Electronic address: farid.gaouar@aphp.fr.;Hepatology department, reference center for inflammatory biliary diseases and autoimmune hepatitis, Saint-Antoine Hospital, Assistance publique-Hôpitaux de Paris, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France. Electronic address: Raoul.poupon@orange.fr.;Hepatology department, reference center for inflammatory biliary diseases and autoimmune hepatitis, Saint-Antoine Hospital, Assistance publique-Hôpitaux de Paris, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France; INSERM, Sorbonne université, centre de recherche Saint-Antoine (CRSA), faculté de médecine, site Saint-Antoine, 27, rue de Chaligny, 75012 Paris, France. Electronic address: Chantal.housset@inserm.fr.;Hepatology department, reference center for inflammatory biliary diseases and autoimmune hepatitis, Saint-Antoine Hospital, Assistance publique-Hôpitaux de Paris, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France; INSERM, Sorbonne université, centre de recherche Saint-Antoine (CRSA), faculté de médecine, site Saint-Antoine, 27, rue de Chaligny, 75012 Paris, France. Electronic address: Christophe.corpechot@aphp.fr.;Hepatology department, reference center for inflammatory biliary diseases and autoimmune hepatitis, Saint-Antoine Hospital, Assistance publique-Hôpitaux de Paris, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France; INSERM, Sorbonne université, centre de recherche Saint-Antoine (CRSA), faculté de médecine, site Saint-Antoine, 27, rue de Chaligny, 75012 Paris, France. Electronic address: Olivier.chazouilleres@aphp.fr.",
"authors": "Lemoinne|Sara|S|;Pares|Albert|A|;Reig|Anna|A|;Ben Belkacem|Karima|K|;Kemgang Fankem|Astrid Donald|AD|;Gaouar|Farid|F|;Poupon|Raoul|R|;Housset|Chantal|C|;Corpechot|Christophe|C|;Chazouillères|Olivier|O|",
"chemical_list": "D002756:Cholagogues and Choleretics; D000960:Hypolipidemic Agents; D014580:Ursodeoxycholic Acid; D000469:Alkaline Phosphatase; D011345:Fenofibrate; D001629:Bezafibrate",
"country": "France",
"delete": false,
"doi": "10.1016/j.clinre.2018.06.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2210-7401",
"issue": "42(6)",
"journal": "Clinics and research in hepatology and gastroenterology",
"keywords": "Cholestasis; Chronic liver diseases; Cirrhosis; Liver fibrosis",
"medline_ta": "Clin Res Hepatol Gastroenterol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase; D001629:Bezafibrate; D002756:Cholagogues and Choleretics; D015209:Cholangitis, Sclerosing; D004359:Drug Therapy, Combination; D005260:Female; D011345:Fenofibrate; D005602:France; D006801:Humans; D000960:Hypolipidemic Agents; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D011537:Pruritus; D012189:Retrospective Studies; D013030:Spain; D014580:Ursodeoxycholic Acid; D055815:Young Adult",
"nlm_unique_id": "101553659",
"other_id": null,
"pages": "521-528",
"pmc": null,
"pmid": "30100231",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Primary sclerosing cholangitis response to the combination of fibrates with ursodeoxycholic acid: French-Spanish experience.",
"title_normalized": "primary sclerosing cholangitis response to the combination of fibrates with ursodeoxycholic acid french spanish experience"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1021452",
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"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "URSODIOL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAdverse drug reactions (ADRs) are responsible for 5 % of hospital admissions, but hospital re-admission induced by ADRs remains poorly documented.\n\n\nOBJECTIVE\nThe aim of this study was to estimate the rate of hospital re-admission and the factors associated with re-admission in the patients over the age of 65 years. Secondary, we described the characteristics of cases of ADRs leading to re-admission for drugs other than chemotherapy agents.\n\n\nMETHODS\nData were extracted from hospital discharge summaries provided by the Department of Medical Information of Toulouse University Hospital. All patients over the age of 65 years admitted to the hospital in 2010 for an ADR, identified from ICD-10 codes, were selected. All subsequent admissions of members of this cohort within 1 year of discharge following the index admission were reviewed retrospectively. The risk factors associated with hospital re-admission for ADRs were analyzed. Medical records were used for descriptive analysis of re-admission due to drugs other than chemotherapy agents.\n\n\nRESULTS\nWe found that 553 of the 1000 patients admitted for ADRs in 2010 were re-admitted to hospital within 1 year. Among them, 87 cases were re-admitted for ADRs (estimated rate of 87/1000 re-admission for an ADR within 1 year). A comparison of the patients re-admitted for ADRs (n = 87) with those of patients re-admitted for other causes (n = 410) suggested that only cancer increased the risk of re-admission for ADRs (OR = 7.69 [4.59-12.88] 95 % CI). ADRs due to the same drug combination were the suspected cause of repeat admission in half the cases (other than chemotherapy). Hospital re-admission was considered avoidable in four cases (22 %).\n\n\nCONCLUSIONS\nThis study shows an estimated rate of re-admission for an ADR around 87/1000 within 1 year, and the same drug combination were the suspected cause of repeat admission in half the cases. At least, 11 % of cases were avoidable.",
"affiliations": "Service de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d'Informations sur le Médicament, Faculté de Médecine de l'Université Paul Sabatier-, INSERM U1027, 37 Allées Jules Guesde, 31000, Toulouse, France.;Service de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d'Informations sur le Médicament, Faculté de Médecine de l'Université Paul Sabatier-, INSERM U1027, 37 Allées Jules Guesde, 31000, Toulouse, France.;Département d'Informations Médicales, CHU Toulouse, Hôtel Dieu St Jacques, 2 Rue Viguerie, 31300, Toulouse, France.;Service de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d'Informations sur le Médicament, Faculté de Médecine de l'Université Paul Sabatier-, INSERM U1027, 37 Allées Jules Guesde, 31000, Toulouse, France.;Département d'Informations Médicales, CHU Toulouse, Hôtel Dieu St Jacques, 2 Rue Viguerie, 31300, Toulouse, France.;Service de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d'Informations sur le Médicament, Faculté de Médecine de l'Université Paul Sabatier-, INSERM U1027, 37 Allées Jules Guesde, 31000, Toulouse, France.;Service de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d'Informations sur le Médicament, Faculté de Médecine de l'Université Paul Sabatier-, INSERM U1027, 37 Allées Jules Guesde, 31000, Toulouse, France. haleh.bagheri@univ-tlse3.fr.",
"authors": "Hauviller|Laurent|L|;Eyvrard|Frédéric|F|;Garnault|Valérie|V|;Rousseau|Vanessa|V|;Molinier|L|L|;Montastruc|Jean Louis|JL|;Bagheri|Haleh|H|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-016-2022-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-6970",
"issue": "72(5)",
"journal": "European journal of clinical pharmacology",
"keywords": "Adverse drug reactions; Avoidability; Hospital re-admission; Pharmacovigilance",
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005602:France; D006785:Hospitals, University; D006801:Humans; D008297:Male; D010359:Patient Readmission; D012189:Retrospective Studies",
"nlm_unique_id": "1256165",
"other_id": null,
"pages": "631-9",
"pmc": null,
"pmid": "26884320",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": "18594048;17047216;24557010;15929472;15617955;18302300;24990220;16842398;16184621;12473007;22739715;25822400;24634164;26223243;25604839;19129307;10764362;15231615;21039769;23252914;4002188;20945504;21454043;11072960;19419237;10860015",
"title": "Hospital re-admission associated with adverse drug reactions in patients over the age of 65 years.",
"title_normalized": "hospital re admission associated with adverse drug reactions in patients over the age of 65 years"
} | [
{
"companynumb": "FR-BAUSCH-BL-2017-032796",
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"activesubstancename": "BROMAZEPAM"
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... |
{
"abstract": "Medications can cause a tubulointerstitial insult leading to acute kidney injury through multiple mechanisms. Acute tubular injury, a dose-dependent process, occurs due to direct toxicity on tubular cells. Acute interstitial nephritis characterized by interstitial inflammation and tubulitis develops from drugs that incite an allergic reaction. Other less common mechanisms include osmotic nephrosis and crystalline nephropathy. The latter complication is rare but has been associated with several drugs, such as sulfadiazine, indinavir, methotrexate, and ciprofloxacin. Triamterene crystalline nephropathy has been reported only rarely, and its histologic characteristics are not well characterized. We report 2 cases of triamterene crystalline nephropathy, one of which initially was misdiagnosed as 2,8-dihydroxyadenine crystalline nephropathy.",
"affiliations": "Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. Electronic address: nasr.samih@mayo.edu.;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.;Oxford Nephrology and Hypertension Associates and North Mississippi Medical Center, Tupelo, MS.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.",
"authors": "Nasr|Samih H|SH|;Milliner|Dawn S|DS|;Wooldridge|Thomas D|TD|;Sethi|Sanjeev|S|",
"chemical_list": "D000959:Antihypertensive Agents; D004338:Drug Combinations; D006852:Hydrochlorothiazide; C020743:hydrochlorothiazide-triamterene; D003404:Creatinine; D014223:Triamterene",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "63(1)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Triamterene; acute kidney injury; crystalline nephropathy; drug nephrotoxicity; kidney biopsy",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D000959:Antihypertensive Agents; D001706:Biopsy; D003404:Creatinine; D003951:Diagnostic Errors; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005455:Fluorescent Antibody Technique; D005919:Glomerular Filtration Rate; D006801:Humans; D006852:Hydrochlorothiazide; D007668:Kidney; D056929:Liddle Syndrome; D008575:Meniere Disease; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic; D016896:Treatment Outcome; D014223:Triamterene; D028761:Withholding Treatment",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "148-52",
"pmc": null,
"pmid": "23958399",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Triamterene crystalline nephropathy.",
"title_normalized": "triamterene crystalline nephropathy"
} | [
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"companynumb": "US-GLAXOSMITHKLINE-US2015GSK004287",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE\\TRIAMTERENE"
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... |
{
"abstract": "Over the course of 4 months in 2015 and 2016, a cluster of seven fatal intoxications involving the opioid-analogue furanylfentanyl occurred in Sweden; toxicological analysis showed presence of furanylfentanyl either as the only drug or in combination with other illicit substances. Previous publications have only reported non-lethal furanylfentanyl intoxications. In the cases presented here, furanylfentanyl intoxication-alone or in combination with other drugs-was determined to be the cause of death by the responsible pathologist. All victims were young (24-37 years old) males, five of which had a well-documented history of drug abuse. Femoral blood concentration of furanylfentanyl ranged from 0.41 ng/g to 2.47 ng/g blood. Five cases presented a complex panel of drugs of abuse and prescription drugs. Moreover, in five cases the concurrent presence of pregabalin corroborates previous observations indicating pregabalin as a possible contributing factor in polydrug intoxications. We conclude that it is difficult to establish a specific lethal concentration of furanylfentanyl, due to incompletely known effects of possible pharmacokinetic and pharmacodynamic interactions with other drugs, as well as to the unknown degree of tolerance to opioids. We suggest that a full toxicological screening-to assess the possibility of drug interactions-together with segmental hair analysis regarding opioids-to estimate the level of opioid tolerance-be carried out to assist in the interpretation of cases involving synthetic opioids such as furanylfentanyl.",
"affiliations": "Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, 58758Linköping, Sweden.;Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, 58758Linköping, Sweden.;Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, 58758Linköping, Sweden.;Department of Oncology-Pathology, Karolinska Institutet, 17177 Stockholm, Sweden.;Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, 58758 Linköping, Sweden.",
"authors": "Guerrieri|Davide|D|;Rapp|Emma|E|;Roman|Markus|M|;Druid|Henrik|H|;Kronstrand|Robert|R|",
"chemical_list": "D005663:Furans; D013287:Illicit Drugs; C000620436:furanyl fentanyl; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkw129",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "41(3)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000328:Adult; D002853:Chromatography, Liquid; D005283:Fentanyl; D049429:Forensic Pathology; D053593:Forensic Toxicology; D005663:Furans; D006801:Humans; D013287:Illicit Drugs; D057230:Limit of Detection; D008297:Male; D013058:Mass Spectrometry; D015203:Reproducibility of Results; D019966:Substance-Related Disorders; D055815:Young Adult",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "242-249",
"pmc": null,
"pmid": "28096302",
"pubdate": "2017-04-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Postmortem and Toxicological Findings in a Series of Furanylfentanyl-Related Deaths.",
"title_normalized": "postmortem and toxicological findings in a series of furanylfentanyl related deaths"
} | [
{
"companynumb": "SE-JNJFOC-20170518693",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nChemoradiotherapy plays an important role in preserving function and morphology in head and neck cancer. However, in a few cases, chemoradiotherapy has been shown to result in late complications, such as hypopharyngeal perforation, which is very rare.\n\n\nMETHODS\nA 65-year-old man, who had undergone chemoradiotherapy for hypopharyngeal cancer 30 months previously, presented with high fever and neck pain. He subsequently developed hypopharyngeal stenosis, hypopharyngeal perforation, and a retropharyngeal abscess followed by pyogenic spondylitis. He underwent surgical treatment (resection with reconstruction) and was administered an antibacterial agent and steroids for an extended period. This treatment regimen was successful, and the patient has survived disease-free without symptoms.\n\n\nCONCLUSIONS\nChemoradiotherapy-induced hypopharyngeal perforation is an extremely rare condition. In the present case, the perforation was large (2cm), and the hypopharyngeal cavity was originally constricted. Pharyngeal reconstruction with a jejunal autograft was therefore necessary. Through the present case, we reconfirmed that although the primary purpose of chemoradiotherapy is organ preservation, it can also lead to organ destruction and fatal complications. It is important that physicians be aware of the possibility of hypopharyngeal perforation so as to avoid delayed diagnosis and treatment of similar rare cases.\n\n\nCONCLUSIONS\nHypopharyngeal perforation can sometimes be fatal because it can lead to pyogenic spondylitis. Suitable surgical techniques and appropriate doses of antibacterial agents for long-term use were appropriate treatments for the patient in this case.",
"affiliations": "Department of Head and Neck Surgery, Japan Community Health Care Organization Kyushu Hospital, Kitakyushu City, Japan. Electronic address: miolovemio@hotmail.co.jp.;Department of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka City, Japan. Electronic address: fumiriki@nk-cc.go.jp.;Department of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka City, Japan. Electronic address: yhigaki@nk-cc.go.jp.;Department of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka City, Japan. Electronic address: masuda.m@nk-cc.go.jp.",
"authors": "Matsuo|Mioko|M|;Rikimaru|Fumihide|F|;Higaki|Yuichiro|Y|;Masuda|Muneyuki|M|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(16)00031-610.1016/j.ijscr.2016.01.020Case ReportA case of hypopharyngeal cancer with stenosis, perforation, and pyogenic spondylitis development after chemoradiotherapy Matsuo Mioko miolovemio@hotmail.co.jpa⁎Rikimaru Fumihide fumiriki@nk-cc.go.jpbHigaki Yuichiro yhigaki@nk-cc.go.jpbMasuda Muneyuki masuda.m@nk-cc.go.jpba Department of Head and Neck Surgery, Japan Community Health Care Organization Kyushu Hospital, Kitakyushu City, Japanb Department of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka City, Japan⁎ Corresponding author at: Division of Head and Neck Surgery, Japan Community Health Care Organization Kyushu Hospital, 1-8-1 Kishinoura, Yahatanishi-ku,Kitakyushu City, Fukuoka 806-8501, Japan. Fax: + 81 93 642 1868. miolovemio@hotmail.co.jp22 1 2016 2016 22 1 2016 20 104 108 24 8 2015 12 1 2016 16 1 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Our patient had hypopharyngeal perforation and pyogenic spondylitis post-CRT.\n\n• Our patient survived after receiving surgical and long-term antibiotic treatment.\n\n• No previous report has described a similar case.\n\n\n\nIntroduction\nChemoradiotherapy plays an important role in preserving function and morphology in head and neck cancer. However, in a few cases, chemoradiotherapy has been shown to result in late complications, such as hypopharyngeal perforation, which is very rare.\n\nPresentation of case\nA 65-year-old man, who had undergone chemoradiotherapy for hypopharyngeal cancer 30 months previously, presented with high fever and neck pain. He subsequently developed hypopharyngeal stenosis, hypopharyngeal perforation, and a retropharyngeal abscess followed by pyogenic spondylitis. He underwent surgical treatment (resection with reconstruction) and was administered an antibacterial agent and steroids for an extended period. This treatment regimen was successful, and the patient has survived disease-free without symptoms.\n\nDiscussion\nChemoradiotherapy-induced hypopharyngeal perforation is an extremely rare condition. In the present case, the perforation was large (2 cm), and the hypopharyngeal cavity was originally constricted. Pharyngeal reconstruction with a jejunal autograft was therefore necessary. Through the present case, we reconfirmed that although the primary purpose of chemoradiotherapy is organ preservation, it can also lead to organ destruction and fatal complications. It is important that physicians be aware of the possibility of hypopharyngeal perforation so as to avoid delayed diagnosis and treatment of similar rare cases.\n\nConclusion\nHypopharyngeal perforation can sometimes be fatal because it can lead to pyogenic spondylitis. Suitable surgical techniques and appropriate doses of antibacterial agents for long-term use were appropriate treatments for the patient in this case.\n\nAbbreviations\nCRT, chemoradiotherapyPEG, percutaneous endoscopic gastrostomyMRI, magnetic resonance imagingKeywords\nChemoradiotherapyHypopharyngeal cancerPyogenic spondylitis\n==== Body\n1 Introduction\nChemoradiotherapy (CRT), an established treatment for head and neck cancers, helps preserve head and neck function and morphology. However, CRT can cause various adverse effects. Hypopharyngeal perforation, although rare, is one such example. Here, we report an extremely rare case of hypopharyngeal perforation after CRT along with a review of the literature.\n\n2 Presentation of case\nThe work has been reported in line with the CARE criteria [1].\n\nA 65-year-old man presented at our hospital in July 2014 with aphagia, neck pain, and fever. He had been previously diagnosed with hypopharyngeal cancer (posterior wall, T2N0M0; Fig. 1) in November 2011 at a different hospital, for which he had received CRT (66 Gy, 2 Gy × 33 fractions; cisplatin, 120 mg/body). In May 2014, he was referred to another hospital because of swallowing difficulty, where he was diagnosed with recurrent hypopharyngeal cancer, deemed inoperable. Palliative treatment was selected, and the patient underwent percutaneous endoscopic gastrostomy. Subsequently, he developed neck pain and fever (38 °C) that persisted for >1 month. In July 2014, he was referred to our department.\n\n2.1 physical examination\nSubjective symptoms at admission consisted of 38 °C fever persisting for 1 month, neck pain, inability to retroflex the neck, and hypoesthesia of the fingers. Computed tomography demonstrated low-density areas with air in the retropharyngeal and pre-vertebral spaces of cervical vertebrae [3], [4], [5]. Suspected fistula formation with the hypopharynx was also observed (Fig. 2a, b). Magnetic resonance imaging (MRI) revealed the disappearance of the pre-vertebral muscles in the same site and pyogenic spondylitis (Fig. 2c). On videofluorography, the contrast medium flowed into the retropharyngeal space from an approximately 2-cm perfusion site in the posterior pharyngeal wall and accumulated in the cecum; in addition, the hypopharyngeal cavity was observed to have originally been narrow (Fig. 2d).\n\n2.2 Treatments\nHypopharyngeal stenosis and perforation due to CRT or recurrent cancer was considered to have resulted in a retropharyngeal abscess, which subsequently led to pyogenic spondylitis. The patient received an antibacterial agent (cefepime, 2 g/day) and steroids (prednisolone, tapered from 60 mg), after which he underwent observation with a curved laryngoscope. Expansion of the hypopharynx revealed a large perforation in the posterior hypopharyngeal wall and pervasion of the necrotized pre-vertebral muscles in the base of the perfusion site and the vertebra itself (Fig. 3a). The left half of the pyriform sinus showed adhesions. Histopathological analysis of the tissues from the blind biopsy of the mucosa surrounding the perforation as well as of the necrotic tissue revealed inflammatory granulation.\n\nAt 3 weeks post-admission, the patient was scheduled for total pharyngo-laryngo-esophagectomy, neck dissection, necrotized pre-vertebral muscle debridement, pharyngeal reconstruction with a free jejunal autograft, and coverage of the anterior aspect of the vertebra with a pectoralis major muscle flap. During surgery, the following were observed: advanced adhesion between the hypopharynx and the surrounding tissue; complete pre-vertebral muscle necrosis at the third and fourth cervical vertebrae; and pervasion of infected granulation tissue in the anterior aspect of the vertebrae. When the unhealthy granulation was completely removed, normal vertebrae were observed; therefore, debridement was terminated (Fig. 3b). The range for the disappearance of normal pre-vertebral muscles was narrower; the anterior aspect of the vertebrae was covered with tissue from the thyroid rather than the pectoralis major muscle. The resected specimen demonstrated a large, 25-mm perforation in the posterior pharyngeal wall and stenosis in the original pharyngeal cavity (Fig. 3c). Pathological examination revealed the recurrence of squamous cell carcinoma in a tiny part of the mucosal surface; however, there was no invasion towards the muscle layer. Most tissues were necrotized, and there was only infected granulation tissue in the anterior aspect of the vertebrae. The patient was diagnosed with recurrent hypopharyngeal cancer (rTisN0M0), CRT-induced hypopharyngeal stenosis and perforation, and perforation-induced pyogenic spondylitis. Oral feeding was initiated 1 week post-operation; the percutaneous endoscopic gastrostomy tube was removed in week 3. Administration of an antibacterial agent alone (minocin, 50 mg/day) was continued, while steroids were discontinued.\n\n2.3 Clinical course\nOne month post-surgery, the patient experienced a relapse of the fever (38 °C) and exacerbation of the lightheadedness, neck pain, and finger numbness. MRI demonstrated retropharyngeal abscess re-formation, epidural abscess, and exacerbation of pyogenic spondylitis compared to that observed pre-operation (Fig. 4a). An orthopedic surgeon was consulted, but there was concern about the risk of death owing to sepsis and spinal paralysis; therefore, surgical therapy was deemed dangerous and unsuitable steroid (dexamethasone, 8 mg) and antibacterial agent (cefepime, 2 g/day) administration was resumed, after which his symptoms improved again. Dexamethasone was tapered from 8 mg to 1 mg over the course of 4 months and ceased thereafter. Additionally, 100 mg minocin was continuously administered as an antibacterial agent for 4 months. The retropharyngeal abscess and epidural abscess then disappeared, while spondylitis also demonstrated incremental improvement (Fig. 4b). Nine months following surgery, the patient is disease-free without symptoms.\n\n3 Discussion\nCRT is superior to other head and neck treatment options in terms of preservation of function. However, post-CRT late effects can become serious and may drastically reduce the quality of life. One such late effect is perforation. The frequency of esophageal CRT-induced perforation is reported to be about 1% [2]; thus, it is known as an adverse event that occurs at a fixed probability. We assume that CRT-induced hypopharyngeal perforation is an extremely rare condition owing to the lack of literature. There are few reports of hypopharyngeal perforation due to other causes (Table 1) [3], [4], [5]. Regarding head and neck cancers, perforation caused by dilation for stenosis has been reported [3], [4], [5]. A number of reports have recently emerged regarding perforation as a complication of transoral robotic surgery and endoscopic laryngo-pharyngeal surgery [6], [7]. We presumed the reason for the perforation was CRT-induced tissue fragility. After CRT, tissues become fibrotic and do not expand. In fact, remarkable stenosis of the original cavity caused by fibrosis was recognized in the present case. Moreover, CRT causes narrowing of the vessels, which results in delayed wound healing and increased risk of infection. Thus, we believe that a small wound in the pharynx after CRT led to the massive perforation.\n\nTreatment for hypopharyngeal perforation includes conservative therapy (fasting, gavage, antibiotics, and hyperbaric oxygen therapy) and surgical treatment (simple suturing, resection, and resection with reconstruction). Surgical treatment is considered necessary for patients with perforations >10 mm in size and patients resistant to conservative therapy [3], [5], [6], [7]. Here, the perforation was larger than 2 cm, and the hypopharyngeal cavity was originally constricted; therefore, total pharyngo-laryngo-esophagectomy and pharyngeal reconstruction with a jejunal autograft was necessary. We used thyroid tissue alone to cover the anterior aspect of the vertebrae, and not the pectoralis major muscle tissue, which is typically the preferred approach. One could argue that the subsequent, temporary exacerbation of spondylitis may not have occurred if the major pectoralis muscle tissue had been used; however, based on the patient's tendency toward healing, the thyroid tissue may ultimately have been appropriate coverage material.\n\nPyogenic spondylitis causes symptoms such as fever and pain, sensory abnormality, paralysis, and spine deformation with loss of support [8], [9], [10]. The principles of treatment are to administer appropriate antibiotics and for the patient to rest completely from an early stage [8], [11]. However, spondylitis requires surgical treatment in some cases. The primary surgical treatment for cases of epidural abscess-induced acute paralysis is laminectomy (a palliative operation for achieving decompression and drainage). For patients resistant to conservative therapy and with advanced vertebral body destruction, the primary surgical treatment is anterior decompression and fusion (a radical operation for curettage of the nidus) [8].\n\nSpondylitis resolution requires a long period of time. Even when conservative therapy appears to improve inflammation, discontinuation of antibacterial agents may lead to relapse; thus, long-term administration (of at least several months) of antibacterial agents is recommended [8], [11], [12]. However, no clear guidelines have been established [11]; decisions are made on a case-by-case basis. In a case where osteoradionecrosis of the spine following CRT for hypopharyngeal cancer resulted in pyogenic spondylitis and epidural abscess, Kuba et al. reported that antibacterial agents were administered for 10 months post-laminectomy [13].\n\nIn the present case, although spondylitis-induced symptoms tended to improve following surgery, the spondylitis was exacerbated, with an epidural abscess developing at 1 month post-surgery. We believe this was a result of insufficient dose of the antibacterial agent. The findings of this case indicate that the treatment for spondylitis requires a sufficient dose of antibacterial agents that is administered over a long term (more than approximately 4 months), as well as an surgical treatment (decompression and drainage, or curettage of the nidus).\n\n4 Conclusion\nWe report the case of a large perforation of the hypopharynx following CRT and pyogenic spondylitis. Despite an extensive review, we found no previous reports of similar cases, leading us to believe that the present case is extremely rare.\n\nConflicts of interest\nNone.\n\nFunding\nNone.\n\nEthical approval\nInformed consent was obtained from the patient. Because this is a case report, ethical approval was not required.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review from the Editor-in-Chief of this journal on request.\n\nAuthors’ contribution\nMioko Matsuo is the first author of this report and surgeon for that surgery. She also analyzed the data and wrote the manuscript. Fumihide Rikimaru, Yuichiro Higaki, and Muneyuki Masuda assisted with the operation.\n\nGuarantor\nThe corresponding author Mioko Matsuo is the guarantor of this work.\n\nAcknowledgment\nWe would like to thank Editage (www.editage.jp) for English language editing.\n\nFig. 1 Fiberscopy findings on initial examination for hypopharyngeal cancer at another hospital.\n\nFig. 2 ((a) and (b)) Computed tomography, (c) magnetic resonance imaging, and (d) transillumination findings.\n\nFig. 3 (a) Curved laryngoscope findings, (b) post-resection cervical findings, and (c) resected specimen.\n\nFig. 4 Magnetic resonance image obtained (a) at the time of cervical spondylosis, and (b) upon improvement of the recurrent cervical spondylosis.\n\nTable 1 Prior reports of all-cause hypopharyngeal perforation.\n\nAuthor\tMao et al. [3]\tStojakov et al. [4]\tHinojar et al. [5]\t\nCase\tDilation for stenosis in 8 cases of head and neck cancer\t15 cases of hypopharyngeal perforation\t7 cases of hypopharyngeal perforation\t\nTreatment\tConservative therapy in 6 cases\tConservative therapy in 3 cases\tConservative therapy in 3 cases\t\n\tSurgical treatment in 2 cases\tSurgical treatment in 12 cases\tSurgical treatment in 4 cases\t\nPrognosis\t–\t13.3% mortality\t–\n==== Refs\nReferences\n1 Gagnier J. Kienle G. Altman D.G. Moher D. Sox H. Riley DS, and the CARE group: the CARE guidelines: consensus-based clinical case report guideline development J. Clin. Epidemiol. 67 1 2014 46 51 24035173 \n2 Nemoto K. Takai Y. Ogawa Y. Kakuto Y. Ariga H. Matsushita H. Fatal hemorrhage in irradiated esophageal cancer patients Acta Oncol. 37 1998 259 262 9677097 \n3 Mao J.C. Kayali F.M. Dworkin J.P. Stachler R.J. Mathog R.H. Conservative management of iatrogenic esophageal perforation in head and neck cancer patients with esophageal stricture Otolaryngol. Head Neck Surg 140 2009 505 511 19328338 \n4 Stojakov D. Sabljak P. Bjelović M. Nenadić B. Ebrahimi K. Spica B. Iatrogenic perforations of the esophagus and hypopharynx—5 year experience at the Center for Esophageal Surgery Acta Chir. Iugosl. 51 2004 93 101 15756794 \n5 Hinojar A.G. Díaz Díaz M.A. Pun Y.W. Hinojar A.A. Management of hypopharyngeal and cervical oesophageal perforations Auris Nasus Larynx 30 2003 175 182 12753990 \n6 Longfield E.A. Holsinger F.C. Selber J.C. Reconstruction after robotic head and neck surgery: when and why J. Reconstr. Microsurg. 28 2012 445 450 22399257 \n7 Moore E.J. Olsen K.D. Martin E.J. Concurrent neck dissection and transoral robotic surgery Laryngoscope 121 2011 541 544 21344431 \n8 Skaf G.S. Domloj N.T. Fehlings M.G. Bouclaous C.H. Sabbagh A.S. Kanafani Z.A. Pyogenic spondylodiscitis: an overview J. Infect. Public Health 3 2010 5 16 20701886 \n9 Malik G.M. McCormick P. Management of spine and intervertebral disc space infection Contemp. Neurosurg. 10 1988 1 6 \n10 Sapico F.L. Montgomerie J.Z. Vertebral osteomyelitis Infect. Dis. Clin. North Am. 4 1990 539 550 2212605 \n11 Grados F. Lescure F.X. Senneville E. Flipo R.M. Schmit J.L. Fardellone P. Suggestions for managing pyogenic (non-tuberculous) discitis in adults Joint Bone Spine 74 2007 133 139 17337352 \n12 Mylona E. Samarkos M. Kakalou E. Fanourgiakis P. Skoutelis A. Pyogenic vertebral osteomyelitis; a systematic review of clinical characteristics Semin. Arthritis Rheum. 39 2009 10 17 18550153 \n13 Kuba K. Inoue H. Matsumura S. Minami K. Takajo F. Morita K. A case of pyogenic spondylitis and epidural abscess after chemoradiotherapy for hypopharyngeal cancer Nihon Jibiinkoka Gakkai Kaiho 116 2013 1326 1331 24558949\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2210-2612",
"issue": "20()",
"journal": "International journal of surgery case reports",
"keywords": "Chemoradiotherapy; Hypopharyngeal cancer; Pyogenic spondylitis",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "104-8",
"pmc": null,
"pmid": "26829460",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "17337352;24035173;20701886;12753990;19328338;24558949;21344431;9677097;15756794;22399257;18550153;2212605",
"title": "A case of hypopharyngeal cancer with stenosis, perforation, and pyogenic spondylitis development after chemoradiotherapy.",
"title_normalized": "a case of hypopharyngeal cancer with stenosis perforation and pyogenic spondylitis development after chemoradiotherapy"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1014157",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nWhile cavernous angioma (CVA) after cranial irradiation has been documented, its development after high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) has not. We present a patient with desmoplastic/nodular medulloblastoma (DNMB) associated with anhidrotic ectodermal dysplasia (AED) who developed CVA 2 years after high-dose chemotherapy and PBSCT.\n\n\nMETHODS\nA 1-year-old boy with ingravescent vomiting was admitted to our institute. He presented with a large head, a depressed nasal bridge, low-set ears, thick lips with peg-shaped teeth, hypohidrosis, sparse hair, thin atrophic skin, scaly dermatitis with frontal bossing, and a bulging anterior fontanel. Neuroradiological examination revealed multiple cerebellar masses with heterogeneous enhancement and speckled calcifications and severe obstructive hydrocephalus. The histological diagnosis of surgical specimens was DNMB, and he underwent postoperative multiple-drug chemotherapy with autologous PBSCT. The outcome was favorable and he did not undergo radiotherapy.\n\n\nRESULTS\nAfter 2 years, intracranial hemorrhage was detected at his regular radiological check-up and he again underwent surgery. The histological diagnosis was CVA.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first report of AED-associated DNMB and CVA.",
"affiliations": "Department of Neurosurgery, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. fyama@hiroshima-u.ac.jp.;Department of Neurosurgery, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Neurosurgery, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan.;Department of Clinical Oncology and Neuro-oncology Program, Hiroshima University Hospital, Hiroshima, 734-8551, Japan.;Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan.;Department of Neurosurgery, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.",
"authors": "Yamasaki|Fumiyuki|F|;Takayasu|Takeshi|T|;Nosaka|Ryo|R|;Kawaguchi|Hiroshi|H|;Sugiyama|Kazuhiko|K|;Kobayashi|Masao|M|;Kurisu|Kaoru|K|",
"chemical_list": "D014750:Vincristine; D005047:Etoposide; D003520:Cyclophosphamide; D016190:Carboplatin; D002945:Cisplatin; D008558:Melphalan; D008727:Methotrexate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00381-015-2848-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0256-7040",
"issue": "32(2)",
"journal": "Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery",
"keywords": "Anhidrotic ectodermal dysplasia; Cavernous angioma; Chemotherapy; Medulloblastoma; Peripheral blood stem cell transplantation",
"medline_ta": "Childs Nerv Syst",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D016190:Carboplatin; D002528:Cerebellar Neoplasms; D002675:Child, Preschool; D002945:Cisplatin; D003520:Cyclophosphamide; D004476:Ectodermal Dysplasia; D005047:Etoposide; D020786:Hemangioma, Cavernous, Central Nervous System; D006801:Humans; D007223:Infant; D020300:Intracranial Hemorrhages; D008297:Male; D008527:Medulloblastoma; D008558:Melphalan; D008727:Methotrexate; D019635:Neurosurgical Procedures; D036102:Peripheral Blood Stem Cell Transplantation; D014750:Vincristine",
"nlm_unique_id": "8503227",
"other_id": null,
"pages": "395-8",
"pmc": null,
"pmid": "26231569",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "3971390;11149610;2429990;3393196;16506497;1411655;1702313;3323518;17566205;11181686;10501915;10882863;9462678;10590059;22015329;25690449;3875817;21234575;9816139;17318212;7611024",
"title": "Cavernous angioma after chemotherapy for desmoplastic/nodular medulloblastoma associated with anhidrotic ectodermal dysplasia.",
"title_normalized": "cavernous angioma after chemotherapy for desmoplastic nodular medulloblastoma associated with anhidrotic ectodermal dysplasia"
} | [
{
"companynumb": "JP-ACCORD-039064",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": null,
"drug... |
{
"abstract": "In a previous trial of antiretroviral therapy (ART) involving pregnant women with human immunodeficiency virus (HIV) infection, those randomly assigned to receive tenofovir, emtricitabine, and ritonavir-boosted lopinavir (TDF-FTC-LPV/r) had infants at greater risk for very premature birth and death within 14 days after delivery than those assigned to receive zidovudine, lamivudine, and ritonavir-boosted lopinavir (ZDV-3TC-LPV/r).\n\n\n\nUsing data from two U.S.-based cohort studies, we compared the risk of adverse birth outcomes among infants with in utero exposure to ZDV-3TC-LPV/r, TDF-FTC-LPV/r, or TDF-FTC with ritonavir-boosted atazanavir (ATV/r). We evaluated the risk of preterm birth (<37 completed weeks of gestation), very preterm birth (<34 completed weeks), low birth weight (<2500 g), and very low birth weight (<1500 g). Risk ratios with 95% confidence intervals were estimated with the use of modified Poisson models to adjust for confounding.\n\n\n\nThere were 4646 birth outcomes. Few infants or fetuses were exposed to TDF-FTC-LPV/r (128 [2.8%]) as the initial ART regimen during gestation, in contrast with TDF-FTC-ATV/r (539 [11.6%]) and ZDV-3TC-LPV/r (954 [20.5%]). As compared with women receiving ZDV-3TC-LPV/r, women receiving TDF-FTC-LPV/r had a similar risk of preterm birth (risk ratio, 0.90; 95% confidence interval [CI], 0.60 to 1.33) and low birth weight (risk ratio, 1.13; 95% CI, 0.78 to 1.64). As compared to women receiving TDF-FTC-ATV/r, women receiving TDF-FTC-LPV/r had a similar or slightly higher risk of preterm birth (risk ratio, 1.14; 95% CI, 0.75 to 1.72) and low birth weight (risk ratio, 1.45; 95% CI, 0.96 to 2.17). There were no significant differences between regimens in the risk of very preterm birth or very low birth weight.\n\n\n\nThe risk of adverse birth outcomes was not higher with TDF-FTC-LPV/r than with ZDV-3TC-LPV/r or TDF-FTC-ATV/r among HIV-infected women and their infants in the United States, although power was limited for some comparisons. (Funded by the National Institutes of Health and others.).",
"affiliations": "From the Departments of Epidemiology (K.R., G.R.S., P.L.W., S.H.-D., K.P.) and Biostatistics (P.L.W., D.E.S.) and the Center for Biostatistics and AIDS Research (Y.H., D.E.S., K.P.), Harvard T.H. Chan School of Public Health, and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (K.R.), Boston; the Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago (E.G.C.); the Department of Medicine and Division of Infectious Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.S.C., R.M.H.); and the Department of Pediatrics, University of Colorado School of Medicine, Aurora (E.B.).;From the Departments of Epidemiology (K.R., G.R.S., P.L.W., S.H.-D., K.P.) and Biostatistics (P.L.W., D.E.S.) and the Center for Biostatistics and AIDS Research (Y.H., D.E.S., K.P.), Harvard T.H. Chan School of Public Health, and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (K.R.), Boston; the Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago (E.G.C.); the Department of Medicine and Division of Infectious Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.S.C., R.M.H.); and the Department of Pediatrics, University of Colorado School of Medicine, Aurora (E.B.).;From the Departments of Epidemiology (K.R., G.R.S., P.L.W., S.H.-D., K.P.) and Biostatistics (P.L.W., D.E.S.) and the Center for Biostatistics and AIDS Research (Y.H., D.E.S., K.P.), Harvard T.H. Chan School of Public Health, and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (K.R.), Boston; the Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago (E.G.C.); the Department of Medicine and Division of Infectious Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.S.C., R.M.H.); and the Department of Pediatrics, University of Colorado School of Medicine, Aurora (E.B.).;From the Departments of Epidemiology (K.R., G.R.S., P.L.W., S.H.-D., K.P.) and Biostatistics (P.L.W., D.E.S.) and the Center for Biostatistics and AIDS Research (Y.H., D.E.S., K.P.), Harvard T.H. Chan School of Public Health, and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (K.R.), Boston; the Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago (E.G.C.); the Department of Medicine and Division of Infectious Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.S.C., R.M.H.); and the Department of Pediatrics, University of Colorado School of Medicine, Aurora (E.B.).;From the Departments of Epidemiology (K.R., G.R.S., P.L.W., S.H.-D., K.P.) and Biostatistics (P.L.W., D.E.S.) and the Center for Biostatistics and AIDS Research (Y.H., D.E.S., K.P.), Harvard T.H. Chan School of Public Health, and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (K.R.), Boston; the Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago (E.G.C.); the Department of Medicine and Division of Infectious Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.S.C., R.M.H.); and the Department of Pediatrics, University of Colorado School of Medicine, Aurora (E.B.).;From the Departments of Epidemiology (K.R., G.R.S., P.L.W., S.H.-D., K.P.) and Biostatistics (P.L.W., D.E.S.) and the Center for Biostatistics and AIDS Research (Y.H., D.E.S., K.P.), Harvard T.H. Chan School of Public Health, and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (K.R.), Boston; the Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago (E.G.C.); the Department of Medicine and Division of Infectious Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.S.C., R.M.H.); and the Department of Pediatrics, University of Colorado School of Medicine, Aurora (E.B.).;From the Departments of Epidemiology (K.R., G.R.S., P.L.W., S.H.-D., K.P.) and Biostatistics (P.L.W., D.E.S.) and the Center for Biostatistics and AIDS Research (Y.H., D.E.S., K.P.), Harvard T.H. Chan School of Public Health, and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (K.R.), Boston; the Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago (E.G.C.); the Department of Medicine and Division of Infectious Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.S.C., R.M.H.); and the Department of Pediatrics, University of Colorado School of Medicine, Aurora (E.B.).;From the Departments of Epidemiology (K.R., G.R.S., P.L.W., S.H.-D., K.P.) and Biostatistics (P.L.W., D.E.S.) and the Center for Biostatistics and AIDS Research (Y.H., D.E.S., K.P.), Harvard T.H. Chan School of Public Health, and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (K.R.), Boston; the Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago (E.G.C.); the Department of Medicine and Division of Infectious Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.S.C., R.M.H.); and the Department of Pediatrics, University of Colorado School of Medicine, Aurora (E.B.).;From the Departments of Epidemiology (K.R., G.R.S., P.L.W., S.H.-D., K.P.) and Biostatistics (P.L.W., D.E.S.) and the Center for Biostatistics and AIDS Research (Y.H., D.E.S., K.P.), Harvard T.H. Chan School of Public Health, and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (K.R.), Boston; the Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago (E.G.C.); the Department of Medicine and Division of Infectious Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.S.C., R.M.H.); and the Department of Pediatrics, University of Colorado School of Medicine, Aurora (E.B.).;From the Departments of Epidemiology (K.R., G.R.S., P.L.W., S.H.-D., K.P.) and Biostatistics (P.L.W., D.E.S.) and the Center for Biostatistics and AIDS Research (Y.H., D.E.S., K.P.), Harvard T.H. Chan School of Public Health, and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (K.R.), Boston; the Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago (E.G.C.); the Department of Medicine and Division of Infectious Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.S.C., R.M.H.); and the Department of Pediatrics, University of Colorado School of Medicine, Aurora (E.B.).;From the Departments of Epidemiology (K.R., G.R.S., P.L.W., S.H.-D., K.P.) and Biostatistics (P.L.W., D.E.S.) and the Center for Biostatistics and AIDS Research (Y.H., D.E.S., K.P.), Harvard T.H. Chan School of Public Health, and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (K.R.), Boston; the Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago (E.G.C.); the Department of Medicine and Division of Infectious Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.S.C., R.M.H.); and the Department of Pediatrics, University of Colorado School of Medicine, Aurora (E.B.).",
"authors": "Rough|Kathryn|K|;Seage|George R|GR|;Williams|Paige L|PL|;Hernandez-Diaz|Sonia|S|;Huo|Yanling|Y|;Chadwick|Ellen G|EG|;Currier|Judith S|JS|;Hoffman|Risa M|RM|;Barr|Emily|E|;Shapiro|David E|DE|;Patel|Kunjal|K|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D061466:Lopinavir; D019259:Lamivudine; D015215:Zidovudine; D000068698:Tenofovir; D000068679:Emtricitabine; D019438:Ritonavir",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1701666",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "378(17)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D015331:Cohort Studies; D018562:Disease Transmission, Infectious; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D019259:Lamivudine; D061466:Lopinavir; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D047928:Premature Birth; D012306:Risk; D019438:Ritonavir; D000068698:Tenofovir; D015215:Zidovudine",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "1593-1603",
"pmc": null,
"pmid": "29694825",
"pubdate": "2018-04-26",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22155907;24801414;20632458;20196654;20539252;22491086;27806243;27035887;11981365;16988514;24409065;26867136;24169122;25383770;27864000;23340561;24001122;24781315;21983213;18177778;25513819;18957630;20860463;22615543;18989231;23052356;22382151;27082506;20532607;24067563;26060285;23204173",
"title": "Birth Outcomes for Pregnant Women with HIV Using Tenofovir-Emtricitabine.",
"title_normalized": "birth outcomes for pregnant women with hiv using tenofovir emtricitabine"
} | [
{
"companynumb": "US-CIPLA LTD.-2018US22329",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITONAVIR"
},
"drugadditional": null,
... |
{
"abstract": "Osteogenesis imperfecta is a congenital disorder resulting in multiple fractures and extremely short stature, usually necessitating cesarean delivery. Identical twins with severe osteogenesis imperfecta each of whom underwent a cesarean delivery with different anesthetic modalities are presented. A review of the literature and anesthetic options for cesarean delivery and postoperative analgesia for women with osteogenesis imperfecta are discussed.",
"affiliations": "Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA.;Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA.;Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA.;Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA.;Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA. Electronic address: rulandau@uw.edu.",
"authors": "Dinges|E|E|;Ortner|C|C|;Bollag|L|L|;Davies|J|J|;Landau|R|R|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-289X",
"issue": "24(1)",
"journal": "International journal of obstetric anesthesia",
"keywords": "Cesarean delivery; Combined spinal–epidural anesthesia; General anesthesia; Osteogenesis imperfecta",
"medline_ta": "Int J Obstet Anesth",
"mesh_terms": "D000328:Adult; D000767:Anesthesia, Epidural; D000768:Anesthesia, General; D000773:Anesthesia, Obstetrical; D002585:Cesarean Section; D036861:Delivery, Obstetric; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010013:Osteogenesis Imperfecta; D011247:Pregnancy; D011248:Pregnancy Complications",
"nlm_unique_id": "9200430",
"other_id": null,
"pages": "64-8",
"pmc": null,
"pmid": "25433579",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Osteogenesis imperfecta: cesarean deliveries in identical twins.",
"title_normalized": "osteogenesis imperfecta cesarean deliveries in identical twins"
} | [
{
"companynumb": "PHHY2015US015526",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"drugad... |
{
"abstract": "OBJECTIVE\nTo investigate the effectiveness and safety of bevacizumab-paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice.\n\n\nMETHODS\nIn this prospective multicenter observational study, bevacizumab-paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors.\n\n\nRESULTS\nBetween November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8-23.6) months in eligible patients; 25.2 (22.4-27.4) months and 13.2 (11.3-16.6) months in cohorts A and B, respectively; and 24.4 (21.9-27.2) months and 17.6 (15.2-20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44-2.14), second-line therapy (1.35, 1.13-1.63), ECOG performance status ≥ 1 (1.28, 1.04-1.57), taxane-based chemotherapy (0.65, 0.49-0.86), cancer-related symptoms (0.56, 0.46-0.68), and visceral metastasis (0.52, 0.40-0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.\n\n\nCONCLUSIONS\nIn Japanese clinical practice, combined bevacizumab-paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously.\n\n\nBACKGROUND\nTrial no. UMIN000009086.",
"affiliations": "Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan. yyamamoto@kumamoto-u.ac.jp.;Department of Breast Surgery, Tenri Yorozu Hospital, Nara, Japan.;Department of Surgery, Kurume University School of Medicine, Fukuoka, Japan.;Department of Breast Oncology, Aichi Cancer Center Hospital, Aichi, Japan.;Division of Breast Surgery, Chiba Cancer Center, Chiba, Japan.;Department of Breast Surgery, Sagara Hospital, Kagoshima, Japan.;Department of Breast Surgery, NHO Hokkaido Cancer Center, Hokkaido, Japan.;Department of Breast Surgery, St. Marianna University School of Medicine, Kanagawa, Japan.;Department of Breast Surgery, Tokyo Medical University, Tokyo, Japan.;Department of Breast Surgery, Osaka International Cancer Institute, Osaka, Japan.;Department of Breast Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan.;Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan.;Department of Breast Oncology, Gunma Prefectural Cancer Center, Gunma, Japan.;Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan.;Department of Breast Surgery, Matsuyama Red Cross Hospital, Ehime, Japan.;Department of Surgery (Breast Surgery), Oita Prefectural Hospital, Oita, Japan.;Department of Breast and Endocrine Surgery, Kobe University Hospital, Hyogo, Japan.;Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Breast Oncology Center, Cancer Institute Hospital, Tokyo, Japan.",
"authors": "Yamamoto|Yutaka|Y|http://orcid.org/0000-0001-6147-6828;Yamashiro|Hiroyasu|H|;Toh|Uhi|U|;Kondo|Naoto|N|;Nakamura|Rikiya|R|;Kashiwaba|Masahiro|M|;Takahashi|Masato|M|;Tsugawa|Koichiro|K|;Ishikawa|Takashi|T|;Nakayama|Takahiro|T|;Ohtani|Shoichiro|S|;Takano|Toshimi|T|;Fujisawa|Tomomi|T|;Toyama|Tatsuya|T|;Kawaguchi|Hidetoshi|H|;Mashino|Kojiro|K|;Tanino|Yuichi|Y|;Morita|Satoshi|S|;Toi|Masakazu|M|;Ohno|Shinji|S|",
"chemical_list": "D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000068258:Bevacizumab; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12282-020-01138-4",
"fulltext": "\n==== Front\nBreast Cancer\nBreast Cancer\nBreast Cancer (Tokyo, Japan)\n1340-6868 1880-4233 Springer Japan Tokyo \n\n32715420\n1138\n10.1007/s12282-020-01138-4\nOriginal Article\nProspective observational study of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for locally advanced or metastatic breast cancer: the JBCRG-C05 (B-SHARE) study\nhttp://orcid.org/0000-0001-6147-6828Yamamoto Yutaka yyamamoto@kumamoto-u.ac.jp 1 Yamashiro Hiroyasu 2 Toh Uhi 3 Kondo Naoto 45 Nakamura Rikiya 6 Kashiwaba Masahiro 7 Takahashi Masato 8 Tsugawa Koichiro 9 Ishikawa Takashi 10 Nakayama Takahiro 11 Ohtani Shoichiro 12 Takano Toshimi 13 Fujisawa Tomomi 14 Toyama Tatsuya 5 Kawaguchi Hidetoshi 15 Mashino Kojiro 16 Tanino Yuichi 17 Morita Satoshi 18 Toi Masakazu 19 Ohno Shinji 20 1 grid.274841.c0000 0001 0660 6749Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556 Japan \n2 Department of Breast Surgery, Tenri Yorozu Hospital, Nara, Japan \n3 grid.410781.b0000 0001 0706 0776Department of Surgery, Kurume University School of Medicine, Fukuoka, Japan \n4 grid.410800.d0000 0001 0722 8444Department of Breast Oncology, Aichi Cancer Center Hospital, Aichi, Japan \n5 grid.260433.00000 0001 0728 1069Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan \n6 grid.418490.00000 0004 1764 921XDivision of Breast Surgery, Chiba Cancer Center, Chiba, Japan \n7 Department of Breast Surgery, Sagara Hospital, Kagoshima, Japan \n8 grid.415270.5Department of Breast Surgery, NHO Hokkaido Cancer Center, Hokkaido, Japan \n9 grid.412764.20000 0004 0372 3116Department of Breast Surgery, St. Marianna University School of Medicine, Kanagawa, Japan \n10 grid.410793.80000 0001 0663 3325Department of Breast Surgery, Tokyo Medical University, Tokyo, Japan \n11 grid.489169.bDepartment of Breast Surgery, Osaka International Cancer Institute, Osaka, Japan \n12 Department of Breast Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan \n13 grid.410813.f0000 0004 1764 6940Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan \n14 Department of Breast Oncology, Gunma Prefectural Cancer Center, Gunma, Japan \n15 grid.416592.d0000 0004 1772 6975Department of Breast Surgery, Matsuyama Red Cross Hospital, Ehime, Japan \n16 grid.416794.90000 0004 0377 3308Department of Surgery (Breast Surgery), Oita Prefectural Hospital, Oita, Japan \n17 grid.411102.70000 0004 0596 6533Department of Breast and Endocrine Surgery, Kobe University Hospital, Hyogo, Japan \n18 grid.258799.80000 0004 0372 2033Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan \n19 grid.258799.80000 0004 0372 2033Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan \n20 grid.486756.e0000 0004 0443 165XBreast Oncology Center, Cancer Institute Hospital, Tokyo, Japan \n26 7 2020 \n26 7 2020 \n2021 \n28 1 145 160\n4 5 2020 16 7 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/.Purpose\nTo investigate the effectiveness and safety of bevacizumab–paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice.\n\nMethods\nIn this prospective multicenter observational study, bevacizumab–paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors.\n\nResults\nBetween November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8–23.6) months in eligible patients; 25.2 (22.4–27.4) months and 13.2 (11.3–16.6) months in cohorts A and B, respectively; and 24.4 (21.9–27.2) months and 17.6 (15.2–20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44–2.14), second-line therapy (1.35, 1.13–1.63), ECOG performance status ≥ 1 (1.28, 1.04–1.57), taxane-based chemotherapy (0.65, 0.49–0.86), cancer-related symptoms (0.56, 0.46–0.68), and visceral metastasis (0.52, 0.40–0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.\n\nConclusions\nIn Japanese clinical practice, combined bevacizumab–paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously.\n\nTrial registration\nTrial no. UMIN000009086.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s12282-020-01138-4) contains supplementary material, which is available to authorized users.\n\nKeywords\nBevacizumabPaclitaxelLocally advanced breast cancerMetastatic breast cancerOverall survivalFirst lineSecond linehttp://dx.doi.org/10.13039/100010795Chugai Pharmaceuticalissue-copyright-statement© The Japanese Breast Cancer Society 2021\n==== Body\nIntroduction\nBevacizumab is a humanized monoclonal antibody for vascular endothelial growth factor (VEGF), which is the most important regulator for angiogenesis in both healthy and pathological states [1]. Its enhanced expression is observed in many types of tumors and promotes tumor growth and metastasis [2]. Bevacizumab binds to VEGF, thereby inhibiting VEGF binding to VEGF receptors 1 and 2 on endothelial cells. The consequent inhibition of tumor angiogenesis at the tumor site is understood to suppress the growth of cancer cells [3]. Additionally, normalization of abnormal vessels in the tumor tissue reduces its interstitial pressure, thereby facilitating penetration by anticancer agents in combination with bevacizumab [4].\n\nA meta-analysis on addition of bevacizumab to chemotherapy for patients with locally advanced or metastatic breast cancer (LA/mBC) showed that addition of bevacizumab to first- or second-line chemotherapy significantly prolongs progression-free survival (PFS) and overall response rate (ORR) but not overall survival (OS) [5]. However, another meta-analysis of factors indicating poor prognosis in patients with LA/mBC showed that addition of bevacizumab to first-line chemotherapy improves 1-year OS and OS in patients with poor prognostic factors, as compared with chemotherapy alone [6]. Regarding adverse events (AEs), addition of bevacizumab increases the incidence of hypertension, proteinuria, and bleeding; however, the incidence of thromboembolism or gastrointestinal perforation is unchanged and that of treatment-related deaths is low [5].\n\nThe JO19901 study, carried out in Japan, was a phase II study of bevacizumab plus paclitaxel in chemotherapy-naive patients with HER2-negative LA/mBC [7]. The primary efficacy endpoint, median PFS, was 12.9 months. Regarding secondary endpoints, ORR was 74% and median OS was 35.8 months. Regarding safety, no new serious AEs were detected. Thus, the study confirmed the reproducibility in Japanese patients of the efficacy and safety results achieved for bevacizumab plus paclitaxel combination therapy in studies conducted outside Japan.\n\nAlthough several cohort studies have been carried out in other countries [8–11], clinical experience of bevacizumab plus paclitaxel combination therapy in Japan has been limited to the small number of patients in the JO19901 study, which enrolled 120 patients [7]. Therefore, we conducted a prospective multicenter observational study to investigate the effectiveness and safety of this combination as first- or second-line therapy for LA/mBC in daily clinical practice. Two cohorts, one comprising patients with hormone receptor-positive breast cancer and the other comprising those with triple-negative breast cancer, were established to enable comparison of prognostic factors in patients with each of these cancer subtypes and in patients receiving first- or second-line therapy.\n\nPatients and methods\nStudy design\nIn this multicenter prospective observational cohort study, patients who met the following inclusion criteria were enrolled: histologically confirmed HER2-negative LA/mBC with confirmed HR status; Eastern Cooperative Oncology Group (ECOG) performance status (PS), 0–3; no history of second-line chemotherapy for LA/mBC; and sufficient bone marrow and major organ functions determined by the attending physician. Exclusion criteria included history of hypersensitivity to the ingredients of bevacizumab or paclitaxel, history of hemoptysis, uncontrolled hypertension, thromboembolism, positive urinary protein test result (≥ 2 +), gastrointestinal perforation, and severe fistula.\n\nPatients were enrolled through central registration and classified by HR status: cohort A comprised patients with HR-positive breast cancer, and cohort B, those with triple-negative breast cancer (TNBC). First-line therapy was defined as treatment for patients who had not previously received chemotherapy for LA/mBC. Second-line therapy was defined as treatment for disease progression after or during receipt of first-line chemotherapy for LA/mBC. In cases of relapse during adjuvant chemotherapy, the first treatment after the relapse was considered the second-line therapy.\n\nWritten informed consent was obtained from all patients. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution. The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/index-j.htm; trial no. UMIN000009086).\n\nStudy treatment\nBecause the study was an observational study conducted in a clinical setting, dosage, treatment schedule, and criteria for dose reduction, interruption, and discontinuation were not specified. However, the study protocol recommended the following standard treatment regimen, which was used in the JO19901 study [7]: bevacizumab 10 mg/kg given every 2 weeks, and paclitaxel 90 mg/m2 given every week for 3 weeks, followed by a 1-week rest. Each combination of bevacizumab and paclitaxel administered as above for 4 weeks was deemed one cycle.\n\nIn cases of discontinuation of either drug due to AEs, the other drug could be continued as monotherapy. The protocol did not specify any treatment after discontinuation.\n\nStudy assessment\nAt screening on registration, medical history, symptoms of cancer, physical findings, pathological findings relating to the primary and metastatic lesions, presence or absence of measurable lesions, and previous treatments were recorded. During the treatment period, treatment schedule, treatment discontinuations, dose reductions, treatment interruption, concomitant drugs, and the last dosing date were recorded by electronic data capture.\n\nRegarding safety, the incidence of five selected AEs of bevacizumab plus paclitaxel (i.e. neutropenia, hypertension, proteinuria, bleeding, and peripheral neuropathy), of any grade, was recorded. For other AEs, only those of grade ≥ 3 were recorded. AEs were evaluated based on CTCAE version 4.0 (Japanese Clinical Oncology Group edition) [12]. Effectiveness was evaluated and recorded in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Japanese Clinical Oncology Group edition) [13]. At the end of the observational period, patients’ disease progression, death, and post-treatment status were recorded.\n\nAnalysis populations and endpoints\nThe eligible patient population (used for the effectiveness analysis) was defined as patients who were registered according to the registration procedure, excluding those with ineligible cases or registration error. The treated patient population (used for the safety analysis and the sensitive analysis) was defined as patients who received bevacizumab plus paclitaxel combination therapy at least once. All evaluations were done by attending physicians.\n\nThe primary endpoint was OS, defined as the period between date of registration and death from any cause. Secondary endpoints were PFS, ORR, and safety. PFS was defined as the period between the registration date and the day when disease progression was determined (if that occurred first) or death (all causes).\n\nStatistical analyses\nThis was an observational study conducted in the setting of daily clinical practice; therefore, the sample size was determined based on feasibility, considering the number of participating institutions, length of the registration period, and epidemiology of patients with HER2-negative LA/mBC. Consequently, the target numbers of patients were determined as 500 for cohort A and 250 for cohort B.\n\nExpected median OS in each cohort according to treatment line (i.e. first- or second-line therapy) was estimated based on data from the prospective studies [7, 8, 14, 15, 17, 18]. Consequently, the expected median OS was 29.0 months and 18.0 months in patients receiving the study treatment as first-line and second-line therapy, respectively, in cohort A, and 17.0 months and 13.0 months in those receiving it as first-line and second-line therapy, respectively, in cohort B. Because the present study included patients who received the study treatment as both first- and second-line therapy, the ratio of first-line therapy patients to second-line therapy patients was assumed to be 5:5–7:3. Therefore, median OS was estimated to be 23.8 months in cohort A patients and 15.2 months in cohort B patients.\n\nFor the eligible patient population, cumulative survival curves for OS, median OS, and survival rate in each year were estimated using the Kaplan–Meier method, and Greenwood’s formula was used to construct 95% confidential intervals (CIs). Subgroup analysis was performed by Cox regression analysis to identify important prognostic factors. Sensitivity analysis was also performed, using data from the treated patient population. The same analyses were performed for PFS as those for OS. ORR was calculated as the proportion of patients achieving complete or partial response as the best overall response in patients with measurable lesions. CIs were calculated using the Clopper–Pearson method.\n\nSafety was assessed using data from the treated patient population. The numbers of AEs, their grades, and their causal relation with the study drug were tabulated.\n\nResults\nStudy population and baseline patient characteristics\nA total of 767 patients were enrolled from 155 institutions across Japan between November 2012 and October 2014. Patient disposition is shown in Supplementary Fig. 1. Of these, the eligible patient population comprised 754 patients after exclusion of ineligible cases. Within this group, 539 (71.5%) were in cohort A and 215 (28.5%) in cohort B. The numbers of patients receiving the study treatment as first- and second-line therapy were 478 (63.4%) and 276 (36.6%), respectively. The treated patient population, that is, those who received the study treatment at least once, comprised 750 patients.\n\nBaseline characteristics of the eligible patient population are shown in Table 1 and Supplementary Table 1a. Median age was 58 years. Most patients had distant metastasis (86.1%). Of these patients, most had visceral metastasis (91.7%), with ≥ 3 organs affected in a minority of cases (14.0%). Symptoms related to cancer (e.g. pain, dyspnea, pleural effusion, ascites, skin ulcer, and tumor fever) were experienced by 57.6% of eligible patients. Baseline characteristics of the treated patient population are shown in Supplementary Table 1c and are similar to those of the eligible patient population.Table 1 Baseline characteristics (eligible patients)\n\n\tAll eligible patients\tCohort Aa\tCohort Bb\tFirst-line therapy\tSecond-line therapy\t\n\tN\t(%)\tn\t(%)\tn\t(%)\tn\t(%)\tn\t(%)\t\nNo. of patients\t754\t100\t539\t100\t215\t100\t478\t100\t276\t100\t\nMedian age (range) (years)\t58.0\t(26–83)\t58.0\t(26–81)\t58.0\t(27–83)\t59.0\t(26–83)\t57.0\t(28–83)\t\nMenopausal status\t\t\t\t\t\t\t\t\t\t\t\n Premenopausal\t198\t26.3\t133\t24.7\t65\t30.2\t127\t26.6\t71\t25.7\t\n Postmenopausal\t532\t70.6\t385\t71.4\t147\t68.4\t337\t70.5\t195\t70.7\t\n Unknown\t24\t3.2\t21\t3.9\t3\t1.4\t14\t2.9\t10\t3.6\t\nECOG PS\t\t\t\t\t\t\t\t\t\t\t\n 0\t522\t69.2\t371\t68.8\t151\t70.2\t345\t72.2\t177\t64.1\t\n 1\t172\t22.8\t122\t22.6\t50\t23.3\t96\t20.1\t76\t27.5\t\n 2\t43\t5.7\t34\t6.3\t9\t4.2\t29\t6.1\t14\t5.1\t\n 3\t17\t2.3\t12\t2.2\t5\t2.3\t8\t1.7\t9\t3.3\t\nER status\t\t\t\t\t\t\t\t\t\t\t\n Negative\t208\t27.6\t8\t1.5\t200\t93.0\t125\t26.2\t83\t30.1\t\n Positive\t544\t72.1\t529\t98.1\t15\t7.0\t351\t73.4\t193\t69.9\t\n Unknown\t2\t0.3\t2\t0.4\t0\t0.0\t2\t0.4\t0\t0.0\t\nPgR status\t\t\t\t\t\t\t\t\t\t\t\n Negative\t332\t44.0\t122\t22.6\t210\t97.7\t203\t42.5\t129\t46.7\t\n Positive\t419\t55.6\t414\t76.8\t5\t2.3\t272\t56.9\t147\t53.3\t\n Unknown\t3\t0.4\t3\t0.6\t0\t0.0\t3\t0.6\t0\t0.0\t\nNuclear grade\t\t\t\t\t\t\t\t\t\t\t\n 1\t120\t15.9\t102\t18.9\t18\t8.4\t79\t16.5\t41\t14.9\t\n 2\t106\t14.1\t82\t15.2\t24\t11.2\t70\t14.6\t36\t13.0\t\n 3\t216\t28.6\t111\t20.6\t105\t48.8\t144\t30.1\t72\t26.1\t\n Unknown\t312\t41.4\t244\t45.3\t68\t31.6\t185\t38.7\t127\t46.0\t\nKi67 index\t\t\t\t\t\t\t\t\t\t\t\n < 30\t141\t18.7\t105\t19.5\t36\t16.7\t103\t21.5\t38\t13.8\t\n ≥ 30\t191\t25.3\t93\t17.3\t98\t45.6\t130\t27.2\t61\t22.1\t\n Unknown\t422\t56.0\t341\t63.3\t81\t37.7\t245\t51.3\t177\t64.1\t\nDiagnosis\t\t\t\t\t\t\t\t\t\t\t\n Locally advanced\t34\t4.5\t20\t3.7\t14\t6.5\t29\t6.1\t5\t1.8\t\n Stage IV\t199\t26.4\t149\t27.6\t50\t23.3\t130\t27.2\t69\t25.0\t\n Recurrence\t521\t69.1\t370\t68.6\t151\t70.2\t319\t66.7\t202\t73.2\t\nDisease-free interval (months)\t\t\t\t\t\t\t\t\t\t\t\n 0\t233\t30.9\t169\t31.4\t64\t29.8\t159\t33.3\t74\t26.8\t\n 0–24\t178\t23.6\t83\t15.4\t95\t44.2\t101\t21.1\t77\t27.9\t\n≥ 4\t292\t38.7\t246\t45.6\t46\t21.4\t190\t39.7\t102\t37.0\t\n Unknown\t51\t6.8\t41\t7.6\t10\t4.7\t28\t5.9\t23\t8.3\t\nDistant metastasis\t\t\t\t\t\t\t\t\t\t\t\n No\t81\t10.7\t47\t8.7\t34\t15.8\t34\t7.1\t47\t17.0\t\n Yes\t649\t86.1\t476\t88.3\t173\t80.5\t422\t88.3\t227\t82.2\t\n Unknown\t24\t3.2\t16\t3.0\t8\t3.7\t22\t4.6\t2\t0.7\t\nMetastatic sitec\t\t\t\t\t\t\t\t\t\t\t\n Non-visceral\t54\t8.3\t36\t7.6\t18\t10.4\t40\t9.5\t14\t6.2\t\n Visceral\t595\t91.7\t440\t92.4\t155\t89.6\t382\t90.5\t213\t93.8\t\nNo. of metastatic organsc\t\t\t\t\t\t\t\t\t\t\t\n < 3\t558\t86.0\t409\t85.9\t149\t86.1\t355\t84.1\t203\t89.4\t\n ≥ 3\t91\t14.0\t67\t14.1\t24\t13.9\t67\t15.9\t24\t10.6\t\nCancer-related symptoms\t\t\t\t\t\t\t\t\t\t\t\n No\t315\t41.8\t230\t42.7\t85\t39.5\t200\t41.8\t115\t41.7\t\n Yes\t434\t57.6\t305\t56.6\t129\t60.0\t275\t57.5\t159\t57.6\t\n Unknown\t5\t0.7\t4\t0.7\t1\t0.5\t3\t0.6\t2\t0.7\t\nTreatment line for locally advanced or metastatic breast cancer\t\t\t\t\t\t\t\t\t\t\t\n First line\t478\t63.4\t345\t64.0\t133\t61.9\t\t\t\t\t\n Second line\t276\t36.6\t194\t36.0\t82\t38.1\t\t\t\t\t\nHistory of adjuvant therapyd\t\t\t\t\t\t\t\t\t\t\t\n Chemotherapy\t370\t71.0\t238\t64.3\t132\t87.4\t227\t71.2\t143\t70.8\t\n Anthracycline\t297\t57.0\t188\t50.8\t109\t72.2\t186\t58.3\t111\t55.0\t\n Taxane\t262\t50.3\t153\t41.4\t109\t72.2\t165\t51.7\t97\t48.0\t\n Endocrine therapy\t336\t64.5\t324\t87.6\t12\t7.9\t205\t64.3\t131\t64.9\t\nPrevious therapy for locally advanced or metastatic breast cancer\t\t\t\t\t\t\t\t\t\t\t\n Chemotherapy\t266\t35.3\t188\t34.9\t78\t36.3\t12\t2.5\t254\t92.0\t\n Anthracycline\t80\t10.6\t63\t11.7\t17\t7.9\t4\t0.8\t76\t27.5\t\n Taxane\t54\t7.2\t36\t6.7\t18\t8.4\t5\t1.0\t49\t17.8\t\n Endocrine therapy\t356\t47.2\t348\t64.6\t8\t3.7\t195\t40.8\t161\t58.3\t\n Radiotherapy\t140\t18.6\t111\t20.6\t29\t13.5\t62\t13.0\t78\t28.3\t\nECOG PS Eastern Cooperative Oncology Group Performance Status, ER estrogen receptor, PgR progesterone receptor\n\naPatients with hormone receptor-positive breast cancer\n\nbPatients with triple-negative breast cancer\n\ncNumber (%) of distant metastasis\n\ndNumber (%) of patients with breast cancer recurrence\n\n\n\nThe proportions of cohort B patients with distant metastasis and metastasis to ≥ 3 organs were generally higher in those receiving first-line therapy than in those receiving second-line therapy; however, there were no differences for the other prognostic factors (Supplementary Table 1a).\n\nTreatment exposure\nMost patients received treatment in accordance with the treatment regimen used in the JO19901 study [7]. Details of treatment exposure in eligible patients are shown in Table 2 and Supplementary Table 2a. Median duration of bevacizumab and paclitaxel exposure was 5.1 and 4.9 months, respectively. Contrary to our expectation, duration of bevacizumab monotherapy after discontinuation of bevacizumab in combination with paclitaxel was extremely short and about 90% of cases discontinued bevacizumab at almost the same time as paclitaxel was discontinued (Table2, Supplementary Table 2a–c).Table 2 Treatment exposure (eligible patients)\n\n\tAll eligible patients\tCohort Aa\tCohort Bb\tFirst-line therapy\tSecond-line therapy\t\n\tN\t(%)\tn\t(%)\tn\t(%)\tn\t(%)\tn\t(%)\t\nNo. of patients\t754\t100\t539\t100\t215\t100\t478\t100\t276\t100\t\nMedian duration of study treatment (25th, 75th percentiles), months\t5.1\t(3.1, 8.7)\t5.5\t(3.3, 9.5)\t4.0\t(2.3, 6.5)\t5.3\t(3.0, 8.7)\t4.8\t(2.4, 8.8)\t\nMedian duration of bevacizumab (25th, 75th percentiles), months\t5.1\t(2.8, 8.5)\t5.4\t(3.3, 9.5)\t3.7\t(2.3, 6.2)\t5.1\t(2.8, 8.5)\t4.6\t(2.4, 8.7)\t\nMedian RDI of bevacizumab (25th, 75th percentiles),\t97.5\t(86.2, 100)\t95.9\t(86.5, 100)\t100\t(85.7, 100)\t95.6\t(87.2–100)\t100\t(84.8–100)\t\nDiscontinuations of bevacizumab, n (%)\t748\t99.2\t536\t99.4\t212\t98.6\t475\t99.4\t273\t98.9\t\nReason for discontinuation of bevacizumab, n (%)\t\t\t\t\t\t\t\t\t\t\t\n Disease progression\t379\t50.7\t261\t48.7\t118\t55.7\t221\t46.5\t158\t57.9\t\n Adverse events\t214\t28.6\t169\t31.5\t45\t21.2\t143\t30.1\t71\t26.0\t\n Other\t152\t20.3\t105\t19.6\t47\t22.2\t109\t22.9\t43\t15.8\t\n Unknown\t3\t0.4\t1\t0.2\t2\t0.9\t2\t0.4\t1\t0.4\t\nBevacizumab dose reductions, n (T)\t15\t2.0\t12\t2.2\t3\t1.4\t13\t2.7\t2\t0.7\t\nReason for bevacizumab dose reduction, n (%)c\t\t\t\t\t\t\t\t\t\t\t\n Hypertension\t3\t20.0\t2\t16.7\t1\t33.3\t3\t23.1\t0\t0.0\t\n Proteinuria\t3\t20.0\t3\t25.0\t0\t0.0\t3\t23.1\t0\t0.0\t\n Bleeding\t1\t6.7\t1\t8.3\t0\t0.0\t1\t7.7\t0\t0.0\t\n Neutropenia\t1\t6.7\t1\t8.3\t0\t0.0\t0\t0.0\t1\t50.0\t\n Other adverse events\t3\t20.0\t3\t25.0\t0\t0.0\t3\t23.1\t0\t0.0\t\n Other\t4\t26.7\t2\t16.7\t2\t66.7\t3\t23.1\t0\t0.0\t\nBevacizumab dose interruptions or delays, n (%)\t263\t34.9\t188\t34.9\t75\t34.9\t155\t32.4\t108\t39.1\t\nReason for bevacizumab dose interruption or delay, n (%)c\t\t\t\t\t\t\t\t\t\t\t\n Hypertension\t18\t6.8\t15\t8.0\t3\t4.0\t16\t10.3\t2\t1.9\t\n Proteinuria\t53\t20.2\t36\t19.1\t17\t22.7\t35\t22.6\t18\t16.7\t\n Bleeding\t3\t1.1\t2\t1.1\t1\t1.3\t2\t1.3\t1\t0.9\t\n Neutropenia\t77\t29.3\t61\t32.4\t16\t21.3\t38\t24.5\t39\t36.1\t\n Other adverse events\t106\t40.3\t77\t41.0\t29\t38.7\t61\t39.4\t45\t41.7\t\n Other\t114\t43.3\t79\t42.0\t35\t46.7\t63\t40.6\t51\t47.2\t\nMedian duration of paclitaxel (25th, 75th percentiles), months\t4.9\t(2.8, 8.1)\t5.3\t(3.2, 9.0)\t3.9\t(2.3, 6.0)\t5.1\t(3.0, 8.1)\t4.6\t(2.4, 8.2)\t\nMedian RDI of paclitaxel (25th, 75th percentiles),\t90.9\t(70.6, 100)\t88.9\t(69.5, 100)\t96.0\t(75.6, 105)\t91.7\t(72.7, 100)\t89.8\t(68.6, 100)\t\nDiscontinuations of paclitaxel, n (%)\t748\t99.2\t536\t99.4\t212\t98.6\t475\t99.4\t273\t98.9\t\nReason for discontinuation of paclitaxel, n (%)\t\t\t\t\t\t\t\t\t\t\t\n Disease progression\t363\t48.5\t245\t45.7\t118\t55.7\t216\t45.5\t147\t53.8\t\n Adverse events\t246\t32.9\t198\t36.9\t48\t22.6\t158\t33.3\t88\t32.2\t\n Other\t136\t18.2\t92\t17.2\t44\t20.8\t99\t20.8\t37\t13.6\t\n Unknown\t3\t0.4\t1\t0.2\t2\t0.9\t2\t0.4\t1\t0.4\t\nPaclitaxel dose reductions, n (%)\t276\t36.6\t208\t38.6\t68\t31.6\t185\t38.7\t91\t33.0\t\nReason for paclitaxel dose reduction, n (%)c\t\t\t\t\t\t\t\t\t\t\t\n Peripheral neutropenia\t114\t41.3\t89\t42.8\t25\t36.8\t81\t43.8\t33\t36.3\t\n Neutropenia\t117\t42.4\t88\t42.3\t29\t42.6\t67\t36.2\t50\t54.9\t\n Other adverse events\t81\t29.3\t61\t29.3\t20\t29.4\t57\t30.8\t24\t26.4\t\n Other\t28\t10.1\t20\t9.6\t8\t11.8\t19\t10.3\t9\t9.9\t\nPaclitaxel dose interruptions or delays, n ()\t351\t46.6\t259\t48.1\t92\t42.8\t207\t43.3\t144\t52.2\t\nReason for paclitaxel dose interruption or delay, n (%)c\t\t\t\t\t\t\t\t\t\t\t\n Peripheral neutropenia\t65\t18.5\t52\t20.1\t13\t14.1\t39\t18.8\t26\t18.1\t\n Neutropenia\t159\t45.3\t123\t47.5\t36\t39.1\t82\t39.6\t77\t53.5\t\n Other adverse events\t168\t47.9\t118\t45.6\t50\t54.3\t94\t45.4\t74\t51.4\t\n Other\t127\t36.2\t90\t34.7\t37\t40.2\t72\t34.8\t55\t38.2\t\nMedian duration of bevacizumab monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months\t1.4 (N = 79)\t0.5, 3.9\t1.4 (N = 65)\t0.5, 3.9\t0.6 (N = 14)\t0.2, 3.0\t1.4 (N = 52)\t0.5, 3.9\t0.8 (N = 27)\t0.3, 3.7\t\nMedian duration of paclitaxel monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months\t0.2 (N = 133)\t0.2, 0.7\t0.2 (N = 86)\t0.2, 0.7\t0.2 (N = 47)\t0.2, 0.9\t0.2 (N = 87)\t0.2, 1.2\t0.2 (N = 46)\t0.2, 0.3\t\nRDI relative dose intensity\n\naPatients with hormone receptor-positive breast cancer\n\nbPatients with triple-negative breast cancer\n\ncMultiple items could be selected\n\n\n\nOf the 754 eligible patients, 748 (99.2%) discontinued the study treatment; of these, 28.6% and 32.9% discontinued bevacizumab and paclitaxel, respectively, due to AEs. Regarding discontinuations due to other reasons, those recorded for ≥ 1% of patients included patient request (4.9%), maximum response (2.8%), breast surgery (2.7%), completion of scheduled treatment (2.3%), and treatment for other disease (1.5%).\n\nThe dose of bevacizumab or paclitaxel was reduced due to AEs in 1.5% and 33.1%, respectively, and it was suspended due to AEs in 19.7% and 29.7%, respectively.\n\nWhen the treatment schedule of bevacizumab plus paclitaxel was the same as that in the JO19901 study [7], relative dose intensity of bevacizumab and paclitaxel was 99.2% and 90.9%, respectively.\n\nDetails of treatment exposure for patents in the treated patient population are shown in Supplementary Table 2b, c. Treatment exposure in this population was similar to that in the eligible patient population.\n\nEffectiveness\nOverall survival\nMedian observation period was 19.7 months. Events occurred in 496 of the 754 eligible patients (65.8%) during observation. Median OS was 21.7 months (95% CI 19.8–23.6 months), 25.2 months (95% CI 22.4–27.4 months), 13.2 months (95% CI 11.3–16.6 months), 24.4 months (95% CI 21.9–27.2 months), and 17.6 months (95% CI 15.2–20.0 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Fig. 1a–c). Additionally, 1-year OS was 71.0%, 77.6%, 54.3%, 74.1%, 65.7%, in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively. Details of OS for eligible populations by cohort and treatment-line are shown in Supplementary Table 3 and Fig. 1d, e. Interestingly, OS was significantly longer in patients receiving the study treatment as first-line therapy than in those receiving it as second-line therapy in cohort A (log-rank test p < 0.0001, Fig. 2d), but not in cohort B (p = 0.3583, Fig. 1e).Fig. 1 Overall survival in the eligible patient population: a all eligible patients; b cohort A (patients with hormone receptor-positive breast cancer) versus cohort B (patients with triple-negative breast cancer); c, all eligible patients receiving first-line versus second-line therapy; d first-line versus second-line therapy in cohort A; e first-line versus second-line therapy in cohort B\n\n\n\nThe results of multivariate analysis for OS in the eligible patient population are summarized in Table 3a. In decreasing order of hazard ratio (HR), the baseline characteristics independently associated with OS were TNBC, second-line therapy, ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, cancer-related symptoms, and visceral metastasis.Table 3 Results of univariate and multivariate analyses for overall survival\n\n(a) All eligible patients\t\t\t\t\t\t\t\t\n\tUnivariate analysis (N = 754)\tMultivariate analysis (N = 736)a\t\nVariable\tN\tHR\t95% CI\tp\tHR\t95% CI\tp\t\nCohort A vs cohort B\t754\t1.63\t1.35–1.97\t < 0.0001\t1.75\t1.44–2.14\t < 0.0001\t\nFirst- vs second-line therapy\t754\t1.46\t1.22–1.74\t < 0.0001\t1.35\t1.13–1.63\t0.0011\t\nAge: < 50 years vs ≥ 50 years\t754\t0.92\t0.77–1.10\t0.3361\t\t\t\t\nECOG PS: 0 vs 1, 2, or 3\t754\t1.59\t1.32–1.91\t < 0.0001\t1.28\t1.04–1.57\t0.0175\t\nVisceral metastasis: yes vs no\t754\t0.55\t0.44–0.70\t < 0.0001\t0.52\t0.40–0.66\t < 0.0001\t\nCancer-related symptoms: yes vs no\t749\t0.57\t0.48–0.69\t < 0.0001\t0.56\t0.46–0.68\t < 0.0001\t\nNeoadjuvant or adjuvant chemotherapy: yes vs no\t741\t0.63\t0.53–0.75\t < 0.0001\t0.87\t0.66–1.14\t0.3139\t\nNeoadjuvant or adjuvant taxane-based chemotherapy: yes vs no\t741\t0.60\t0.50–0.72\t < 0.0001\t0.65\t0.49–0.86\t0.0026\t\nHistory of taxane-based chemotherapy: yes vs no\t754\t0.90\t0.64–1.26\t0.5380\t\t\t\t\nHistory of anthracycline-based chemotherapy: yes vs no\t754\t1.04\t0.78–1.38\t0.8108\t\t\t\t\nHistory of hormone therapy: yes vs no\t754\t1.02\t0.86–1.22\t0.8031\t\t\t\t\nNuclear grade: ≤ 2 vs 3\t442\t1.31\t1.05–1.64\t0.0186\t\t\t\t\nKi-67 index: < 30 vs ≥ 30\t332\t1.64\t1.25–2.16\t0.0004\t\t\t\t\nDisease-free interval: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months\t703\t1.02\t0.92–1.13\t0.7575\t\t\t\t\n(b) Patients with recurrent breast cancer\t\t\t\n\tUnivariate analysis (n = 521)\tMultivariate analysis (n = 456)a\t\nVariable\tn\tHR\t95% CI\tP\tHR\t95% CI\tP\t\nCohort A vs cohort B\t521\t1.52\t1.22–1.90\t0.0002\t1.27\t0.94–1.71\t0.1251\t\nFirst- vs second-line therapy\t521\t1.33\t1.08–1.64\t0.0069\t1.20\t0.95–1.52\t0.1210\t\nAge: < 50 years vs ≥ 50 years\t521\t0.92\t0.75–1.13\t0.4072\t\t\t\t\nECOG PS: 0 vs 1, 2, or 3\t521\t1.65\t1.32–2.06\t < 0.0001\t1.32\t1.02–1.71\t0.0333\t\nVisceral metastasis: yes vs no\t521\t0.58\t0.44–0.77\t0.0001\t0.53\t0.39–0.72\t0.0001\t\nCancer-related symptoms: yes vs no\t518\t0.50\t0.41–0.62\t < 0.0001\t0.52\t0.41–0.66\t < 0.0001\t\nNeoadjuvant or adjuvant chemotherapy: yes vs no\t508\t0.68\t0.53–0.86\t0.0016\t1.08\t0.76–1.54\t0.6634\t\nNeoadjuvant or adjuvant taxane-based chemotherapy: yes vs no\t508\t0.66\t0.53–0.81\t0.0001\t0.70\t0.51–0.95\t0.0209\t\nHistory of taxane-based chemotherapy: yes vs no\t521\t0.86\t0.56–1.32\t0.4944\t\t\t\t\nHistory of anthracycline-based chemotherapy: yes vs no\t521\t0.88\t0.57–1.36\t0.5617\t\t\t\t\nHistory of hormone therapy: yes vs no\t521\t1.28\t1.04–1.57\t0.0190\t1.14\t0.87–1.50\t0.3367\t\nNuclear grade: ≤ 2 vs 3\t299\t1.17\t0.90–1.52\t0.2389\t\t\t\t\nKi-67 index: < 30 vs ≥ 30\t178\t1.81\t1.27–2.57\t0.0011\t\t\t\t\nDisease-free interval 1: ≤ 24 months vs > 24 months\t470\t0.45\t0.36–0.56\t < 0.0001\t0.50\t0.39–0.63\t < 0.0001\t\nCI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio\n\nVariables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis\n\n\n\nThe results of multivariate analysis in the 521 patients with recurrent breast cancer are summarized in Table 3b. The following baseline characteristics were identified as independent predictors of OS: ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, visceral metastasis, cancer-related symptoms, and disease-free interval (DFI) ≤ 24 months.\n\nThe results of univariate and multivariate analyses of baseline characteristics associated with OS by cohort are shown in Supplementary Tables 4 and 5.\n\nProgression-free survival and objective response rates\nMedian PFS was 8.5 months (95% CI 7.8–9.2 months), 9.4 months (95% CI 8.7–10.7 months), 6.0 months (95% CI 5.5–7.4 months), 9.3 months (95% CI 8.5–10.7 months), and 7.2 months (95% CI 6.0–8.4 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Supplementary Fig. 2a, 2b, 2c). Details of PFS for eligible populations by cohort and treatment line are shown in Supplementary Table 6 and Supplementary Fig. 2d, 2e.\n\nMultivariate analysis identified the following baseline characteristics independently associated with PFS (Table 4a): TNBC, ECOG PS ≥ 1, history of endocrine therapy, cancer-related symptoms, history of neoadjuvant or adjuvant chemotherapy, history of neoadjuvant or adjuvant taxane-based chemotherapy, and visceral metastasis.Table 4 Results of univariate and multivariate analyses for progression-free survival\n\n(a) All eligible patients\t\t\t\n\tUnivariate analysis (n = 754)\tMultivariate analysis (n = 687)a\t\nVariable\tn\tHR\t95% CI\tP\tHR\t95% CI\tP\t\nCohort A vs cohort B\t754\t1.33\t1.13–1.58\t0.0008\t1.56\t1.26–1.93\t0.0001\t\nFirst- vs second-line therapy\t754\t1.40\t1.20–1.64\t < 0.0001\t1.19\t0.99–1.42\t0.0622\t\nAge: < 50 years vs ≥ 50 years\t754\t1.00\t0.86–1.16\t0.9589\t\t\t\t\nECOG PS: 0 vs 1, 2, or 3\t754\t1.60\t1.36–1.88\t < 0.0001\t1.36\t1.13–1.64\t0.0013\t\nVisceral metastasis: yes vs no\t754\t0.63\t0.52–0.76\t < 0.0001\t0.68\t0.55–0.85\t0.0005\t\nCancer-related symptoms: yes vs no\t749\t0.68\t0.58–0.79\t < 0.0001\t0.72\t0.60–0.86\t0.0003\t\nNeoadjuvant or adjuvant chemotherapy: yes vs no\t741\t0.62\t0.53–0.72\t < 0.0001\t0.71\t0.53–0.95\t0.0227\t\nNeoadjuvant or adjuvant taxane-based chemotherapy: yes vs no\t741\t0.61\t0.52–0.72\t < 0.0001\t0.69\t0.54–0.89\t0.0044\t\nHistory of taxane-based chemotherapy: yes vs no\t754\t0.69\t0.52–0.92\t0.0113\t0.82\t0.58–1.14\t0.2358\t\nHistory of anthracycline-based chemotherapy: yes vs no\t754\t1.04\t0.80–1.31\t0.8458\t\t\t\t\nHistory of endocrine therapy: yes vs no\t754\t0.85\t0.73–0.99\t0.0411\t0.76\t0.62–0.93\t0.0075\t\nNuclear grade: ≤ 2 vs 3\t442\t1.18\t0.97–1.44\t0.0961\t\t\t\t\nKi-67 index: < 30 vs ≥ 30\t332\t1.54\t1.22–1.96\t0.0003\t\t\t\t\nDisease-free interval 1: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months\t703\t1.07\t0.99–1.17\t0.1040\t0.89\t0.78–1.01\t0.0663\t\n(b) Patients with recurrent breast cancer\t\t\t\n\tUnivariate analysis (n = 521)\tMultivariate analysis (n = 456)a\t\nVariable\tn\tHR\t95% CI\tp\tHR\t95% CI\tp\t\nCohort A vs cohort B\t521\t1.31\t1.08–1.60\t0.0073\t1.12\t0.89–1.40\t0.3505\t\nFirst- vs second-line therapy\t521\t1.33\t1.11–1.60\t0.0021\t1.16\t0.94–1.43\t0.1643\t\nAge: < 50 years vs ≥ 50 years\t521\t1.01\t0.84–1.20\t0.9470\t\t\t\t\nPS: 0 vs 1, 2, or 3\t521\t1.74\t1.43–2.11\t < 0.0001\t1.49\t1.19–1.88\t0.0006\t\nVisceral metastasis: yes vs no\t521\t0.74\t0.59–0.93\t0.0086\t0.78\t0.60–1.00\t0.0518\t\nCancer-related symptoms: yes vs no\t518\t0.62\t0.52–0.74\t < 0.0001\t0.67\t0.55–0.83\t0.0002\t\nNeoadjuvant or adjuvant chemotherapy: yes vs no\t508\t0.66\t0.54–0.81\t0.0001\t0.85\t0.63–1.14\t0.2795\t\nNeoadjuvant or adjuvant taxane-based chemotherapy: yes vs no\t508\t0.67\t0.56–0.81\t < 0.0001\t0.78\t0.60–1.01\t0.0573\t\nHistory of taxane-based chemotherapy: yes vs no\t521\t0.66\t0.45–0.97\t0.0361\t0.75\t0.47–1.21\t0.2333\t\nHistory of anthracycline-based chemotherapy: yes vs no\t521\t0.88\t0.60–1.28\t0.5067\t\t\t\t\nHistory of hormone therapy: yes vs no\t521\t1.07\t0.89–1.28\t0.4891\t\t\t\t\nNuclear grade: ≤ 2 vs 3\t299\t1.05\t0.83–1.33\t0.6669\t\t\t\t\nKi-67 index: < 30 vs ≥ 30\t178\t1.46\t1.07–2.00\t0.0174\t\t\t\t\nDisease-free interval 1: ≤ 24 months vs > 24 months\t470\t0.51\t0.42–0.61\t < 0.0001\t0.54\t0.44–0.67\t < 0.0001\t\nVariables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis\n\nCI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio\n\n\n\nMultivariate analysis also identified several baseline characteristics as independent predictors of prognosis in the 521 patients with recurrent breast cancer (Table 4b): ECOG PS ≥ 1, cancer-related symptoms, and DFI ≤ 24 months.\n\nIn the sensitivity analysis, the results for OS and PFS in treated patients were similar to those for the eligible patient population (Supplementary Tables 3 and 6).\n\nORR in patients with measurable lesions was 56.1%, 59.3%, 48.8%, 62.2%, and 45.1% in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Table 5a). ORRs by cohort and treatment line are summarized in Table 5b.Table 5 Overall response rate in patients with measurable lesions\n\n(a) All eligible patients\t\n\tAll eligible patients\tCohort Aa\tCohort Bb\tP\tFirst-line therapy\tSecond-line therapy\tp\t\nNo. of patients with target lesions\t545\t383\t162\t\t352\t193\t\t\nBest response, n (%)\t\t\t\t\t\t\t\t\n CR\t14 (2.6%)\t8 (2.1%)\t6 (3.7%)\t0.0180 (W)\t10 (2.8%)\t4 (2.1%)\t0.0001 (W)\t\n PR\t292 (53.6%)\t219 (57.2%)\t73 (45.1%)\t\t209 (59.4%)\t83 (43.0%)\t\t\n SD\t139 (25.5%)\t104 (27.2%)\t35 (21.6%)\t\t77 (21.9%)\t62 (32.1%)\t\t\n PD\t71 (13.0%)\t36 (9.4%)\t35 (21.6%)\t\t35 (9.9%)\t36 (18.7%)\t\t\n NE\t29 (5.3%)\t16 (4.2%)\t13 (8.0%)\t\t21 (6.0%)\t8 (4.1%)\t\t\nResponse rate, n (%)\t\t\t\t\t\t\t\t\n CR plus PR\t306 (56.1%)\t227 (59.3%)\t79 (48.8%)\t0.0297 (F)\t219 (62.2%)\t87 (45.1%)\t0.0001 (F)\t\n 95% CI\t51.9–60.4\t54.2–64.2\t40.8–56.7\t\t56.9–67.3\t37.9–52.4\t\t\n(b) Cohorts A and B\t\n\tCohort Aa\tFirst-line therapy\tSecond-line therapy\tP\tCohort Bb\tFirst-line therapy\tSecond-line therapy\tp\t\nNo. of patients with target lesions\t383\t252\t131\t\t162\t100\t62\t\t\nBest response\t\t\t\t\t\t\t\t\t\n CR\t8 (2.1%)\t6 (2.4%)\t2 (1.5%)\t0.0048 (W)\t6 (3.7%)\t4 (4.0%)\t2 (3.2%)\t0.0011 (W)\t\n PR\t219 (57.2%)\t155 (61.5%)\t64 (48.9%)\t\t73 (45.1%)\t54 (54.0%)\t19 (30.6%)\t\t\n SD\t104 (27.2%)\t57 (22.6%)\t47 (35.9%)\t\t35 (21.6%)\t20 (20.0%)\t15 (24.2%)\t\t\n PD\t36 (9.4%)\t21 (8.3%)\t15 (11.5%)\t\t35 (21.6%)\t14 (14.0%)\t21 (33.9%)\t\t\n NE\t16 (4.2%)\t13 (5.2%)\t3 (2.3%)\t\t13 (8.0%)\t8 (8.0%)\t5 (8.1%)\t\t\nResponse rate\t\t\t\t\t\t\t\t\t\n CR plus PR\t227 (59.3%)\t161 (63.9%)\t66 (50.4%)\t0.0119 (F)\t79 (48.8%)\t58 (58.0%)\t21 (33.9%)\t0.0036 (F)\t\n 95% CI\t54.2–64.2\t57.6–69.8\t41.5–59.2\t\t40.8–56.7\t47.7–67.8\t22.3–47.0\t\t\nCR complete response, F Fisher’s exact test, NE not evaluable, PD progressive disease, PR partial response, SD stable disease, W Wilcoxon rank sum test\n\naPatients with hormone receptor-positive breast cancer\n\nbPatients with triple-negative breast cancer\n\n\n\nSafety\nThe great majority of eligible patients (96.3%) experienced at least one AE, and 63.1% experienced one or more grade ≥ 3 AEs. Table 6 lists the AEs in treated patients. Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.Table 6 Incidence of adverse events (AEs)\n\n\tTreated patient population\tCohort Aa\tCohort Bb\tFirst-line therapy\tSecond-line therapy\t\n\tn\t(%)\tn\t(%)\tn\t(%)\tn\t(%)\tn\t(%)\t\n(a) Selected AEs\t\t\t\t\t\t\t\t\t\t\t\n No. of patients\t750\t100\t538\t100\t212\t100\t475\t100\t275\t100\t\n Hypertension\t\t\t\t\t\t\t\t\t\t\t\n All grades\t602\t80.3\t429\t79.7\t173\t81.6\t383\t80.6\t219\t79.6\t\n Grade ≥ 3\t268\t35.7\t190\t35.3\t78\t36.8\t167\t35.2\t101\t36.7\t\n Peripheral neuropathy\t\t\t\t\t\t\t\t\t\t\t\n All grades\t535\t71.3\t400\t74.3\t135\t63.7\t341\t71.8\t194\t70.5\t\n Grade ≥ 3\t54\t7.2\t41\t7.6\t13\t6.1\t36\t7.6\t18\t6.5\t\n Neutropenia\t\t\t\t\t\t\t\t\t\t\t\n All grades\t347\t46.3\t256\t47.6\t91\t42.9\t203\t42.7\t144\t52.4\t\n Grade ≥ 3\t204\t27.2\t151\t28.1\t53\t25.0\t115\t24.2\t89\t32.4\t\n Proteinuria\t\t\t\t\t\t\t\t\t\t\t\n All grades\t223\t29.7\t160\t29.7\t63\t29.7\t156\t32.8\t67\t24.4\t\n Grade ≥ 3\t28\t3.7\t18\t3.3\t10\t4.7\t20\t4.2\t8\t2.9\t\n Bleeding\t\t\t\t\t\t\t\t\t\t\t\n All grades\t131\t17.5\t96\t17.8\t35\t16.5\t87\t18.3\t44\t16.0\t\n Grade ≥ 3\t2\t0.3\t2\t0.4\t0\t0.0\t1\t0.2\t1\t0.4\t\n(b) Bevacizumab-specific AEs other than the selected adverse events (grade ≥ 3)\t\n No. of patients\t750\t100\t538\t100\t212\t100\t475\t100\t275\t100\t\n Congestive heart failure\t5\t0.7\t4\t0.7\t1\t0.5\t3\t0.6\t2\t0.7\t\n Gastrointestinal perforation\t2\t0.3\t2\t0.4\t0\t0.0\t2\t0.4\t0\t0.0\t\n Thromboembolism\t3\t0.4\t3\t0.6\t0\t0.0\t2\t0.4\t1\t0.4\t\n Wound dehiscence\t2\t0.3\t1\t0.2\t1\t0.5\t0\t0.0\t2\t0.7\t\n(c) Other adverse events grade ≥ 3\t\t\t\t\t\t\t\t\t\t\t\n No. of patients\t750\t100\t538\t100\t212\t100\t475\t100\t275\t100\t\n Fatigue\t12\t1.6\t6\t1.1\t6\t2.8\t4\t0.8\t8\t2.9\t\n Stomatitis\t6\t0.8\t6\t1.1\t0\t0.0\t3\t0.6\t3\t1.1\t\n Febrile neutropenia\t4\t0.5\t2\t0.4\t2\t0.9\t1\t0.2\t3\t1.1\t\n Other infections\t23\t3.1\t18\t3.3\t5\t2.4\t15\t3.2\t8\t2.9\t\n Skin disorders\t11\t1.5\t10\t1.9\t1\t0.5\t9\t1.9\t2\t0.7\t\n Anemia\t10\t1.3\t8\t1.5\t2\t0.9\t5\t1.1\t5\t1.8\t\n AST/ALT elevation\t10\t1.3\t6\t1.1\t4\t1.9\t8\t1.7\t2\t0.7\t\n Appetite loss\t7\t0.9\t5\t0.9\t2\t0.9\t3\t0.6\t4\t1.5\t\n Diarrhea\t5\t0.7\t3\t0.6\t2\t0.9\t5\t1.1\t0\t0.0\t\n Drug-induced pneumonitis\t5\t0.7\t4\t0.7\t1\t0.5\t2\t0.4\t3\t1.1\t\n Pain\t4\t0.5\t3\t0.6\t1\t0.5\t2\t0.4\t2\t0.7\t\n Others\t31\t4.1\t24\t4.5\t7\t3.3\t13\t2.7\t18\t6.5\t\nALT alanine aminotransferase, AST aspartate aminotransferase\n\naPatients with hormone receptor-positive breast cancer\n\nbPatients with triple-negative breast cancer\n\n\n\nSerious AEs were recorded in 66 patients (8.8%) including 15 patients with infection, five patients with congestive heart failure and 4 patients with drug-induced pneumonitis, fracture, gastrointestinal perforation, or liver dysfunction (Supplementary Table 7). Treatment-related deaths occurred in 6 patients (0.8%); the causes were liver failure (3 patients), acute gastroenteritis and heart failure (1 patient), gastrointestinal bleeding (1 patient), and gastrointestinal perforation (1 patient). Of the 3 deaths due to liver failure, one had liver failure associated with disease progression, and the other two had so-called pseudocirrhosis, which is associated with liver atrophy due to acute tumor response by chemotherapy on massive liver metastases and disorder of subsequent liver regeneration process.\n\nDiscussion\nThe B-SHARE study was a prospective observational study to investigate the effectiveness and safety of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for HER2-negative LA/mBC under real-world clinical conditions in Japan. During the median observation period of 19.7 months, median OS for eligible patients was 21.7 months, and median OS for eligible patients receiving first-line therapy was 24.4 months. These results are within the range (21.6–30.2 months) achieved in previous phase III studies [14–16] and observational studies [8–11, 17]. Although there have been no previous observational studies on bevacizumab plus paclitaxel as second-line therapy, median OS for eligible patients receiving second-line therapy in the present study (17.6 months) was similar to the 18.0 months achieved in the RIBBON-2 study conducted as second-line chemotherapy [18], in which the efficacy and safety of bevacizumab combined with standard chemotherapy was compared with standard chemotherapy alone.\n\nThe 74.1% 1-year median OS for first-line therapy was a good result and similar to that determined by a meta-analysis of data from randomized controlled studies of bevacizumab combined with chemotherapy as first-line therapy (i.e. 71%) [6], showing that bevacizumab combined with chemotherapy may improve 1-year OS when compared with chemotherapy alone in high-risk patients.\n\nThe multivariate analysis results for OS in eligible patients identified TNBC, second-line therapy, poor PS, perioperative history of taxane therapy, cancer-related symptoms, DFI ≤ 2 years (i.e. recurrent breast cancer), and visceral metastasis as independent factors for poor prognosis. This is similar to the findings of previous studies on chemotherapy with [19] or without bevacizumab [20–23].\n\nOS was significantly longer in patients receiving first-line therapy than in those receiving second-line therapy in cohort A but not in cohort B. Regarding baseline characteristics in cohort B, the proportions of patients with distant metastasis and metastasis to ≥ 3 organs were higher in those receiving first-line therapy than in those receiving second-line therapy, but no differences were found for the other factors. After completion of the study treatment, a greater proportion of patients receiving first-line therapy in cohort B were transferred to best supportive care compared with those in cohort A (33.1% and 21.2%, respectively). These findings suggest that patients with TNBC are less likely than those with hormone receptor-positive cancer to continue therapy because of many poor prognostic factors, but when patients were able to undergo second-line and subsequent therapy, they are likely to have a better prognosis.\n\nAs for first-line therapy, median PFS in eligible patients was 9.3 months and ORR in those with measurable lesions was 62.2%. As with OS, the results were consistent with those of previous randomized controlled studies [14, 15, 24, 25] and observational studies [8–11, 17]. For second-line therapy, median PFS was 7.2 months and ORR was 45.1%, similar to the results of the RIBBON-2 study [18].\n\nThe multivariate analysis results for PFS in eligible patients, including those with advanced disease, identified TNBC, poor PS, history of endocrine therapy, cancer-related symptoms, history of perioperative chemotherapy, history of perioperative taxane, and visceral metastasis as factors indicating poor prognosis. However, in patients with recurrent breast cancer, poor PS, cancer-related symptoms, and DFI ≤ 2 years were independent factors for poor prognosis. Therefore, poor prognostic factors for PFS differed with patient background. Although poor PS and cancer-related symptoms may be considered mutually associated, they were independent poor prognostic factors for both OS and PFS, regardless of whether the cancer was advanced or recurrent. The possibility that cancer-related symptoms are a poor prognostic factor in LA/mBC is supported by several other studies [23, 26, 27].\n\nDespite the similarity in effectiveness (i.e. OS, PFS, and ORR) shown in the present study to that obtained in randomized controlled studies [14–16, 24] and observational studies [8–11, 17], the dosing period for bevacizumab in first-line therapy (5.3 months) was shorter than in randomized controlled studies [24, 25]. In fact, the bevacizumab dosing period tends to be shorter in observational studies [8–11, 17] than in randomized controlled studies [24, 25]. However, the bevacizumab dosing period in a retrospective cohort study [11] using information from the French Epidemiological Strategy and Medical Economics database was similar to that of the present study. The shorter dosing period in the present study compared with in randomized controlled studies may have been due to differences in patient selection (with poorer PS) and adherence to treatment. In the present study, 15.3% of patients were aged ≥ 70 years, and 8.0% had PS of ≥ 2. About 30% of patients discontinued treatment because of AEs, which is similar to that in the randomized controlled studies, whereas about 20% discontinued treatment without having disease progress (e.g. undergoing surgery after tumor shrinkage or switching to endocrine therapy).\n\nNo new AEs related to bevacizumab plus paclitaxel were detected in the present study. Incidence of all grades of AEs (96.3%) and those of grade ≥ 3 (63.1%) were higher than in previous randomized controlled studies [14, 18, 24, 25] and observational studies [8–10, 17]. However, there was no increase in the incidence of serious AEs or treatment-related deaths. We experienced 2 cases of treatment-related death due to so-called pseudocirrhosis during treatment of bevacizumab plus paclitaxel. Pseudocirrhosis is characterized by morphological changes in the liver that resembling cirrhosis on the radiological findings without typical histopathology of cirrhosis [28]. Pseudocirrhosis as adverse events by chemotherapy is not rare and an important complication of chemotherapy in patients with liver metastases. Recently, Oliai et al. [29] reported that pseudocirrhosis developed in 37 (55%) of 67 metastatic breast cancer patients with liver metastasis and was associated with poor prognosis in patients with live metastasis. They also described that chemotherapy agents associated with the development of pseudocirrhosis were albumin-bound paclitaxel, capecitabine, cisplatin, everolimus and vinorelbine. This adverse event is not bevacizumab-specific. However, the possibility that bevacizumab may inhibit the process of liver regeneration after treatment-induced hepatic injury cannot be ruled out.\n\nThe present study had several limitations. First, it was a single-arm observational study of bevacizumab plus paclitaxel combination therapy, so there was no direct comparison in terms of the effectiveness and safety between bevacizumab plus paclitaxel and paclitaxel alone. Second, treatment effectiveness (PFS and ORR) was assessed by attending physicians, and HR and HER2 status were also assessed at each facility. Central assessment or review was not done for the evaluation of effectiveness and those receptors status. Third, most patients received treatment in accordance with the treatment regimen used in the JO19901 study. Therefore, we could not examine the relationship between the dosage or the schedule of bevacizumab plus paclitaxel and its effectiveness to find the optimal use of this combination. Fourth, because the present study was done under daily clinical conditions, discontinuation due to the wishes of the patient or the decision of the attending physician was possible, regardless of whether the effects of treatment were sustained. During the course of treatment, various strategies were adopted after tumor reduction due to study treatment, such as discontinuation of treatment, switching to hormonal therapy for maintenance, or surgical intervention, which are uncommon in randomized controlled studies. The limitations of the present study make it difficult to obtain a true result for PFS and ORR. However, OS is a robust endpoint and we consider the OS reported here to be close to its true value, because it was achieved in patients treated with bevacizumab plus paclitaxel under real clinical conditions.\n\nIn conclusion, bevacizumab plus paclitaxel as first- or second-line chemotherapy in Japanese patients with HER2-negative LA/mBC was as effective as in previous randomized controlled studies and prospective observational studies. Furthermore, the good tolerability of this regimen was confirmed.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.Supplementary file1 (XLSX 85 kb)\n\n Supplementary file2 (PDF 953 kb)\n\n \n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors thank patients who participated in this study and their families, as well as the ranchers and medical staff involved in the study.\n\nFunding\nThe study was funded by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.\n\nCompliance with ethical standards\nConflict of interest\nYamamoto Y reports grants and personal fees from Daiichi-Sankyo, grants and personal fees from Eisai, grants and personal fees from Eli Lilly, grants and personal fees from Takeda, personal fees from Sysmex, personal fees from GE Health Care Japan, personal fees from AstraZeneca, grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Nihon Kayaku, grants and personal fees from Kyowa-Kirin, grants and personal fees from Taiho, grants and personal fees from Chugai, outside the submitted work; and A board member of the Japanese Breast Cancer Society, A board member of the Japan Breast Cancer Research Group. Yamashiro H reports personal fees from Chugai, personal fees from Daiich Sankyo, personal fees from Pfizer, personal fees from Kyowa Kirin, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Takeda, personal fees from Taiho outside the submitted work; Toh U reports remuneration from Chugai, Kyowa Kirin, Daiichi Sankyo, Taiho, Nihon Kayaku and Eisai, outside the submitted work; Kondo N reports personal fees from Chugai, personal fees from Eli Lilly, personal fees from Pfizer, personal fees from AstraZeneca, outside the submitted work; Nakamura R reports personal fees from Chugai, outside the submitted work; Kashiwaba M reports Speaker's bureaus from Chugai, Novartis, Kyowa Kirin, Pfizer, AstraZeneca, Taiho, Eisai, Daiichi Sankyo and Shionogi, outside the submitted work; Takahashi M reports personal fees from Chugai, grants and personal fees from Nippon Kayaku, outside the submitted work; Tsugawa K reports grants and personal fees from AstraZeneca, grants and personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, grants and personal fees from Takeda, grants and personal fees from Nippon Kayaku, grants from MSD, personal fees from Eli Lilly, personal fees from Daiichi Sankyo, personal fees from Pfizer, during the conduct of the study; Ishikawa T reports grants and other from Eisai, grants and other from Nihon Kayaku, grants and other from Chugai, grants and other from Taiho, grants from Sanofi, grants and other from Eli Lilly, other from Pfizer, outside the submitted work; Nakayama T reports personal fees from Chugai, personal fees from Novartis, personal fees from Eli Lilly, personal fees from AstraZeneca, personal fees from Taiho, personal fees from Eisai, personal fees from Takeda, outside the submitted work; Ohtani S reports other from Chugai, other from Eisai, other from AstraZeneca, other from Pfizer, other from Eli Lilly, outside the submitted work; Takano T reports grants and personal fees from Daiichi Sankyo, grants and personal fees from Kyowa Kirin, grants and personal fees from Eisai, personal fees from Pfizer, personal fees from Eli Lilly, grants from Ono, grants from MSD, grants from Merck Serono, grants from Taiho, grants from Novartis, grants from Chugai, outside the submitted work; Fujisawa T reports personal fees from Chugai, personal fees from Eli Lilly, during the conduct of the study; Toyama T reports grants and personal fees from Chugai, grants and personal fees from Novartis, grants and personal fees from Eisai, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Taiho, personal fees from Daiichi Sankyo, personal fees from Nippon Kayaku, personal fees from Pfizer, personal fees from Takeda, during the conduct of the study; Kawaguchi H reports personal fees from Pfizer, personal fees from Chugai, personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Eisai, personal fees from Kyowa Kirin, personal fees from Novartis, personal fees from Taiho, personal fees from Takeda, personal fees from Nippon Chemiphar, personal fees from Daiichi Sankyo, during the conduct of the study; Mashino K reports personal fees from Chugai, outside the submitted work; Tanino Y reports grants from Sysmex Corporation, other from Ono, other from Chugai, other from Novartis, other from Pfizer, other from Daiichi-Sankyo, other from Eli Lilly, other from Taiho, other from Eisai, outside the submitted work; Dr. Morita reports personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb Company, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from MSD, personal fees from Pfizer, personal fees from Taiho, outside the submitted work; Toi M reports grants and personal fees from Chugai, grants and personal fees from Takeda, grants and personal fees from Pfizer, grants and personal fees from Kyowa Kirin, grants and personal fees from C & C Res Lab, grants and personal fees from Taiho, grants from JBCRG association, grants and personal fees from Eisai, grants and personal fees from Daiichi Sankyo, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from MSD, personal fees from Genomic Health, personal fees from Novartis, personal fees from Konica Minolta, grants from Astellas, outside the submitted work; and Board of directors; JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast cancer Research Network. Ohno S reports personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Nippon Kayaku, outside the submitted work;\n\nEthical statement\nThe study was carried out in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research of the Ministry of Health, Labour and Welfare of Japan. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution.\n\nInformed consent\nWritten informed consent was obtained from all patients.\n==== Refs\nReferences\n1. Ferrara N Hillan KJ Gerber HP Novotny W Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer Nat Rev Drug Discov 2004 3 391 400 10.1038/nrd1381 15136787 \n2. Toi M Matsumoto T Bando H Vascular endothelial growth factor: its prognostic, predictive, and therapeutic implications Lancet Oncol 2001 2 667 673 10.1016/S1470-2045(01)00556-3 11902537 \n3. Presta LG Chen H O’Connor SJ Chisholm V Meng YG Krummen L Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders Cancer Res 1997 57 4593 4599 9377574 \n4. Willett CG Boucher Y di Tomaso E Duda DG Munn LL Tong RT Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer Nat Med 2004 10 145 147 10.1038/nm988 14745444 \n5. Wagner AD, Thomssen C, Haerting J, Unverzagt S. Vascular-endothelial-growth-factor (VEGF) targeting therapies for endocrine refractory or resistant metastatic breast cancer. Cochrane Database Syst Rev. 2012;11:CD008941. 10.1002/14651858.CD008941.pub2.\n6. Miles DW Diéras V Cortés J Duenne AA Yi J O’Shaughnessy J First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients Ann Oncol 2013 24 2773 2780 10.1093/annonc/mdt276 23894038 \n7. Aogi K Masuda N Ohno S Oda T Iwata H Kashiwaba M First-line bevacizumab in combination with weekly paclitaxel for metastatic breast cancer: efficacy and safety results from a large, open-label, single-arm Japanese study Breast Cancer Res Treat 2011 129 829 838 10.1007/s10549-011-1685-x 21805309 \n8. Smith IE Pierga JY Biganzoli L Cortés-Funes H Thomssen C Pivot X Fabi A First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients Ann Oncol 2011 22 595 602 10.1093/annonc/mdq430 20819780 \n9. Dank M Budi L Piko B Mangel L Erfan J Cseh J First-line bevacizumab-paclitaxel in 220 patients with metastatic breast cancer: results from the AVAREG study Anticancer Res 2014 34 1275 1280 24596372 \n10. Schneeweiss A Förster F Tesch H Aktas B Gluz O Geberth M First-line bevacizumab-containing therapy for HER2-negative metastatic breast cancer: final results from a prospective German study Anticancer Res 2016 36 967 974 26976985 \n11. Delaloge S Pérol D Courtinard C Brain E Asselain B Bachelot T Paclitaxel plus bevacizumab or paclitaxel as first-line treatment for HER2-negative metastatic breast cancer in a multicenter national observational study Ann Oncol 2016 27 1725 1732 10.1093/annonc/mdw260 27436849 \n12. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (Japanese Clinical Oncology Group edition). 2020. https://www.jcog.jp/doctor/tool/CTCAEv4J_20170912_version.pdf\n13. Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Japanese Clinical Oncology Group edition). 2020. https://www.jcog.jp/doctor/tool/RECISTv11J_20100810.pdf\n14. Miller K Wang M Gralow J Dickler M Cobleigh M Perez EA Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer N Engl J Med 2007 357 2666 2676 10.1056/NEJMoa072113 18160686 \n15. Gray R Bhattacharya S Bowden C Miller K Comis RL Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer J Clin Oncol 2009 27 4966 4972 10.1200/JCO.2008.21.6630 19720913 \n16. Miles D Cameron D Hilton M Garcia J O’Shaughnessy J Overall survival in MERiDiAN, a double-blind placebo-controlled randomised phase III trial evaluating first-line bevacizumab plus paclitaxel for HER2-negative metastatic breast cancer Eur J Cancer 2018 90 153 155 10.1016/j.ejca.2017.10.018 29174181 \n17. Smith I, Pierga JY, Biganzoli L, Cortes-Funes H, Thomssen C, Saracchini S, et al. Final overall survival results and effect of prolonged (≥1 year) first-line bevacizumab-containing therapy for metastatic breast cancer in the ATHENA trial. Breast Cancer Res Treat. 2011;130:133–143. 10.1007/s10549-011-1695-8.\n18. Brufsky AM Hurvitz S Perez E Swamy R Valero V O’Neill V RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer J Clin Oncol 2011 29 4286 4293 10.1200/JCO.2010.34.1255 21990397 \n19. Llombart-Cussac A Pivot X Biganzoli L Cortes-Funes H Pritchard KI Pierga JY A prognostic factor index for overall survival in patients receiving first-line chemotherapy for HER2-negative advanced breast cancer: an analysis of the ATHENA trial Breast 2014 23 656 662 10.1016/j.breast.2014.06.017 25047747 \n20. Yamamoto N Watanabe T Katsumata N Omuro Y Ando M Fukuda H Construction and validation of a practical prognostic index for patients with metastatic breast cancer J Clin Oncol 1998 16 2401 2408 10.1200/JCO.1998.16.7.2401 9667257 \n21. Kramer JA Curran D Piccart M de Haes JC Bruning P Klijn J Identification and interpretation of clinical and quality of life prognostic factors for survival and response to treatment in first-line chemotherapy in advanced breast cancer Eur J Cancer 2000 36 1498 1506 10.1016/S0959-8049(00)00144-1 10930797 \n22. Sledge GW Neuberg D Bernardo P Ingle JN Martino S Rowinsky EK Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193) J Clin Oncol 2003 21 588 592 10.1200/JCO.2003.08.013 12586793 \n23. Smyth EN Shen W Bowman L Peterson P John W Melemed A Patient-reported pain and other quality of life domains as prognostic factors for survival in a phase III clinical trial of patients with advanced breast cancer Health Qual Life Outcomes 2016 14 52 10.1186/s12955-016-0449-z 27016084 \n24. Robert NJ Diéras V Glaspy J Brufsky AM Bondarenko I Lipatov ON RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer J Clin Oncol 2011 29 1252 1260 10.1200/JCO.2010.28.0982 21383283 \n25. Miles D Cameron D Bondarenko I Manzyuk L Alcedo JC Lopez RI Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): a double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation Eur J Cancer 2017 70 146 155 10.1016/j.ejca.2016.09.024 27817944 \n26. Niikura N Liu J Hayashi N Palla SL Tokuda Y Hortobagyi GN Retrospective analysis of antitumor effects of zoledronic acid in breast cancer patients with bone-only metastases Cancer 2012 118 2039 2047 10.1002/cncr.26512 22139648 \n27. Niikura N Hayashi N Masuda N Takashima S Nakamura R Watanabe K Treatment outcomes and prognostic factors for patients with brain metastases from breast cancer of each subtype: a multicenter retrospective analysis Breast Cancer Res Treat 2014 147 103 112 10.1007/s10549-014-3090-8 25106661 \n28. Adike A Karline N Menias C Carey EJ Pseudocirrhosis: a case series and literature review Case Rep Gastroenterol 2016 10 381 391 10.1159/000448066 27721722 \n29. Oliai C Douek ML Rhoane C Bhutada A Ge PS Runyon BA Clinical features of pseudocirrhosis in metastatic breast cancer Breast Cancer Res Treat 2019 177 409 417 10.1007/s10549-019-05311-y 31175499\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1340-6868",
"issue": "28(1)",
"journal": "Breast cancer (Tokyo, Japan)",
"keywords": "Bevacizumab; First line; Locally advanced breast cancer; Metastatic breast cancer; Overall survival; Paclitaxel; Second line",
"medline_ta": "Breast Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D014408:Biomarkers, Tumor; D001940:Breast; D001943:Breast Neoplasms; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D011379:Prognosis; D000077982:Progression-Free Survival; D011446:Prospective Studies; D018719:Receptor, ErbB-2; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone",
"nlm_unique_id": "100888201",
"other_id": null,
"pages": "145-160",
"pmc": null,
"pmid": "32715420",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "27016084;27817944;12586793;31175499;24596372;10930797;21830015;20819780;9377574;23894038;22139648;26976985;19720913;25106661;22786517;11902537;25047747;27436849;18160686;9667257;21990397;14745444;21383283;15136787;27721722;29174181;21805309",
"title": "Prospective observational study of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for locally advanced or metastatic breast cancer: the JBCRG-C05 (B-SHARE) study.",
"title_normalized": "prospective observational study of bevacizumab combined with paclitaxel as first or second line chemotherapy for locally advanced or metastatic breast cancer the jbcrg c05 b share study"
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"companynumb": "JP-PFIZER INC-2021054068",
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"activesubstancename": "BEVACIZUMAB"
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... |
{
"abstract": "OBJECTIVE\nTo describe zolpidem-associated complex behaviors, including both daytime automatisms and sleep-related parasomnias.\n\n\nMETHODS\nA case series of eight clinical patients and six legal defendants is presented. Patients presented to the author after an episode of confusion, amnesia, or somnambulism. Legal defendants were being prosecuted for driving under the influence, and the author reviewed the cases as expert witness for the defense. Potential predisposing factors including comorbidities, social situation, physician instruction, concomitant medications, and patterns of medication management were considered.\n\n\nRESULTS\nPatients and defendants exhibited abnormal behavior characterized by poor motor control and confusion. Although remaining apparently interactive with the environment, all reported amnesia for 3 to 5 hours. In some cases, the episodes began during daytime wakefulness because of accidental or purposeful ingestion of the zolpidem and are considered automatisms. Other cases began after ingestion of zolpidem at the time of going to bed and are considered parasomnias. Risk factors for both wake and sleep-related automatic complex behaviors include the concomitant ingestion of other sedating drugs, a higher dose of zolpidem, a history of parasomnia, ingestion at times other than bedtime or when sleep is unlikely, poor management of pill bottles, and living alone. In addition, similar size and shape of two medications contributed to accidental ingestion in at least one case.\n\n\nCONCLUSIONS\nSleep driving and other complex behaviors can occur after zolpidem ingestion. Physicians should assess patients for potential risk factors and inquire about parasomnias. Serious legal and medical complications can occur as a result of these forms of automatic complex behaviors.",
"affiliations": "Division of Neurology, Scripps Clinic, La Jolla, CA 92037, USA. spoceta@cox.net",
"authors": "Poceta|J Steven|JS|",
"chemical_list": "D006993:Hypnotics and Sedatives; D011725:Pyridines; D000077334:Zolpidem",
"country": "United States",
"delete": false,
"doi": "10.5664/jcsm.1468",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1550-9389",
"issue": "7(6)",
"journal": "Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine",
"keywords": "Zolpidem; automatism; parasomnia; sleep driving",
"medline_ta": "J Clin Sleep Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D001332:Automatism; D001334:Automobile Driving; D005260:Female; D005500:Follow-Up Studies; D006261:Headache; D006801:Humans; D006993:Hypnotics and Sedatives; D016365:Liability, Legal; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D011725:Pyridines; D018570:Risk Assessment; D012494:Sampling Studies; D012720:Severity of Illness Index; D007319:Sleep Initiation and Maintenance Disorders; D013009:Somnambulism; D000077334:Zolpidem",
"nlm_unique_id": "101231977",
"other_id": null,
"pages": "632-8",
"pmc": null,
"pmid": "22171202",
"pubdate": "2011-12-15",
"publication_types": "D016428:Journal Article",
"references": "17542950;9456462;18690971;11210892;16025317;21367628;19670914;20363670;18463368;10831020;21056232;19961034;10221293;12454557;3413202;9008515;2878460;18954831;18998740;2226217;10525757;11090095;14607350;17162987;19294961;19393793;10510148;17417081;8690830;8195460;15451764;10367554;20532117;19552733",
"title": "Zolpidem ingestion, automatisms, and sleep driving: a clinical and legal case series.",
"title_normalized": "zolpidem ingestion automatisms and sleep driving a clinical and legal case series"
} | [
{
"companynumb": "US-VIVIMED-2018SP004043",
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"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ZOLPIDEM\\ZOLPIDEM TARTRATE"
},
"drugadditiona... |
{
"abstract": "We describe a case of invasive fungal infection caused by Volvariella volvacea following double umbilical cord blood transplantation (UCBT). Although infections caused by several mushroom species have been documented, we believe this to be the first published report of invasive infection with Volvariella volvacea, an edible mushroom belonging to Agaricales.",
"affiliations": "Medical Oncology Branch, National Cancer Institute, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases,5 NIH, Bethesda, Maryland 20892, USA.",
"authors": "Salit|R B|RB|;Shea|Y R|YR|;Gea-Banacloche|J|J|;Fahle|G A|GA|;Abu-Asab|M|M|;Sugui|J A|JA|;Carpenter|A E|AE|;Quezado|M M|MM|;Bishop|M R|MR|;Kwon-Chung|K J|KJ|",
"chemical_list": "D004271:DNA, Fungal; D004275:DNA, Ribosomal; D021903:DNA, Ribosomal Spacer; D012340:RNA, Ribosomal, 5.8S",
"country": "United States",
"delete": false,
"doi": "10.1128/JCM.01222-10",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0095-1137",
"issue": "48(11)",
"journal": "Journal of clinical microbiology",
"keywords": null,
"medline_ta": "J Clin Microbiol",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D001921:Brain; D036101:Cord Blood Stem Cell Transplantation; D004271:DNA, Fungal; D004275:DNA, Ribosomal; D021903:DNA, Ribosomal Spacer; D017809:Fatal Outcome; D005260:Female; D020459:Genes, rRNA; D006651:Histocytochemistry; D006801:Humans; D008279:Magnetic Resonance Imaging; D008853:Microscopy; D008969:Molecular Sequence Data; D009181:Mycoses; D012340:RNA, Ribosomal, 5.8S; D013902:Radiography, Thoracic; D017422:Sequence Analysis, DNA; D014057:Tomography, X-Ray Computed; D055367:Volvariella",
"nlm_unique_id": "7505564",
"other_id": null,
"pages": "4329-32",
"pmc": null,
"pmid": "20826647",
"pubdate": "2010-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D052060:Research Support, N.I.H., Intramural",
"references": "9316933;11158771;17580255;17453963;20042628;15695724;17135442;12476288;19640404",
"title": "Death by edible mushroom: first report of Volvariella volvacea as an etiologic agent of invasive disease in a patient following double umbilical cord blood transplantation.",
"title_normalized": "death by edible mushroom first report of volvariella volvacea as an etiologic agent of invasive disease in a patient following double umbilical cord blood transplantation"
} | [
{
"companynumb": "US-PFIZER INC-202200103290",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nIn acute optic neuritis, high dose steroid therapy as first - line treatment is contraindicated in early pregnancy, therapeutic plasma exchanges (TPE) represent an alternative. We report a case of a pregnant woman with progressive, acute optic neuritis subjected to membrane-based therapeutic plasma exchange with extracorporal citrate-based anticoagulation.\n\n\nMETHODS\nA 35 year-old second-time pregnant woman (4th week of gravidity) of Caucasian ethnicity complained of visual impairment of the right eye. She was hospitalized for suspected optic neuritis. In the eye exam central and peripheral scotoma of the right side were found. T2 weighted Magnetic-Resonance Imaging revealed an isolated, prechiasmal lesion of the right optic nerve, and the patient had a delayed p100 latency of visually evoked potentials of the right eye. Cerebrospinal-fluid investigation was unrevealing. The diagnosis of right sided optic neuritis was established. Due to early pregnancy, steroids were contraindicated. Visual disturbances further deteriorated by day 2 in hospital. For therapy, 5 sessions of membrane-based therapeutic plasma exchange with albumin solution were performed. An extracorporal anticoagulation using citrate with calcium substitution was applied. After the second session, there was a subjective improvement of symptoms. At discharge on day 14, visual acuity was no longer impaired, sensitivity to bright light remained. In eye exam at 3.5 months after discharge, the patient ha d a complete recovery. Follow-up gynecological exams were unrevealing.\n\n\nCONCLUSIONS\nThis case of unilateral acute optic neuritis supports the view that membrane-based therpautic plasma exchange without systemic anticoagulation represents a safe intervention in pregnancy.",
"affiliations": "Department of Diabetology & Nephrology, Carl-Thiem Hospital Cottbus, Germany.;Department of Neurology, Carl-Thiem Hospital Cottbus, Germany.;Department of Neurology, Carl-Thiem Hospital Cottbus, Germany.;Department of Radiology, Carl-Thiem Hospital Cottbus, Germany.;Department of Ophthalmology, Carl-Thiem Hospital Cottbus, Germany.;Department of Ophthalmology, Carl-Thiem Hospital Cottbus, Germany.;Department of Diabetology & Nephrology, Carl-Thiem Hospital Cottbus, Germany.;Department of Diabetology & Nephrology, Carl-Thiem Hospital Cottbus, Germany. Electronic address: rpliquett@endothel.de.",
"authors": "Shkodivskyi|Pavlo|P|;Dressel|Alexander|A|;Handreka|Robert|R|;Schulz|Thomas|T|;Kabtimer|Wondwossen|W|;Stelzle|Fabian|F|;Gudowski|Christin|C|;Pliquett|Rainer U|RU|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.transci.2021.103178",
"fulltext": null,
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"issn_linking": "1473-0502",
"issue": "60(5)",
"journal": "Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis",
"keywords": "Anticoagulation; CItrate; Optic neuritis; Plasma exchange; Pregnancy",
"medline_ta": "Transfus Apher Sci",
"mesh_terms": null,
"nlm_unique_id": "101095653",
"other_id": null,
"pages": "103178",
"pmc": null,
"pmid": "34099404",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A case of acute optic neuritis during pregnancy treated by membrane-based therapeutic plasma exchanges without systemic anticoagulation.",
"title_normalized": "a case of acute optic neuritis during pregnancy treated by membrane based therapeutic plasma exchanges without systemic anticoagulation"
} | [
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"companynumb": "DE-LUPIN PHARMACEUTICALS INC.-2022-05047",
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"abstract": "BACKGROUND\nMethotrexate-induced pneumonitis is a rare but potentially fatal side effect. It is a diagnosis of exclusion. There are early and late forms and different cell patterns in the bronchoalveolar lavage (BAL).\n\n\nMETHODS\nWe present a case of acute interstitial lung disease in a 54-year-old patient who had been taking methotrexate for a year and a half for rheumatoid arthritis. After excluding other causes and based on the diagnostic criteria of Searles and McKendry, we could reasonably identify methotrexate as the cause of the lung disease. It was of late onset and the BAL showed neutrophilia and eosinophilia.\n\n\nCONCLUSIONS\nMethotrexate-induced pneumonitis is a diagnosis of exclusion. A late onset combined with the predominance of neutrophils and eosinophils in BAL is rare in the literature, demonstrating the wide heterogeneity of methotrexate-related interstitial lung disease.",
"affiliations": "Service de pneumologie, centre hospitalier universitaire de Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe. Electronic address: benjaminbernier.bb@gmail.com.;Service de pneumologie, centre hospitalier universitaire de Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe.;Service de pneumologie, centre hospitalier universitaire de Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe.",
"authors": "Bernier|B|B|;Gallois|J-C|JC|;Cadelis|G|G|",
"chemical_list": "D008727:Methotrexate",
"country": "France",
"delete": false,
"doi": "10.1016/j.rmr.2020.08.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0761-8425",
"issue": "37(10)",
"journal": "Revue des maladies respiratoires",
"keywords": "Bronchoalveolar lavage; Diagnosis; Diagnostic; Interstitial pneumonia; Lavage broncho-alvéolaire; Methotrexate; Méthotrexate; Pneumopathie interstitielle; Polyarthrite rhumatoïde; Rheumatoid arthritis.",
"medline_ta": "Rev Mal Respir",
"mesh_terms": "D000208:Acute Disease; D001992:Bronchoalveolar Lavage Fluid; D004802:Eosinophilia; D005260:Female; D006801:Humans; D007964:Leukocytosis; D017563:Lung Diseases, Interstitial; D008727:Methotrexate; D008875:Middle Aged; D009504:Neutrophils; D012213:Rheumatic Fever; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8408032",
"other_id": null,
"pages": "829-832",
"pmc": null,
"pmid": "33069501",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute interstitial pneumonia in a patient treated with methotrexate: Late-onset with neutrophilia and eosinophilia in bronchoalveolar lavage fluid.",
"title_normalized": "acute interstitial pneumonia in a patient treated with methotrexate late onset with neutrophilia and eosinophilia in bronchoalveolar lavage fluid"
} | [
{
"companynumb": "FR-PFIZER INC-2020423443",
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"abstract": "Aripiprazole is a third-generation atypical antipsychotic medication, which is widely used for various psychiatric disorders across the lifespan. Aripiprazole can cause side effects including headache, insomnia, agitation, nervousness, lightheadedness, dizziness, somnolence, akathisia, and weight gain. Neutropenia is a less frequent side effect of aripiprazole. The current article reviews a case of a 10-year-old African American boy who developed neutropenia with aripiprazole. It is important for clinicians to be aware of this rare side effect. [Journal of Psychosocial Nursing and Mental Health Services, 56(5), 21-24.].",
"affiliations": null,
"authors": "Felin|Tricia|T|;Naveed|Sadiq|S|;Chaudhary|Amna M|AM|",
"chemical_list": "D014150:Antipsychotic Agents; D000068180:Aripiprazole",
"country": "United States",
"delete": false,
"doi": "10.3928/02793695-20180419-02",
"fulltext": null,
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"issn_linking": "0279-3695",
"issue": "56(5)",
"journal": "Journal of psychosocial nursing and mental health services",
"keywords": null,
"medline_ta": "J Psychosoc Nurs Ment Health Serv",
"mesh_terms": "D014150:Antipsychotic Agents; D000068180:Aripiprazole; D002648:Child; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008297:Male; D009503:Neutropenia",
"nlm_unique_id": "8200911",
"other_id": null,
"pages": "21-24",
"pmc": null,
"pmid": "29715374",
"pubdate": "2018-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Aripiprazole-Induced Neutropenia: Case Report and Literature Review.",
"title_normalized": "aripiprazole induced neutropenia case report and literature review"
} | [
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"activesubstancename": "GUANFACINE HYDROCHLORIDE"
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"abstract": "There is a dearth of robust evidence regarding coronavirus disease 2019 (COVID-19)-related coetaneous manifestations, complications and adverse treatment events. Upon review of the literature there are only a few cases reported of acute generalized exanthematous pustulosis (AGEP) in COVID-19 patients after treatment. Therefore, we are reporting a case of a 34-year-old male not known to have any chronic illness. His severe COVID-19 infection resolved four days prior to presentation to the Emergency Department with pustular rash on erythematous base over his face, neck, upper limbs, anterior and posterior trunk including oral cavity and tounge. The rash started after he took azithromycin, oseltamivir, ribavirin, lopinavir, hydroxychloroquine, prednisolone, ceftriaxone, clindamycin, interferon (IFN) beta, and ceftazidime for COVID-19. Skin punch biopsy was done and he was diagnosed with AGEP but it was still not known if it was related to COVID-19 or a drug-induced condition. Patient was treated with betamethasone valerate 0.1% ointment and lotion, promethazine hydrochloride 25mg tablet, paracetamol 500mg tablet, calcipotriol 50mcg/g and betamethasone 0.5mg/g gel. He discharged the same day to manage at home despite not improving. In the end, we found only a few studies that describe the cutaneous manifestations of COVID-19 infection, which were mainly case reports. We can't be sure that AGEP is a late and severe complication of COVID-19 infection. However, AGEP could be a rare adverse effect of hydroxychloroquine therapy. Improving the knowledge about a wide range of different signs and symptoms of the disease and its severity in addition to all possible adverse treatment events and complications can improve patient safety, survival rate, and quality of life.",
"affiliations": "Medicine, Imam Abdulrahman Bin Faisal University, Dammam, SAU.;Emergency Department, Imam Abdulrahman Bin Faisal University, Dammam, SAU.;Emergency Department, Imam Abdulrahman Bin Faisal University, King Fahad University Hospital, Dammam, SAU.",
"authors": "Alzahrani|Malak J|MJ|;Moussa|Mohamed M|MM|;Alfaraj|Dunya|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.11609",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.11609\nDermatology\nEmergency Medicine\nInfectious Disease\nAcute Generalized Exanthematous Pustulosis After COVID‐19 Infection: A Case Report From Saudi Arabia\nMuacevic Alexander Adler John R Alzahrani Malak J 1 Moussa Mohamed M 2 Alfaraj Dunya 3 \n1 \nMedicine, Imam Abdulrahman Bin Faisal University, Dammam, SAU \n\n2 \nEmergency Department, Imam Abdulrahman Bin Faisal University, Dammam, SAU \n\n3 \nEmergency Department, Imam Abdulrahman Bin Faisal University, King Fahad University Hospital, Dammam, SAU \n\nMalak J. Alzahrani malak-7m@hotmail.com\n21 11 2020 \n11 2020 \n12 11 e1160921 11 2020 Copyright © 2020, Alzahrani et al.2020Alzahrani et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/43493-acute-generalized-exanthematous-pustulosis-after-covid19-infection-a-case-report-from-saudi-arabiaThere is a dearth of robust evidence regarding coronavirus disease 2019 (COVID-19)-related coetaneous manifestations, complications and adverse treatment events. Upon review of the literature there are only a few cases reported of acute generalized exanthematous pustulosis (AGEP) in COVID‐19 patients after treatment.\n\nTherefore, we are reporting a case of a 34-year-old male not known to have any chronic illness. His severe COVID-19 infection resolved four days prior to presentation to the Emergency Department with pustular rash on erythematous base over his face, neck, upper limbs, anterior and posterior trunk including oral cavity and tounge. The rash started after he took azithromycin, oseltamivir, ribavirin, lopinavir, hydroxychloroquine, prednisolone, ceftriaxone, clindamycin, interferon (IFN) beta, and ceftazidime for COVID-19. Skin punch biopsy was done and he was diagnosed with AGEP but it was still not known if it was related to COVID-19 or a drug-induced condition. Patient was treated with betamethasone valerate 0.1% ointment and lotion, promethazine hydrochloride 25mg tablet, paracetamol 500mg tablet, calcipotriol 50mcg/g and betamethasone 0.5mg/g gel. He discharged the same day to manage at home despite not improving.\n\nIn the end, we found only a few studies that describe the cutaneous manifestations of COVID-19 infection, which were mainly case reports. We can’t be sure that AGEP is a late and severe complication of COVID-19 infection. However, AGEP could be a rare adverse effect of hydroxychloroquine therapy. Improving the knowledge about a wide range of different signs and symptoms of the disease and its severity in addition to all possible adverse treatment events and complications can improve patient safety, survival rate, and quality of life.\n\nacute generalized exanthematous pustulosishydroxychloroquinecovid-19cutaneous manifestations of covid-19The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nAlthough cutaneous manifestations in coronavirus disease 2019 (COVID-19) patients are considered an uncommon presentation, there are various cutaneous manifestations reported including exanthems, purpura, urticaria, and varicella‐like vesicles. The first case was reported in Thailand where the patient presented with petechiae rash mimicking a dengue fever and then a few other cases followed [1]. Upon review of the literature we only found a few cases reported worldwide of acute generalized exanthematous pustulosis in COVID‐19 patients after treatment as in our case. The mechanism of this skin manifestation is still poorly understood and there is no evidence yet if it is related to the infection itself or is a serious side effect related to hydroxychloroquine which became widely utilized in the COVID‐19 pandemic. It is important to know these skin manifestations to help the clinicians in diagnosing patients who present with rare COVID-19 symptoms.\n\nCase presentation\nA 34-year-old male not known to have any chronic illness resolved of severe COVID-19 infection four days before presenting to the Emergency Department with pustular rash on erythematous base over his face, neck, upper limbs, anterior and posterior trunk including oral cavity and tongue (Figure 1). He had no previous similar episode nor a family history of any dermatological disease and was not known to be allergic. He was admitted during the last three weeks for COVID-19 and treated with azithromycin, oseltamivir, ribavirin, lopinavir, hydroxychloroquine, prednisolone, ceftriaxone, clindamycin, interferon (IFN) beta and ceftazidime. Vital signs in the Emergency Department were temperature: 39 C, heart rate: 125 bpm, respiratory rate: 22 bpm, blood pressure: 122/60 mmHg, O2: 97% on room air. For the investigation, complete blood count (CBC) result was significant for white blood cells (WBCs) (Table 1).\n\nFigure 1 Clinical presentation of Acute Generalized Exanthematous Pustulosis\na, b, c Marked erythema involved neck, upper limbs, anterior and posterior trunk with multiple distributed pustules.\n\nTable 1 Blood investigations upon admission\nCBC: complete blood count, BUN: blood urea nitrogen, LDH: Lactate dehydrogenase, PT: prothrombin time, PTT: partial thromboplastin time, INR: international normalized ratio.\n\nInvestigations\tReference Range\tPatient Result\t\nCBC\t \t \t\nTotal white blood cells\t4.0-11.0 k/µL\t16.2\t\nHemoglobin\t13.0-18.0 g/dL\t14.0\t\nBiochemistry\t \t \t\nCreatinine\t0.6-1.3 mg/dL\t0.79\t\nBUN\t8.4-21 mg/dL\t7\t\nCa+\t8.4-10.2 mg/dL\t8.1\t\nNa+\t136-146 mEq/L\t137\t\nK+\t3.5-5.1 mEq/L\t4.1\t\nCL-\t98-107 mEq/L\t107\t\nLDH\t81-234 units/L\t203\t\nTotal serum bilirubin\t6.4-8.3 g/dL\t5.9\t\nDirect bilirubin\t0.1-0.5 mg/dL\t0.4\t\nAlbumin\t3.2-5.2 g/dL\t3.3\t\nAlkaline phosphatase\t40-150 units/L\t76\t\nArterial Blood gases\t \t \t\npH\t7.35-7.45\t 7.45\t\npO2\n\t83-108 mmHg\t56.3\t\npCO2\n\t35-45 mmHg\t33.1\t\nCoagulation profile\t \t \t\nPT\t12.9-15.9 seconds\t14.5\t\nPTT\t25.6-42.3 seconds\t35.9\t\nINR\t-\t1.05\t\nSkin punch biopsy was done, and he was diagnosed with acute generalized exanthematous pustulosis (AGEP) but it was still not known if it was related to COVID-19 infection or a drug-induced condition. Patient treated with betamethasone valerate 0.1% ointment and lotion, promethazine hydrochloride 25mg tablet, paracetamol 500mg tablet, calcipotriol 50mcg/g and betamethasone 0.5mg/g gel. He was discharged the same day to manage at home despite not improving because the hospital was occupied with COVID-19 patients.\n\nDiscussion\nA study conducted by Suchonwanit et al. found that the majority of reported COVID-19 cases with cutaneous manifestations from January 1, 2020 to April 19, 2020 have diffuse/scattered papulovesicular lesions on the trunk followed by erythematous rash. Also, AGEP was documented as rare adverse effect of hydroxychloroquine and lopinavir/ritonavir treatment [2]. Similarly, a review done by Marraha et al. about dermatological manifestations of COVID-19 infection found that the most skin rashes were acral areas of erythema with vesicles or pustules and pernio-like lesions followed by erythematous maculopapular lesions [3].\n\nMoreover, Litaiem et al. reported a case in Tunisia of a 39‐year‐old female patient diagnosed with COVID‐19 infection and 18 days after hydroxychloroquine (600 mg daily) initiation she developed cephalocaudal spread of erythematous and pustular plaques. The diagnosis of AGEP was made based on clinical and histopathological examinations. Eventually, the skin lesions were significantly improving after hydroxychloroquine withdrawal. The relation of AGEP and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection or its treatment remain poorly understood [4]. The AGEP generally occurs within 48 hours of treatment initiation but, AGEP arising after hydroxychloroquine treatment is distinguishable by longer incubation period it can be up to two to three weeks. In our case the patient was started on 200 mg tablet orally every 12 hours of hydroxychloroquine treatment on June 5, 2020 after he was diagnosed with COVID-19 and he started to have this skin manifestation on June 27, 2020 while he still on treatment.\n\nOn the other hand, Galván Casas et al. conducted a prospective trial involving 375 cases of COVID-19 patients to study the cutaneous manifestations of COVID-19. He found that the most common skin lesions were maculopapular eruptions (47%) followed by areas of erythema with vesicles or pustules (19%) and urticarial lesions (19%). In addition to that, 59% of erythematous patterns associated with vesicles or pustules that tended to appear late in the evolution of the COVID-19 disease, as opposed to other skin manifestations which tend to appear in the presence of other COVID-19 symptoms [5].\n\nOne of the literature reviews reported that skin manifestations often occurred after initiation or withdrawal of the offending agent. The most known conditions were Johnson syndrome and Toxic Epidermal Necrolysis and the lesser-known AGEP [6]. However, most of those patients were non-COVID-19 patients and used hydroxychloroquine treatment for other reasons including rheumatological diseases. Moreover, the overlap between different cases makes it difficult to know whether these specific dermatological conditions are related to infection or drug-induced.\n\nConclusions\nIn the end, we found only a few studies describing cutaneous manifestations of COVID-19 infection and the majority were case reports. We can’t confirm that AGEP be considered as a late and severe complication of COVID-19 infection. However, AGEP could be a rare adverse effect of hydroxychloroquine therapy. We still need more studies with a large sample size to be more accurate. Improving the knowledge about a wide range of different signs, symptoms of the disease and its severity in addition to all possible treatment adverse events and complications can improve patient safety, survival rate, and quality of life.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study. . issued approval .. Ethical approval:\nNot applicable. The study is exempt from ethical approval in our institution.\nConsent:\nConsent has been obtained from the patient. No identifying details have been used in the article.\n==== Refs\nReferences\n1 COVID-19 can present with a rash and be mistaken for dengue J Am Acad Dermatol Joob B Wiwanitkit V 177 82 2020 \n2 Cutaneous manifestations in COVID-19: lessons learned from current evidence J Am Acad Dermatol Suchonwanit P Leerunyakul K Kositkuljorn C 57 60 83 2020 \n3 A review of the dermatological manifestations of coronavirus disease 2019 (COVID-19) Dermatol Res Pract Marraha F Al Faker I Gallouj S 1 9 2020 2020 \n4 Acute generalized exanthematous pustulosis after COVID‐19 treatment with hydroxychloroquine Dermatol Ther Litaiem N Hajlaoui K Karray M Slouma M Zeglaoui F 1 2 33 2020 \n5 Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases Br J Dermatol Galván Casas C Català A Carretero Hernández G 71 77 183 2020 32348545 \n6 AGEP overlap induced by hydroxychloroquine: a case report and literature review J Community Hosp Intern Med Perspect Mercogliano C Khan M Lin C Mohanty E Zimmerman R 360 362 8 2018 30559945\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(11)",
"journal": "Cureus",
"keywords": "acute generalized exanthematous pustulosis; covid-19; cutaneous manifestations of covid-19; hydroxychloroquine",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e11609",
"pmc": null,
"pmid": "33240733",
"pubdate": "2020-11-21",
"publication_types": "D002363:Case Reports",
"references": "32348545;32213305;32401410;30559945;32339706",
"title": "Acute Generalized Exanthematous Pustulosis After COVID-19 Infection: A Case Report From Saudi Arabia.",
"title_normalized": "acute generalized exanthematous pustulosis after covid 19 infection a case report from saudi arabia"
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"companynumb": "SA-STRIDES ARCOLAB LIMITED-2021SP006116",
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"abstract": "Panayiotopoulos syndrome is a common idiopathic benign epilepsy that has a peak age of onset in early childhood. The syndrome is multifocal and shows significant electroencephalogram (EEG) variability, with occipital predominance. Although a benign syndrome often refers to the absence of neurological and neuropsychological deficits, the syndrome has recently been associated with cognitive impairments. Also, despite frequent occipital EEG abnormalities, research regarding the visual functioning of patients is less reported and often contradictory. The purpose of this study was to gain additional knowledge regarding the neurocognitive functioning of patients with Panayiotopoulos syndrome and specifically to address any visual processing deficits associated with the syndrome. Following diagnosis of the syndrome based on typical clinical and electrophysiological criteria, three patients, aged 5, 8, and 10years were referred by epileptologists for neuropsychological evaluation. Neuropsychological findings suggest that the patients had notable impairments on visual memory tasks, especially in comparison with verbal memory. Further, they demonstrated increased difficulty on picture memory suggesting difficulty retaining information from a crowded visual field. Two of the three patients showed weakness in visual processing speed, which may account for weaker retention of complex visual stimuli. Abilities involving attention were normal for all patients, suggesting that inattention is not responsible for these visual deficits. Academically, the patients were weak in numerical operations and spelling, which both rely partially on visual memory and may affect achievement in these areas. Overall, the results suggest that patients with Panayiotopoulos syndrome may have visual processing and visual memory problems that could potentially affect their academic capabilities. Identifying such difficulties may be helpful in creating educational and remedial assistance programs for children with this syndrome, as well as developing appropriate presentation of information to these children in school.",
"affiliations": "Institute of Biomedical Studies, Baylor University, Waco, TX, USA. Electronic address: Samantha_Hodges@baylor.edu.;Jane and John Justin Neurosciences Center, Cook Children's Medical Center, Fort Worth, TX, USA.;Jane and John Justin Neurosciences Center, Cook Children's Medical Center, Fort Worth, TX, USA.",
"authors": "Hodges|Samantha L|SL|;Gabriel|Marsha T|MT|;Perry|M Scott|MS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "1525-5050",
"issue": "54()",
"journal": "Epilepsy & behavior : E&B",
"keywords": "Neuropsychological outcomes; Occipital epilepsy; Panayiotopoulos syndrome; Visual deficits",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders; D004569:Electroencephalography; D004828:Epilepsies, Partial; D005260:Female; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D013577:Syndrome",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "158-62",
"pmc": null,
"pmid": "26709104",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Neuropsychological findings associated with Panayiotopoulos syndrome in three children.",
"title_normalized": "neuropsychological findings associated with panayiotopoulos syndrome in three children"
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"activesubstancename": "LEVETIRACETAM"
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... |
{
"abstract": "BACKGROUND\nRecent advances have led to the development of oral iron chelators, which have changed clinical practice. The objective of this study was to descriptively assess the use of one such agent, deferasirox, as standard of care treatment in a large pediatric hematology center.\n\n\nMETHODS\nWe retrospectively studied all patients at the Texas Children's Hematology Center who were previously or currently treated with deferasirox. We gathered data on demographics, clinical diagnoses, length of time on chronic transfusions, previous use of deferoxamine, adherence to therapy, and reasons for discontinuation. We also assessed changes in serum ferritin, liver function tests, and creatinine for those on deferasirox for a minimum of 12 months.\n\n\nRESULTS\nFifty-nine patients were studied. Eighty-one percent of patients treated with deferasirox had a diagnosis of sickle cell disease. The mean baseline ferritin level for our study population was 2,117 ng/ml (range 754-7,211). Fifty-three percent of patients had been previously treated with deferoxamine. Adherence to oral therapy was documented in 76% of patients. For those on deferasirox for a minimum of 12 months, serum ferritin decreased in 30% of patients (44% of compliant patients, 11% of poorly compliant patients). Changes in creatinine and liver function tests were mild and did not result in long-term discontinuation of deferasirox in any cases.\n\n\nCONCLUSIONS\nOutside of controlled clinical trials, deferasirox can be utilized safely as an oral iron chelator in children although adherence to therapy and the complex interaction of factors that contribute to iron overload still present challenges for clinicians.",
"affiliations": "Department of Pediatrics, Baylor College of Medicine, Texas Children's Sickle Cell Center, Houston, Texas, USA. Raphael@bcm.edu",
"authors": "Raphael|Jean L|JL|;Bernhardt|M Brooke|MB|;Mahoney|Donald H|DH|;Mueller|Brigitta U|BU|",
"chemical_list": "D001565:Benzoates; D007502:Iron Chelating Agents; D014230:Triazoles; D005293:Ferritins; D000077588:Deferasirox",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.21929",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "52(5)",
"journal": "Pediatric blood & cancer",
"keywords": null,
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000284:Administration, Oral; D001565:Benzoates; D002648:Child; D002675:Child, Preschool; D000077588:Deferasirox; D005260:Female; D005293:Ferritins; D006405:Hematology; D006761:Hospitals; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007502:Iron Chelating Agents; D019190:Iron Overload; D008297:Male; D010372:Pediatrics; D014230:Triazoles",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "616-20",
"pmc": null,
"pmid": "19148949",
"pubdate": "2009-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Oral iron chelation and the treatment of iron overload in a pediatric hematology center.",
"title_normalized": "oral iron chelation and the treatment of iron overload in a pediatric hematology center"
} | [
{
"companynumb": "PHBS2009US00785",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DEFERASIROX"
},
"drugadditional": null,
"drug... |
{
"abstract": "Hepatitis C virus (HCV) infection is common among end-stage renal disease patients undergoing hemodialysis. The standard treatment for HCV infection has been interferon-ribavirin combination prior to renal transplantation. However, compared to direct-acting antiviral agents (DAAs), the risk of graft rejection is higher with interferon therapy. Many recent studies have investigated the efficacy and safety of DAAs for treating HCV infection in kidney disease in adults; however, it has not been established in pediatric patients. To the best of our knowledge, this is the first report describing successful treatment using the DAAs sofosbuvir/daclatasvir in two pediatric kidney transplant recipients who had HCV genotype 1a infection without liver fibrosis.\nCase 1 describes a 13-year-old Indonesian boy who had undergone hemodialysis since 2014 after being diagnosed with end-stage renal disease (ESRD) secondary to bilateral renal hypoplasia. Later, he had HCV infection and was treated with interferon-based therapy with ribavirin prior to living-related renal transplantation (LRRT). The HCV was undetected and his liver function normalized six months after treatment initiation. However, 10 months after treatment initiation, he had HCV virological breakthrough, leading to cessation of interferon therapy. Plans for LRRT were continued and HCV treatment using DAAs was set up to be given post LRRT. Case 2 describes a 14-year-old Indonesian girl who also had hemodialysis prior to LRRT after she was diagnosed with ESRD secondary to nephrotic syndrome. Later, she had HCV infection and was treated with interferon and ribavirin prior to the live-unrelated renal transplantation. HCV infection did not resolve, in addition, she experienced thrombocytopenia-which is a side effect of interferon-resulting in termination of interferon treatment. Both cases were treated with DAAs one year following renal transplantation after reaching stable graft function, leading to achievement of sustained virological response at 24 weeks.\nPost-transplantation treatment of chronic HCV is preferred in KTRs. The sofosbuvir/daclatasvir regimen as an interferon-free therapy is a safe, effective option for HCV infection in pediatric KTRs, who can tolerate sofosbuvir/daclatasvir well and respond favorably without significant adverse events.",
"affiliations": "Department of Child Health, Faculty of Medicine, Universitas Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia.;Department of Child Health, Faculty of Medicine, Universitas Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia.;Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia.;Department of Child Health, Faculty of Medicine, Universitas Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia.;Department of Child Health, Faculty of Medicine, Universitas Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia.",
"authors": "Ambarsari|Cahyani Gita|CG|0000-0003-0387-1031;Hidayati|Eka Laksmi|EL|0000-0003-2896-3645;Hasan|Irsan|I|0000-0003-0656-5216;Grace|Angela|A|0000-0002-1560-972X;Oswari|Hanifah|H|0000-0003-4310-5841",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IJNRD.S248632",
"fulltext": "\n==== Front\nInt J Nephrol Renovasc Dis\nInt J Nephrol Renovasc Dis\nIJNRD\nijnrd\nInternational Journal of Nephrology and Renovascular Disease\n1178-7058 Dove \n\n248632\n10.2147/IJNRD.S248632\nCase Series\nSuccessful Treatment of Hepatitis C Virus Infection Using Direct-Acting Antiviral Agents (DAAs) in Adolescents with Kidney Transplantation: A Case Series\nAmbarsari et alAmbarsari et alhttp://orcid.org/0000-0003-0387-1031Ambarsari Cahyani Gita 1 http://orcid.org/0000-0003-2896-3645Hidayati Eka Laksmi 1 http://orcid.org/0000-0003-0656-5216Hasan Irsan 2 http://orcid.org/0000-0002-1560-972XGrace Angela 1 http://orcid.org/0000-0003-4310-5841Oswari Hanifah 1 1 Department of Child Health, Faculty of Medicine, Universitas Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia\n2 Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia\nCorrespondence: Cahyani Gita Ambarsari Department of Child Health, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Diponegoro 71, Jakarta Pusat10430, IndonesiaTel +62 812-1314-4888Fax +62-21-3907743 Email cahyani.ambarsari@ui.ac.id\n08 6 2020 \n2020 \n13 139 146\n06 2 2020 14 5 2020 © 2020 Ambarsari et al.2020Ambarsari et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Introduction\nHepatitis C virus (HCV) infection is common among end-stage renal disease patients undergoing hemodialysis. The standard treatment for HCV infection has been interferon-ribavirin combination prior to renal transplantation. However, compared to direct-acting antiviral agents (DAAs), the risk of graft rejection is higher with interferon therapy. Many recent studies have investigated the efficacy and safety of DAAs for treating HCV infection in kidney disease in adults; however, it has not been established in pediatric patients. To the best of our knowledge, this is the first report describing successful treatment using the DAAs sofosbuvir/daclatasvir in two pediatric kidney transplant recipients who had HCV genotype 1a infection without liver fibrosis.\n\nCase Presentation\nCase 1 describes a 13-year-old Indonesian boy who had undergone hemodialysis since 2014 after being diagnosed with end-stage renal disease (ESRD) secondary to bilateral renal hypoplasia. Later, he had HCV infection and was treated with interferon-based therapy with ribavirin prior to living-related renal transplantation (LRRT). The HCV was undetected and his liver function normalized six months after treatment initiation. However, 10 months after treatment initiation, he had HCV virological breakthrough, leading to cessation of interferon therapy. Plans for LRRT were continued and HCV treatment using DAAs was set up to be given post LRRT. Case 2 describes a 14-year-old Indonesian girl who also had hemodialysis prior to LRRT after she was diagnosed with ESRD secondary to nephrotic syndrome. Later, she had HCV infection and was treated with interferon and ribavirin prior to the live-unrelated renal transplantation. HCV infection did not resolve, in addition, she experienced thrombocytopenia—which is a side effect of interferon—resulting in termination of interferon treatment. Both cases were treated with DAAs one year following renal transplantation after reaching stable graft function, leading to achievement of sustained virological response at 24 weeks.\n\nConclusion\nPost-transplantation treatment of chronic HCV is preferred in KTRs. The sofosbuvir/daclatasvir regimen as an interferon-free therapy is a safe, effective option for HCV infection in pediatric KTRs, who can tolerate sofosbuvir/daclatasvir well and respond favorably without significant adverse events.\n\nVideo abstract\n\n\nPoint your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use:\n\nhttps://youtu.be/t4Ld_DRvcSM\n\nKeywords\nkidney failurechronicinterferonrenal transplantationantiviral agentshepatitis C\n==== Body\nIntroduction\nHepatitis C virus (HCV) infection is associated with significant morbidity and mortality among renal disease patients undergoing hemodialysis (HD).1 Additionally, in adult kidney transplant recipients (KTR), HCV infection pre-transplantation increases the risk of graft failure and death.1\n\nIn 2009, Kidney Disease Improving Global Outcomes (KDIGO) recommended interferon-based therapy pre-renal transplantation or DAAs post-transplantation for adult KTR with HCV.2 However, recent KDIGO (2018) no longer encourages interferon-based therapy to treat HCV infection in chronic kidney disease (CKD).3 Moreover, direct-acting antiviral agents (DAAs) are recommended for treating chronic HCV-infected KTR because of the poor efficacy and higher risk of acute allograft rejection associated with interferon-based therapy.4 However, there are limited literatures about the use of DAAs in pediatrics and clinical trials are ongoing.5\n\nIn this case series, we report achieving successful eradication—via using DAAs sofosbuvir/daclatasvir regimen—of HCV infection in pediatric KTR without liver fibrosis who experienced treatment failure with interferon and ribavirin prior to renal transplantation. To the best of our knowledge, this is the first report describing successful treatment using DAAs in two pediatric KTR who had HCV genotype 1a infection.\n\nCase Presentation\nCase 1\nA 13-year-old Indonesian boy who experienced successful living-related renal transplantation (LRRT) in 2017 (his 50-year-old father was his kidney donor) has been living with normal graft function. He underwent hemodialysis (HD) in 2014 after being diagnosed with end-stage renal disease (ESRD) secondary to bilateral renal hypoplasia. He was prepared for LRRT in March 2015; however, two months prior to the procedure he was infected with the hepatitis A virus (HAV). The HAV infection subsequently resolved, and LRRT preparations proceeded. Unfortunately, seven days prior to the scheduled LRRT procedure, there was a sudden significant rise in alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, resulting in cancellation of the procedure. The rise in ALT and AST levels was later revealed to be caused by HCV seroconversion (Figure 1). The patient was always hemodialyzed with a single-use dialyzer, and there was no history of blood transfusions or family history of viral hepatitis; however, there was an HCV outbreak in our pediatric dialysis unit in 2015.Figure 1 Course of disease and treatment (Case 1).\n\n\n\nIn April 2015, his liver function markers rose (AST 498 U/L, ALT 816 U/L, Gamma-Glutamyltransferase (GGT) 170 U/L) and he was subsequently diagnosed with HCV infection (viral load 3.75 × 105 IU/mL, 5.57 log IU/mL of serum HCV RNA) (Figure 1). HCV RNA genotype testing was conducted using hybridization probe (The Versant HCV Genotype 2.0 Assay (LiPA), Siemens), which revealed HCV genotype 1a. A 7.3-kPa liver stiffness was observed with transient elastography (fibroscan), which was categorized as F1-F2 (mild–moderate liver fibrosis) (Figure 1).\n\nHe received interferon-based therapy with ribavirin post-HD once a week since September 2015. Six months after treatment initiation, the HCV was undetected and his liver function normalized. However, 10 months after treatment initiation, he had HCV virological breakthrough, suggested by HCV RNA of 1.28 × 104 IU/mL (4.11 Log IU/mL), leading to cessation of interferon therapy.\n\nPlans for LRRT were continued and HCV treatment was set up to be given a year post LRRT when stable renal graft function was achieved. In September 2017, LRRT was conducted. One year post-LRRT, graft function was normal; thus, treatment with DAAs for chronic HCV infection was commenced. Owing to a lack of evidence regarding treatment safety with DAAs in pediatrics, we arranged a thorough discussion with the Hospital Ethics Committee to obtain parental consent. In December 2018, he began receiving sofosbuvir/daclatasvir for 12 weeks. Evaluation immediately after (March 2019), at 12 weeks (June 2019), and at 24 weeks (October 2019) following treatment cessation showed no HCV recurrence (Figure 1). Adverse effects, such as mild fever, fatigue, musculoskeletal pain, decreased appetite, itching and nasal congestion, were not found during treatment with DAAs.\n\nCase 2\nA 14-year-old Indonesian girl who experienced successful live-unrelated renal transplantation from a 21-year-old donor in April 2017 has been living with normal graft function. In November 2014 she was diagnosed with ESRD secondary to nephrotic syndrome and started regular HD via single-use dialyzer. She had a history of repeated blood transfusions but no family history of viral hepatitis.\n\nShe was diagnosed with HCV infection with a high viral load (2.69 × 106 IU/mL, 6.43 log IU/mL of serum HCV RNA) and rising liver function markers (AST 180 U/L, ALT 133 IU/L, GGT 142 U/L) in September 2015 (Figure 2). HCV RNA genotype testing was conducted using hybridization probe (The Versant HCV Genotype 2.0 Assay (LiPA), Siemens), revealing HCV genotype 1a. A 4.8-kPa liver stiffness was observed with transient elastography (fibroscan), which was categorized as F0-F1 (mild liver fibrosis) (Figure 2).Figure 2 Course of disease and treatment (Case 2).\n\n\n\nShe began receiving pegylated interferon and ribavirin in October 2015 prior to renal transplantation. Ten months later (August 2016), real-time PCR still showed the presence of HCV RNA (2.56 × 106 IU/mL, 5.41 Log IU/mL). In addition, she experienced thrombocytopenia—which is a side effect of interferon—resulting in termination of treatment.\n\nIn April 2017, she received kidney transplantation. At two months post-transplantation, she was diagnosed with post-transplant diabetes mellitus (PTDM), which manifested as a spontaneous inguinal abscess (10 × 3 × 0.5 cm), hyperglycemia (617 mg/dL), and ketonemia without acidosis. This PTDM is believed to be associated with her status as HCV-infected KTR, in addition to the side effect of tacrolimus–corticosteroid combination. PTDM resolved after tapering off methylprednisolone and seven months of insulin therapy.\n\nAt 20 months post-renal transplantation, graft function was normal; thus, treatment of HCV infection with DAAs was initiated. Since data about the treatment safety with DAAs in pediatrics are limited, we obtained parental consent after arranging meticulous discussion with the Hospital Ethics Committee. She started receiving sofosbuvir/daclatasvir in December 2018. HCV RNA with real-time PCR immediately after, at 12 weeks, and at 24 weeks after treatment initiation showed no HCV RNA (Figure 2). There were no adverse effects during treatment with DAAs.\n\nDiscussion\nPrevalence of adult hepatitis C in Indonesia is 1.01% (approximately 2.6 million people) in 2017.6 However, its prevalence in children, especially children with ESRD, is unknown. In Egypt, 18% of pediatric CKD cases had HCV infections.7 In our pediatric dialysis unit, the trend of HCV infection fluctuated from 0 to 5 cases among 26 to 38 HD cases per year over the past 6 years. HD is also known as a risk factor of HCV infection in dialysis units; moreover, mortality among the dialysis population with HCV infection in Asia Pacific was higher.8 This fact is dismaying, considering that in Indonesia, the cost of HD per patient annually may reach USD $12,000, two-fold higher than peritoneal dialysis (PD) (USD $6000).9 However, more patients in our setting prefer HD to PD, while the seroconversion rate of HCV was lower in PD compared to HD.8 Nonetheless, we also have been facing challenges in PD setting due to the mechanical complications,9–11 as well as the PD-related infections,9,12 which may contribute to patients’ inclination to HD. Particularly in our unit, these HCV infection cases are good examples to other dialysis patients that in HD unit, there has always a risk of developing HCV infection.\n\nAdaptive and humoral immune responses in HCV infection are commonly delayed by one and two months; hence, HCV specific antibodies can only be detected starting three months after infection. However, the rise of serum transaminases secondary to the infection occurs in advance (approximately two months after initial infection).13 In our first case, there was a significant rise in serum transaminases without detected HCV antibodies, and anti-HCV was reactive in the following month. This phenomenon aligned with the natural course of HCV infection; however, it hindered our diagnosis of HCV infection.\n\nThe major goal of HCV infection treatment in KTR is to prevent viral replication after kidney transplantation.14 A recent recommendation suggests starting DAA treatment after kidney transplantation in CKD with HCV infection to gain 0.5 quality-adjusted live years and to save more than $40,000 over the remaining life span of a KTR.15 Compared to interferon-based therapy, DAAs for HCV infection in KTR has better efficacy and tolerability post-transplantation.16 Side effects of interferon-based therapy include hematological disorder, which is consistent with case 2 in our report who had thrombocytopenia as a side effect of interferon and ribavirin therapy.17 Minor adverse events such as mild fever, fatigue, musculoskeletal pain, decreased appetite, itching and nasal congestion were reported in cases of previous use of DAAs in adolescents.18 Other adverse events in adults were tinnitus, diarrhea, elevation in serum creatinine, abdominal pain, and unstable blood pressure. No such events were noted in our cases.\n\nIn Indonesia, less than 1% of the HCV-infected population was treated with DAAs.19 Recently, FDA approved DAAs (sofosbuvir/ledipasvir) use for children, who are 12 years old or older and weigh at least 35 kg, to treat HCV genotypes 1, 4, 5 and 6 infections.5 Because of the unavailability of sofosbuvir/ledipasvir (Harvoni©) in Indonesia, we used sofosbuvir/daclatasvir regimen, which is being supported by the government. Use of Harvoni© in our country would require importing the regimen from abroad. It would also be costly, because patients have to independently fund the medications. This situation is sometimes found in our country; as a developing country, we found constraints in resources to provide the standardized medical service. Previously, there were publications from Indonesia describing a similar challenge due to the unavailability of supporting laboratories,20–22 which could require specimen transfer to laboratories outside the country and necessitated out-of-pocket expenses. As a matter of fact, the gross domestic product per capita of Indonesia in 2018 was USD $3893.60, while the cost of Harvoni© is USD $94,500 for a 12-week-treatment (in America).23,24 Therefore, sofosbuvir/daclatasvir regimen was preferred for the benefit of the patients. Sofosbuvir/daclatasvir as regimen of choice for HCV-infected KTR is efficient and safe in adults; however, only partial results of two pediatric trials involving chronic HCV infection population have been reported to date.5,25 Additionally, a recent study in Egypt revealed that there were no differences in efficacy and safety between the use of sofosbuvir/ledipasvir and sofosbuvir/daclatasvir in adolescents with HCV non-KTR without other comorbidities.26 In their study, all of the subjects achieved SVR12 regardless of the treatment regimen, which justified our decision to use sofosbuvir/daclatasvir regimen in our patients.\n\nTacrolimus target levels post-transplantation in pediatric KTR were 10–12 ng/mL (month one), 8–10 ng/mL (months two to three), 6–8 ng/mL (months four to six) and 4–6 ng/mL (after month six).27 Therefore, we monitored tacrolimus levels accordingly after transplantation and particularly during administration of DAAs (Figure 1). The first tacrolimus measurements within a month post-DAAs initiation in our cases showed elevation past the target level (Figure 3). Moreover, there was a significant increase in serum creatinine level in case 1 (Figure 3A), raising a suspicion that DAAs may potentiate tacrolimus nephrotoxicity. A 2017 review stated that the incidence of nephrotoxicity is higher in patients receiving a medium-dose regimen of tacrolimus (0.15 mg/kgBW/day) compared to a low-dose regimen (0.1 mg/kgBW/day).28 This explains the rise of serum creatinine in case 1 (Figure 3A) compared to the stability of serum creatinine in case 2 (Figure 3B). Older donor age in kidney transplantation also contributes to the nephrotoxicity side effects of tacrolimus,29 thus aligning with the fact that case 1 received kidney from his 50-year-old father, whereas the donor for case 2 was 21 years old. Therefore, the tacrolimus dose was reduced to maintain a level within the desired target for both cases, and also to preserve graft function particularly for case 1. However, when DAAs were discontinued, the tacrolimus levels dropped in both cases, necessitating an increased dose of tacrolimus.Figure 3 (A) Tacrolimus and creatinine serum levels changes while on treatment with DAAs (Case 1). (B) Tacrolimus and creatinine serum levels changes while on treatment with DAAs (Case 1).\n\n\n\nTacrolimus is a substrate of liver cytochrome (CYP) 3A4, which is commonly repressed during chronic HCV infection by the inflammatory cytokines.30 Treatment with DAAs overrides the inflammatory inhibition of CYP3A4 and enhances tacrolimus metabolism, leading to decreased concentration and eventually requiring an increase in tacrolimus dose.4,30 In our cases, tacrolimus levels rose during DAAs treatment. Only one study in 2016 reported an increase of tacrolimus levels and serum creatinine levels during DAAs treatment in 13 out of 47 subjects.4 A recent pharmacology study in 2018 suggested that the bioavailability of tacrolimus administered in Asians is greater,31 implying that the tacrolimus dose requirement may be lower generally in our cases and required adjustment while on DAAs.\n\nCase 1 exhibited a timely course of HCV infection and that the first measurement of anti-HCV was non-reactive. This hindered the diagnosis of HCV. Moreover, hepatitis A infection occurred prior to HCV infection, and LRRT added the unique feature of this case. Another hallmark of this case series is the PTDM phenomenon that occurred in case 2. HCV-infected KTR patients are known to have an increased risk of developing PTDM, particularly those who receive tacrolimus and corticosteroid post-transplantation.32 Inhibitory actions on the insulin regulatory pathways of the liver by HCV lead to insulin resistance and eventually result in PTDM.32\n\nUltimately, both cases achieved sustained virological response (SVR) at 24 weeks (SVR24), indicating that treatment for HCV infection using DAAs is effective and well tolerated in post-transplantation patients, particularly in the pediatric population. This is similar to a 2016 study in China, which revealed successful treatment using sofosbuvir/daclatasvir in adult HCV-infected KTR genotype 1 without liver involvement, achieving SVR at 12 weeks.25 In addition, sofosbuvir/daclatasvir combination has recently been reported as effective and safe to treat chronic HCV genotype 4 infection without other comorbidities in children aged 8 to 18 years old.18 To the best of our knowledge, this is the first report describing successful treatment using DAAs in two pediatric KTR who had HCV genotype 1a infection.\n\nConclusion\nSofosbuvir/daclatasvir, preferably administered post-transplantation, is a safe and effective interferon-free treatment option in chronic HCV-infected pediatric KTRs. Further studies are warranted to confirm the efficacy and safety of DAAs in pediatric KTRs with chronic HCV infection, and to elucidate the effects of DAAs on tacrolimus levels and nephrotoxicity.\n\nAcknowledgments\nWe would like to express our gratitude to Professor Taralan Tambunan, Professor Partini Pudjiastuti Trihono, Sudung Oloan Pardede, MD, PhD and Henny Adriani Puspitasari, MD for their care of the patients in the Department of Child Health; Professor Mei-Hwei Chang from Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan for providing guidance in therapy; Farhan Haidar Fazlur Rahman, MD and Tiara Nien Paramita, MD for the assistance in data recruitment; and ENAGO for the careful reading and editing of this manuscript.\n\nEthical Statements\nIn both cases, the organs were donated voluntarily with written informed consent, and the transplantations were conducted in accordance with the Declaration of Istanbul. Written informed consent for the publication of this case series and accompanying images was obtained from the patients’ guardian. A copy of the written consent is available for review from the editor of this journal. Further institutional approval is not required to publish de-identified case information.\n\nAuthor Contributions\nAll authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Dzekova-Vidimliski \nP , Sikole \nA . Hepatitis C virus infection in kidney transplant patients: current treatment options\n. Exp Clin Transplant . 2017 ;15 :587 –593\n.29219790 \n2. Kidney Disease: Improving Global Outcomes Transplant Work Group . KDIGO clinical practice guideline for the care of kidney transplant recipients\n. Am J Transplant . 2009 ;9 :S1 .\n3. Kidney Disease: Improving Global Outcomes Hepatitis C Work Group . KDIGO 2018 clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease\n. Kidney Int Suppl . 2018 ;8 (3 ):91 . doi:10.1016/j.kisu.2018.06.001 \n4. Fernández \nI , Muñoz-Gómez \nR , Pascasio \nJM , et al. Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C\n. J Hepatol . 2017 ;13 (4 ):1225 . doi:10.1016/j.jhep.2016.12.020 \n5. Indolfi \nG , Thorne \nC , El Sayed \nMH , Giaquinto \nC , Gonzalez-Peralta \nRP . The challenge of treating children with hepatitis C virus infection\n. J Pediatr Gastroenterol Nutr . 2017 ;64 (6 ):851 –854\n. doi:10.1097/MPG.0000000000001589 28362694 \n6. Kementerian Kesehatan Republik Indonesia . 150 ribu orang potensial alami hepatitis kronis\n; 2017 \nAvailable from : https://www.kemkes.go.id/article/view/17072800006/150-ribu-orang-potensial-alami-hepatitis-kronis.html. Accessed 10 23 , 2019.\n7. Youssef \nDM , Abdo \nH , Alakhras \nA , Adham \nT , Mohamoud \nAH . Hepatitis C in children with chronic kidney disease: a single-center, Egypt\n. Saudi J Kidney Dis Transpl . 2017 ;28 :102 . doi:10.4103/1319-2442.198161 28098110 \n8. Johnson \nDW , Dent \nH , Yao \nQ , et al. Frequencies of hepatitis B and C infections among haemodialysis and peritoneal dialysis patients in Asia-Pacific countries: analysis of registry data\n. Nephrol Dial Transplant . 2008 ;24 :1598 –1603\n. doi:10.1093/ndt/gfn684 19096083 \n9. Ambarsari \nCG , Trihono \nPP , Kadaristiana \nA , et al. Five-year experience of continuous ambulatory peritoneal dialysis in children: a single center experience in a developing country\n. Med J Indones . 2019 ;28 (4 ):329 –337\n. doi:10.13181/mji.v28i4.3807 \n10. Ambarsari \nCG , Bermanshah \nEK , Putra \nMA , Rahman \nFHF , Pardede \nSO . Effective management of peritoneal dialysis-associated hydrothorax in a child: a case report\n. Case Rep Nephrol Dial . 2020 ;10 (1 ):18 –25\n. doi:10.1159/000506119 32232056 \n11. Ambarsari \nCG , Rahman \nFHF , Bermanshah \nEK , Kadaristiana \nA . An unusual case of peritoneal dialysis twisted catheter in a child\n. J Indones Med Assoc . 2020 ;70 (2 ):27 –31\n.\n12. Ambarsari \nCG , Mushahar \nL , Kadaristiana \nA , Hidayati \nEL . Dressing versus non-dressing technique for exit-site care in children on chronic ambulatory peritoneal dialysis: a pilot retrospective cohort\n. Med J Indones . 2020 .\n13. Rehermann \nB , Nascimbeni \nM . Immunology of hepatitis B virus and hepatitis C virus infection\n. Nat Rev Immunol . 2005 ;5 (3 ):215 . doi:10.1038/nri1573 15738952 \n14. Gutierrez \nJA , Lawitz \nEJ , Poordad \nF . Interferon free, direct acting antiviral therapy for chronic hepatitis C\n. J Viral Hepat . 2015 ;22 (11 ):861 –870\n. doi:10.1111/jvh.12422 26083155 \n15. Wong \nG , Coates \nT . To transplant early or treat first? A dilemma for hepatitis C–positive recipients\n. Kidney Int . 2019 ;96 (3 ):535 –539\n. doi:10.1016/j.kint.2019.02.024 31113678 \n16. Kwo \nPY , Badshah \nMB . New hepatitis C virus therapies: drug classes and metabolism, drug interactions relevant in the transplant settings, drug options in decompensated cirrhosis, and drug options in end-stage renal disease\n. Curr Opin Organ Transplant . 2015 ;20 (3 ):235 –241\n. doi:10.1097/MOT.0000000000000198 25944238 \n17. Chopra \nA , Klein \nPL , Drinnan \nT , Lee \nSS . How to optimize HCV therapy in genotype 1 patients: management of side effects\n. Liver Int . 2013 ;33 :30 –34\n. doi:10.1111/liv.12080 23286843 \n18. Abdel Ghaffar \nTY , El Naghi \nS , Abdel Gawad \nM , et al. Safety and efficacy of combined sofosbuvir/daclatasvir treatment of children and adolescents with chronic hepatitis C genotype 4\n. J Viral Hepat . 2019 ;26 (2 ):263 –270\n. doi:10.1111/jvh.13032 30380158 \n19. Hill \nAM , Nath \nS , Simmons \nB . The road to elimination of hepatitis C: analysis of cures versus new infections in 91 countries\n. J Virus Erad . 2017 ;3 (4 ):117 .28758018 \n20. Ambarsari \nCG , Sindih \nRM , Saraswati \nM , Trihono \nPP . Delayed admission and management of pediatric acute kidney injury and multiple organ dysfunction syndrome in children with multiple wasp stings: a case series\n. Case Rep Nephrol Dial . 2019 ;9 (3 ):137 –148\n. doi:10.1159/000504043 31828077 \n21. Ambarsari \nCG , Cahyadi \nD , Sari \nL , et al. Late diagnosis of Lesch–Nyhan disease complicated with end-stage renal disease and tophi burst: a case report\n. Ren Fail . 2020 ;42 (1 ):113 –121\n. doi:10.1080/0886022X.2020.1713805 31985336 \n22. Ambarsari \nCG , Trihono \nPP , Kadaristiana \nA , et al. Low-dose maintenance intravenous iron therapy can prevent anemia in children with end-stage renal disease undergoing chronic hemodialysis\n. Int J Nephrol . 2020 .\n23. GDP per capita (current US$) . 2018 \nAvailable from : https://data.worldbank.org/indicator/ny.gdp.pcap.cd. Accessed 11 11 , 2019.\n24. Rachel Nall \nR . How much does hepatitis C treatment cost?\n\n2018 \nAvailable from: \nhttps://www.medicalnewstoday.com/articles/323767.php-drug-types-and-costs. Accessed 11 11 , 2019.\n25. Xue \nY , Zhang \nL-X , Wang \nL , Li \nT , Qu \nY-D , Liu \nF . Efficacy and safety of sofosbuvir and daclatasvir in treatment of kidney transplantation recipients with hepatitis C virus infection\n. World J Gastroenterol . 2017 ;23 (32 ):5969 . doi:10.3748/wjg.v23.i32.5969 28932089 \n26. Hanno \nAH , Hamouda \nS , Abdelgawad \nM , Aboelkheir \nH , Ahmed \nM . Comparison between safety and efficacy of two treatment regimens for pediatric patients with chronic hepatitis C virus infection: sofosbuvir/ledipasvir versus sofosbuvir/daclatasvir regimen\n. Acta Sci GI Disord . 2019 ;2 (7 ):3 –7\n. doi:10.31080/ASGIS.2019.02.0069 \n27. Transplant BC . Clinical guidelines for transplant medications. Vol AMB.03.007 Rev11: British Columbia Transplant\n; 2019 \nAvailable from: \nhttp://www.transplant.bc.ca/Documents/HealthProfessionals/Clinicalguidelines/ClinicalGuidelinesforTRANSPLANTMEDICATIONS.pdf.\n28. Andrews \nLM , Li \nY , De Winter \nBCM , et al. Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients\n. Expert Opin Drug Metab Toxicol . 2017 ;13 (12 ):1225 –1236\n. doi:10.1080/17425255.2017.1395413 29084469 \n29. Xia \nT , Zhu \nS , Wen \nY , et al. Risk factors for calcineurin inhibitor nephrotoxicity after renal transplantation: a systematic review and meta-analysis\n. Drug Des Dev Ther . 2018 ;12 :417 . doi:10.2147/DDDT.S149340 \n30. Fernández‐Ruiz \nM , Polanco \nN , García‐Santiago \nA , et al. Impact of anti‐HCV direct antiviral agents on graft function and immunosuppressive drug levels in kidney transplant recipients: a call to attention in the mid term follow up in a single center cohort study\n. Transpl Int . 2018 ;31 (8 ):887 –899\n. doi:10.1111/tri.13118 29356211 \n31. Lu \nZ , Bonate \nP , Keirns \nJ . Population pharmacokinetics of immediate‐and prolonged‐release tacrolimus formulations in liver, kidney and heart transplant recipients\n. Br J Clin Pharmacol . 2019 ;85 (8 ):1692 –1703\n. doi:10.1111/bcp.13952 30950096 \n32. Palepu \nS , Prasad \nGVR . New-onset diabetes mellitus after kidney transplantation: current status and future directions\n. World J Diabetes . 2015 ;6 (3 ):445 . doi:10.4239/wjd.v6.i3.445 25897355\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-7058",
"issue": "13()",
"journal": "International journal of nephrology and renovascular disease",
"keywords": "antiviral agents; chronic; hepatitis C; interferon; kidney failure; renal transplantation",
"medline_ta": "Int J Nephrol Renovasc Dis",
"mesh_terms": null,
"nlm_unique_id": "101550217",
"other_id": null,
"pages": "139-146",
"pmc": null,
"pmid": "32606888",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "29356211;30950096;29219790;28098110;28758018;32232056;25944238;25897355;19845597;26083155;30380158;28039098;29535503;29084469;31113678;28362694;28932089;19096083;30675443;31985336;15738952;23286843;31828077",
"title": "Successful Treatment of Hepatitis C Virus Infection Using Direct-Acting Antiviral Agents (DAAs) in Adolescents with Kidney Transplantation: A Case Series.",
"title_normalized": "successful treatment of hepatitis c virus infection using direct acting antiviral agents daas in adolescents with kidney transplantation a case series"
} | [
{
"companynumb": "ID-ACCORD-190881",
"fulfillexpeditecriteria": "1",
"occurcountry": "ID",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Autoimmune hepatitis (AIH) is an extremely rare complication of anastrozole therapy. It presents with elevated liver function tests. The diagnosis is established by detecting high titers of autoantibodies such as antinuclear antibodies, anti-smooth muscle antibodies, and elevated immunoglobulins. It is confirmed with a liver biopsy showing interface rosetting and an increased number of plasma cells. Early diagnosis of anastrozole-induced AIH is important because it allows anastrozole to be discontinued and immunomodulatory treatment to be promptly initiated.\n\n\n\nWe present the case of a 71-year-old female patient diagnosed with early-stage breast cancer. The patient developed AIH as a result of treatment with anastrozole. Its clinicopathological presentation, diagnosis, and treatment are reviewed.\n\n\n\nThis case report intends to make clinicians aware of this rare complication of anastrozole therapy. AIH should be suspected in any patient on anastrozole (and possibly, other aromatase inhibitors) who develops elevated liver function tests.",
"affiliations": "Division of Hematology/Oncology and Stem Cell Transplant, Rush University Medical Center, Chicago, IL, U.S.A.;Section of Hepatology, Department of Medicine, Rush University Medical Center, Chicago, IL, U.S.A.;Department of Pathology, Rush University Medical Center, Chicago, IL, U.S.A.;Section of Hepatology, Department of Medicine, Rush University Medical Center, Chicago, IL, U.S.A.;Division of Hematology/Oncology and Stem Cell Transplant, Rush University Medical Center, Chicago, IL, U.S.A. lydia_usha@rush.edu.",
"authors": "Klapko|Oleksandra|O|;Ghoulam|Elie|E|;Jakate|Shriram|S|;Eswaran|Sheila|S|;Usha|Lydia|L|",
"chemical_list": "D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077384:Anastrozole",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.11805",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "37(8)",
"journal": "Anticancer research",
"keywords": "Anastrozole; adverse effects; autoimmune hepatitis; breast cancer; drug-induced liver injury",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000368:Aged; D000077384:Anastrozole; D047072:Aromatase Inhibitors; D001706:Biopsy; D001943:Breast Neoplasms; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D008099:Liver; D009367:Neoplasm Staging; D009570:Nitriles; D014230:Triazoles",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "4173-4176",
"pmc": null,
"pmid": "28739702",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anastrozole-induced Autoimmune Hepatitis: A Rare Complication of Breast Cancer Therapy.",
"title_normalized": "anastrozole induced autoimmune hepatitis a rare complication of breast cancer therapy"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/17/0092557",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null... |
{
"abstract": "OBJECTIVE\nNot all patients with autoimmune hepatitis (AIH) respond to standard medical therapy with corticosteroids and azathioprine. Such patients may develop end-stage liver disease with poor prognosis unless transplantation is considered. Alternatively, the introduction of new therapeutic strategies could potentially ameliorate deterioration of liver function. Patients in our tertiary center were selected for everolimus therapy when exhibiting nonresponse or intolerance to combinations of the standard and empirical drugs in use (e.g., mycophenolate mofetil, calcineurin inhibitors [CNIs]). We here report the efficacy of everolimus treatment of patients with AIH.\n\n\nMETHODS\nSeven patients (six female, mean age 47 years, range 22-62 years) in whom disease control could not be achieved with standard therapy or the alternative drugs in use were included.\n\n\nRESULTS\nTreatment with everolimus induced a clear reduction of transaminases within 2 weeks. After 3-5 months three patients had normal alanine aminotransferase (ALT) levels (10-45 IU) and four patients had ALT levels below 55 IU compared to a three- to fivefold elevated level prior to everolimus treatment. Sustained remission after 1 year of treatment was observed in three patients; in another two patients ALT was 45-68 U/L. Four patients in remission after 3 years were rebiopsied. Two showed no histological progression, and in two the fibrosis had decreased. Side effects noted were myalgias and minor bacterial infections not leading to discontinuation of the drug.\n\n\nCONCLUSIONS\nOur experience indicates that everolimus may be of value in selected patients with therapy-resistant AIH and comorbidity/side effects that excludes the use of CNIs.",
"affiliations": "Department of Hepatology A-2121, Rigshospitalet, University of Copenhagen , Copenhagen , Denmark.",
"authors": "Ytting|Henriette|H|;Larsen|Fin Stolze|FS|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D000068338:Everolimus; D000410:Alanine Transaminase; D009173:Mycophenolic Acid; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.3109/00365521.2014.998271",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0036-5521",
"issue": "50(8)",
"journal": "Scandinavian journal of gastroenterology",
"keywords": "alternative treatment; autoimmune hepatitis; everolimus; mammalian target of rapamycin inhibitor; nonresponse; poor response; treatment",
"medline_ta": "Scand J Gastroenterol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000410:Alanine Transaminase; D001379:Azathioprine; D018432:Drug Resistance, Multiple; D000068338:Everolimus; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D007166:Immunosuppressive Agents; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D012074:Remission Induction; D062606:Tertiary Care Centers; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0060105",
"other_id": null,
"pages": "1025-31",
"pmc": null,
"pmid": "25862144",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Everolimus treatment for patients with autoimmune hepatitis and poor response to standard therapy and drug alternatives in use.",
"title_normalized": "everolimus treatment for patients with autoimmune hepatitis and poor response to standard therapy and drug alternatives in use"
} | [
{
"companynumb": "PHHY2015DK044558",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nTo describe the use of topical 0.03% tacrolimus in patients with symptomatic corneal subepithelial infiltrates (SEIs) secondary to adenoviral keratoconjunctivitis (AK) that were resistant to tapering of corticosteroid eye drops.\n\n\nMETHODS\nThis was a prospective, nonrandomized, noncomparative interventional case series that included consecutive patients treated with tacrolimus for resistant SEIs after AK. The patients had active SEIs and corrected distance visual acuity (CDVA) of 20/25 or worse when treatment was initiated. The recorded data included age, sex, CDVA, intraocular pressure, duration and intensity of symptoms, biomicroscopy findings, and duration of therapy. The treatment was considered successful if there was a reduction in SEIs, as well as CDVA stabilization or improvement. The treatment was considered unsuccessful if the patient could not tolerate tacrolimus or if there was an increase in SEIs.\n\n\nRESULTS\nSeven patients were included (10 eyes). The mean age was 36.7 ± 12.3 years. The mean duration of tacrolimus therapy was 8.8 ± 2.4 months, and the mean duration of follow-up was 13.6 ± 10.7 months. Treatment was successful in 8 eyes of 6 patients. One patient could not tolerate the medication. Statistically significant improvement in the CDVA was observed (from a mean of 0.29 to 0.07) (P = 0.001). No statistically significant changes in the intraocular pressure were observed (P = 0.574). SEI scores showed a significant reduction from 2.20 ± 0.92 to 0.25 ± 0.46 (P = 0.011). All patients who completed treatment had improvement in ocular symptoms.\n\n\nCONCLUSIONS\nTopical 0.03% tacrolimus seemed to be an effective corticosteroid-sparing agent for the treatment of SEIs after AK.",
"affiliations": "*Cornea Department, Sadalla Amin Ghanem Eye Hospital, Joinville, Brazil; and †Univille University, Joinville, Brazil.",
"authors": "Ghanem|Ramon Coral|RC|;Vargas|Juliana Ferreira da Costa|JF|;Ghanem|Vinícius Coral|VC|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D009883:Ophthalmic Solutions; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000000247",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "33(11)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000258:Adenovirus Infections, Human; D000287:Administration, Topical; D000328:Adult; D024882:Drug Resistance, Viral; D004847:Epithelial Cells; D015828:Eye Infections, Viral; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D007637:Keratoconjunctivitis; D008297:Male; D008875:Middle Aged; D009883:Ophthalmic Solutions; D011446:Prospective Studies; D012008:Recurrence; D011795:Surveys and Questionnaires; D016559:Tacrolimus; D055815:Young Adult",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "1210-3",
"pmc": null,
"pmid": "25188789",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Tacrolimus for the treatment of subepithelial infiltrates resistant to topical steroids after adenoviral keratoconjunctivitis.",
"title_normalized": "tacrolimus for the treatment of subepithelial infiltrates resistant to topical steroids after adenoviral keratoconjunctivitis"
} | [
{
"companynumb": "BR-MYLANLABS-2015M1032402",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Idiopathic pneumonia syndrome (IPS) is a fatal non-infectious respiratory complication that develops after hematopoietic stem cell transplantation (HSCT). Because of the poor prognosis of post-HSCT patients with IPS requiring mechanical ventilatory support, performing extracorporeal membrane oxygenation (ECMO) has been regarded as relatively contraindicated in these patients. A tumor necrosis factor-alpha inhibitor, etanercept, has been reported to be a promising treatment option for post-HSCT patients with IPS; however, the phase III clinical trial of etanercept has recently been terminated without definitive conclusion. If post-HSCT patients with IPS really benefit from etanercept, mechanical ventilation (MV)-dependent IPS patients might be worth receiving ECMO treatment in line with the protective lung strategy. We therefore performed veno-venous ECMO (VV-ECMO), which substantially acted as an extracorporeal carbon dioxide removal, on a 56-year-old post-HSCT male with severe MV-dependent IPS due to graft-versus-host disease. Although a serious bleeding complication due to post-HSCT thrombocytopenia occurred, the VV-ECMO was continued for 11 days. The patient successfully entered remission of the IPS and was finally extubated on the 12th MV day. However, the patient soon complained of dyspnea, probably due to cytomegalovirus infection and/or exacerbation of the IPS, and was reintubated after 3 days of extubation. The patient then rapidly developed irreversible type II respiratory failure despite the administration of etanercept and an anti-cytomegalovirus agent and died on the eighth re-MV day. The autopsy findings of the patient revealed diffuse alveolar damage and alveolar hemorrhage, accompanied with bronchitis obliterans in his lungs, as well as whole body cytomegalovirus infection, which were compatible with the clinical diagnosis of the patient. We think that the legitimacy of this treatment strategy is dependent on the overall prognosis of IPS, which is influenced by the complications induced by immunosuppressants and ECMO, especially infections and bleeding.",
"affiliations": "Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498 Japan.;Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498 Japan.;Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498 Japan.;Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498 Japan.;Division of Hematology, Department of Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498 Japan.",
"authors": "Koinuma|Toshitaka|T|;Nunomiya|Shin|S|;Wada|Masahiko|M|;Koyama|Kansuke|K|;Suzuki|Takahiro|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40560-014-0048-1",
"fulltext": "\n==== Front\nJ Intensive CareJ Intensive CareJournal of Intensive Care2052-0492BioMed Central London 4810.1186/s40560-014-0048-1Case ReportConcurrent treatment with a tumor necrosis factor-alpha inhibitor and veno-venous extracorporeal membrane oxygenation in a post-hematopoietic stem cell transplant patient with idiopathic pneumonia syndrome: a case report Koinuma Toshitaka numacchi@jichi.ac.jp Nunomiya Shin nunomiya@jichi.ac.jp Wada Masahiko mwada@jichi.ac.jp Koyama Kansuke k_koyama@jichi.ac.jp Suzuki Takahiro tasuzuki@jichi.ac.jp Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498 Japan Division of Hematology, Department of Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498 Japan 22 8 2014 22 8 2014 2014 2 1 4817 4 2014 6 8 2014 © Koinuma et al.; licensee BioMed Central Ltd. 2014This 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 credited. 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.Idiopathic pneumonia syndrome (IPS) is a fatal non-infectious respiratory complication that develops after hematopoietic stem cell transplantation (HSCT). Because of the poor prognosis of post-HSCT patients with IPS requiring mechanical ventilatory support, performing extracorporeal membrane oxygenation (ECMO) has been regarded as relatively contraindicated in these patients. A tumor necrosis factor-alpha inhibitor, etanercept, has been reported to be a promising treatment option for post-HSCT patients with IPS; however, the phase III clinical trial of etanercept has recently been terminated without definitive conclusion. If post-HSCT patients with IPS really benefit from etanercept, mechanical ventilation (MV)-dependent IPS patients might be worth receiving ECMO treatment in line with the protective lung strategy. We therefore performed veno-venous ECMO (VV-ECMO), which substantially acted as an extracorporeal carbon dioxide removal, on a 56-year-old post-HSCT male with severe MV-dependent IPS due to graft-versus-host disease. Although a serious bleeding complication due to post-HSCT thrombocytopenia occurred, the VV-ECMO was continued for 11 days. The patient successfully entered remission of the IPS and was finally extubated on the 12th MV day. However, the patient soon complained of dyspnea, probably due to cytomegalovirus infection and/or exacerbation of the IPS, and was reintubated after 3 days of extubation. The patient then rapidly developed irreversible type II respiratory failure despite the administration of etanercept and an anti-cytomegalovirus agent and died on the eighth re-MV day. The autopsy findings of the patient revealed diffuse alveolar damage and alveolar hemorrhage, accompanied with bronchitis obliterans in his lungs, as well as whole body cytomegalovirus infection, which were compatible with the clinical diagnosis of the patient. We think that the legitimacy of this treatment strategy is dependent on the overall prognosis of IPS, which is influenced by the complications induced by immunosuppressants and ECMO, especially infections and bleeding.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s40560-014-0048-1) contains supplementary material, which is available to authorized users.\n\nKeywords\nIdiopathic pneumonia syndromeExtracorporeal membrane oxygenationExtracorporeal carbon dioxide removalTumor necrosis factor-alpha inhibitorEtanerceptHematopoietic stem cell transplantationGraft-versus-host diseaseissue-copyright-statement© The Author(s) 2014\n==== Body\nBackground\nPatients with hematological malignancies after hematopoietic stem cell transplantation (HSCT) often suffer from respiratory complications [1], and those who require mechanical ventilation (MV) are known to have a poor prognosis [2]. Idiopathic pneumonia syndrome (IPS), one of the non-infectious respiratory complications that occurs after HSCT, is regarded as an extremely life-threatening condition, and its prevalence is estimated to be 3% to 15% in post-HSCT patients [3]. In particular, MV-dependent post-HSCT patients with IPS have been reported to have a 95% to 100% mortality rate [4-6].\n\nRecently, the effectiveness of a tumor necrosis factor-alpha (TNF-alpha) inhibitor, etanercept, has been aggressively studied to post-HSCT IPS patients [7-9], and thus, MV-dependent IPS patients may also benefit from etanercept treatment [7,8]. Therefore, a lung-protective strategy for MV-dependent IPS patients is considered to be important to avoid volutrauma and/or ventilator-induced lung injury (VILI) until etanercept can exert its effects.\n\nThe usefulness of extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) has been reported in recent years [10], but in general, ECMO is considered to be ineffective for patients with malignancies [11,12], and the post-HSCT patients with respiratory complications have been regarded to be relatively contraindicated for ECMO [13]. However, if post-HSCT patients with IPS exhibit an improvement or reversal of their condition by the administration of etanercept, MV-dependent IPS patients might be worth receiving ECMO treatment in line with a lung-protective strategy.\n\nWe herein report a post-HSCT case with IPS, in whom we performed veno-venous ECMO (VV-ECMO) because the patient was expected to have a reversal of his condition by the induction treatment with a TNF-alpha inhibitor. To the best of our knowledge, only one very recent case report has been published on an IPS patient who underwent VV-ECMO [14], so our report will be the first on a post-HSCT patient with IPS who was concurrently treated with VV-ECMO and a TNF-alpha inhibitor.\n\nCase presentation\nA 56-year-old male had developed nephrotic syndrome due to primary amyloidosis 12 years earlier and had gone into complete remission following melphalan-prednisone therapy. However, after continuing the melphalan-prednisone therapy for about 10 years, bicytopenia was detected, and he was diagnosed with chronic myelomonocytic leukemia and underwent allogenic bone marrow transplantation (BMT) from a human leukocyte antigen identical sibling donor 11 months prior to his presentation at our hospital. The engraftment of hematopoietic stem cells was observed 24 days after BMT, and acute graft-versus-host disease (GVHD) was not observed while the patient was being treated using cyclosporine as an immunosuppressant. However, the follow-up chimerism analysis revealed the survival of recipient-derived cells, so the cyclosporine was reduced in the hopes of inducing a graft-versus-leukemia (GVL) effect approximately 4 months after the BMT. The cyclosporine was then gradually decreased and discontinued, and the recipient-derived cells almost disappeared due to the GVL effect.\n\nOne month before the intensive care unit (ICU) admission, he suffered from an influenza A infection and developed dyspnea with GVHD exacerbation. Cyclosporine re-administration was initiated for the GVHD aggravation, and concurrently, antibiotics, antifungal agents, and antiviral agents were introduced empirically. Despite these therapies, his respiratory symptoms got worse, and he was transferred to the ICU. A computed tomography (CT) examination of his chest revealed bilateral peripheral dominant patchy consolidations accompanied with diffuse ground glass opacity (Figure 1).Figure 1 \nComputed tomography scans of the patient taken on the first ICU day. These images show the widespread bilateral peripheral field-dominant patchy consolidations accompanied with diffuse ground glass opacity.\n\n\n\nOn admission to the ICU, tachypnea (respiratory rate 36/min) and dyspnea with a low oxygen saturation value by pulse oximetry were observed. We considered that the patient might be suffering from IPS because of the GVHD-related respiratory symptoms, so high-dose methylprednisolone therapy (1 g/day for three days) under non-invasive positive pressure ventilation was initiated from the first ICU day. Unfortunately, that night, the patient developed severe hypoxemia and his consciousness rapidly deteriorated, so he was finally intubated and received MV (Figure 2). The initial MV mode was biphasic positive airway pressure, with an inspiratory fraction of oxygen (FIO2) of 0.8, a peak inspiratory pressure (PIP) of 28 cmH2O, positive end-expiratory pressure (PEEP) of 10 cmH2O, respiratory frequency of 15/min and tidal volume of around 6 ml/ideal body weight (BW). However, as his spontaneous breathing force gradually increased, probably due to poor oxygenation and respiratory acidosis (pH 7.159, PaCO2 77.4 mmHg, HCO3− 27.8 mmol/l, PaO2/FIO2 135), along with his poor lung compliance (lung compliance 18 ml/cm H2O), his strong inspiratory effort generated a large tidal volume up to 10 ml/ideal BW and an asynchrony with the ventilator was observed. His large tidal volume and asynchrony were sustained irrespective of deep sedation and ventilator setting changes, raising concerns about volutrauma and/or VILI. As he already fulfilled the severity criteria for VV-ECMO due to his Murray's score of 3.25 points on the following day, we decided to introduce ECMO therapy with an expectation of a recovery in his lung injury by the administration of etanercept for the IPS.Figure 2 \nThe ICU course of the patient.\nBIPAP bilevel positive airway pressure, F\nI\nO\n2 fraction of inspired oxygen, mPSL methylprednisolone, Nasal HF nasal high flow system, NPPV non-invasive positive pressure ventilation, PaCO\n2 partial pressure of carbon dioxide, PaO\n2 partial pressure of oxygen, PEEP positive end-expiratory pressure, PIP peak inspiratory pressure, PSV pressure support ventilation, sPSL soluble prednisolone, VV-ECMO veno-venous extracorporeal membrane oxygenation.\n\n\n\nAfter obtaining informed consent, the patient was cannulated with a 19 Fr. cannula for venous drainage into his right femoral vein and a 15 Fr. cannula for oxygen-supplemented blood infusion into his right internal jugular vein. Due to the narrow vascular size of the patient, the catheters we used were smaller in diameter than the general recommendation of VV-ECMO. Because of this small diameter, the ECMO session was initiated with an extracorporeal blood flow of 1.5 to 2 l/min, which was relatively low flow rate, with a sweep gas flow of 2 l/min at 80% oxygen (centrifugal pump, CAPIOX® SP101 PLUS; oxygenator, CAPIOX® LX, TERUMO, Tokyo, Japan), and anticoagulation therapy with unfractionated heparin was initiated to maintain an activated clotting time over 150 s.\n\nSoon after the induction of VV-ECMO, the patient was performed bronchoalveolar lavage (BAL) and confirmed to have IPS without any active pulmonary infections based on BAL fluid testing 72 h later, so we administered etanercept subcutaneously at a dose of 16 mg (0.4 mg/kg) twice a week from the fifth ICU day, accompanied by methylprednisolone consolidation therapy (80 mg/day for 7 days and 40 mg/day for the subsequent 7 days). During the ECMO session, he was administered with adequate sedatives and analgesics, and pressure support (PS) ventilation was used with a PEEP of 10 cmH2O, PS of 5 cmH2O, and FIO2 of 0.3, so as to maintain lung-rest and prevent alveolar collapse. A few days after the administration of etanercept, his oxygenation was ameliorated up to PaO2/FIO2 353 mmHg in spite of the low extracorporeal flow rate; nevertheless, his chest X-p showed no sign of improvement of the bilateral consolidations. Therefore, we considered that the patient still had not entered the remission phase of IPS and continued the VV-ECMO, which was substantially acted as ‘extracorporeal carbon dioxide removal (ECCO2R)’ , in line with a lung-protective strategy. After further several days, the consolidations in his bilateral lung field almost vanished (Figure 3), so we considered that he had successfully entered remission from the IPS.Figure 3 \nComputed tomography scans of the patient taken on the 12th ICU day. These images show the amelioration of the consolidations of the bilateral lung fields.\n\n\n\nOn the other hand, he suffered from severe bleeding complications from the vascular access sites used for ECMO, probably due to post-HSCT-related thrombocytopenia, which persisted at less than 2 × 104/μl, and transfusions of platelet concentrate and packed red blood cells were required almost every day during the ECMO session. On the 12th ICU day (the 11th VV-ECMO day), the patient was withdrawn from the ECMO without ventilator setting changes and was successfully extubated on the 13th ICU day. A blood gas analysis performed just before the extubation showed improved oxygenation (pH 7.444, PaCO2 46.5 mm Hg, HCO3− 31.2 mmol/l, PaO2/FIO2 294) under pressure support ventilation with a PEEP of 5 cmH2O, PS of 5 cmH2O and FIO2 of 0.4 (Additional file 1: Table S1).\n\nHowever, the patient experienced a gradually worsening severe cough beginning the day after extubation, and his oxygen saturation was deteriorating despite oxygen therapy, he received a humidified high-flow nasal cannula on the 14th ICU day. As his chest radiography study revealed an exacerbation of the bilateral consolidation, and his blood sample examination revealed seropositivity for the cytomegalovirus antigen, the patient was considered to have developed cytomegalovirus pneumonia and/or an exacerbation of the remitted IPS. Despite the concurrent administration of an anti-cytomegalovirus agent and etanercept, his oxygenation worsened and he required both reintubation and MV support on the 16th ICU day. A few days later, he developed type II respiratory failure, and he died on the 22nd ICU day. The autopsy findings revealed diffuse alveolar damage and alveolar hemorrhage, accompanied with bronchitis obliterans in his lung, as well as whole body cytomegalovirus infection, which were compatible with the clinical diagnosis of the patient.\n\nDiscussion\nIn 1993, the definition of IPS was proposed as a widespread alveolar injury after HSCT in the absence of active lower respiratory tract infection, which was based upon a BAL examination or lung biopsy, without cardiogenic causes of pulmonary dysfunction [3]. Many factors, such as the use of chemotherapies before BMT, GVHD, and various other factors, including the hematopoietic stem cell donor characteristics, were identified as risk factors for IPS, and it was revealed that TNF-alpha also participates in the onset of IPS [4]. In recent years, a positive impact of a TNF-alpha inhibitor, etanercept, on post-HSCT patients with IPS was reported [7,8], and a phase III clinical trial of etanercept for IPS is conducted [9]. Unfortunately, this trial was not able to show the effectiveness of etanercept for post-HSCT patients with IPS, the definitive conclusion should not be made based on this trial alone because of its inadequate power and small sample size.\n\nAccording to the report of the Extracorporeal Life Support Organization (ELSO) registry, the results of ECMO for severe respiratory failure in adult patients with malignancy were extremely poor [11]. That study included four adult post-HSCT cases; however, the ELSO registry concluded that it is impossible to make any recommendations because of the small number of cases. The ELSO registry also reported that the result of ECMO for the severe respiratory failure of pediatric post-HSCT patients was extremely poor [12]. Therefore, performing ECMO for post-HSCT patients with severe respiratory failure has been generally considered to be relatively contraindicated by these reports [13]. However, although four adult post-HSCT patients were included in the ELSO report and all had indication of ECMO for pulmonary support [11], there was no mention about their individual causes of respiratory failure, and thus, we have no information about whether these patients suffered from IPS or other diseases. Conversely, a first case report which performed VV-ECMO for an MV-dependent IPS patient was recently published [14]. That paper reported the successful use of VV-ECMO along with conventional treatment for IPS, mainly by glucocorticoid administration, without etanercept. This case report might show the usefulness of the lung rest introduced by ECMO in MV-dependent IPS patients.\n\nAlthough it is not known whether the results of the CESAR trial [10], which showed the usefulness of VV-ECMO for ARDS, are applicable for other types of severe respiratory failure, such as IPS, we applied the entry criteria of the CESAR trial, especially the Murray's score [15] ≥3 points, to determine whether to introduce VV-ECMO in our case, as it was the only reported case of the successful use of VV-ECMO for IPS [14]. According to the Berlin definition of ARDS [16], however, this case was defined as not the ‘severe type’ but the ‘moderate type’ of ARDS and generally recommended less invasive respiratory supports than ECMO. However, considering the extremely poorer prognosis of MV-dependent IPS patients compared with even ‘severe’ ARDS in the Berlin definition (mortality, 95%–100% [4-6] vs. 45% [16]), we assume that vulnerabilities of MV-dependent IPS patients would be underestimated when we applied this definition to IPS patient population. Moreover, because of our several experiences of IPS patients equivalent to ‘moderate’ ARDS prior to this case, whom were easily complicated VALI in spite of the conventional lung-protective MV setting, we decided to introduce VV-ECMO after due consideration.\n\nBecause ECMO is a highly invasive and expensive treatment, it is necessary to judge the indications carefully. Even if using ECMO for IPS is valid to prevent VILI, as was suggested in the aforementioned case report [14], the careful evaluation of the risk-effect ratio with treatment alternatives, which are less invasive and/or less expensive than ECMO, is essential. In particular, it is important to take into consideration the risk of hemorrhagic complications, which may be induced by anticoagulation therapy and serious post-HSCT thrombocytopenia, as was seen in our case.\n\nThe reason why the patient exhibited aggravated symptoms soon after the extubation may have included not only a re-exacerbation of IPS but also the cytomegalovirus infection. If the immunosuppression induced by etanercept, along with the high-dose methylprednisolone therapy, is excessive, the concurrent treatment with the induction of etanercept and VV-ECMO for post-HSCT patients with IPS may be considered as a relative contraindication, as is mentioned in the ELSO registry guideline [13].\n\nAlthough some unresolved problems exist, such as uncertainty of the efficacy of etanercept and VV-ECMO for IPS, the risks of immunosuppression generated by etanercept and other immunosuppressants and the bleeding tendency due to post-HSCT-related thrombocytopenia, we consider that the usefulness of concurrent therapy of immunosuppressants including etanercept and ECMO for IPS deserves an evaluation. However, it should be evaluated by not only the short-term prognosis, such as IPS remission or MV withdrawal, but also the long-term prognosis, such as the overall survival.\n\nConclusions\nTo the best of our knowledge, our case is the second reported post-HSCT patient with IPS on MV who underwent VV-ECMO. In addition, this is the first case treated with concurrent etanercept and VV-ECMO for MV-dependent IPS. We think that the legitimacy of this treatment strategy is dependent on the overall prognosis of IPS, which is influenced by the complications induced by immunosuppressants including etanercept and ECMO, especially infections and bleeding. Further studies on this treatment modality are anticipated in the future.\n\nConsent\nWritten informed consent was obtained from the family of the patient for the publication of this case report. A copy of the written consent is available for review by the editor-in-chief of this journal.\n\nAdditional file\nAdditional file 1: Table S1. The oxygen profile and ECMO setting of the patient during the VV-ECMO session.\n\n\n\nCompeting interests\n\nThere are no financial competing interests (political, personal, religious, ideological, academic, intellectual, commercial, or any other) to declare in relation to this manuscript.\n\nAuthors' contributions\n\nTK, SN, MW, KK, and TS treated the patient. TK wrote the manuscript, and SN revised and edited the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors would like to thank JMC (info@japan-mc.co.jp) for the English language review.\n==== Refs\nReferences\n1. Chi AK Soubani AO White AC Miller KB An update on pulmonary complications of hematopoietic stem cell transplantation Chest 2013 144 1913 1922 10.1378/chest.12-1708 24297123 \n2. Soubani AO Kseibi E Bander JJ Klein JL Khanchandani G Ahmed HP Guzman JA Outcome and prognostic factors of hematopoietic stem cell transplantation recipients admitted to a medical ICU Chest 2004 126 1604 1611 10.1378/chest.126.5.1604 15539734 \n3. Clark JG Hansen JA Hertz MI Parkman R Jensen L Peavy HH Idiopathic pneumonia syndrome after bone marrow transplantation Am Rev Respir Dis 1993 147 1601 1606 10.1164/ajrccm/147.6_Pt_1.1601 8503576 \n4. Panoskaltsis-Mortari A Griese M Madtes DK Belperio JA Haddad IY Folz RJ Cooke KR An official American Thoracic Society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome Am J Respir Crit Care Med 2011 183 1262 1279 10.1164/rccm.2007-413ST 21531955 \n5. Fukuda T Hackman RC Guthrie KA Sandmaier BM Boeckh M Maris MB Maloney DG Deeg HJ Martin PJ Storb RF Madtes DK Risk and outcomes of idiopathic pneumonia syndrome and conventional conditioning regimens for allogeneic hematopoietic stem cell transplantation Blood 2003 102 2777 2785 10.1182/blood-2003-05-1597 12855568 \n6. Zhu KE Hu JY Zhang T Chen J Zhong J Lu YH Incidence, risks, and outcome of idiopathic pneumonia syndrome early after allogeneic hematopoietic stem cell transplantation Eur J Haematol 2008 81 461 466 10.1111/j.1600-0609.2008.01149.x 18774951 \n7. Yanik GA Ho VT Levine JE White ES Braun T Antin JH Whitfield J Custer J Jones D Ferrara JLM Cooke KR The impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation Blood 2008 112 3073 3081 10.1182/blood-2008-03-143412 18664626 \n8. Tizon R Frey N Heitjan DF Tan KS Goldstein SC Hexner EO Loren A Reshef R Tsai D Vogl D Davis J Vozniak M Fuchs B Stadtmauer EA Porter DL High-dose corticosteroids with or without etanercept for the treatment of idiopathic pneumonia syndrome after allo-SCT Bone Marrow Transplant 2012 47 1332 1337 10.1038/bmt.2011.260 22307018 \n9. Yanik GA Horowitz MM Weisdorf DJ Logan BR Ho VT Soiffer RJ Carter SL Wu J Wingard JR Difronzo NL Ferrara JL Giralt S Madtes DK Drexler R White ES Cooke KR Randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation: blood and marrow transplant clinical trials network protocol Biol Blood Marrow Transplant 2014 20 858 864 10.1016/j.bbmt.2014.02.026 24607553 \n10. Peek GJ Mugford M Tiruvoipati R Wilson A Allen E Thalanany MM Hibbert CL Truesdale A Clemens F Cooper N Firmin RK Elbourne D Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicenter randomised controlled trial Lancet 2009 374 1351 1363 10.1016/S0140-6736(09)61069-2 19762075 \n11. Gow KW Lao OB Leong T Fortenberry JD Extracorporeal life support for adults with malignancy and respiratory or cardiac failure: the extracorporeal life support experience Am J Surg 2010 199 669 675 10.1016/j.amjsurg.2010.01.018 20466114 \n12. Gow KW Heiss KF Wulkan ML Katzenstein HM Rosenberg ES Heard ML Rycus PT Fortenberry JD Extracorporeal life support for support of children with malignancy and respiratory or cardiac failure: the extracorporeal life support experience Crit Care Med 2009 37 1308 1316 10.1097/CCM.0b013e31819cf01a 19242331 \n13. ELSO guidelines for adult respiratory failure. [http://elsonet.org/resources/guidelines]\n14. Liao WI Tsai SH Chiu SK Successful use of extracorporeal membrane oxygenation in a hematopoietic stem cell transplant patient with idiopathic pneumonia syndrome Respir Care 2013 58 e6 e10 10.4187/respcare.01716 23359731 \n15. Murray JF Matthay MA Luce JM Flick MR An expanded definition of the respiratory distress syndrome Am Rev Respir Dis 1988 138 720 723 10.1164/ajrccm/138.3.720 3202424 \n16. Definition Task Force ARDS Ranieri VM Rubenfeld GD Thompson BT Ferguson ND Caldwell E Fan E Camporota L Slutsky AS Acute respiratory distress syndrome: the Berlin definition JAMA 2012 307 2526 2533 22797452\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2052-0492",
"issue": "2(1)",
"journal": "Journal of intensive care",
"keywords": "Etanercept; Extracorporeal carbon dioxide removal; Extracorporeal membrane oxygenation; Graft-versus-host disease; Hematopoietic stem cell transplantation; Idiopathic pneumonia syndrome; Tumor necrosis factor-alpha inhibitor",
"medline_ta": "J Intensive Care",
"mesh_terms": null,
"nlm_unique_id": "101627304",
"other_id": null,
"pages": "48",
"pmc": null,
"pmid": "25705409",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "20466114;21531955;22307018;3202424;22797452;24297123;12855568;19242331;18664626;24607553;23359731;15539734;19762075;18774951;8503576",
"title": "Concurrent treatment with a tumor necrosis factor-alpha inhibitor and veno-venous extracorporeal membrane oxygenation in a post-hematopoietic stem cell transplant patient with idiopathic pneumonia syndrome: a case report.",
"title_normalized": "concurrent treatment with a tumor necrosis factor alpha inhibitor and veno venous extracorporeal membrane oxygenation in a post hematopoietic stem cell transplant patient with idiopathic pneumonia syndrome a case report"
} | [
{
"companynumb": "PHHY2015JP054893",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nMalignant external otitis (MEO) is an aggressive infection occurring in immunocompromised hosts. Increasing antimicrobial resistance is making the disease more difficult to treat.\n\n\nOBJECTIVE\nDetermine if there has been a shift in the microbiology and outcomes of MEO.\n\n\nMETHODS\nA retrospective case series at a tertiary care institution.\n\n\nMETHODS\nInpatient and outpatient tertiary care hospital.\n\n\nMETHODS\n12 cases of recent MEO were reviewed.\nThe primary outcome was progression of disease. Secondary outcomes were drug resistance and complications of MEO.\n\n\nRESULTS\nOnly 4 patients were cured of MEO. Four patients expired during the study period and at least one of these deaths was a direct result of the MEO. 7 patients developed Cranial nerve palsies, and 3 patients developed abscesses.\n\n\nCONCLUSIONS\nSelect cases of MEO now require multi-drug and long-term parenteral antibiotic therapy with extended hospital stays.",
"affiliations": "Department of Otolaryngology - Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: daniel.carlton@mountsinai.org.;Department of Otolaryngology - Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Otolaryngology - Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.",
"authors": "Carlton|Daniel A|DA|;Perez|Enrique E|EE|;Smouha|Eric E|EE|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjoto.2017.05.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0709",
"issue": "39(1)",
"journal": "American journal of otolaryngology",
"keywords": null,
"medline_ta": "Am J Otolaryngol",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D015331:Cohort Studies; D048909:Diabetes Complications; D018450:Disease Progression; D024881:Drug Resistance, Bacterial; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D007297:Inpatients; D008279:Magnetic Resonance Imaging; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010032:Otitis Externa; D010045:Outpatients; D011552:Pseudomonas Infections; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D062606:Tertiary Care Centers; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "8000029",
"other_id": null,
"pages": "41-45",
"pmc": null,
"pmid": "29042067",
"pubdate": "2018",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Malignant external otitis: The shifting treatment paradigm.",
"title_normalized": "malignant external otitis the shifting treatment paradigm"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-264421",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"d... |
{
"abstract": "Alveolar soft part sarcoma (ASPS) is a rare malignancy with high rates of metastasis at presentation, defined by an unclear cellular origin and a unique unbalanced ASPSCR1-TFE3 translocation (der(17)t(X:17)(p11:q25)).1 ASPS is insensitive to chemotherapy and has been reported to involve the bladder only twice in the pediatric literature; once as a primary malignancy,2 and once as a secondary malignancy after cytotoxic chemotherapy.3 Herein, we report the third case of pediatric bladder ASPS in a female patient who received cytotoxic chemotherapy for low-risk neuroblastoma. This would represent the second case of pediatric bladder ASPS as a secondary malignancy after prior chemotherapy.",
"affiliations": "Department of Pediatric Urology, Children's Mercy Hospital, Kansas City, MO. Electronic address: jpenticuff@kumc.edu.;Department of Pediatric Hematology/Oncology, Children's Mercy Hospital, Kansas City, MO.;Department of Pediatric Urology, Children's Mercy Hospital, Kansas City, MO.;Department of Pediatric Urology, Children's Mercy Hospital, Kansas City, MO.;Department of Pediatric Hematology/Oncology, Children's Mercy Hospital, Kansas City, MO.;Department of Pediatric Urology, Children's Mercy Hospital, Kansas City, MO.",
"authors": "Penticuff|Justin|J|;McDermott|Sarah|S|;Carrasco|Alonso|A|;Bowlin|Paul|P|;Lewing|Karen|K|;Koenig|Joel F|JF|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.urology.2019.04.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-4295",
"issue": "130()",
"journal": "Urology",
"keywords": null,
"medline_ta": "Urology",
"mesh_terms": "D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D008297:Male; D016609:Neoplasms, Second Primary; D009447:Neuroblastoma; D018234:Sarcoma, Alveolar Soft Part; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "0366151",
"other_id": null,
"pages": "148-150",
"pmc": null,
"pmid": "30986487",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Second Reported Case of Pediatric Bladder Alveolar Soft Part Sarcoma as Secondary Malignancy After Prior Cytotoxic Chemotherapy.",
"title_normalized": "second reported case of pediatric bladder alveolar soft part sarcoma as secondary malignancy after prior cytotoxic chemotherapy"
} | [
{
"companynumb": "US-ACCORD-152453",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nEpileptic myoclonus in infancy is associated with various pathological conditions. In the absence of an identifiable central nervous system lesion, an underlying metabolic genetic cause is often suspected.\n\n\nMETHODS\nWe describe two infants with glucose transporter 1 deficiency syndrome who presented with epileptic myoclonus. One infant presented with an electroclinical phenotype mimicking benign myoclonic epilepsy of infancy; the other infant had a novel mutation and presented with opsoclonus and epileptic myoclonus with a robust response to high-dose steroids. Both infants began the ketogenic diet after the diagnosis of glucose transporter 1 deficiency syndrome, with good yet variable treatment responses.\n\n\nCONCLUSIONS\nThese infants demonstrate that an evaluation for glucose transporter 1 deficiency syndrome is warranted in patients presenting with an electroclinical picture compatible with benign myoclonic epilepsy of infancy as well as in patients with intractable epilepsy who demonstrate a significant response to steroid therapy.",
"affiliations": "Department of Pediatric Neurology, Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, Arizona.;Department of Pediatric Neurology, Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, Arizona.;Division of Epilepsy, Department of Pediatric Neurology, Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, Arizona. Electronic address: mobeid@phoenixchildrens.com.",
"authors": "Appavu|Brian|B|;Mangum|Tara|T|;Obeid|Makram|M|",
"chemical_list": "D009004:Monosaccharide Transport Proteins",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-8994",
"issue": "53(4)",
"journal": "Pediatric neurology",
"keywords": "GLUT1; developmental delays; epilepsy; myoclonus; opsoclonus",
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D002239:Carbohydrate Metabolism, Inborn Errors; D055423:Diet, Ketogenic; D004831:Epilepsies, Myoclonic; D005260:Female; D006801:Humans; D007223:Infant; D009004:Monosaccharide Transport Proteins; D015835:Ocular Motility Disorders",
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "364-6",
"pmc": null,
"pmid": "26385057",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Glucose Transporter 1 Deficiency: A Treatable Cause of Opsoclonus and Epileptic Myoclonus.",
"title_normalized": "glucose transporter 1 deficiency a treatable cause of opsoclonus and epileptic myoclonus"
} | [
{
"companynumb": "US-JNJFOC-20150927541",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "We report 2 cases of patients with solid tumors and coagulopathy who experienced avascular necrosis (AVN) of the bone following chemotherapy. Both cases exhibited nontraumatic bilateral AVN of the femoral heads, and one also showed bilateral AVN of the humeral heads. One case had multiple thromboembolic complications, including pulmonary obstructive syndrome and paraneoplastic pain. The other showed multiple paraneoplastic syndromes, with hypercalcemia and thrombocytosis. Groin pain and claudication of the lower extremities developed and persisted. Both patients eventually received bilateral hip arthroplasty due to AVN of both femoral heads.",
"affiliations": "Division of Chinese Acupuncture and Traumatology, Department of Traditional Chinese Medicine, Chang-Gung Memorial Hospital and Chang-Gung University College of Medicine, Taoyuan, Taiwan.;Division of Hemato-Oncology, Department of Internal Medicine, Chang-Gung Memorial Hospital and Chang-Gung University College of Medicine, Taoyuan, Taiwan.;Department of Orthopedic Surgery, Chang-Gung Memorial Hospital and Chang-Gung University College of Medicine, Taoyuan, Taiwan.;Department of Medical Imaging and Intervention, Chang-Gung Memorial Hospital and Chang-Gung University College of Medicine, Taoyuan, Taiwan.;Division of Hemato-Oncology, Department of Internal Medicine, Chang-Gung Memorial Hospital and Chang-Gung University College of Medicine, Taoyuan, Taiwan.",
"authors": "Hsu|Hui-Ching|HC|;Liao|Tzu-Yao|TY|;Chen|Dave Wei-Chih|DW|;Juan|Yu-Hsiang|YH|;Liaw|Chuang-Chi|CC|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000488102",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. 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.ch 10.1159/000488102cro-0011-0185Case ReportAvascular Necrosis of Bone following Chemotherapy in Cancer Patients with Coagulopathy: Report of Two Cases Hsu Hui-Ching aLiao Tzu-Yao bChen Dave Wei-Chih cJuan Yu-Hsiang dLiaw Chuang-Chi b*aDivision of Chinese Acupuncture and Traumatology, Department of Traditional Chinese Medicine, Chang-Gung Memorial Hospital and Chang-Gung University College of Medicine, Taoyuan, TaiwanbDivision of Hemato-Oncology, Department of Internal Medicine, Chang-Gung Memorial Hospital and Chang-Gung University College of Medicine, Taoyuan, TaiwancDepartment of Orthopedic Surgery, Chang-Gung Memorial Hospital and Chang-Gung University College of Medicine, Taoyuan, TaiwandDepartment of Medical Imaging and Intervention, Chang-Gung Memorial Hospital and Chang-Gung University College of Medicine, Taoyuan, Taiwan*Chuang-Chi Liaw, MD, Division of Hemato-Oncology, Department of Internal Medicine, Chang-Gung Memorial Hospital, 5, Fusing St., Gueishan Township, Taoyuan City 333 (Taiwan), E-Mail e102309@adm.cgmh.org.twJan-Apr 2018 27 3 2018 27 3 2018 11 1 185 190 28 2 2018 1 3 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.We report 2 cases of patients with solid tumors and coagulopathy who experienced avascular necrosis (AVN) of the bone following chemotherapy. Both cases exhibited nontraumatic bilateral AVN of the femoral heads, and one also showed bilateral AVN of the humeral heads. One case had multiple thromboembolic complications, including pulmonary obstructive syndrome and paraneoplastic pain. The other showed multiple paraneoplastic syndromes, with hypercalcemia and thrombocytosis. Groin pain and claudication of the lower extremities developed and persisted. Both patients eventually received bilateral hip arthroplasty due to AVN of both femoral heads.\n\nKeywords\nAvascular necrosis of boneSolid tumorChemotherapyCoagulopathyLow-molecular-weight heparinBipolar arthroplasty\n==== Body\nIntroduction\nAvascular necrosis (AVN) of the femoral head is a pathological process that results from disruption of the blood supply to the bone and occurs most commonly in the femoral epiphysis [1]. Patients usually present with pain and limited joint motion [1]. The risk factors are not completely understood [2, 3]. Nontraumatic necrosis of the femoral head was also mentioned [4, 5]. The mechanism involves impaired circulation to a specific area that ultimately becomes necrotic. Furthermore, coagulation disorders have been reported in patients with AVN of the femoral head [6]. AVN is most frequently associated with high doses of oral and intravenous corticosteroids and prolonged duration of therapy [7]. Cancer patients receiving chemotherapy are usually also treated with corticosteroids for the prophylaxis of emesis [8]. AVN of the humeral head has rarely been reported [9], although one case of bilateral AVN of the humeral heads has been reported in a patient with Hodgkin lymphoma following therapy [10].\n\nWe report 2 cases of cancer patients with coagulopathy following chemotherapy. The first was a patient with breast cancer and bilateral AVN of the femoral and humeral heads. The second was a patient with malignant thymoma and bilateral AVN of the femoral heads.\n\nCase Reports\nCase 1\nCase 1 was a 54-year-old woman with recurrent bilateral breast cancer, who was hospitalized in July 2009 with dyspnea. Her chest X-rays showed no abnormalities, but the chest computed tomography (CT) scan showed a tumor or thrombus over the right pulmonary vein and entering the left atrium (Fig. 1a). The D-dimer value was 518 ng/mL (normal range < 500 ng/dL). The patient received chemotherapy with 5-fluorouracil, leucovorin, vinorelbine, and cisplatin every 4 weeks, as well as daily subcutaneous treatment with a low-molecular-weight heparin (LMWH), Fraxiparine (GlaxoSmithKline). The dyspnea improved during the chemotherapy course, but migrating pain, paraneoplastic pain, and swelling occurred over the left infra-auricular area. Dexamethasone was given for the prophylaxis of emesis and to improve the coagulation disorder.\n\nThe patient complained of pain and numbness localized to the bilateral groin area, especially the left side, and from July 2012 had difficulty walking. The pelvis X-ray showed bilateral AVN of the femoral heads (Fig. 1b). Bipolar hip arthroplasty was performed on the left hip in September 2012 and on the right hip in November 2012. The CT scan showed osteonecrosis of the right femoral head after bipolar surgery had been performed on the left femoral head (Fig. 1c). Pathological specimens of both femoral heads showed AVN, but no cancer cells were seen.\n\nThe patient also complained of bilateral shoulder pain, especially on the left side. The plain X-ray showed osteonecrosis of both the humeral heads (Fig. 2a, b). The chest CT scan revealed bilateral osteonecrosis of the humeral heads, which was more severe on the left side (Fig. 2c).\n\nThe patient received a total of 40 courses of chemotherapy. She complained of severe left chest pain from October 2014, and we suspected acute coronary syndrome related to cancer with coagulopathy. The chest X-ray revealed cardiomegaly, and echocardiography showed a large quantity of pericardial effusion. The patient died of tumor progression and brain death in November 2014.\n\nCase 2\nCase 2 was a 51-year-old man with malignant thymoma, who was hospitalized in 2012 with dyspnea. He also exhibited paraneoplastic syndromes with hypercalcemia (serum calcium 12.4 mg/dL, normal range 7.9–9.9 mg/dL) and thrombocytosis (platelet count 824 × 103/µL, normal range 50–450 × 103/µL). His D-dimer value was > 10,000 ng/mL (normal range < 500 ng/dL). The chest X-ray and CT scan revealed a large anterior mediastinal mass (Fig. 3a). The patient received chemotherapy with 5-fluorouracil, leucovorin, and cisplatin every 4 weeks as well as daily subcutaneous treatment with an LMWH, enoxaparin (Sanofi-Aventis). Dexamethasone was given for the prophylaxis of emesis.\n\nThe anterior mediastinal mass decreased in size following chemotherapy. The subsequent CT scan revealed this decrease as well as a tumor or thrombus over the right pulmonary vein and left atrium (Fig. 3b). The patient received regular chemotherapy but refused radiotherapy. An initial tumor response was noted; however, later this lesion progressed.\n\nThe patient complained of pain localized to the groin area and difficulty in walking in November 2012. The pelvis X-ray revealed bilateral AVN of the femoral heads (Fig. 3c). Bipolar hip arthroplasty was performed on the left hip in January 2013 and on the right hip in April 2013. Pathological specimens of both femoral heads showed AVN, but no cancer cells were seen. The patient received a total of 10 courses of chemotherapy, but died of tumor progression and respiratory failure in February 2014.\n\nDiscussion\nThese 2 cases experienced nontraumatic bilateral AVN of the femoral heads, and one also had bilateral humeral head AVN. Both received chemotherapy and exhibited coagulopathy with a tumor or thrombus over the right pulmonary vein and left atrium. One also had multiple thromboembolic complications, including pulmonary obstructive syndrome [11] and paraneoplastic pain [12]. The other showed multiple paraneoplastic syndromes, including hypercalcemia and thrombocytosis.\n\nThe disruption of the blood supply to the hip and shoulder was due to arterial insufficiency in these areas, probably caused by paradoxical embolism [13, 14]. Paradoxical embolism is defined as the passage of a clot (thrombus) from a vein to an artery [11]. A tumor or thrombus was observed in the right pulmonary vein and left atrium in both cases. When a clot in a vein breaks off, it can lodge in an artery, causing localized ischemia. This can occur in the limbs, causing resting pain, as well as in the brain, causing a cerebral infarction [13, 14]. Claudication is defined as the pain caused by insufficient blood flow to an area, usually during exercise. This condition generally affects the legs, but can also affect the arms [15].\n\nThrombosis in arteries has long been recognized in cancer patients, although the exact mechanisms remain obscure [16]. A potential mechanism may be endothelial damage in the arterial wall, causing the loss of the blood's natural anticoagulant properties [16, 17]. Virchow described three factors (venous stasis, endothelial injury, and hypercoagulability) that are thought to contribute to venous and arterial thrombosis [16]. The mechanism of the prothrombotic state is complex in cancer patients: cancer cells can activate the hemostatic system via the expression of adhesion molecules, the release of inflammatory cytokines, and the production of hemostatic factors [18]. Cytokine production is intricately related to both tumor production and the patient's reaction to factors such as infection, chemotherapy, and invasive therapeutic procedures [19].\n\nBoth patients in this case study experienced multiple courses of chemotherapy, resulting in increased production of cytokines, which caused the formation of thrombi and decreased arterial blood supply. Blood disruption to the epiphyses of the femoral and humeral heads led to the development of AVN. The first case exhibited multiple thromboembolic complications, including pulmonary obstructive syndrome, dyspnea [11], and paraneoplastic migratory pain [12]. These cases were unusual, since AVN usually occurs in patients with hematological malignancies [20, 21, 22] and is rarely seen in cases with solid tumors [23].\n\nAfter detection of the tumor or thrombus in the pulmonary vein and left atrium, both patients received regular scheduled chemotherapy, as well as continuous LMWH at the beginning of the chemotherapy course. The first case also received prolonged dexamethasone and intravenous fluid therapy in order to decrease cytokine production, because of multiple episodes of thromboembolic complications. There has been no benefit reported from using LMWH or oral anticoagulant treatment for intermittent claudication [24]. Both patients eventually received bilateral hip arthroplasty due to AVN of both femoral heads [25], and both died of cancer with coagulopathy: one from brain death and the other from respiratory failure.\n\nConclusion\nCancer patients with coagulopathy undergo chemotherapy and anticoagulant therapy. When they complain of groin pain and claudication, AVN of the femoral head should be the differential diagnosis.\n\nStatements of Ethics\nThe study was approved by the Chang Gung Medical Foundation.\n\nInstitutional Review Board IRB No.: 201701703B0.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nNo funding was given for this case report.\n\nFig. 1 Case 1 was a 54-year-old female with breast cancer who was receiving chemotherapy. a The chest CT scan (axial view) showed a tumor or thrombus (arrowhead) over the right posterior proximal pulmonary vein and entering the left atrium. b The plain X-ray revealed bilateral osteonecrosis of the femoral heads (arrows). c The pelvis CT scan (axial view) showed osteonecrosis of the right femoral head (arrow) after arthroplasty of the left hip joint.\n\nFig. 2 Shoulder lesions of case 1. The plain X-ray revealed osteonecrosis of the right humeral head (arrow) (a) and the left humeral head (arrow) (b). c The chest CT scan (coronary view) showed bilateral osteonecrosis of the humeral heads (arrows), which was more severe on the left side.\n\nFig. 3 Case 2 was a 53-year-old male with malignant thymoma who was receiving chemotherapy. a The initial chest X-ray showed a large mediastinal mass. b The chest CT scan (axial view) revealed a tumor or thrombus over the right posterior proximal pulmonary vein and left atrium (arrowhead). c The pelvis X-ray showed bilateral osteonecrosis of the femoral heads (arrows).\n==== Refs\nReferences\n1 Kerachian MA Harvey EJ Cournoyer D Chow TY Séguin C Avascular necrosis of the femoral head vascular hypotheses Endothelium 2006 Jul-Aug 13 (4) 237 44 16990180 \n2 Shah KN Racine J Jones LC Aaron RK Pathophysiology and risk factors for osteonecrosis Curr Rev Musculoskelet Med 2015 Sep 8 (3) 201 9 26142896 \n3 Tsai SW Wu PK Chen CF Chiang CC Huang CK Chen TH Etiologies and outcome of osteonecrosis of the femoral head etiology and outcome study in a Taiwan population J Chin Med Assoc 2016 Jan 79 (1) 39 45 26387635 \n4 Mont MA Cherian JJ Sierra RJ Jones LC Lieberman JR Nontraumatic Osteonecrosis of the Femoral Head Where Do We Stand Today? A Ten-Year Update J Bone Joint Surg Am 2015 Oct 97 (19) 1604 27 26446969 \n5 Etienne G Mont MA Ragland PS The diagnosis and treatment of nontraumatic osteonecrosis of the femoral head Instr Course Lect 2004 53 67 85 15116601 \n6 Garcia FL Ramalli EL Picado CH Coagulation disorders in patients with femoral head osteonecrosis Acta Ortop Bras 2013 Jan 21 (1) 43 5 24453643 \n7 Chan KL Mok CC Glucocorticoid-induced avascular bone necrosis diagnosis and management Open Orthop J. 2012 6 449 57 23115605 \n8 Barbour SY Corticosteroids in the treatment of chemotherapy-induced nausea and vomiting J Natl Compr Canc Netw 2012 Apr 10 (4) 493 9 22491048 \n9 Harreld KL Marker DR Wiesler ER Shafiq B Mont MA Osteonecrosis of the humeral head J Am Acad Orthop Surg 2009 Jun 17 (6) 345 55 19474444 \n10 Virgolini L De Maglio A Bilateral aseptic necrosis of the humeral head following combined therapy for Hodgkin's lymphoma Ital J Orthop Traumatol 1992 18 (4) 543 6 1345650 \n11 Liaw CC Chang H Yang TS Wen MS Pulmonary venous obstruction in cancer patients J Oncol. 2015 2015 210916 26425121 \n12 Ripamonti CI Santini D Maranzano E Berti M Roila F Management of cancer pain ESMO clinical recommendations Ann Oncol. 2012 Oct 23 Suppl 7 vii39 154 \n13 Windecker S Stortecky S Meier B Paradoxical embolism J Am Coll Cardiol 2014 Jul 64 (4) 403 15 25060377 \n14 Travis JA Fuller SB Ligush J Jr Plonk GW Jr Geary RL Hansen KJ Diagnosis and treatment of paradoxical embolus J Vasc Surg 2001 Nov 34 (5) 860 5 11700487 \n15 Schainfeld RM Management of peripheral arterial disease and intermittent claudication J Am Board Fam Pract. 2001 Nov-Dec 14 (6) 443 50 11757887 \n16 Blann AD Dunmore S Arterial and venous thrombosis in cancer patients Cardiol Res Pract. 2011 Mar 2011 394740 21403876 \n17 Ross JS Stagliano NE Donovan MJ Breitbart RE Ginsburg GS Atherosclerosis a cancer of the blood vessels? Am J Clin Pathol. 2001 Dec 116 Suppl S97 107 11993705 \n18 Bagot CN Arya R Virchow and his triad a question of attribution Br J Haematol 2008 Oct 143 (2) 180 90 18783400 \n19 Falanga A Marchetti M Vignoli A Coagulation and cancer biological and clinical aspects J Thromb Haemost 2013 Feb 11 (2) 223 33 23279708 \n20 Hui L Wiernik PH Avascular necrosis of bone after adult acute lymphocytic leukemia treatment with methotrexate and dexamethasone (MOAD) Am J Hematol 1996 Jul 52 (3) 184 8 8756084 \n21 Abhyankar D Nair R Menon H Kapoor B Advani S Avascular necrosis of head of femur in a patient with acute promyelocytic leukemia Leuk Lymphoma. 2000 May 37 (5–6) 635 7 11042527 \n22 Sakakura M Nishii K Usui E Monma F Tsukada T Shiku H Bilateral osteonecrosis of the head of the femur during treatment with retinoic acid in a young patient with acute promyelocytic leukemia Int J Hematol 2006 Apr 83 (3) 252 3 16720557 \n23 van den Berkmortel F de Wit R de Rooy J DeMulder P Osteonecrosis in patients with testicular tumours treated with chemotherapy Neth J Med 2004 Jan 62 (1) 23 7 15061230 \n24 Cosmi B Conti E Coccheri S Anticoagulants (heparin low molecular weight heparin and oral anticoagulants) for intermittent claudication Cochrane Database Syst Rev. 2014 May 7 (5) CD001999 \n25 Roth A Beckmann J Bohndorf K Fischer A Heiß C Kenn W S3-Guideline non-traumatic adult femoral head necrosis Arch Orthop Trauma Surg 2016 Feb 136 (2) 165 74 26667621\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "11(1)",
"journal": "Case reports in oncology",
"keywords": "Avascular necrosis of bone; Bipolar arthroplasty; Chemotherapy; Coagulopathy; Low-molecular-weight heparin; Solid tumor",
"medline_ta": "Case Rep Oncol",
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"title": "Avascular Necrosis of Bone following Chemotherapy in Cancer Patients with Coagulopathy: Report of Two Cases.",
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"abstract": "Sirolimus is an immunosuppressive agent used in organ rejection prophylaxis in solid-organ transplantation, graft-vs-host disease prophylaxis in hematopoietic stem cell transplantation, and as an immune modulator for patients with lymphangioleiomyomatosis and vascular malformations. Sirolimus has a narrow therapeutic index with potential severe side effects, including hypertension, hepatotoxicity, nephrotoxicity, and neurotoxicity.\n\n\n\nWe report a case of a 19-year-old woman with severe sickle cell disease who underwent a matched unrelated hematopoietic stem cell transplantation, whose course was complicated by sirolimus toxicity. This case was challenging because sirolimus has no specific antidote, is largely bound to red blood cells (RBCs), has a high distribution volume, and cannot be removed by dialysis or plasmapheresis.\n\n\n\nDue to the concern for toxicity, we looked into possibilities for rapid sirolimus clearance using automated RBC exchange. The treatment was effective in decreasing blood sirolimus levels within the therapeutic ranges.\n\n\n\nThe use of RBC exchange is potentially safe and effective in the management of a case of sirolimus toxicity.",
"affiliations": "Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, Arizona, USA.;Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, Arizona, USA.;Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, Arizona, USA.;Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, Arizona, USA.",
"authors": "Nizzi|Frank|F|;Rees|Melissa|M|;Salzberg|Dana|D|;Ngwube|Alexander|A|0000-0003-4780-5642",
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"keywords": "hematopoietic stem cell transplantation; plasmapheresis; sirolimus toxicity",
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"mesh_terms": "D000328:Adult; D064591:Allografts; D000755:Anemia, Sickle Cell; D004912:Erythrocytes; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D020123:Sirolimus",
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"title": "Successful management of sirolimus toxicity in a hematopoietic stem cell transplant patient using automated red blood cell exchange.",
"title_normalized": "successful management of sirolimus toxicity in a hematopoietic stem cell transplant patient using automated red blood cell exchange"
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"abstract": "OBJECTIVE\nTo report on the occurrence and management of subdural haematoma after shunt implantation for normal pressure hydrocephalus and to determine the risk of recurrence in the setting of antiplatelet medication.\n\n\nMETHODS\nFrom a consecutive series of 80 patients implanted with a cerebrospinal fluid shunt for normal pressure hydrocephalus, records from 11 patients taking antiplatelet drugs, who subsequently had surgery for subdural haematoma were extracted and retrospectively reviewed.\n\n\nRESULTS\nPatients were followed up for a mean of 1819 days after shunt implantation. Subdural haematomas occurred at a median of 335 days after shunt implantation - four ipsilateral, five contralateral and two bilateral with respect to the ventricular catheter. Three patients had reoperations done within a week without having resumed antiplatelet medication in the interim. One of them had three further reoperations done before the subdural collection disappeared. Only one patient had a late recurrence almost 11 years after shunt implantation.\n\n\nCONCLUSIONS\nSubdural haematoma in the setting of a ventriculoperitoneal implantation for normal pressure hydrocephalus and concomitant antiplatelet medication can be managed along usual lines. Antiplatelet medication can be recommenced in due course with a low risk of recurrence.",
"affiliations": "a Department of Neurosurgery , Odense University Hospital , Odense , Denmark ;;b Department of Orthopaedic Surgery , Odense University Hospital , Odense , Denmark ;;a Department of Neurosurgery , Odense University Hospital , Odense , Denmark ;",
"authors": "Birkeland|Peter|P|;Lauritsen|Jens|J|;Poulsen|Frantz Rom|FR|",
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"title": "Subdural haematoma complicating shunting for normal pressure hydrocephalus in the setting of concomitant antiplatelet medication - a report of 11 cases.",
"title_normalized": "subdural haematoma complicating shunting for normal pressure hydrocephalus in the setting of concomitant antiplatelet medication a report of 11 cases"
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"abstract": "High dose insulin euglycemia therapy - an important addition to the treatment arsenal in severe toxic myocardial depression Fifty-nine patients who developed hemodynamic symptoms necessitating treatment with vasopressors or inotropes after poisoning with calcium channel blockers (CCB) and beta blockers (BB) between January 2010 and August 2016 were identified by a search of the Poisons Information Centre database. In-hospital circulatory arrest occurred in 16/59 (27 %) and the mortality rate was 7/59 (12 %). Two cases of analytically confirmed combined BB and CCB poisoning were treated with high dose insulin therapy (HIE) and are presented in detail. The outcome in both cases was good. They were the only cases in the study population treated with HIE, although signs of cardiac dysfunction was present in 55/59 (93%) and in all cases of circulatory arrest. Animal studies and international clinical cases indicate that HIE is a safe and effective method to improve cardiac function in CCB and BB poisoning, and its implementation in Sweden may improve the outcome for this at risk population.",
"affiliations": "Läkemedelsverket - Giftinformationscentralen Stockholm, Sweden Läkemedelsverket - Giftinformationscentralen Stockholm, Sweden.;Anestesi- och Intensivvårdskliniken, Danderyds sjukhus - Stockholm, Sweden Anestesi- och Intensivvårdskliniken, Danderyds sjukhus - Stockholm, Sweden.;Operations- och intensivvårdskliniken, Hallands sjukhus Varberg - Varberg, Sweden Operations- och intensivvårdskliniken, Hallands sjukhus Varberg - Varberg, Sweden.;Giftinformationscentralen - Stockholm, Sweden Giftinformationscentralen - Stockholm, Sweden.",
"authors": "Lindeman|Erik|E|;Baer Eriksson|Lovisa|L|;Thorsson|Martin|M|;Nordmark Grass|Johanna|J|",
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"mesh_terms": "D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D005260:Female; D005947:Glucose; D006801:Humans; D007328:Insulin; D008875:Middle Aged; D017410:Practice Guidelines as Topic; D012769:Shock",
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"title": "High dose insulin euglycemia therapy – an important addition to the treatment arsenal in severe toxic myocardial depression.",
"title_normalized": "high dose insulin euglycemia therapy an important addition to the treatment arsenal in severe toxic myocardial depression"
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"abstract": "Beta-lactam-associated acute tubulointerstitial nephritis (ATIN) is a rare condition in childhood. We report the case of an infant with penicillin-associated ATIN and concomitant acute pyelonephritis resulting in the development of severe acute kidney injury (AKI). The treatment consisted of penicillin suspension and appropriate AKI management, which required a short period of dialysis. Finally, full recovery and normalization of laboratory parameters occurred. We present here the first case of oral penicillin-associated ATIN in childhood.",
"affiliations": "Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Praha, Czech Republic.",
"authors": "Zieg|Jakub|J|;Hacek|Jaromir|J|",
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"mesh_terms": "D000208:Acute Disease; D058186:Acute Kidney Injury; D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D007223:Infant; D010406:Penicillins; D010530:Peritoneal Dialysis; D011704:Pyelonephritis",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Oral penicillin-associated acute kidney injury in an infant with acute pyelonephritis.",
"title_normalized": "oral penicillin associated acute kidney injury in an infant with acute pyelonephritis"
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"dru... |
{
"abstract": "Tick-borne relapsing fever (TBRF) is endemic in Israel. Military activities pose a particular risk for TBRF, and its prevention is based on heightened awareness and risk stratification by active surveillance of tick bites and selective postexposure prophylaxis (PEP) with doxycycline for tick-bitten individuals. We report three outbreaks of TBRF affecting 35 exposed military personnel, with an average recognized tick bite rate of approximately 50% and an attack rate of 25-50%. Of 10 TBRF cases, 20% had no evidence of tick bites and thus restriction of PEP administration to individuals with recognized tick bites contributed to TBRF occurrence. As a result of a revised policy, 24 soldiers (including eight with recognized and 16 with unrecognized tick bites) received antimicrobials following the diagnosis of TBRF among their cohorts, and none of these individuals subsequently developed TBRF. The probability for TBRF among exposed individuals associated with well-established cases of TBRF warrants that prompt doxycycline administration be considered in all individuals who share risk factors, regardless of tick bite status.",
"affiliations": "1 Medical Corps , Israel Defense Force, Israel .",
"authors": "Moran-Gilad|Jacob|J|;Levine|Hagai|H|;Schwartz|Eli|E|;Bartal|Carmi|C|;Huerta-Hartal|Michael|M|;Schwaber|Mitchell J|MJ|;Ostfeld|Ishay|I|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004318:Doxycycline",
"country": "United States",
"delete": false,
"doi": "10.1089/vbz.2013.1347",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-3667",
"issue": "13(11)",
"journal": "Vector borne and zoonotic diseases (Larchmont, N.Y.)",
"keywords": null,
"medline_ta": "Vector Borne Zoonotic Dis",
"mesh_terms": "D000818:Animals; D000900:Anti-Bacterial Agents; D001096:Arachnid Vectors; D001898:Borrelia; D015331:Cohort Studies; D004196:Disease Outbreaks; D004318:Doxycycline; D006801:Humans; D007557:Israel; D008889:Military Personnel; D056990:Post-Exposure Prophylaxis; D012061:Relapsing Fever; D064927:Tick Bites; D013984:Tick Infestations; D013987:Ticks",
"nlm_unique_id": "100965525",
"other_id": null,
"pages": "791-7",
"pmc": null,
"pmid": "24107216",
"pubdate": "2013-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Postexposure prophylaxis of tick-borne relapsing fever: lessons learned from recent outbreaks in Israel.",
"title_normalized": "postexposure prophylaxis of tick borne relapsing fever lessons learned from recent outbreaks in israel"
} | [
{
"companynumb": "IL-MYLANLABS-2015M1038988",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE"
},
"drugadditional": null,
... |
{
"abstract": "A 69-year-old woman underwent proximal gastrectomy with distal pancreatectomy and splenectomy for a gastrointestinal stromal tumor of the stomach.Adjuvant imatinib was administered for a year.Two years after resection of the tumor, liver metastasis in S8 was detected.Therefore, imatinib was re-administered at 300mg/day.After a year of re-administration, the patient suffered muscle cramps in the hands, and therefore imatinib was administered with intervals, such as 4 weeks administration and 4 weeks rest.Re -administration of imatinib was effective and her liver metastasis decreased in size.It was not detected with CT after 1 year and 4 months and remained in complete response(CR)for 3 years and 8 months.After she suffered a brain infarction, imatinib administration was stopped for 4 months.Consequently, the liver metastasis was detectable in S8 again.This clinical course suggested that low-dose and interval administration of imatinib is effective in the treat- ment of GIST.",
"affiliations": "Dept. of Surgery, Fujioka General Hospital.",
"authors": "Morinaga|Nobuhiro|N|;Saito|Hideyuki|H|;Komine|Chika|C|;Matsumoto|Asuka|A|;Katoh|Toshihide|T|;Tanaka|Naritaka|N|;Nakazato|Kenji|K|;Nakamura|Takuro|T|;Shitara|Yoshinori|Y|;Ishizaki|Masatoshi|M|",
"chemical_list": "D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "44(2)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D005260:Female; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D000068877:Imatinib Mesylate; D008113:Liver Neoplasms; D012008:Recurrence; D013274:Stomach Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "161-164",
"pmc": null,
"pmid": "28223675",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Low-Dose and Interval Administration of Imatinib in a Patient with Liver Metastasis of the Gastrointestinal Stromal Tumor of the Stomach - A Case Report.",
"title_normalized": "low dose and interval administration of imatinib in a patient with liver metastasis of the gastrointestinal stromal tumor of the stomach a case report"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-147642",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugad... |
{
"abstract": "We present a case of ocular tuberculosis (TB) presenting as scleral abscess with choroidal detachment. A 60-year-old woman presented with intense pain, redness, watering and decreased vision in the right eye (RE) for 1 week duration. Slit lamp examination of RE revealed diffuse scleritis with two pus-pointing areas in the supero-temporal quadrant suggesting scleral abscess. Fundus examination of the RE showed choroidal detachment in the temporal and inferior quadrant. Left eye examination was unremarkable. Ziehl-Neelsen staining of scleral biopsy showed acid-fast bacilli. PCR of the scleral tissue was also positive for Mycobacterium tuberculosis genome. The final diagnosis of tuberculous scleral abscess with choroidal detachment was made and patient showed good response to antitubercular treatment. In countries endemic for TB, it should be considered as a differential diagnosis for scleral abscess, since prompt diagnosis and treatment will ensure good visual outcome as depicted in our case.",
"affiliations": "Department of Ophthalmology, Jawaharlal Institute of Post Graduate Medical Education, Pondicherry, India.;Jawaharlal Institute of Post Graduate Medical Education, Pondicherry, Puducherry, India.;Jawaharlal Institute of Post Graduate Medical Education, Pondicherry, Puducherry, India.;Department of Ophthalmology, JIPMER, Pondicherry, Pondicherry, India.",
"authors": "Parchand|Swapnil Madhukar|SM|http://orcid.org/0000-0002-3048-7951;Kumar|Aswanthi Sadesh|AS|;Kaliaperumal|Subashini|S|;Srinivasan|Renuka|R|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-217544",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000038:Abscess; D000359:Aftercare; D000368:Aged; D000995:Antitubercular Agents; D015862:Choroid Diseases; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D009169:Mycobacterium tuberculosis; D015423:Scleritis; D016896:Treatment Outcome; D014392:Tuberculosis, Ocular",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28062426",
"pubdate": "2017-01-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11024419;14220487;14574263;18029267;22463821;23429033;24235809;25615807;26511718;27134484",
"title": "Tuberculous scleral abscess with choroidal detachment.",
"title_normalized": "tuberculous scleral abscess with choroidal detachment"
} | [
{
"companynumb": "ALCN2017IN001596",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nLow back pain is a highly common problem and causes much morbidity and socioeconomic loss in the community. Although the use of caudal epidural injections in the management of the low back pain with radicular signs is commonplace, it has not been well investigated. We compare the effectiveness of caudal epidural injection versus non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of low back pain accompanied with radicular pain.\n\n\nMETHODS\nThe study was a controlled prospective unblinded trial. A total of consecutive 64 patients with subacute or chronic low back pain accompanied with radicular pain were included. The patients were randomly allocated to two groups. First group was caudal epidural injection plus therapeutic exercise group, and the second group was NSAIDs plus therapeutic exercise group. Patients were assessed with 10 cm visual analogue scale for pain, straight leg raising test and Oswestry low back pain disability questionnaire at the beginning and at 15th day, 1st and 3rd month.\n\n\nRESULTS\nIt was seen that both groups' improvement were good and statistically significant. On the other hand, caudal epidural injection group's improvement was better and faster than the NSAID group's, and the differences between assessment scores of the groups were statistically significant, except the 3rd month Oswestry scores.\n\n\nCONCLUSIONS\nFinally, caudal epidural injection in the management of the subacute/chronic low back and radicular pain is a preferable choice, if applied by experienced specialists.",
"affiliations": "Department of Physical Medicine and Rehabilitation, Gulhane Military Medical Academy, Haydarpasa Training Hospital, Istanbul, Turkey. drumitdincer@yahoo.com",
"authors": "Dincer|Umit|U|;Kiralp|Mehmet Zeki|MZ|;Cakar|Engin|E|;Yasar|Evren|E|;Dursan|Hasan|H|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000082:Acetaminophen",
"country": "France",
"delete": false,
"doi": "10.1016/j.jbspin.2006.09.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1297-319X",
"issue": "74(5)",
"journal": "Joint bone spine",
"keywords": null,
"medline_ta": "Joint Bone Spine",
"mesh_terms": "D000082:Acetaminophen; D000208:Acute Disease; D000328:Adult; D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002908:Chronic Disease; D006801:Humans; D007268:Injections, Epidural; D017116:Low Back Pain; D018579:Patient Selection; D011843:Radiculopathy",
"nlm_unique_id": "100938016",
"other_id": null,
"pages": "467-71",
"pmc": null,
"pmid": "17587625",
"pubdate": "2007-10",
"publication_types": "D018848:Controlled Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Caudal epidural injection versus non-steroidal anti-inflammatory drugs in the treatment of low back pain accompanied with radicular pain.",
"title_normalized": "caudal epidural injection versus non steroidal anti inflammatory drugs in the treatment of low back pain accompanied with radicular pain"
} | [
{
"companynumb": "TR-PFIZER INC-2020206318",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE ACETATE"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nDose intense chemotherapy may improve efficacy with acceptable toxicity. A phase II study was conducted to determine the feasibility of a dose-intense two weekly schedule of capecitabine, oxaliplatin, and bevacizumab in metastatic colorectal cancer (mCRC).\n\n\nMETHODS\n49 patients with previously untreated mCRC were recruited. Nineteen received capecitabine (1750 mg/m(2) oral BD days 1-7)oxaliplatin (85 mg/m(2)i.v. day 1) and bevacizumab (5 mg/kg i.v. day 1) using a 14-day cycle (C1750). Following toxicity concerns capecitabine was reduced to 1500 mg/m2oral BD (C1500) and 30 further patients recruited.\n\n\nRESULTS\nOver 80% of patients received at least 75% of planned chemotherapy doses over the first two cycles. At C1750 Grade 3 or higher toxicity occurred in 74% (95% CI 49% to 91%) and on C1500 in 70% (95% CI 51% to 85%). The median progression-free survival was 6.9 months (95% CI 4.7 to 8.7) for C1750 dose and 8.9 months (95% CI 4.1 to 12.4) for C1500. 3 treatment-related deaths occurred.\n\n\nCONCLUSIONS\nDose intense capecitabine and oxaliplatin with bevacizumab does not show additional efficacy and has potentially significant toxicity. Its use outside of clinical trials is not recommended.\n\n\nBACKGROUND\nISRCTN41540878.",
"affiliations": "Cancer Trials New Zealand, University of Auckland, Level 1, Building 505, 85 Park Road, Grafton, Auckland, New Zealand. mp.findlay@auckland.ac.nz.",
"authors": "Jackson|Christopher G C A|CG|;Sharples|Katrina|K|;Thompson|Paul I|PI|;O'Donnell|Anne|A|;Robinson|Bridget Anne|BA|;Perez|David J|DJ|;Adams|Jacqui|J|;Isaacs|Richard|R|;Deva|Sanjeev|S|;Hinder|Victoria A|VA|;Findlay|Michael P|MP|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1186/1471-2407-14-737",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 25274181491410.1186/1471-2407-14-737Research ArticleDose-intense capecitabine, oxaliplatin and bevacizumab as first line treatment for metastatic, unresectable colorectal cancer: a multi-centre phase II study Jackson Christopher GCA christopher.jackson@southerndhb.govt.nz Sharples Katrina katrina.sharples@otago.ac.nz Thompson Paul I pault@adhb.govt.nz O’Donnell Anne anne.odonnell@ccdhb.govt.nz Robinson Bridget Anne bridget.robinson@cdhb.health.nz Perez David J david.perez@southerndhb.govt.nz Adams Jacqui jacqui.adams@health.sa.gov.au Isaacs Richard richard.isaacs@midcentraldhb.govt.nz Deva Sanjeev SanjeevD@adhb.govt.nz Hinder Victoria A v.hinder@auckland.ac.nz Findlay Michael P mp.findlay@auckland.ac.nz Department of Medicine, University of Otago, Dunedin, New Zealand Preventive and Social Medicine, University of Otago, Dunedin, New Zealand Cancer Trials New Zealand, University of Auckland, Level 1, Building 505, 85 Park Road, Grafton, Auckland, New Zealand Auckland City Hospital, Auckland, New Zealand Wellington Cancer Centre, Capital and Coast Health, Wellington, New Zealand Christchurch School of Medicine, University of Otago, Christchurch, New Zealand University of Otago, Dunedin, New Zealand Lyell McEwin Hospital, Elizabeth Vales, South Australia Australia Regional Cancer Treatment Service, MidCentral Health, Palmerston North, New Zealand 2 10 2014 2 10 2014 2014 14 7375 3 2013 23 9 2014 © Jackson et al.; licensee BioMed Central Ltd. 2014This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background\nDose intense chemotherapy may improve efficacy with acceptable toxicity. A phase II study was conducted to determine the feasibility of a dose-intense two weekly schedule of capecitabine, oxaliplatin, and bevacizumab in metastatic colorectal cancer (mCRC).\n\nMethods\n49 patients with previously untreated mCRC were recruited. Nineteen received capecitabine (1750 mg/m2 oral BD days 1–7)oxaliplatin (85 mg/m2i.v. day 1) and bevacizumab (5 mg/kg i.v. day 1) using a 14-day cycle (C1750). Following toxicity concerns capecitabine was reduced to 1500 mg/m2oral BD (C1500) and 30 further patients recruited.\n\nResults\nOver 80% of patients received at least 75% of planned chemotherapy doses over the first two cycles. At C1750 Grade 3 or higher toxicity occurred in 74% (95% CI 49% to 91%) and on C1500 in 70% (95% CI 51% to 85%). The median progression-free survival was 6.9 months (95% CI 4.7 to 8.7) for C1750 dose and 8.9 months (95% CI 4.1 to 12.4) for C1500. 3 treatment-related deaths occurred.\n\nConclusions\nDose intense capecitabine and oxaliplatin with bevacizumab does not show additional efficacy and has potentially significant toxicity. Its use outside of clinical trials is not recommended.\n\nTrial registration\nISRCTN41540878\n\nKeywords\n(6 in alphabetical order) bevacizumabCapecitabineDose-intenseColorectal cancerissue-copyright-statement© The Author(s) 2014\n==== Body\nBackground\nColorectal cancer (CRC) is the second most incident solid tumour and the second leading cause of cancer-related death worldwide with over 1.2 million new cancer cases and 608,700 deaths estimated to have occurred in 2008\n[1]. Due to an increasing incidence in developing countries as well as an aging population structure, the burden of colorectal cancer will continue to rise despite reductions in mortality in western countries\n[2]. With the use of chemotherapy and targeted agents for stage 4 disease, median overall survival has increased from 6 months with supportive care alone to over 20 months. The monoclonal antibody against vascular endothelial growth factor, bevacizumab (Avastin, Roche), improved progression-free and over-all survival when combined with IFL chemotherapy\n[3], and increased progression-free survival with a non-statistically significant increase in overall survival when combined with oxaliplatin based chemotherapy\n[4] and has been widely adapted as a standard component of first line therapy.\n\nCapecitabine is an oral pro-drug of 5-fluorouracil, which in combination with Oxaliplatin (CapOx) has similar efficacy to the reference regimen FOLFOX-4, and obviates the need for a central venous access device and so is more convenient. Studies comparing CapOx in combination with bevacizumab have demonstrated similar PFS and overall survival to FOLFOX4-Bevacizumab\n[4, 5]. However up to 20% of patients receiving CapOx experienced grade 3/4 diarrhoea\n[5–8] hence toxicity improvements in this schedule that maintain or improve efficacy are required.\n\nThe standard CapOx regimen is given on a 21-day cycle, with oxaliplatin 130 mg/m2iv on Day 1 and capecitabine 1000 mg/m2 PO BD on days 1–14. Mathematical modelling as well as pre-clinical studies in breast cancer mouse xenografts have indicated that a dose-dense regimen of 7 days treatment with capecitabine followed by 7 days rest may result in a higher maximum tolerated dose being achieved\n[9]. Other groups have investigated the use of dose-dense capecitabine with oxaliplatin\n[10], adopting a two-weekly cycle with oxaliplatin 85 mg/m2 on Day 1, and a 7 day administration of capecitabine. In a dose escalation study using this 7/7 schedule, a maximum tolerated dose of capecitabine was reached at 1750 mg/m2 PO BDd1-7. The effective daily dose of capecitabine in a 21 day schedule is 1333 mg/m2/day, whereas in the 14 day schedule using 1750 mg/m2 the daily dose received of capecitabine is 1750/m2/day – a 30% increase in total capecitabine delivered.\n\nIn the follow-on phase II trial\n[11] 89 patients were randomised to receive either dose-intense CapOx or a standard 21 day regimen. Those allocated to the dose intense arm had a significantly longer median progression-free survival time than those in the control arm (10.5 v 6.0 months; HR 2.15: 95% CI 1.43 to 4.35; p = 0.0013). In addition, there were comparable rates of haematological and non-haematological toxicities, and only 12% Grade 3/4 diarrhoea observed in the dose-dense arm.\n\nGiven that the addition of bevacizumab to chemotherapy appears to improve PFS, and that dose-dense chemotherapy may improve efficacy, we considered that dose-intense CapOx with bevacizumab warranted exploration. We undertook a phase II study to determine the feasibility and safety of a dose-intense capecitabine and oxaliplatin schedule with bevacizumab for patients with previously untreated advanced colorectal cancer.\n\nMethods\nThis national, multicentre, open-label, single arm, phase II clinical trial had the primary objective of determining the feasibility and safety of a dose-dense Capecitabine-Oxaliplatin-Bevacizumab regimen. Feasibility was determined by dose delivery, measured by the proportion of patients who received at least 75% of the planned dose for the first two cycles. Safety was measured according to Common Toxicity Criteria for Adverse Events v3.0. Secondary end-points included radiologic response rate, progression free survival and overall survival. The trial was approved by the Multi-Region Ethics Committee (MEC/06/04/041). The study was registered as ISRCTN41540878.\n\nPatient selection\nPatients were eligible if aged 18 years of age or older with previously untreated, histologically or cytologically confirmed locally recurrent or metastatic colorectal adenocarcinoma, ECOG performance status of 0 or 1, absolute neutrophil count of ≥1.5×109/L, platelet count of ≥75×109/L, serum total bilirubin <30 umol/L, negative urinary protein on dipstick testing or <1 g/24 hour collection, and creatinine clearance ≥ 50 mL/min by Cockcroft Gault calculation or direct measurement in accordance with local practice. All patients provided written informed consent. Prior adjuvant therapy was allowed if completed more than 6 months prior to enrollment. Exclusion criteria included prior chemotherapy for advanced CRC, tumour invasion of major blood vessels, recent major surgery, clinically significant cerebrovascular or cardiovascular disease including uncontrolled hypertension, congenital or acquired coagulopathy or full anti-coagulation prior to registration. Patients were enrolled from all 6 New Zealand Cancer Centres.\n\nTreatment\nPatients received capecitabine 1750 mg/m2 PO BD days 1–7, oxaliplatin 85 mg/m2 i.v. day 1 and bevacizumab 5 m/kg i.v. day 1 of a 14 day cycle (C1750). After an interim safety analysis the capecitabine dose was reduced to 1500 mg/m2 PO BD d1-7 (C1500) with doses of the other agents unchanged. Treatment was continued until disease progression, unacceptable toxicity or patient decision. All patients were followed for adverse events until 31st May 2008 and until 1 July 2009 for survival.\n\nStatistical considerations\nDose delivery was assessed as the proportion of patients who received at least 75% of the planned chemotherapy dose over the first two cycles. Dose intensity for each patient was calculated as the average proportion of the per protocol dose given per day while still on study chemotherapy over the first two cycles. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v 3.0 (NCI-CTCAE v3.0). Progression-free survival was calculated from day 1 of treatment until first documented evidence of disease progression or death from any cause. Modified RECIST 1.0 criteria were used to determine the tumour response, with confirmatory scans at 8 weeks (as opposed to 4) to reduce the burden of investigational procedures for the patients. For key outcome measures 95% confidence intervals are reported for estimates of proportions. The Kaplan-Meier product limit estimator\n[12] was used to estimate progression free survival and overall survival. Median survival was reported, with confidence intervals calculated using the method of Brookemeyer and Crowley\n[13] with log transform. All analyses were stratified by planned capecitabine dose. A sample size of 60 patients was chosen to allow a precision of ± 0.09 for a 95% confidence interval around an observed proportion of 0.8.\n\nResults\nPatient characteristics\nBetween June 2006 and June 2007, 49 patients were recruited. Characteristics are summarized in Table \n1. Nineteen patients received capecitabine at 1750 mg/m2 (C1750 group). An interim safety analysis was planned after 20 patients were recruited but was conducted after 19 patients due to investigator concerns about gastrointestinal toxicity. This resulted in a dose reduction in capecitabine to 1500 mg/m2/BD (C1500 group), which was then received by 30 patients. Following 2 further deaths at this dose level, the study was terminated. The median follow-up was 23 months for the C1750 group and 15 months for the C1500 group.Table 1 \nPatient demographic and disease characteristics\n\n\n\tTotal\tC1750 mg/m2\n\tC1500 mg/m2\n\t\n\tn = 49\tn = 19\tn = 30\t\n\nAge at registration, median (IQ range)\n\t63 (55, 67)\t64 (52, 68)\t62 (55, 65)\t\n\nGender, n (%)\n\t\t\t\t\nFemale\t31 (63.3)\t11 (57.9)\t20 (66.7)\t\nMale\t18 (36.7)\t8 (42.1)\t10 (33.3)\t\n\nEthnicity, n (%)\n\t\t\t\t\nEuropean\t47 (96.0)\t18 (94.7)\t29 (96.7)\t\nMaori\t1 (2.0)\t1 (5.3)\t0 (0.0)\t\nOther\t1 (2.0)\t0 (0.0)\t1 (3.3)\t\n\nHistology, n (%)\n\t\t\t\t\nAdenocarcinoma - NOS\t20 (40.8)\t7 (36.8)\t13 (43.3)\t\nAdenocarcinoma - poorly differentiated\t4 (8.2)\t2 (10.5)\t2 (6.7)\t\nAdenocarcinoma - moderately differentiated\t17 (34.7)\t9 (47.4)\t8 (26.7)\t\nAdenocarcinoma - well differentiated\t1 (2.0)\t1 (5.3)\t0 (0.0)\t\nMucinious\t7 (14.3)\t0 (0.0)\t7 (23.3)\t\n\nDisease Status, n (%)\n\t\t\t\t\nDistant metastases only\t41 (83.7)\t17 (89.5)\t24 (80.0)\t\nLocal recurrence\t5 (10.2)\t2 (10.5)\t3 (10.0)\t\nDistant metastases and local recurrence\t3 (6.1)\t0 (0.0)\t3 (10.0)\t\n\nPrior Anticancer Treatment, n (%)\n\t\t\t\t\nPrior Adjuvant Chemotherapy\t11 (22.4)\t5 (26.3)\t6 (20.0)\t\nRadiotherapy\t8 (16.3)\t3 (15.8)\t5 (16.7)\t\nSurgery\t44 (89.8)\t17 (89.5)\t27 (90.0)\t\n\nWHO Performance Status, n (%)\n\t\t\t\t\n0\t42 (85.7)\t18 (94.7)\t24 (80.0)\t\n1\t7 (14.3)\t1 (5.3)\t6 (20.0)\t\n\n\nDose delivery of chemotherapy\nOver 80% of patients received at least 75% of the planned dose of all three drugs in both dose groups (Table \n2). The median dose-intensity for each drug over all cycles received was 0.8 for the C1750 group and was 0.96-1.0 in the C1500 group. Median number of cycles received was 7 for C1750 and 8 for C1500 (Figure \n1, Table \n2). The principal reasons for early discontinuation were gastrointestinal adverse events, fatigue, or pain. At the lower dose level, 15/30 patients discontinued treatment prior to progression. The main adverse events in this group were gastrointestinal, infection, sensory neuropathy and fatigue.Table 2 \nCompliance with chemotherapy\n\n\n\tTotal\tC1750 mg/m2\n\tC1500 mg/m2\n\t\n\tn = 49\tn = 19\tn = 30\t\n\nReason for discontinuation of chemotherapy, n (%)\n\t\t\t\t\nProgression\t12 (24.5)\t4 (21.1)\t8 (26.7)\t\nNeed for surgery\t6 (12.2)\t2 (10.5)\t4 (13.3)\t\nDeath (treatment-related cause)\t3 (6.1)\t1 (5.3)\t2 (6.7)\t\nOther toxicity\t16 (32.7)\t5 (26.3)\t11(36.7)\t\nPatient or investigator decision not otherwise specified\t11 (22.4)\t7 (36.8)\t4 (13.3)\t\nStill on treatment\t1 (2.0)\t0 (0.0)\t1 (3.3)\t\n\nReceipt ofat least 75% of planned dose in first two cycles, n (%)\n\t\t\t\t\nEach drug separately\t\t\t\t\nCapecitabine\t42 (85.7)\t18 (94.7)\t24 (80.0)\t\nOxaliplatin\t46 (93.9)\t19 (100.0)\t27 (90.0)\t\nBevacizumab\t44 (89.8)\t17 (89.5)\t27 (90.0)\t\nAll three drugs\t40 (82.6)\t16 (84.0)\t24 (80.0)\t\n\nDose intensity while on chemotherapy, median (IQ range)\n\t\t\t\nCapecitabine\t0.95 (0.66, 1)\t0.8(0.57,1)\t0.96 (0.67,1)\t\nOxaliplatin\t1 (0.8, 1)\t0.8 (0.67,1)\t1 (1,1)\t\nBevacizumab\t1 (0.8, 1)\t0.8 (0.67,1)\t1 (1,1)\t\nFigure 1 \nNumber of cycles of chemotherapy completed. The median number of cycles completed was 8 (IQ range (5,12)) on dose C1750mg/m2 and 7 (IQ range (5,13)) on C1500 mg/m2.\n\n\n\nSafety\nAmong the 19 patients on C1750, 14 patients developed a grade 3 or greater toxicity (74%; 95% CI 49-91%); at C1500 grade 3/4 toxicity occurred in 21 of 30 patients (70%; 95% CI 51-85%) (Table \n3). The most common toxicities at both dose levels were hand-foot syndrome, diarrhoea and nausea and vomiting. There were three treatment related deaths: one in the C1750 group due to an oesophageal perforation following chemotherapy induced emesis; two occurred in the C1500 group, with one patient developing fulminant diarrhea and subsequent sepsis 7 days after commencement of therapy, suggestive of DPD deficiency, and the other due to bowel perforation and sepsis in a patient with an unresected rectal primary. Following the third treatment-related death, the study was closed.Table 3 \nNumbers of patients experiencing a grade 3 or higher adverse event up to 28 days after stopping chemotherapy\n\n\n\tTotal n = 49\tC1750 mg/m2\n\tC1500 mg/m2\n\t\nn = 19\tn = 30\t\nHand-foot skin reaction (≥grade 2)\t14\t(28.6)\t6\t(31.6)\t8\t(26.7)\t\nDiarrhoea\t13\t(26.5)\t6\t(31.6)\t7\t(23.3)\t\nNausea and vomiting\t9\t(18.4)\t4\t(21.1)\t5\t(16.7)\t\nPain – abdomen\t4\t(8.2)\t2\t(10.5)\t2\t(6.7)\t\nPerforation\t4\t(8.2)\t3\t(15.8)\t1\t(3.3)\t\nObstruction\t2\t(4.1)\t0\t(0.0)\t2\t(6.7)\t\nSensory neuropathy\t5\t(10.2)\t2\t(10.5)\t3\t(10.0)\t\nFatigue\t4\t(8.2)\t2\t(10.5)\t2\t(6.7)\t\nThrombosis/thrombus/embolism\t4\t(8.2)\t2\t(10.5)\t2\t(6.7)\t\nHypokalemia\t4\t(8.2)\t2\t(10.5)\t2\t(6.7)\t\nInfection – sepsis\t3\t(6.1)\t0\t(0.0)\t3\t(10.0)\t\nFebrile neutropenia\t2\t(4.1)\t1\t(5.3)\t1\t(3.3)\t\nALT\t1\t(2.0)\t1\t(5.3)\t0\t(0.0)\t\nHypertension\t0\t(0.0)\t0\t(0.0)\t0\t(0.0)\t\nAcute respiratory distress syndrome\t1\t(2.0)\t0\t(0.0)\t1\t(3.3)\t\nAny grade 3 or higher adverse event\t35\t(71.4)\t14\t(73.8)\t21\t(70.0)\t\n95% confidence interval\t(56.7, 83.4)\t(48.8, 90.9)\t50.6, 85.3)\t\n\n\nEfficacy\nForty-three patients were evaluable for response (Table \n4), with two confirmed complete responses, and 20 partial responses (13 confirmed at 8 weeks). Of the seven unconfirmed responses, new lesions were found at the confirmatory scan in three patients, one patient died, and the remaining three stopped treatment so no confirmatory scan was carried out. The response rates (confirmed) were 47.1% (95% CI 23.0-72.2%) for C1750 and 26.9% (95% CI 11.6-47.8) for C1500.\n\nThe median progression free and overall survival (Figures\n2 and\n3) for C1750 was 6.9 months (95% CI 5.9 to 10.3) and 19.9 months (95% CI 11.9-26.3), and for the C1500 group was 8.4 months (95% CI 5.2 to 12.4) and 15.9 months (95% CI 13.1-27.7).Table 4 \nTumour response, progression and death\n\n\n\tTotal\tC1750 mg/m2\n\tC1500 mg/m2\n\t\nn = 49\tn = 19\tn = 30\t\n\nPatient status at end of follow-up, n (%)\n\t\nAlive, without disease progression\t9 (18.4)\t1 (5.3)\t8 (26.7)\t\nAlive with disease progression\t19 (38.8)\t9 (47.4)\t10 (33.3)\t\nDeath after disease progression\t15 (30.6)\t6 (31.6)\t9 (30.0)\t\nDeath without disease progression\t6 (12.2)\t3 (15.8)\t3 (10.0)\t\n\nNon measurable disease, n\n\t6\t2\t4\t\n\nBest overall response, n (%)\n\tn = 43\tn = 17\tn = 26\t\nComplete response\t2 (4.7)\t1 (5.9)\t1 (3.9)\t\nPartial response\t20 (46.5)\t8 (47.1)\t12 (46.2)\t\nStable disease\t15 (34.9)\t8 (47.1)\t7 (26.9)\t\nProgressive disease\t5 (11.6)\t0 (0.0%)\t5 (19.2)\t\nDied\t1 (2.3)\t0 (0.0%)\t1 (3.9)\t\n\nComplete or partial response (%, 95% CI)\n\t51.2% (35.5, 66.7)\t52.9% (27.8, 77.0)\t50.0% (29.9, 70.0)\t\n\nConfirmed response, n (%)\n\tn = 43\tn = 17\tn = 26\t\nComplete response\t2 (4.7)\t1 (5.9)\t1 (3.9)\t\nPartial response\t13 (30.2)\t7 (41.2)\t6 (23.1)\t\nStable disease\t8 (18.6)\t2 (11.8)\t6 (23.1)\t\nProgressive disease\t15 (34.9)\t5 (29.4)\t10 (38.5)\t\nDied\t5 (11.6)\t2 (11.8)\t3 (11.5)\t\n\nConfirmed complete or partial response (%, 95% CI)\n\t34.9% (21.0, 50.9)\t47.1% (23.0, 72.2)\t26.9% (11.6, 47.8)\t\nFigure 2 \nKaplan-Meier estimates of progression free survival. The median progression-free survival was 6.9 months (95% CI (5.9, 10.3)) in the capecitabine 1750 mg/m2 group and 8.4 months (95% CI(5.2, 12.4)) in the capecitabine 1500 mg/m2 group.\n\nFigure 3 \nKaplan-Meier estimates of overall survival. The median survival was 19.9 months (95% CI (11.9, 26.2)) in the Capecitabine 1750 mg/m2 group and 15.9 months (95% CI (13.1, 27.7)) in the capecitabine 1500 mg/m2 group.\n\n\n\nDiscussion and conclusions\nCombination chemotherapy with capecitabine is a convenient alternative to infusional regimens with preserved efficacy, and dose-intense chemotherapy may result in greater dose delivery and enhanced efficacy over 21 day schedules. At the time of study inception, we were not aware of any published reports of a dose-intense capecitabine-oxaliplatin schedule combined with bevacizumab.\n\nNorton-Simon mathematical and pre-clinical models of capecitabine administration in breast cancer mouse xenografts have indicated that a 7 day treatment schedule followed by a seven day rest (7/7 schedule) may result in a higher maximum tolerated dose of capecitabine being achieved, with lower toxicity\n[9]. A phase 1 trial of capecitabine monotherapy in breast cancer found this 7/7 schedule was well tolerated with 1/21 patients experiencing grade 3 diarrhoea\n[14]. A subsequent phase 2 study of fixed-dose capecitabine 2000 mg/PO/BD 7/7 combined with bevacizumab 10 mg/kg q14d had activity and reported 0% grade 3/4 diarrhoea\n[15]. A randomised phase 2 study containing 89 patients compared standard CapOx (Cap1000 mg/m2/BD d1-14 q21d; Ox130 mg/m2 d1 q21d) with dose intense CapOx (Cap 1750 mg/m2/BD d1-7, Ox85 mg/m2/d1; q14d) and reported a higher confirmed radiological response rate (54.5% v 42.2%) and longer PFS (10.5 v 6.0 months, p = 0.0013) favouring the dose intense schedule. Grade 3/4 diarrhoea rates were reported as 9 and 12% for the standard and dose intense arms respectively\n[11]. Reported rates of grade 3/4 diarrhoea of have been reported with three weekly CapOx-B regimens\n[16]. This contrasts with the results of a randomised phase 3 study, published following the completion of our study, of 435 patients of patients with advanced colorectal cancer, comparing 21 day Capecitabine with Oxaliplatin (Capecitabine 850 mg/m2/BD d1-14 q21d; Oxaliplatin 130 mg/m2 IV d1 q21d) to a 14 day schedule with increased dose capecitabine (Cap 1500 mg/m2/BD d1-7 q14d,Oxaliplatin 85 mg/m2 IV d1 q14d). This study showed the dose-intense regimen had a non-significantly shorter PFS compared to the standard regimen (8.4 months v 9.7 months; hazard ratio [HR] = 0.84; 95% CI = 0.62-1.13). Patients in the dose intense group experienced higher rates of grade 3/4 diarrhoea (29% vs 24%), hand-foot syndrome (12% vs 8%), and treatment discontinuation rates (40% vs 20%)\n[17]. A summary of studies of dose-intense regimens is described in Table \n5.Table 5 \nPublished studies of a dose-intense regimen of capecitabine and oxaliplatin\n\n\nTrial\tn\tChemotherapy\tRelative dose intensity*\tOverall response (%)\tPFS (months)\tGd 3/4 diarrhoea (%)\t\nOx\tCape\t\n\nThis trial\n\t\n_________\t\tq2w\tOxali 85 mg/m2\n\t\t\t\t\t\t\n\t19\t\tCape 1750 mg/m2 BDd1-7\t98%\t131%\t47.1%\t6.9\t31.6%\t\n30\t\tCape 1500 mg/m2 BD d1-7\t98%\t113%\t26.9%\t8.9\t23.3%\t\nBevac 5 mg/kg\t\n\nPhase II trials\n\t\nScheithauer\n[11]\t89\tq2w\tOxali 85 mg/m2\n\t98%\t131%\t54.5%\t10.5\t9%\t\nCape 1750 mg/m2 BDd1-7\t\nvs.\t\nq3w\tOxali 130 mg/m2\n\t\t\t42.2%\t6\t12%\t\nCape 1000 mg/m2 BD d1-14\t\nFedele\n[19]\t47**\tq2w\tOxali 100 mg/m2\n\t115%\t75%\t51%\t-\t4.3%\t\nCape 1000 mg/m2BD d1-7\t\nYuan\n[20]\t23**\tq2w\tOxali 85 mg/m2\n\t98%\tN/A\t61%\t-\t26%\t\nCape 2500 mg BD d1-7\t\nCetux 250 or 500 mg/m2\n\t\nLembersky\n[21]\t\tq2w\tOxali 85 mg/m2\n\t\t\t38%\t10\t18%\t\n11***\t\tCape 1250 mg/m2BDd1-7\t98%\t94%\t\t\t\t\n29\t\tCape 1500 mg/m2 BDd1-7\t98%\t113%\t\nBevac 5 mg/kg\t\n\nPhase III trials\n\t\nHurwitz\n[17]\t435\tq2w\tOxali 85 mg/m2\n\t98%\t113%\t21.7%\t8.4\t29%\t\n\tCape 1500 mg/m2 BD d1-7\t\t\t\t\t\t\nBevac 5 mg/kg\t\nvs.\t\n\t\tq3w\tOxali 130 mg/m2\n\t\t\t29.4%\t9.7\t24%\t\nCape 850 mg/m2 BD d1-7\t\nBevac 5 mg/kg\t\nTournigand\n[22]\t200\tq2w\tOxali 100 mg/m2\n\t115%\t94%\t-\t-\t21%\t\n\tCape 1250 mg/m2BD d1-7\t\t\t-\t-\t\t\nBevac 5 mg/kg\t\nvs.\t\nq2w\tOxali 100 mg/m2\n\t\t\t\t\t5%\t\nLV 400 mg/m2\n\t\t\t\t\t\t\n5FU 2400 mg/m2 ci 46 hrs\t\n\tBevac 5 mg/kg\t\t\nOxali: Oxaliplatin; Cape: Capecitabine; Bevac: Bevacizumab; LV: leucovorin; 5FU: 5-fluorouracil.\n\n*Compared to standard CapeOx: oxaliplatin 130 mg/m2 on Day 1 and capecitabine 1000 mg/m2/BD D1-14.\n\n**Number eligible for toxicity analysis.\n\n***Dose of capecitabine was increased in trial due to tolerability at low dose.\n\n\n\nOur study tested a dose of Capecitabine at the upper range of doses previously tested, with the addition of bevacizumab. Our observed rate of 23% G3/4 diarrhoea is comparable to other studies of Capecitabine-based doublets. Indeed our overall grade 3/4 adverse event rate of 74% is comparable to the 80% grade 3/4 adverse event rate for FOLFOX4/CapOx-Bev arms seen in the NO16966 study\n[6]. However the 3 deaths represented unacceptably high toxicity, and we observed more perforations than seen in the NO16966 study. The overwhelming diarrhoea that resulted in the death of one patient happened after 7 days of therapy, suggesting that there may have been underlying DPD deficiency, and this death may not have been attributable to the dose-intense schedule. One of the deaths was from tumour site perforation that was deemed treatment-related. In the BEAT study, a phase 4 study of bevacizumab 5 mg/kg (biweekly regimens) or 7.5 mg/kg (3-weekly regimens) in combination with FOLFOX, CapOx (18% of patients), FOLFIRI or 5-FU, tumour site perforation occurred in 3 of 223 patients with unresected colorectal cancers, indicating that this is a rare event\n[18]. The rates of perforation in our study were higher than seen in other studies. This may be either a chance finding or due to an interaction with this schedule. With these events our study could not demonstrate safety of the dose-intense CapOx-Bev regimen.\n\nThe response rate in the C1750 group was similar to other 5-FU-Oxaliplatin-Bevacizmab regimens and may have been higher if confirmatory scans were completed at 4 weeks instead of 8. The response rate was lower at the reduced dose of capecitabine, however the study was not powered to compare the response rate between dose levels. The median PFS and OS of seen in our study are similar to other reported regimens. Our data are similar to the phase III trial published recently\n[17], with lower response rates than in the initial phase II studies, suggesting difficulty translating studies in more selected small groups of patients to the more general phase 3 population, even when performance status was relatively good. It is also noted that the eligible patients did not have resectable disease and were at the worse end of the spectrum for metastatic/recurrent disease.\n\nThe cluster of adverse events, particularly perforation and toxic death reminiscent of DPD deficiency may have been due to chance occurrence or may have been due to the toxicity of a dose intense regimen. A phase one design with a smaller population may not have detected these events, whereas a larger, randomised study may have balanced events between arms (if the adverse events are due to chance). These factors are limitations of a single-arm phase 2 design study.\n\nThe primary endpoint of the study was safety and feasibility as measured by the proportion of patients who received at least 75% of the planned dose for the first two cycles. Whilst this was achieved for 80% of participants, the toxicity over the course of treatment was too great. Despite preclinical modelling and two other studies of similar dose-intense regimens showing possible enhanced efficacy with acceptable toxicity, we could not demonstrate this with our regimen. We conclude that dose intense CapOx-Bev should not be used outside of clinical studies.\n\nCompeting interests\n\nRoche New Zealand provided a grant to support core funding to Cancer Trials New Zealand separate to the funding of this study. MF is a Director of CTNZ. CJ received travel assistance to attend an educational meeting from Roche New Zealand. All remaining authors have declared no conflicts of interest.\n\nAuthors’ contributions\n\nConception and design: MF KS. Provision of study materials or patients: MF KS PT AO BR DP JA RI VH. Collection and assembly of data: KS VH. Data analysis and interpretation: MF KS VH SD CJ. Manuscript writing: CJ SD MF. Final approval of manuscript: all authors.\n\nAcknowledgements\nThis study was supported by a grant from Roche New Zealand.\n\nManufacturer name:\n\nCapecitabine, Bevacizumab: Roche\n\nOxaliplatin: Sanofi Aventis\n==== Refs\nReferences\n1. Jemal A Bray F Center MM Ferlay J Ward E Forman D Global cancer statistics CA: A Cancer Journal for Clinicians 2011 61 2 69 90 21296855 \n2. Jemal A Center MM DeSantis C Ward EM Global patterns of cancer incidence and mortality rates and trends Cancer Epidemiol Biomark Prev 2010 19 1893 1907 10.1158/1055-9965.EPI-10-0437 \n3. 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"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D000069287:Capecitabine; D015179:Colorectal Neoplasms; D003841:Deoxycytidine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016019:Survival Analysis; D016896:Treatment Outcome",
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"title": "Dose-intense capecitabine, oxaliplatin and bevacizumab as first line treatment for metastatic, unresectable colorectal cancer: a multi-centre phase II study.",
"title_normalized": "dose intense capecitabine oxaliplatin and bevacizumab as first line treatment for metastatic unresectable colorectal cancer a multi centre phase ii study"
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"abstract": "The use of intranasal steroid drops for nasal obstruction in infants is common practice and can prevent more invasive surgical procedures; however, it is not without complication. We describe 2 cases of iatrogenic Cushing's secondary to nasal steroids in infants with nasal obstruction, discuss the etiology of this unusual complication, and review previous literature reports. While reporting in the literature is sparse, these cases highlight the risk of development of adrenal insufficiency with usage of nasal steroid drops in infants as well as the need for close monitoring of administration and tapering of the drops. Additionally, we suggest an approach to the infant with symptomatic nasal obstruction that addresses the usage of intranasal steroid drops and emphasizes the need for quick tapering and possible endocrine consultation when appropriate.",
"affiliations": "Weill Cornell Medical College, 428 East 72nd Street, Oxford Building, Suite 100, New York, NY 10021, USA. Electronic address: roj9047@nyp.org.;Weill Cornell Medical College, 428 East 72nd Street, Oxford Building, Suite 100, New York, NY 10021, USA. Electronic address: aam9008@med.cornell.edu.",
"authors": "Joshi|Rohan R|RR|;Maresh|Alison|A|",
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"keywords": "Adrenal insufficiency; Cushing's; Dexamethasone; Nasal obstruction; Pyriform Aperture Stenosis; Steroid drops",
"medline_ta": "Int J Pediatr Otorhinolaryngol",
"mesh_terms": "D000281:Administration, Intranasal; D000309:Adrenal Insufficiency; D003480:Cushing Syndrome; D003907:Dexamethasone; D005938:Glucocorticoids; D006801:Humans; D007049:Iatrogenic Disease; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D015508:Nasal Obstruction; D014057:Tomography, X-Ray Computed",
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"title": "Iatrogenic Cushing's syndrome and adrenal insufficiency in infants on intranasal dexamethasone drops for nasal obstruction - Case series and literature review.",
"title_normalized": "iatrogenic cushing s syndrome and adrenal insufficiency in infants on intranasal dexamethasone drops for nasal obstruction case series and literature review"
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"abstract": "Purpose: The purpose of the report is to describe a patient with warfarin-induced skin necrosis in the presence of acute hepatic injury and significant risk factors for venous thromboembolism, including protein C deficiency and May-Thurner syndrome. Summary: A 44-year-old female with multiple comorbidities presented to the emergency department with a significantly elevated international normalized ratio (INR > 15.9) rapidly reversed with vitamin K and fresh frozen plasma. Due to the findings of bilateral acute on chronic deep vein thromboses (DVTs) and suspected warfarin-induced skin necrosis, a heparin infusion was initiated but later discontinued due to endogenous partial thromboplastin times (PTT) elevations despite dose reductions. Although the necrosis encompassed large areas of the fatty tissue, the depth of necrosis remained mostly superficial. Supportive care and wound management were provided following warfarin reversal; no skin grafts or amputations were performed. Conclusion: A 44-year-old female developed a complicated probable warfarin-induced skin necrosis in the setting of acute liver failure, septic shock, May-Thurner syndrome, previously failed anticoagulation, and acute deep vein thrombosis.",
"affiliations": "Novant Health Forsyth Medical Center, Winston-Salem, NC, USA.;Wingate University, NC, USA.;Novant Health Forsyth Medical Center, Winston-Salem, NC, USA.;Novant Health Forsyth Medical Center, Winston-Salem, NC, USA.",
"authors": "Tilton|Carrie|C|;Livengood|Spencer|S|;Hodges|Jeremy|J|;Marshall|Jessica|J|",
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"issue": "54(2)",
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"keywords": "May-Thurner syndrome; anticoagulation; cardiology; protein C deficiency; skin necrosis; venous thromboembolism; warfarin; warfarin-induced skin necrosis",
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"title": "Warfarin-Induced Skin Necrosis in the Presence of Acute Hepatic Injury and May-Thurner Syndrome.",
"title_normalized": "warfarin induced skin necrosis in the presence of acute hepatic injury and may thurner syndrome"
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"abstract": "Pathological transformation to squamous cell carcinoma after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatment has been reported, but details of the transformation remain unclear. We report two cases with transformation to squamous cell carcinoma. The first case was a 61-year-old man who was an ex-smoker with stage IV lung adenocarcinoma harbouring EGFR exon 19 insertion. He experienced squamous cell transformation after 28 months of erlotinib therapy. Next-generation sequencing (NGS) analysis showed EGFR T790M and genomic alterations in PTEN, PDGFR, and HRAS. The second case was a 72-year-old man who was an ex-smoker with stage IV lung adenocarcinoma harbouring EGFR exon 21 L858R. He experienced squamous cell transformation after nine months of erlotinib therapy. NGS analysis showed EGFR T790M and genomic alterations in PTEN, SMARCB1, TP53, and KIT. Both patients had PTEN genomic alterations and the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway might play an important role in squamous cell transformation.",
"affiliations": "Department of Respiratory Medicine, Respiratory Center Toranomon Hospital Tokyo Japan.;Okinaka Memorial Institute for Medical Research Tokyo Japan.;Department of Pathology and Clinical Laboratories National Cancer Center Hospital East Kashiwa Japan.;Department of Respiratory Medicine, Respiratory Center Toranomon Hospital Tokyo Japan.;Department of Respiratory Medicine, Respiratory Center Toranomon Hospital Tokyo Japan.;Department of Respiratory Medicine, Respiratory Center Toranomon Hospital Tokyo Japan.",
"authors": "Uruga|Hironori|H|https://orcid.org/0000-0001-8290-7703;Fujii|Takeshi|T|;Nakamura|Nobuyuki|N|;Moriguchi|Shuhei|S|;Kishi|Kazuma|K|;Takaya|Hisashi|H|",
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"doi": "10.1002/rcr2.521",
"fulltext": "\n==== Front\nRespirol Case RepRespirol Case Rep10.1002/(ISSN)2051-3380RCR2Respirology Case Reports2051-3380John Wiley & Sons, Ltd Chichester, UK 10.1002/rcr2.521RCR2521Case ReportCase ReportsSquamous cell transformation as a mechanism of acquired resistance to tyrosine kinase inhibitor in EGFR‐mutated lung adenocarcinoma: a report of two cases Squamous transformation after EGFR‐TKIsH. Uruga et al.Uruga Hironori https://orcid.org/0000-0001-8290-7703\n1\n\n2\n\n3\nuruga.hironori@gmail.com Fujii Takeshi \n3\n\n4\nNakamura Nobuyuki \n5\nMoriguchi Shuhei \n1\nKishi Kazuma \n1\n\n2\n\n3\n\n6\nTakaya Hisashi \n1\n\n2\n\n1 \nDepartment of Respiratory Medicine, Respiratory Center\nToranomon Hospital\nTokyo\nJapan\n\n2 \nDepartment of Respiratory Medicine\nToranomon Hospital Kajigaya\nKawasaki\nJapan\n\n3 \nOkinaka Memorial Institute for Medical Research\nTokyo\nJapan\n\n4 \nDepartment of Pathology\nToranomon Hospital Kajigaya\nKawasaki\nJapan\n\n5 \nDepartment of Pathology and Clinical Laboratories\nNational Cancer Center Hospital East\nKashiwa\nJapan\n\n6 \nDepartment of Respiratory Medicine\nToho University Graduate School of Medicine\nTokyo\nJapan\n* Correspondence\n\nHironori Uruga, Department of Respiratory Medicine, Respiratory Center, Toranomon Hospital, 2‐2‐2 Toranomon, Minato‐ku, Tokyo 105‐8470, Japan. E‐mail: uruga.hironori@gmail.com\n14 1 2020 3 2020 8 2 10.1002/rcr2.v8.2e0052106 12 2019 16 12 2019 20 12 2019 © 2020 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of RespirologyThis 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.Pathological transformation to squamous cell carcinoma after epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor treatment has been reported, but details of the transformation remain unclear. We report two cases with transformation to squamous cell carcinoma. The first case was a 61‐year‐old man who was an ex‐smoker with stage IV lung adenocarcinoma harbouring EGFR exon 19 insertion. He experienced squamous cell transformation after 28 months of erlotinib therapy. Next‐generation sequencing (NGS) analysis showed EGFR T790M and genomic alterations in PTEN, PDGFR, and HRAS. The second case was a 72‐year‐old man who was an ex‐smoker with stage IV lung adenocarcinoma harbouring EGFR exon 21 L858R. He experienced squamous cell transformation after nine months of erlotinib therapy. NGS analysis showed EGFR T790M and genomic alterations in PTEN, SMARCB1, TP53, and KIT. Both patients had PTEN genomic alterations and the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway might play an important role in squamous cell transformation.\n\nPathological transformation to squamous cell carcinoma after epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) treatment has been reported, but details of the transformation remain unclear. Here, we report two cases with transformation to squamous cell carcinoma after treatment with EGFR‐TKIs. Both patients had PTEN genomic alterations and the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway might play an important role in squamous cell transformation.\n\n\nEpidermal growth factor receptor‐tyrosine kinase inhibitornon‐small cell lung cancerPI3K/AKT/mTORPTENsquamous cell transformationOkinaka Memorial Institute for Medical Research 10.13039/100012832 source-schema-version-number2.0cover-dateMarch 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.4 mode:remove_FC converted:14.01.2020\n\n\nUruga , H \n, \nFujii , T \n, \nNakamura , N \n, \nMoriguchi , S \n, \nKishi , K \n, \nTakaya , H \n. (2020 ) Squamous cell transformation as a mechanism of acquired resistance to tyrosine kinase inhibitor in EGFR‐mutated lung adenocarcinoma: a report of two cases . Respirology Case Reports , 8 (2 ), e00521\n10.1002/rcr2.521 \n\n\n\nAssociate Editor: James Ho\n==== Body\nIntroduction\nChemotherapy‐naïve patients with epidermal growth factor receptor (EGFR) mutations show a high response rate of 60–70% to first‐ and second‐generation EGFR‐tyrosine kinase inhibitors (TKIs) 1. However, almost all patients treated with EGFR‐TKIs subsequently develop EGFR‐TKI resistance. The most common mechanism of resistance to first‐ and second‐generation EGFR‐TKIs is the T790M mutation, accounting for 60% of patients 2, 3. EGFR and mesenchymal–epithelial transition proto‐oncogene amplifications and phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha gene (PIK3CA) mutations have also been reported as molecular resistance mechanisms 2. Pathological transformation after EGFR‐TKI treatment has not been adequately studied, but transformation to small cell carcinoma and epithelial–mesenchymal transition are the most common 2, 4. Although pathological transformation to squamous cell carcinoma has been described in some case reports 5, 6, 7, 8, 9, 10, the details have not been elucidated. Here, we report two cases with transformation to squamous cell carcinoma after treatment with EGFR‐TKIs.\n\nCase Report\nCase 1\nA 61‐year‐old man who was an ex‐smoker underwent computed tomography‐guided percutaneous lung biopsy. On the basis of the American Joint Committee on Cancer staging system, seventh edition, he was diagnosed as having stage IV (T2bN2M1a) adenocarcinoma of the lung (Fig. 1A–1C) harbouring EGFR exon 19 insertion without T790M mutation. He received erlotinib (150 mg daily) and showed a partial response. After 28 months of therapy, the primary lung lesion started to advance. Transbronchial lung biopsy of the lesion showed adenosquamous carcinoma harbouring EGFR exon 19 insertion without EGFR T790M mutation (Fig. 1D, E). He received four cycles of combination chemotherapy with immune checkpoint inhibitor plus carboplatin (area under the concentration–time curve 5 on day 1 and every three weeks), paclitaxel (200 mg/m2 on day 1 and every three weeks), and atezolizumab (1200 mg on day 1 and every three weeks), then following maintenance therapy of atezolizumab (1200 mg every three weeks), and showed a partial response. After 14 months of therapy, the primary lung lesion worsened, and new lesions developed with bone metastases to the spine. Transbronchial lung biopsy of the lesion showed squamous cell carcinoma (Fig. 1F, G). Next‐generation sequencing (NGS) analysis of the specimen with Ion AmpliSeq Cancer Hotspot Panel version 2 (Thermo Fisher Scientific, USA) showed EGFR c.2369C>T (p.T790M), PTEN c.963 del (p.N323Mfs*21), c.964_964 delA (p.N323Mfs*21), c.968 del (p.N323Mfs*21), PDGFRA c.2472C>T (p.V824V), and HRAS c.81T>C (p.H27H). PTEN expression was assessed immunohistochemically using the H‐score 11, and a score of 50 or higher was judged as positive. H‐score of PTEN expression was negative both before and after erlotinib therapy. Osimertinib (80 mg daily) was started and achieved stable disease over three months. Following disease progression with osimertinib, the patient was started on pembrolizumab (200 mg on day 1 and every three weeks) but after the first administration, the disease continued to progress. Then, S‐1 (100 mg/kg body weight on days 1–14 and every three weeks) was administered over three months. However, the patient died of lung cancer 58 months after diagnosis, and 17 months after transformation to squamous cell carcinoma.\n\nFigure 1 Case 1. Histology of computed tomography‐guided percutaneous lung biopsy specimen before erlotinib therapy (A–C). (A) Haematoxylin and eosin, (B) TTF‐1 and CK5/6, and (C) p40 and napsin A staining. Histology of transbronchial lung biopsy specimen after erlotinib therapy, suggesting squamous cell transformation (D–F). (D) Haematoxylin and eosin, (E) TTF‐1 and CK5/6, and (F) p40 and napsin A staining. Histology of transbronchial lung biopsy specimen after combination chemotherapy (G–I). (G) Haematoxylin and eosin, (H) TTF‐1 and CK5/6, and (I) p40 and napsin A staining.\n\nCase 2\nA 72‐year‐old man who was an ex‐smoker underwent transbronchial lung biopsy. He was diagnosed as having stage IV (T2bN2M1a) adenocarcinoma of the lung (Fig. 2A–2C) harbouring EGFR exon 21 L858R without T790M mutation. He received erlotinib (150 mg daily) and showed a partial response. After nine months of this therapy, the primary lung lesion started to advance. Transbronchial lung biopsy of the lesion showed adenosquamous carcinoma (Fig. 2D–2F). NGS analysis of the specimen using Ion AmpliSeq Cancer Hotspot Panel showed EGFR c.2573T>G (p.L858R), c.2369C>T (p.T790M), PTEN c.963 del (p.N323Mfs*21), c.964_964 delA (p.N323Mfs*21), c.968 del (p.N323Mfs*21), SMARCB1 c.1119‐41G>A (unknown), TP53 c.892G>T (p.E298*), and KIT c.1621A>C (p.M541L). H‐score of PTEN expression had converted from positive to negative after erlotinib therapy (Fig. 2G, H). Osimertinib (80 mg daily) was then started and achieved stable disease over three months. Following disease progression with osimertinib, he could not receive cytotoxic chemotherapy because of poor performance status; thus, he was started on pembrolizumab (200 mg on day 1 and every three weeks) but showed disease progression after the first administration. The patient died of lung cancer 31 months after diagnosis, and eight months after transformation to squamous cell carcinoma.\n\nFigure 2 Case 2. Histology of transbronchial lung biopsy specimen before erlotinib therapy (A–C). (A) Haematoxylin and eosin, (B) TTF‐1 and CK5/6, and (C) p40 and napsin A staining. Histology of transbronchial lung biopsy specimen after erlotinib therapy, suggesting squamous cell transformation (D–F). (d) Haematoxylin and eosin, (E) TTF‐1 and CK5/6, and (F) p40 and napsin A staining. PTEN staining before erlotinib therapy (G) and after erlotinib therapy (H).\n\nDiscussion\nWe encountered two patients with pathological transformation to squamous cell carcinoma as a mechanism of resistance to EGFR inhibitors. NGS analysis of both specimens after erlotinib therapy showed genomic alterations in PTEN.\n\nSquamous cell transformation as a resistance mechanism to EGFR inhibitors has been investigated clinically. Roca et al. 12 performed a pooled analysis of 17 patients and showed that most of these patients were smokers and harboured original EGFR mutations. In addition to squamous cell transformation, they observed coexisting EGFR T790M mutation in approximately half of the patients. Prognosis after squamous cell transformation was poor, with a median overall survival of 3.5 months. In our two patients, osimertinib was administered because of the coexisting EGFR T790M mutation in specimens after erlotinib therapy. However, we achieved control of the lung cancer with squamous cell transformation and EGFR T790M by osimertinib for only three months in both patients. AURA3 was a phase 3 study comparing osimertinib and platinum‐pemetrexed in patients with EGFR T790M‐positive non‐small cell lung cancer after erlotinib therapy or gefitinib therapy. In this study, patients with squamous cell histology were three of 279 (1%) in osimertinib group, and zero of 140 (0%) in platinum plus pemetrexed group. The study showed that osimertinib resulted in significantly better progression‐free survival (PFS) than platinum‐pemetrexed (10.1 vs. four months, respectively, P < 0.001) 13. This was better than the PFS of three months in our patients with squamous cell transformation and EGFR T790M mutation. Thus, the prognosis of lung cancer patients with squamous cell transformation and EGFR T790M mutation appears to be worse than that of patients with only EGFR T790M mutation. This is consistent with a report by Roca et al. 12.\n\nAt the molecular level, PTEN genomic alterations were identified in our patients with squamous cell transformation. In a study of surgically resected specimens, PTEN mutations were more often identified in ex‐smokers and in squamous cell carcinomas than in adenocarcinomas 14. Park et al. 15 performed NGS analysis of specimens before and after squamous cell transformation following EGFR‐TKI therapy, and showed genomic alterations in PTEN and PIK3CA in each two of four patients. Another case report by Kuiper et al. 5 also showed genomic alteration of PIK3CA in a specimen after squamous cell transformation. Park et al. 15 hypothesized that the PI3K/AKT/mTOR pathway was activated by EGFR‐TKIs and loss of PTEN, which facilitates cell proliferation and resulted in squamous cell transformation. Interestingly, they found that one of four patients received everolimus (an mTOR (mammalian target of rapamycin) inhibitor) and showed radiological improvement. Further studies and more case reports are warranted to clarify the clinical utility of mTOR inhibitors in EGFR‐mutated patients with squamous cell transformation.\n\nThe present report has several limitations. First, the primary lung cancer before treatment with erlotinib therapy could have been adenosquamous cell carcinoma ab initio. We could not rule out this possibility because both patients were diagnosed using biopsy specimens. Second, we could not perform NGS analysis of the specimens before treatment with erlotinib, because the specimen volume was inadequate for analysis.\n\nIn summary, we encountered two cases of EGFR mutation in lung adenocarcinoma with pathological transformation to squamous cell carcinoma. NGS analysis showed PTEN genomic alterations in both cases. Osimertinib was not fully effective in patients with squamous cell transformation, thus cytotoxic chemotherapies were probably better for these patients. Further studies and more case reports are warranted to elucidate the underlying mechanisms and investigate treatment modalities for patients with squamous cell transformation.\n\nDisclosure Statement\nAppropriate written informed consent was obtained for publication of this case report and accompanying images.\n\nAcknowledgment\nThis work was supported by Okinaka Memorial Institute for Medical Research, Tokyo, Japan.\n==== Refs\nReferences\n1 \n\nMaemondo \nM \n, \nInoue \nA \n, \nKobayashi \nK \n, et al. 2010 \nGefitinib or chemotherapy for non‐small‐cell lung cancer with mutated EGFR . N. Engl. J. Med. \n362 :2380 –2388 .20573926 \n2 \n\nSequist \nLV \n, \nWaltman \nBA \n, \nDias‐Santagata \nD \n, et al. 2011 \nGenotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors . Sci. Transl. Med. \n3 :75ra26.\n3 \n\nYu \nHA \n, \nArcila \nME \n, \nRekhtman \nN \n, et al. 2013 \nAnalysis of tumor specimens at the time of acquired resistance to EGFR‐TKI therapy in 155 patients with EGFR‐mutant lung cancers . Clin. Cancer Res. \n19 :2240 –2247 .23470965 \n4 \n\nNiederst \nMJ \n, \nSequist \nLV \n, \nPoirier \nJT \n, et al. 2015 \nRB loss in resistant EGFR mutant lung adenocarcinomas that transform to small‐cell lung cancer . Nat. Commun. \n6 :6377.25758528 \n5 \n\nKuiper \nJL \n, \nRonden \nMI \n, \nBecker \nA \n, et al. 2015 \nTransformation to a squamous cell carcinoma phenotype of an EGFR‐mutated NSCLC patient after treatment with an EGFR‐tyrosine kinase inhibitor . J. Clin. Pathol. \n68 :320 –321 .25661795 \n6 \n\nHaratani \nK \n, \nHayashi \nH \n, \nWatanabe \nS \n, et al. 2016 \nTwo cases of EGFR mutation‐positive lung adenocarcinoma that transformed into squamous cell carcinoma: successful treatment of one case with rociletinib . Ann. Oncol. \n27 :200 –202 .26483048 \n7 \n\nJukna \nA \n, \nMontanari \nG \n, \nMengoli \nMC \n, et al. 2016 \nSquamous cell carcinoma \"transformation\" concurrent with secondary T790M mutation in resistant EGFR‐mutated adenocarcinomas . J. Thorac. Oncol. \n11 :e49 –e51 .26746366 \n8 \n\nLongo \nL \n, \nMengoli \nMC \n, \nBertolini \nF \n, et al. 2017 \nSynchronous occurrence of squamous‐cell carcinoma \"transformation\" and EGFR exon 20 S768I mutation as a novel mechanism of resistance in EGFR‐mutated lung adenocarcinoma . Lung Cancer \n103 :24 –26 .28024692 \n9 \n\nIzumi \nH \n, \nYamasaki \nA \n, \nUeda \nY \n, et al. 2018 \nSquamous cell carcinoma transformation from EGFR‐mutated lung adenocarcinoma: a case report and literature review . Clin. Lung Cancer \n19 :e63 –e66 .29126779 \n10 \n\nYao \nY \n, \nZhu \nZ \n, \nWu \nY \n, et al. 2018 \nHistologic transformation from adenocarcinoma to both small cell lung cancer and squamous cell carcinoma after treatment with gefitinib: a case report . Medicine (Baltimore). \n97 :e0650.29718881 \n11 \n\nGarg \nK \n, \nBroaddus \nRR \n, \nSoslow \nRA \n, et al. 2012 \nPathologic scoring of PTEN immunohistochemistry in endometrial carcinoma is highly reproducible . Int. J. Gynecol. Pathol. \n31 :48 –56 .22123723 \n12 \n\nRoca \nE \n, \nPozzari \nM \n, \nVermi \nW \n, et al. 2019 \nOutcome of EGFR‐mutated adenocarcinoma NSCLC patients with changed phenotype to squamous cell carcinoma after tyrosine kinase inhibitors: a pooled analysis with an additional case . Lung Cancer \n127 :12 –18 .30642539 \n13 \n\nMok \nTS \n, \nWu \nYL \n, \nAhn \nMJ \n, et al. 2017 \nOsimertinib or platinum‐pemetrexed in EGFR T790M‐positive lung cancer . N. Engl. J. Med. \n376 :629 –640 .27959700 \n14 \n\nJin \nG \n, \nKim \nMJ \n, \nJeon \nHS \n, et al. 2010 \nPTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non‐small cell lung cancers . Lung Cancer \n69 :279 –283 .20018398 \n15 \n\nPark \nS \n, \nShim \nJH \n, \nLee \nB \n, et al. 2019 \nPaired genomic analysis of squamous cell carcinoma transformed from EGFR‐mutated lung adenocarcinoma . Lung Cancer \n134 :7 –15 .31319998\n\n",
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"title": "Squamous cell transformation as a mechanism of acquired resistance to tyrosine kinase inhibitor in EGFR-mutated lung adenocarcinoma: a report of two cases.",
"title_normalized": "squamous cell transformation as a mechanism of acquired resistance to tyrosine kinase inhibitor in egfr mutated lung adenocarcinoma a report of two cases"
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"abstract": "BACKGROUND\nThe combination of capecitabine and vinorelbine is a potentially valuable treatment regimen for patients with advanced-stage breast cancer. The drugs are easy to administer and do not cause significant alopecia. In order to identify the spectrum of toxicity of a regimen containing 2 drugs, we conducted an extended phase I study aimed at defining maximum tolerated doses, recommended doses, safety, and efficacy in patients with pretreated advanced-stage breast cancer.\n\n\nMETHODS\nForty-nine patients with advanced-stage breast cancer were treated with escalating doses of oral capecitabine from 500 mg/m2 to 1375 mg/m2 twice daily on days 1-14 and escalating doses of vinorelbine from 12.5 mg/m2 to 25 mg/m2 intravenously (I.V.) on days 1 and 3 every 3 weeks. Almost all patients (90%) had received >or= 3 previous treatments for metastatic disease (anthracyclines, 76%; 5-flourouracil, 76%; taxanes, 29%).\n\n\nRESULTS\nDose level 9 (capecitabine 1250 mg/m2 twice daily on days 1-14 and vinorelbine 22.5 mg/m2 I.V. on days 1 and 3) was identified as the maximum tolerated dose. The most frequent clinical adverse events were nausea (78%), asthenia (59%), constipation (51%), mucositis (47%), and hand-foot syndrome (41%). The majority of events were mild to moderate; the only grade 4 clinical adverse events were diarrhea, fever, and thromboembolism, each of which occurred in 1 patient (2%) at dose level 8. Objective confirmed responses were observed in 18 patients (37%), including 1 complete response (2%) and 17 partial responses (35%). Disease was stable in an additional 10 patients (20%), with a median duration of 6.3 months (range, 4-24 months).\n\n\nCONCLUSIONS\nThe combination of the 2 drugs is very well tolerated and effective, especially considering the previous exposure to chemotherapy. The recommended dose for further phase II studies should be capecitabine 1250 mg/m2 twice daily on days 1-14 and vinorelbine 22.5 mg/m2 I.V. on days 1 and 3.",
"affiliations": "Department of Medicine, European Institute of Oncology, Milan, Italy. franco.nole@ieo.it",
"authors": "Nolè|Franco|F|;Catania|Chiara|C|;Munzone|Elisabetta|E|;Rocca|Andrea|A|;Verri|Elena|E|;Sanna|Giuseppina|G|;Ascione|Gilda|G|;Adamoli|Laura|L|;Zampino|Maria G|MG|;Minchella|Ida|I|;Goldhirsch|Aron|A|",
"chemical_list": "D003841:Deoxycytidine; D014747:Vinblastine; D000069287:Capecitabine; D000077235:Vinorelbine; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.3816/CBC.2006.n.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-8209",
"issue": "6(6)",
"journal": "Clinical breast cancer",
"keywords": null,
"medline_ta": "Clin Breast Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000069287:Capecitabine; D003841:Deoxycytidine; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007262:Infusions, Intravenous; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D016896:Treatment Outcome; D014747:Vinblastine; D000077235:Vinorelbine",
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "518-24",
"pmc": null,
"pmid": "16595035",
"pubdate": "2006-02",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Capecitabine/vinorelbine: an effective and well-tolerated regimen for women with pretreated advanced-stage breast cancer.",
"title_normalized": "capecitabine vinorelbine an effective and well tolerated regimen for women with pretreated advanced stage breast cancer"
} | [
{
"companynumb": "IT-ROCHE-1507412",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINORELBINE\\VINORELBINE TARTRATE"
},
"drugadditional"... |
{
"abstract": "The treatment of elderly multimorbid patients according to clinical guidelines often results in polypharmacy. An individual risk assessment is required to consider the possibility of deprescribing especially potentially inappropriate medication in the elderly. This exemplary case report describes a medication review of a patient with multiple chronic cardiovascular diseases taking into account the impact on renal function.",
"affiliations": null,
"authors": "Franken|Peter Raphael|PR|;Woltersdorf|Ronja|R|",
"chemical_list": "D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D004008:Diclofenac; D013148:Spironolactone; D004077:Digoxin; D017257:Ramipril; D011188:Potassium",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0342-9601",
"issue": "39(10)",
"journal": "Medizinische Monatsschrift fur Pharmazeuten",
"keywords": null,
"medline_ta": "Med Monatsschr Pharm",
"mesh_terms": "D000369:Aged, 80 and over; D001281:Atrial Fibrillation; D002227:Carbazoles; D000077261:Carvedilol; D004008:Diclofenac; D004077:Digoxin; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006333:Heart Failure; D006801:Humans; D006973:Hypertension; D007676:Kidney Failure, Chronic; D009203:Myocardial Infarction; D011188:Potassium; D000067561:Potentially Inappropriate Medication List; D011412:Propanolamines; D017257:Ramipril; D012307:Risk Factors; D013148:Spironolactone",
"nlm_unique_id": "7802665",
"other_id": null,
"pages": "421-6",
"pmc": null,
"pmid": "29979537",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Risk of renal dysfunction in an elderly patient with chronic heart failure.",
"title_normalized": "risk of renal dysfunction in an elderly patient with chronic heart failure"
} | [
{
"companynumb": "DE-BAUSCH-BL-2018-030701",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TILIDINE"
},
"drugadditional": "3",
... |
{
"abstract": "Immune reconstitution after hematopoietic stem cell transplantation (HSCT) is a complex process. Impacts of the reconstitution of different immune cells over time are complex and difficult to understand. New mathematical models are needed to better understand this process. In this study, we used principal component analysis to better analyze the process of immune reconstitution after HSCT. Forty-six consecutive patients receiving HSCT for malignant and nonmalignant disorders were included in the study. All patients were followed for at least 24 months after transplantation with regular blood sampling for analysis of lymphocyte subset numbers and function. Exponentially transformed lymphocyte subset counts and lymphocyte functional markers were analyzed to identify major trends in the reconstitution process. Using our multivariate model for mapping immune reconstitution after HSCT, we showed that dysfunctional reconstitution patterns precede severe complications, such as chronic graft-versus-host disease, relapse, and death.",
"affiliations": "Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. Electronic address: karin.mellgren@vgregion.se.;Muvara bv, Multivariate Analysis of Research Data, Leiderdorp, The Netherlands.;Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.",
"authors": "Mellgren|Karin|K|;Nierop|Andreas F M|AFM|;Abrahamsson|Jonas|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2019.06.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "25(10)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Immune reconstitution; Multivariate analysis; Stem cell transplantation",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000074243:Immune Reconstitution; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D015999:Multivariate Analysis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "2045-2053",
"pmc": null,
"pmid": "31247315",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Use of Multivariate Immune Reconstitution Patterns to Describe Immune Reconstitution after Allogeneic Stem Cell Transplantation in Children.",
"title_normalized": "use of multivariate immune reconstitution patterns to describe immune reconstitution after allogeneic stem cell transplantation in children"
} | [
{
"companynumb": "SE-OTSUKA-2019_036115",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
"drugaddi... |
{
"abstract": "The 75 year old patient was hospitalized because of vertigo, exertional dyspnea and clamminess. Based on ischemic heart disease with sick sinus syndrome a pacemaker was implanted 5.5 years ago. In consequence of non-permanent atrial fibrillation Dronedaron was added to medication 8 months ago.\n\n\n\nThe patient presented unstable. The ECG showed a second-degree atrioventricular block with wenckebach periodic and a frequency of 29 bpm. The pacemaker survey showed primary a proper atrial function but ineffective ventricular stimulation.\n\n\n\nAfter initial external pacing the pacemaker was reprogrammed and in this way the ventricle stimulated effectively. Dronedaron was ceased after checking trigger factors and the patient left hospital after 3 days free of complaints. The pacemaker survey 18 days later showed a proper function with stabilized pacing threshold close to the old level.\n\n\n\nIn patients with dysfunction of a permanent pacemaker an increased pacing threshold should be excluded and if any the current medication needs to be controlled. Caution should be exercised to Dronedaron here.",
"affiliations": "Warnow-Klinik Bützow, Klinik für Innere Medizin.;Warnow-Klinik Bützow, Klinik für Innere Medizin.;Südstadtklinikum Rostock, Klinik für Innere Medizin I, Abteilung für Kardiologie.",
"authors": "Wedler|Katharina|K|;Dávid|Árpad|Á|;Körber|Thomas|T|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000077764:Dronedarone",
"country": "Germany",
"delete": false,
"doi": "10.1055/a-1025-2610",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-0472",
"issue": "145(4)",
"journal": "Deutsche medizinische Wochenschrift (1946)",
"keywords": null,
"medline_ta": "Dtsch Med Wochenschr",
"mesh_terms": "D000368:Aged; D000889:Anti-Arrhythmia Agents; D001281:Atrial Fibrillation; D002304:Cardiac Pacing, Artificial; D000077764:Dronedarone; D006321:Heart; D006801:Humans; D010138:Pacemaker, Artificial; D012804:Sick Sinus Syndrome",
"nlm_unique_id": "0006723",
"other_id": null,
"pages": "249-251",
"pmc": null,
"pmid": "32069492",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Increased Ventricular Pacing Threshold Caused by Intake of Dronedaron.",
"title_normalized": "increased ventricular pacing threshold caused by intake of dronedaron"
} | [
{
"companynumb": "DE-SA-2020SA143470",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TAFLUPROST"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nTo assess efficacy and safety of treatment simplification to co-formulated Rilpivirine/Emtricitabine/Tenofovir (RPV/FTC/TDF) in virologically suppressed patients.\n\n\nMETHODS\nEndpoints of the analysis were: (a) treatment discontinuation of RPV/FTC/TDF for any reasons and (b) occurrence of virological failure (VF) defined as confirmed HIV-RNA >50 cp/mL).\n\n\nRESULTS\nOverall, 508 patients from five Italian reference centres were included: male gender 71.9%; median age 47 years (IQR 40-52); IVDU as HIV risk 17.7%; HCV-AB positive 23.4%; CDC-C stage 17.5%; median CD4 cells/µL at switch 655 (IQR: 487-843); median number of previous regimens three (IQR 2-7). In a median follow-up of 196 days (IQR: 84-287), 31 patients discontinued RPV/FTC/TDF (virological failure n=5, hypersensitivity reaction n=2, GI-toxicity n=6, liver toxicity n=1, CNS-toxicity n=4, kidney toxicity n=5, patient's decision/lost in follow-up n=10). Moreover, VF occurred in eight patients (five discontinued regimen, while three remained on RPV/FTC/TDF). At survival analysis, the probabilities of treatment discontinuation or VF were 5.5% and 1.2% at 6 months, 13.2% and 2.8% at 12 months, respectively (Figure 1). At adjusted Cox model, factors associated with discontinuation were: <200 CD4 cells/µL at switch (HR 5.3, 95% CI 1.1-25.9, p=0.038), number of pre-switch regimens (for each extra regimen: HR 1.05, 95% CI 1.01-1.10, p=0.024), male gender (HR 0.4, 95% CI 0.2-0.9, p=0.032). Only the number of pre-switch regimens was associated with VF (HR 1.13, 95% CI 1.06-1.21, p=0.001). Type of pre-switch regimen was not associated with discontinuation or failure, but no VF was observed if switching from co-formulated Efavirenz/FTC/TDF or from Raltegravir containing regimens. Switching to RPV/FTC/TDF led to significant improvement in fasting lipids levels: the decrease in cholesterol, LDL and triglycerides was observed switching from any regimen, but was more marked from boosted PI. In contrast, a moderate increase in transaminase (switching from all regimens except NNRTI-containing) and creatinine (except from TDF-containing regimens) were observed.\n\n\nCONCLUSIONS\nOur data suggest that switching to RPV/FTC/TDF in virologically suppressed patients could be a good strategy with low risk of virological failure or treatment discontinuation; the switch is also associated with significant improvement in lipid profile.",
"affiliations": "Clinical Department, National Institute for the Infectious Diseases, Rome, Italy.;Department of Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.;Division of Infectious Diseases, Ospedali Riuniti, Bergamo, Italy.;Clinical Department, National Institute for the Infectious Diseases, Rome, Italy.;Department of Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.;Clinical Department, National Institute for the Infectious Diseases, Rome, Italy.;Department of Dermatology and Infectious Diseases, San Gallicano Institute, Rome, Italy.;Clinical Department, National Institute for the Infectious Diseases, Rome, Italy.;Clinical Department, National Institute for the Infectious Diseases, Rome, Italy.;Division of Infectious Diseases, 'Careggi' Hospital, Florence, Italy.;Clinical Department, National Institute for the Infectious Diseases, Rome, Italy.;Clinical Department, National Institute for the Infectious Diseases, Rome, Italy.;Clinical Department, National Institute for the Infectious Diseases, Rome, Italy.;Clinical Department, National Institute for the Infectious Diseases, Rome, Italy.",
"authors": "Pinnetti|Carmela|C|;Di Giambenedetto|Simona|S|;Maggiolo|Franco|F|;Lorenzini|Patrizia|P|;Fabbiani|Massimiliano|M|;Tommasi|Chiara|C|;Latini|Alessandra|A|;Ammassari|Adriana|A|;Loiacono|Laura|L|;Sterrantino|Gaetana|G|;Bellagamba|Rita|R|;Boumis|Evangelo|E|;Antinori|Andrea|A|;Zaccarelli|Mauro|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.7448/IAS.17.4.19812",
"fulltext": "\n==== Front\nJ Int AIDS SocJ Int AIDS SocJIASJournal of the International AIDS Society1758-2652International AIDS Society 1981210.7448/IAS.17.4.19812Poster Sessions – Abstract P280Simplification to co-formulated rilpivirine/emtricitabine/tenofovir in virologically suppressed patients: Data from a multicenter cohort Pinnetti Carmela 1Di Giambenedetto Simona 2Maggiolo Franco 3Lorenzini Patrizia 1Fabbiani Massimiliano 2Tommasi Chiara 1Latini Alessandra 4Ammassari Adriana 1Loiacono Laura 1Sterrantino Gaetana 5Bellagamba Rita 1Boumis Evangelo 1Antinori Andrea 1Zaccarelli Mauro 11 Clinical Department, National Institute for the Infectious Diseases, Rome, Italy2 Department of Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy3 Division of Infectious Diseases, Ospedali Riuniti, Bergamo, Italy4 Department of Dermatology and Infectious Diseases, San Gallicano Institute, Rome, Italy5 Division of Infectious Diseases, ‘Careggi’ Hospital, Florence, Italy02 11 2014 2014 17 4Suppl 3 19812© 2014 Pinnetti C et al; licensee International AIDS Society2014This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nTo assess efficacy and safety of treatment simplification to co-formulated Rilpivirine/Emtricitabine/Tenofovir (RPV/FTC/TDF) in virologically suppressed patients.\n\nMaterials and Methods\nEndpoints of the analysis were: (a) treatment discontinuation of RPV/FTC/TDF for any reasons and (b) occurrence of virological failure (VF) defined as confirmed HIV-RNA >50 cp/mL).\n\nResults\nOverall, 508 patients from five Italian reference centres were included: male gender 71.9%; median age 47 years (IQR 40–52); IVDU as HIV risk 17.7%; HCV-AB positive 23.4%; CDC-C stage 17.5%; median CD4 cells/µL at switch 655 (IQR: 487–843); median number of previous regimens three (IQR 2–7). In a median follow-up of 196 days (IQR: 84–287), 31 patients discontinued RPV/FTC/TDF (virological failure n=5, hypersensitivity reaction n=2, GI-toxicity n=6, liver toxicity n=1, CNS-toxicity n=4, kidney toxicity n=5, patient's decision/lost in follow-up n=10). Moreover, VF occurred in eight patients (five discontinued regimen, while three remained on RPV/FTC/TDF). At survival analysis, the probabilities of treatment discontinuation or VF were 5.5% and 1.2% at 6 months, 13.2% and 2.8% at 12 months, respectively (Figure 1). At adjusted Cox model, factors associated with discontinuation were: <200 CD4 cells/µL at switch (HR 5.3, 95% CI 1.1–25.9, p=0.038), number of pre-switch regimens (for each extra regimen: HR 1.05, 95% CI 1.01–1.10, p=0.024), male gender (HR 0.4, 95% CI 0.2–0.9, p=0.032). Only the number of pre-switch regimens was associated with VF (HR 1.13, 95% CI 1.06–1.21, p=0.001). Type of pre-switch regimen was not associated with discontinuation or failure, but no VF was observed if switching from co-formulated Efavirenz/FTC/TDF or from Raltegravir containing regimens. Switching to RPV/FTC/TDF led to significant improvement in fasting lipids levels: the decrease in cholesterol, LDL and triglycerides was observed switching from any regimen, but was more marked from boosted PI. In contrast, a moderate increase in transaminase (switching from all regimens except NNRTI-containing) and creatinine (except from TDF-containing regimens) were observed.\n\nConclusions\nOur data suggest that switching to RPV/FTC/TDF in virologically suppressed patients could be a good strategy with low risk of virological failure or treatment discontinuation; the switch is also associated with significant improvement in lipid profile.\n==== Body\nFigure 1 Probability of a) treatment discontinuation; b) virological failure at 6 and 12 months of patients treated with co-formulated rilpivirine/emtricitabine/tenofovir for treatment simplification.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1758-2652",
"issue": "17(4 Suppl 3)",
"journal": "Journal of the International AIDS Society",
"keywords": null,
"medline_ta": "J Int AIDS Soc",
"mesh_terms": null,
"nlm_unique_id": "101478566",
"other_id": null,
"pages": "19812",
"pmc": null,
"pmid": "25397556",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Simplification to co-formulated rilpivirine/emtricitabine/tenofovir in virologically suppressed patients: Data from a multicenter cohort.",
"title_normalized": "simplification to co formulated rilpivirine emtricitabine tenofovir in virologically suppressed patients data from a multicenter cohort"
} | [
{
"companynumb": "IT-GILEAD-2015-0159608",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EMTRICITABINE\\RILPIVIRINE\\TENOFOVIR DISOPROXIL FUMARATE"
... |
{
"abstract": "Background: Neuroendocrine carcinomas (NECs) are rare malignancies with limited treatment options beyond surgery. Peptide receptor radionuclide therapy (PRRT) is a process by which a somatostatin analog (octreotate) is combined with a chelator (DOTA) and a radionuclide (lutetium-177 [177Lu-dotatate]). This therapy targets receptors on neuroendocrine cells, causing internalization of the radionuclide by the tumor cell, which results in cellular damage and apoptosis. Case Report: We describe the clinical and therapeutic course of a 69-year-old male with a metastatic rectal NEC in whom progressive disease was noted after multiple therapies were attempted. After PRRT with 177Lu-dotatate, the patient was asymptomatic and demonstrated a near-complete radiologic response. Conclusion: This case illustrates that treatment with PRRT may improve the outcome of patients with metastatic rectal NEC. Our case highlights the importance of further research into the use of PRRT in patients with a Ki-67 <55% and uptake on somatostatin receptor imaging.",
"affiliations": "Neuroendocrine Tumor Clinic, Ochsner Clinic Foundation, Kenner, LA.;Neuroendocrine Tumor Clinic, Ochsner Clinic Foundation, Kenner, LA.;Neuroendocrine Tumor Clinic, Ochsner Clinic Foundation, Kenner, LA.;Department of Radiology, Division of Interventional Radiology, Ochsner Clinic Foundation, New Orleans, LA.;Neuroendocrine Tumor Clinic, Ochsner Clinic Foundation, Kenner, LA.;Neuroendocrine Tumor Clinic, Ochsner Clinic Foundation, Kenner, LA.",
"authors": "Thomas|Katharine E|KE|;Boudreaux|J Philip|JP|;Thiagarajan|Ramcharan|R|;Marsala|Andrew|A|;Voros|Brianne A|BA|;Ramirez|Robert A|RA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.31486/toj.20.0098",
"fulltext": "\n==== Front\nOchsner J\nOchsner J\nTOJ\nochjnl\nThe Ochsner Journal\n1524-5012\n1524-5012\nAcademic Division of Ochsner Clinic Foundation\n\n10.31486/toj.20.0098\ntoj.20.0098\nCase Reports and Clinical Observations\nA Peptide Meets a Radionuclide to Combat a Rare Tumor\nThomas, KE\nPeptide Receptor Radionuclide Therapy in Metastatic Rectal Neuroendocrine Carcinoma\nThomas Katharine E. MD 1 2\nBoudreaux J. Philip MD, FACS 1 3\nThiagarajan Ramcharan MBBS, FACS 1 3\nMarsala Andrew MD 4\nVoros Brianne A. MS 1 3\nRamirez Robert A. DO, FACP 1 5 *\n1 Neuroendocrine Tumor Clinic, Ochsner Clinic Foundation, Kenner, LA\n2 Department of Hematology/Oncology, Louisiana State University Health Sciences Center, New Orleans, LA\n3 Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA\n4 Department of Radiology, Division of Interventional Radiology, Ochsner Clinic Foundation, New Orleans, LA\n5 Department of Internal Medicine, Division of Hematology/Oncology, Ochsner Clinic Foundation, New Orleans, LA\n*Dr Ramirez is now affiliated with the Department of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN.\n\nAddress correspondence to Robert A. Ramirez, DO, FACP, Vanderbilt University Medical Center, 2220 Pierce Ave., Nashville, TN 37232. Tel: (615) 421-2899. Email: robert.ramirez@vumc.org\nFall 2021\nFall 2021\n21 3 306311\n©2021 by the author(s); Creative Commons Attribution License (CC BY)\n2021\nhttps://creativecommons.org/licenses/by/4.0/ ©2021 by the author(s); licensee Ochsner Journal, Ochsner Clinic Foundation, New Orleans, LA. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (creativecommons.org/licenses/by/4.0/legalcode) that permits unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.\n\nBackground: Neuroendocrine carcinomas (NECs) are rare malignancies with limited treatment options beyond surgery. Peptide receptor radionuclide therapy (PRRT) is a process by which a somatostatin analog (octreotate) is combined with a chelator (DOTA) and a radionuclide (lutetium-177 [177Lu-dotatate]). This therapy targets receptors on neuroendocrine cells, causing internalization of the radionuclide by the tumor cell, which results in cellular damage and apoptosis.\n\nCase Report: We describe the clinical and therapeutic course of a 69-year-old male with a metastatic rectal NEC in whom progressive disease was noted after multiple therapies were attempted. After PRRT with 177Lu-dotatate, the patient was asymptomatic and demonstrated a near-complete radiologic response.\n\nConclusion: This case illustrates that treatment with PRRT may improve the outcome of patients with metastatic rectal NEC. Our case highlights the importance of further research into the use of PRRT in patients with a Ki-67 <55% and uptake on somatostatin receptor imaging.\n\nKeywords:\n\nCarcinoma–neuroendocrine\ngallium Ga 68 dotatate\nlutetium-177\nreceptors–somatostatin\n==== Body\npmcINTRODUCTION\n\nNeuroendocrine tumors (NETs) are rare malignancies that increased 6.4-fold between 1973 (1.09 per 100,000) and 2012 (6.98 per 100,000).1 These malignancies occur most commonly in the gastrointestinal tract. Beyond surgery, treatment options are limited to chemotherapy. In patients with high-grade, poorly differentiated (PD) tumors, termed neuroendocrine carcinomas (NECs), therapeutic options are even more limited.\n\nPeptide receptor radionuclide therapy (PRRT) provides another therapeutic option for patients with advanced, progressive, somatostatin receptor (SSTR)–positive NETs of the midgut.2 By combining a somatostatin analog (SSA) (octreotate) with a chelator (DOTA) and a radionuclide (lutetium-177 [177Lu-dotatate]), PRRT takes advantage of the SSTRs that are expressed on the surface of most NETs.3 This therapy targets the SSTRs on NET cells, allowing internalization of the radionuclide by the tumor cell. Once inside the tumor cell, beta emission from the radionuclide results in cellular damage.3\n\nWe describe a patient with a metastatic rectal NEC who had a near-complete response with 177Lu-dotatate treatment.\n\nCASE REPORT\n\nA 69-year-old male with a history of a metastatic rectal NEC was referred to our center for evaluation. The patient had been diagnosed in October 2014 after developing rectal bleeding. Colonoscopy had shown a fungating, infiltrative, ulcerating, nonobstructive mass measuring 3 cm in length within the rectum. Pathology identified a PD NEC. The tumor was present within the lamina propria and muscularis mucosa, no small-cell features were seen, and the Ki-67 proliferative index was 40%. Computed tomography (CT) showed asymmetric wall thickening involving approximately 50% of the circumference of the rectum and enlarged adjacent perirectal lymph nodes abutting the mesorectal fascia (Figure 1A). CT also revealed innumerable hepatic masses, bilateral pulmonary nodules, and a sclerotic lesion in the right ilium (Figure 2A). Fluorodeoxyglucose positron emission tomography (PET) CT confirmed uptake in multiple liver metastases, which were too numerous to count, as well as uptake in the rectal neoplasm and perirectal lymph node. In January 2015, the patient began treatment with carboplatin area under the curve 5 and etoposide 100 mg/m2 every 3 weeks and completed 6 cycles of therapy. Treatment was interrupted because surgery was needed for an expanding meningioma. Scans revealed stable disease, and the patient was judged to be a candidate for prophylactic cranial irradiation. The patient underwent 25 Gy in 10 fractions in August 2015.\n\nFigure 1. (A) Axial pretreatment contrast-enhanced computed tomography (CT) at the level of the rectum demonstrates the primary rectal tumor (arrowhead). (B) Axial contrast-enhanced CT obtained 8 weeks after completion of peptide receptor radionuclide therapy (PRRT) demonstrates a significant decrease in the size of the primary rectal tumor (arrowhead). (C) Axial fused pretreatment gallium-68 dotatate positron emission tomography (PET)/CT scan demonstrates uptake within the somatostatin receptor-rich primary rectal tumor (arrowhead). (D) Axial fused gallium-68 dotatate PET/CT scan obtained 8 weeks after completion of PRRT demonstrates near-resolution of tracer uptake within the primary rectal tumor (arrowhead).\n\nFigure 2. (A) Axial pretreatment contrast-enhanced computed tomography (CT) at the level of the right portal vein demonstrates innumerable hepatic metastatic lesions with index lesion (arrow). (B) Axial contrast-enhanced CT obtained 8 weeks after completion of peptide receptor radionuclide therapy (PRRT) demonstrates a decrease in the size of all lesions, including the index lesion (arrow). (C) Axial fused pretreatment gallium-68 dotatate positron emission tomography (PET)/CT scan demonstrates somatostatin receptor-rich hepatic metastatic lesions with index lesion (arrow). (D) Axial fused gallium-68 dotatate PET/CT scan obtained 8 weeks after completion of PRRT demonstrates resolution of tracer uptake within the metastatic lesions, including the index lesion (arrow).\n\nBecause of progressive disease in the liver, the patient was started on topotecan 1.5 mg/m2 on days 1 through 5 every 3 weeks in October 2015. Following the first cycle of treatment, he developed symptomatic hypoglycemia, and insulin was elevated at 67.7 μU/mL (reference range, 0-30 μU/mL). Hypoglycemia was hypothesized to be related to his metastatic liver disease, and the patient underwent transarterial chemoembolization (TACE). Symptoms improved, and he started a second cycle of topotecan in December 2015. In January 2016, the patient started combination capecitabine 750 mg/m2 twice daily on days 1 through 14 of a 28-day cycle and temozolomide 200 mg/m2 on days 10 through 14 of a 28-day cycle (CAPTEM), along with lanreotide, and was noted to have uptake on somatostatin scintigraphy.\n\nThe patient underwent repeat TACE in July 2016 and continued CAPTEM until November 2016 when he was noted to have progression in the liver. In December 2016, the patient was started on treatment with fluorouracil (5-FU) 400 mg/m2 followed by a 2,400 mg intravenous infusion over 2 days, leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2 every 2 weeks (FOLFOX). The patient's disease remained stable until November 2017, when he again had progression in the liver. In December 2017, the patient was started on ipilimumab 1 mg/kg for 30 minutes daily on day 1 and nivolumab 3 mg/kg for 30 minutes daily on days 1, 15, and 29 through a clinical trial. Following 4 cycles of treatment, the patient was noted to have progression of disease and declining performance status. The last treatment was in May 2018.\n\nThe patient sought follow-up in our clinic in May 2018. At that time, he was extremely symptomatic with fatigue, weight loss, and abdominal and rectal pain, and he required assistance to ambulate. After nutritional support and pain control, he was judged to be a candidate for further treatment. Gallium-68 dotatate PET/CT scan in June 2018 showed uptake in diffuse metastatic disease throughout the liver causing hepatomegaly (Figure 3A). Uptake in metastatic lymph nodes in the left lower neck, mediastinum, and rectum was also noted. Axial fused pretreatment gallium-68 dotatate PET/CT scan demonstrated SSTR-rich primary rectal tumor and hepatic metastatic lesions with index lesion (Figures 1C and 2C).\n\nFigure 3. (A) Pretreatment gallium-68 dotatate positron emission tomography (PET) scan demonstrates burden of hepatic metastatic disease, with primary rectal tumor obscured by tracer in the urinary bladder. (B) Gallium-68 dotatate PET scan obtained 8 weeks after completion of PRRT demonstrates near-resolution of abnormal tracer uptake.\n\nIn August 2018, the patient was initiated on 177Lu-dotatate and received 200 mCi. He repeated this treatment every 8 weeks for 4 cycles. During this time, his symptoms improved, and he gained weight. By February 2019, when he received his final cycle, the patient was completely asymptomatic. Repeat imaging that included a gallium-68 dotatate PET/CT scan in April 2019 revealed a near-complete response to therapy (Figures 1D, 2D, and 3B). CT of the abdomen and pelvis also revealed partial response (Figures 1B and 2B). A subsequent scan showed responsive disease.\n\nDISCUSSION\n\nThe United States Food and Drug Administration approved 177Lu-dotatate in 2018 based on data from the NETTER (Neuroendocrine Tumors Therapy)-1 trial.2 The NETTER-1 trial randomized 229 patients with low- and intermediate-grade midgut NETs who had progressed on an SSA to either high-dose octreotide 60 mg every 4 weeks or 177Lu-dotatate 200 mCi every 8 weeks for a total of 4 doses with a primary endpoint of progression-free survival (PFS). The results showed that 177Lu-dotatate was superior with a median PFS not yet reached in the 177Lu-dotatate group and 8.4 months in the high-dose octreotide group (hazard ratio 0.21, 95% CI 0.13-0.33; P<0.0001). Responses occurred in 18% of patients, with the majority of patients having stable disease.\n\nOur patient differed from patients in the NETTER-1 study, as he was classified as having an NEC (Ki-67 40%) with PD morphology, and he had a hindgut tumor. The data on high-grade tumors are scarce, and thus, PRRT is not currently a recommended treatment for NEC.4 The majority of research on the effectiveness of PRRT has been in low- or intermediate-grade NETs because of the demonstrated inverse relationship between grade and SSTR expression.5-7 As previously described, PRRT uses the SSTRs to gain internal access to the cell; therefore, the more SSTRs that a tumor cell expresses, the more successful PRRT is. The current (2019) National Comprehensive Cancer Network treatment guidelines for PD NECs state that somatostatin scintigraphy is not recommended in the evaluation of NECs unless evidence suggests well-differentiated morphology.4 Contrary to the current guidelines, however, studies have demonstrated high SSTR expression in certain patients with NEC, despite concomitant PD morphology.8,9 For example, Welin et al reported that 62% of patients with NECs had a positive SSTR expression, and Binderup et al described 69% of patients with PD NECs as SSTR positive during their initial evaluation.8,9 Congruently, our patient demonstrated SSTR expression and an excellent response to PRRT, despite both a high proliferation rate and PD morphology.\n\nOur patient's response was in line with a patient described by Garske and collegues.10 The patient with an NEC of unknown primary with liver metastasis and a Ki-67 10% to 50% had a successful response to PRRT after progression of disease on 2 chemotherapies.10 Similarly, our patient was pretreated with multiple lines of chemotherapy, with the addition of liver-directed therapy and immunotherapy.\n\nThe current first-line treatment for unresectable NEC is chemotherapy using a platinum-based treatment in combination with etoposide.4 The NORDIC (Neuro-Ophthalmology Research Disease Investigator Consortium) NEC trial demonstrated a median overall survival (OS) of 11 months and a median PFS of 4 months in patients when first-line chemotherapy was used in NECs.11 Thang et al conducted a recent (2018) retrospective study examining PRRT in NEC and reported more favorable results than the NORDIC NEC trial, with a median OS of 19 months and a median PFS of 9 months in patients who underwent PRRT.12 Patients with a Ki-67 <55% did remarkably better with PRRT (46 months vs 14 months) compared to chemotherapy treatment; however, those with a Ki-67 ≥55% had a shorter OS with PRRT compared to treatment with chemotherapy (7 months vs 10 months, respectively).11,12 In line with the results reported by Thang and colleagues, Carlsen et al conducted a retrospective cohort study of 149 patients with NEC treated with PRRT and found that those with a Ki-67 21% to 54% experienced longer PFS and OS compared to patients with a Ki-67 ≥55% (16 vs 6 months [P<0.001] and 31 vs 9 months [P<0.001], respectively).13 Parallel to our patient, the majority of subjects examined by Thang et al and Carlsen et al failed prior treatment with chemotherapy (79% and 69.8%, respectively) but responded favorably to PRRT.12,13\n\n177Lu-dotatate is indicated for SSTR-positive gastroenteropancreatic NETs, including foregut, midgut, and hindgut in adults.4 As of October 2020, no grade is specified as a cutoff. Although the NETTER-1 study did not include these patients, considering this treatment for patients with widespread SSTR-positive disease is reasonable.\n\nOur patient demonstrated an excellent response to PRRT, perhaps because of his lower proliferation rate, in spite of having PD morphology. These results demonstrate that, conceivably, PRRT is a more advantageous therapy than chemotherapy for patients with NEC who have a proliferation rate <55%.\n\nNot only did our patient have a dramatic radiologic improvement, but he also improved clinically and became symptom-free. When compared to chemotherapy, PRRT appears to be tolerated well with less adverse effects. The safety of 177Lu-dotatate was studied in 504 patients with NETs and was found to produce digestive (such as diarrhea, vomiting, and abdominal pain) and hematologic (neutropenia, anemia, thrombocytopenia [World Health Organization grades 3 or 4]) side effects in 25% and 3.6% of administrations, respectively.14 Serious adverse effects, including myelodysplastic syndrome and nonfatal liver toxicity, were reported in <1% of patients.14 The side effect profile of PRRT illustrates that 177Lu-dotatate may serve as a well-tolerated therapy for patients with NEC.\n\nCONCLUSION\n\nOur case accentuates the importance of further investigation of PRRT in NEC, specifically in patients with a Ki-67 <55% and uptake on SSTR imaging.\n\nACKNOWLEDGMENTS\n\nRobert A. Ramirez, DO, FACP, serves as a consultant for Advanced Accelerator Applications, Curium, and Novartis Pharmaceuticals, as well as a speaker for Merck & Co, Genetech, AstraZeneca, Guardant, Advanced Accelerator Applications, and Ipsen Biopharmaceuticals. J. Philip Boudreaux, MD, FACS, serves as a speaker and consultant for Ipsen Biopharmaceuticals and Lexicon Pharmaceuticals and as a speaker for Novartis Pharmaceuticals. The other authors have no conflicts of interest to disclose.\n\nThis article meets the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties Maintenance of Certification competencies for Patient Care and Medical Knowledge.\n==== Refs\nREFERENCES\n\n1. Dasari A , Shen C , Halperin D , Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3 (10 ):1335-1342. doi: 10.1001/jamaoncol.2017.0589 28448665\n2. Strosberg J , El-Haddad G , Wolin E , et al ; NETTER-1 Trial Investigators. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376 (2 ):125-135. doi: 10.1056/NEJMoa1607427 28076709\n3. Hirmas N , Jadaan R , Al-Ibraheem A . Peptide receptor radionuclide therapy and the treatment of gastroentero-pancreatic neuroendocrine tumors: current findings and future perspectives. Nucl Med Mol Imaging. 2018;52 (3 ):190-199. doi: 10.1007/s13139-018-0517-x 29942397\n4. Neuroendocrine and adrenal tumors version 1.2019. National Comprehensive Cancer Network. 2019. Updated June 2019. Accessed August 28, 2019. http://www.arupconsult.com/reference/nccn-neuroendocrine-and-adrenal-tumors-version-12019\">\n5. Ezziddin S , Logvinski T , Yong-Hing C , Factors predicting tracer uptake in somatostatin receptor and MIBG scintigraphy of metastatic gastroenteropancreatic neuroendocrine tumors. J Nucl Med. 2006;47 (2 ):223-233.16455627\n6. Ezziddin S , Khalaf F , Vanezi M , Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2014;41 (5 ):925-933. doi: 10.1007/s00259-013-2677-3 24504504\n7. Kayani I , Bomanji JB , Groves A , Functional imaging of neuroendocrine tumors with combined PET/CT using 68Ga-DOTATATE (DOTA-DPhe1,Tyr3-octreotate) and 18F-FDG. Cancer. 2008;112 (11 ):2447-2455. doi: 10.1002/cncr.23469 18383518\n8. Welin S , Sorbye H , Sebjornsen S , Knappskog S , Busch C , Öberg K . Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy. Cancer. 2011;117 (20 ):4617-4622. doi: 10.1002/cncr.26124 21456005\n9. Binderup T , Knigge U , Loft A , Functional imaging of neuroendocrine tumors: a head-to-head comparison of somatostatin receptor scintigraphy, 123I-MIBG scintigraphy, and 18F-FDG PET. J Nucl Med. 2010;51 (5 ):704-712. doi: 10.2967/jnumed.109.069765 20395333\n10. Garske U , Sandström M , Johansson S , Lessons on tumour response: imaging during therapy with (177)Lu-DOTA-octreotate. A case report on a patient with a large volume of poorly differentiated neuroendocrine carcinoma. Theranostics. 2012;2 (5 ):459-471. doi: 10.7150/thno.3594 22768026\n11. Sorbye H , Welin S , Langer SW , Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2012;24 (1 ):152-160. doi: 10.1093/annonc/mds276 22967994\n12. Thang SP , Lung MS , Kong G , Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single-institution retrospective analysis. Eur J Nucl Med Mol Imaging. 2018;45 (2 ):262-277. doi: 10.1007/s00259-017-3821-2 28894897\n13. Carlsen EA , Fazio N , Granberg D , Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study. Endocr Relat Cancer. 2019;26 (2 ):227-239. doi: 10.1530/ERC-18-0424\n14. Kwekkeboom DJ , de Herder WW , Kam BL , Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26 (13 ):2124-2130. doi: 10.1200/JCO.2007.15.2553 18445841\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1524-5012",
"issue": "21(3)",
"journal": "The Ochsner journal",
"keywords": "Carcinoma–neuroendocrine; gallium Ga 68 dotatate; lutetium-177; receptors–somatostatin",
"medline_ta": "Ochsner J",
"mesh_terms": null,
"nlm_unique_id": "101125795",
"other_id": null,
"pages": "306-311",
"pmc": null,
"pmid": "34566515",
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"title": "A Peptide Meets a Radionuclide to Combat a Rare Tumor.",
"title_normalized": "a peptide meets a radionuclide to combat a rare tumor"
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"abstract": "BACKGROUND\nCapsule endoscopy (SBCE) has developed a relevant role in patients with established Crohn's Disease (CD). However, evaluation of the impact in clinical management has been scarce.\n\n\nOBJECTIVE\nTo evaluate therapeutic impact of SBCE in an 11-year real-life cohort of known CD patients.\n\n\nMETHODS\nRetrospective single center study including all patients with established CD submitted to SBCE procedure from 01/01/2008 to 31/12/2019. Patency capsule was used in selected patients. Small bowel mucosal inflammation was quantified using Lewis score. Therapeutic impact was defined as a change in CD-related treatment recommended based on SBCE results. Patients were assigned to four groups regarding SBCE indication: staging, flare, post-op and remission.\n\n\nRESULTS\nFrom the 432 SBCE performed 87.5% were conclusive. Active disease was present in 63.7 of patients; 41.6% mild inflammation and 21.9% moderate-to-severe activity. A change of management was guided by SBCE in 51.3% of procedures: 199 (46.1%) escalation and 23 (5.3%) de-escalation, with significant changes in all groups. Escalation increased with disease activity: 57.8% in mild and 89.5% in moderate-to-severe disease. De-escalation was conducted in 13.9% procedures with mucosal healing and 1.1% with mild disease.\n\n\nCONCLUSIONS\nSBCE is a useful tool for guiding therapeutic management in CD patients both for treatment escalation and de-escalation.",
"affiliations": "Gastroenterology Unit, Hospital García Orcoyen, Calle Santa Soria 22, Estella, Navarra 31200, Spain. Electronic address: alfonso.elosua@gmail.com.;Gastroenterology Unit, Hospital García Orcoyen, Calle Santa Soria 22, Estella, Navarra 31200, Spain.;Gastroenterology Department, Complejo Hospitalario de Navarra, Calle Irunlarrea 3, Pamplona 31008, Spain.;Gastroenterology Department, Complejo Hospitalario de Navarra, Calle Irunlarrea 3, Pamplona 31008, Spain.;Gastroenterology Department, Complejo Hospitalario de Navarra, Calle Irunlarrea 3, Pamplona 31008, Spain.;Gastroenterology Department, Complejo Hospitalario de Navarra, Calle Irunlarrea 3, Pamplona 31008, Spain.;Gastroenterology Department, Complejo Hospitalario de Navarra, Calle Irunlarrea 3, Pamplona 31008, Spain.;Gastroenterology Department, Complejo Hospitalario de Navarra, Calle Irunlarrea 3, Pamplona 31008, Spain.;Gastroenterology Department, Complejo Hospitalario de Navarra, Calle Irunlarrea 3, Pamplona 31008, Spain.",
"authors": "Elosua|Alfonso|A|;Rullan|María|M|;Rubio|Saioa|S|;Oquiñena|Susana|S|;Rodríguez|Cristina|C|;Macías|Elena|E|;Borda|Ana|A|;Fernández-Urién|Ignacio|I|;Nantes|Óscar|Ó|",
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"journal": "Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver",
"keywords": "Capsule endoscopy; Crohn's disease; Fecal calprotectin; Patency capsule",
"medline_ta": "Dig Liver Dis",
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"pmid": "34518128",
"pubdate": "2021-09-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Does capsule endoscopy impact clinical management in established Crohn's disease?",
"title_normalized": "does capsule endoscopy impact clinical management in established crohn s disease"
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"abstract": "Cerebral toxoplasmosis is a rare complication of systemic lupus erythematosus (SLE). An 18 year old male student, newly diagnosed to have SLE, developed neurological symptoms two days after completing intravenous methylprednisolone. Computed tomography (CT) scan showed features consistent with a diagnosis of probable cerebral toxoplasmosis. He responded dramatically to antitoxoplasma therapy. To our knowledge, this is the first case report in the literature that presents a newly diagnosed SLE patient who rapidly developed cerebral toxoplasmosis following administration of intravenous methylprednisolone. Our case illustrates that this drug is potentially fatal and the importance of differentiating cerebral infection from neuropsychiatric lupus.",
"affiliations": "Columbia Asia Hospital Nusajaya, Persiaraan Afiat, Taman Kesihatan Afiat, 79250 Nusajay Malaysia. pagal72@gmail.com.",
"authors": "Pagalavan|L|L|;Kan|F K|FK|",
"chemical_list": "D008775:Methylprednisolone",
"country": "Malaysia",
"delete": false,
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"issn_linking": "0300-5283",
"issue": "66(1)",
"journal": "The Medical journal of Malaysia",
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"mesh_terms": "D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008775:Methylprednisolone; D016781:Toxoplasmosis, Cerebral",
"nlm_unique_id": "0361547",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Cerebral toxoplasmosis in systemic lupus erythematosus following intravenous methylprednisolone.",
"title_normalized": "cerebral toxoplasmosis in systemic lupus erythematosus following intravenous methylprednisolone"
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"companynumb": "MY-FRESENIUS KABI-FK201602950",
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"abstract": "The COVID-19 pandemic has caused more than 3 million deaths worldwide. Recently developed genetically engineered vaccines are the most critical solution for controlling the pandemic. Clinical trials on a large number of participants confirmed their safety and efficacy. However, with the growing number of vaccinated people, new infrequent adverse effects have been reported, not described in the medicinal product characteristics. We would like to report a case of acute pancreatic injury that occurred shortly after administering Pfizer BioNTech COVID-19 mRNA vaccine (Comirnaty). The report points out the potential need for close monitoring of patients reporting abdominal pain after vaccination (unresponsive to standard oral painkillers) because such symptom can be associated with acute pancreatitis.",
"affiliations": "Department of Clinical Pharmacology, Poznan University of Medical Sciences, 61-861 Poznan, Poland.;1st Department of Cardiology, Poznan University of Medical Sciences, 61-848 Poznan, Poland.;Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznan, Poland.;Department of Clinical Pharmacology, Poznan University of Medical Sciences, 61-861 Poznan, Poland.;1st Department of Cardiology, Poznan University of Medical Sciences, 61-848 Poznan, Poland.;Department of Clinical Pharmacology, Poznan University of Medical Sciences, 61-861 Poznan, Poland.",
"authors": "Cieślewicz|Artur|A|0000-0001-9918-5989;Dudek|Magdalena|M|;Krela-Kaźmierczak|Iwona|I|;Jabłecka|Anna|A|;Lesiak|Maciej|M|0000-0003-2630-5016;Korzeniowska|Katarzyna|K|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/vaccines9060576",
"fulltext": "\n==== Front\nVaccines (Basel)\nVaccines (Basel)\nvaccines\nVaccines\n2076-393X\nMDPI\n\n34205898\n10.3390/vaccines9060576\nvaccines-09-00576\nCase Report\nPancreatic Injury after COVID-19 Vaccine—A Case Report\nhttps://orcid.org/0000-0001-9918-5989\nCieślewicz Artur 1*\nDudek Magdalena 2\nKrela-Kaźmierczak Iwona 3\nJabłecka Anna 1\nhttps://orcid.org/0000-0003-2630-5016\nLesiak Maciej 2\nKorzeniowska Katarzyna 1\nMartinez-Sobrido Luis Academic Editor\n1 Department of Clinical Pharmacology, Poznan University of Medical Sciences, 61-861 Poznan, Poland; ajablecka@ump.edu.pl (A.J.); katakorz@wp.pl (K.K.)\n2 1st Department of Cardiology, Poznan University of Medical Sciences, 61-848 Poznan, Poland; magdalena.dudek@skpp.edu.pl (M.D.); maciej.lesiak@ump.edu.pl (M.L.)\n3 Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznan, Poland; ikrela-kazmierczak@ump.edu.pl\n* Correspondence: artcies@ump.edu.pl; Tel.: +48-61-668-78-21\n01 6 2021\n6 2021\n9 6 57626 4 2021\n25 5 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/).\nThe COVID-19 pandemic has caused more than 3 million deaths worldwide. Recently developed genetically engineered vaccines are the most critical solution for controlling the pandemic. Clinical trials on a large number of participants confirmed their safety and efficacy. However, with the growing number of vaccinated people, new infrequent adverse effects have been reported, not described in the medicinal product characteristics. We would like to report a case of acute pancreatic injury that occurred shortly after administering Pfizer BioNTech COVID-19 mRNA vaccine (Comirnaty). The report points out the potential need for close monitoring of patients reporting abdominal pain after vaccination (unresponsive to standard oral painkillers) because such symptom can be associated with acute pancreatitis.\n\npancreatitis\npancreatic injury\nCOVID-19\ncoronavirus vaccine\nComirnaty\nCOVID-19 mRNA vaccine\n==== Body\n1. Introduction\n\nThe COVID-19 pandemic has already caused more than 3 million deaths worldwide [1]. An essential method for controlling the pandemic has recently been provided by vaccines—modern genetically engineered preparations designed to trigger the immune response to coronavirus antigen. A few such vaccines have been registered by the FDA and EMA [2,3,4,5]. Their safety and efficacy were assessed on large groups of participants (the combined number of recruits was >130,000). The most common adverse effects were similar in all preparations and included pain at the injection site, fatigue, headache, myalgia, arthralgia, pyrexia and nausea [2,3,4,5]. With the growing number of vaccinated people, more and more adverse effects are being reported, including adverse events not described in medicinal product characteristics. The report we would like to present describes a very rare case of pancreatic injury and suspected acute pancreatitis that occurred shortly after administering the Pfizer BioNTech COVID-19 mRNA vaccine (Comirnaty) to a young and healthy patient.\n\n2. Case\n\nThe patient, an MD and a healthcare worker, is a 29-year-old female Caucasian with no history of pancreatitis, concomitant diseases and allergic reactions to drugs or vaccines. She is a healthy woman, breastfeeding mother who did not consume alcohol or drugs. On 8 January 2021, she was administered the first dose of Pfizer BioNTech COVID-19 mRNA vaccine. A few minutes after receiving the vaccine, she reported severe pain at the injection site, radiating to her left hand and neck.\n\nTwelve hours after vaccination, the patient experienced muscle pain, headache, chills and general weakness, which lasted for about 3 h. Twenty hours after vaccination, she woke up in the night because of severe abdominal pain. Despite taking paracetamol (2 × 500 mg, orally), the pain level increased over the next hours and became radiating to the spine. Twenty-eight hours after vaccination, the patient still suffered from severe pain in the upper abdomen, unresponsive to standard oral painkillers. Moreover, fever up to 40 °C occurred. The timeline of adverse effects is presented in Figure 1.\n\nThe patient went to the hospital, suspecting pancreatitis. Laboratory analyses were carried out the next day after vaccination. Blood morphology was normal (Table 1), except for minor disturbances in neutrophil and lymphocyte percentage, slightly increased mean corpuscular haemoglobin concentration (MCHC) and increased platelet anisocytosis (PDW). Biochemical analysis revealed significantly increased CRP and urine amylase (Table 2). Nasopharyngeal swab for RT-PCR COVID-19 testing taken in Emergency Room was negative. Abdominal ultrasonography was performed, resulting in hyperechoic lesion in the right lobe of the liver, gallbladder not enlarged with normal wall, intrahepatic bile ducts not dilated, pancreas clearly visible in the head and body area not enlarged, homogeneous, without calcification, pancreatic tail obscured by intestinal gases difficult to assess, kidneys of normal and comparable size, without signs of stagnation and calcified deposits, unexpanded spleen. Magnetic resonance imaging of the abdomen was performed and revealed no significant changes, suggesting mild pancreatic injury.\n\nIn the hospital, the patient received paracetamol 1g iv and was discharged home (on her demand, despite indications for hospital treatment) with the recommendation of a strict diet (fluids only, 2–3 litres daily), gastro-resistant capsules of pancreatic enzymes (10,000 units orally, three times daily) and proton pump inhibitors (pantoprazole 40 mg orally, two times daily). Biochemical parameters were then assessed two days later (Table 2), showing a significant decrease in CRP (still above norm) and urine amylase (normal result). Moreover, slightly elevated total bilirubin was found. The analysis performed eight days later revealed correct CRP and urine amylase values and slightly increased total and direct bilirubin.\n\nBecause the patient is an actively working physician, it was concluded that the risk of serious complications after infection with SARS-CoV-2 outweighs the risk of potential mild pancreatic injury. As a result, the patient received a second dose of vaccine on her demand on 5 March 2021. No such severe reaction was observed at that time. The pain at the injection site was felt 2–3 h after vaccination. Twelve hours after receiving the vaccine, muscle and joint pains along with hyperesthesia appeared. Twenty-four hours after vaccination, lymphadenopathy under the left armpit was found, with lymph nodes enlarged to about 2–3 cm. The lymph nodes were painful for about four days.\n\n3. Discussion\n\nThe described patient was a healthy woman, without any risk factors associated with the development of pancreatitis. She did not take any drugs or supplements and had no family history of pancreatitis. The pancreatic injury symptoms appeared shortly after the administration of the COVID-19 vaccine. Therefore, the temporal relationship may indicate the need for close monitoring of patients reporting abdominal pain after vaccination.\n\nVaccine-induced pancreatitis is an uncommon adverse reaction that was described for some viral vaccines such as Mumps–Measles–Rubella (MMR), Hepatitis A and B and Human papillomavirus [6,7,8]. Bizjak et al. identified in their paper important factors that suggest a possible link between vaccination and pancreatitis. These factors include [8]:the chronology of events associated with the onset of adverse reaction;\n\npositive rechallenge and exacerbation of symptoms after repeated exposure to the vaccine;\n\nsimilar case reports describing pancreatitis after using the same vaccine;\n\na probable causal relationship of the vaccine to other kinds of autoimmune diseases;\n\ncase reports describing pancreatitis observed after different vaccines;\n\nprobable mechanism between the vaccine and acute pancreatitis.\n\nAccording to Pfizer’s data, one case of pancreatitis and one obstructive pancreatitis adverse reaction was observed during Phase 2/3 clinical trial of COVID-19 mRNA vaccine [9]. The trial included about 38,000 participants, indicating that such a time link between vaccination and pancreatitis is a very rare adverse reaction. Similar information can be obtained from UK databases—a collection of spontaneous reports received between 9 December 2020 and 21 March 2021 for the mRNA Pfizer/BioNTech vaccine contains 40,883 reports of adverse reactions with one case of obstructive pancreatitis, three cases of pancreatitis, one case of acute pancreatitis and one case of necrotising pancreatitis [10].\n\nThe mechanism responsible for vaccine-induced pancreatitis remains unclear. Currently, the most probable hypothesis was proposed in the molecular mimicry theory, stating that amino acid sequences similarities between viral and self-antigens can result in autoimmune reaction [11]. Induction of such an autoimmune response can result in the production of cytotoxic antibodies with affinity for pancreatic acinar cells [8]. Indeed, recently published data revealed that antibodies against SARS-CoV-2 spike protein and nucleoprotein presented cross-reactivity against many human tissue antigens [12,13]. Other hypotheses that have been discussed include polyclonal activation of lymphocytes, “bystander activation” of self-reactive lymphocytes, somatic mutations of immunoglobulin variable genes, vaccine-induced vasculitis and triggering the release of histamine and leukotrienes [6].\n\nFurthermore, pancreatitis can result from viral infection [14]. The scientific literature provides information on incidents of infectious pancreatitis caused by mumps (the first case of pancreatitis caused by virus ever described), hepatitis viruses (with hepatitis B virus being the most commonly associated with acute pancreatitis), human immunodeficiency virus (incidence of acute pancreatitis 40% in HIV-positive patients compared to 2% in the general population), coxsackie virus type B, herpes simplex virus, cytomegalus virus, varicella-zoster virus, and some other viruses [14,15]. Coronaviruses (CoVs) are a large family of single-stranded RNA viruses, infecting humans and animals and causing various organ symptoms [16,17]. It is worth noting that pancreatic injury was observed in 17% of COVID-19 cases [18]. Such injury might be caused by the direct cytopathic effect of SARS-CoV-2, as ACE2 receptors (used by the virus to infect the cell) were highly expressed in pancreas cells. However, another explanation underlines the role of systemic inflammatory and immune response in the development of pancreatitis during the COVID-19 course [18,19]. It is possible that a similar mechanism may be responsible for the adverse reaction observed in the described patient. The ongoing multi-centre observational study COVIDPAN, focused on acute pancreatitis during the COVID-19 course, together with retrospective analysis of vaccine adverse effects, may in the future provide data supporting this hypothesis [20].\n\n4. Conclusions\n\nTo our knowledge, the presented case is the first report of acute pancreatitis, observed shortly after the COVID-19 vaccine, described in the scientific literature. It is consistent with the data from clinical trials, where only two cases of pancreatitis were reported in the group of almost 38,000 participants. The report shows that severe abdominal pain after vaccination should not be disregarded, as it can be a symptom of acute pancreatitis, and patients reporting this symptom should be closely monitored. Moreover, the analysis of the presented case can conclude that the presence of such adverse effect is not necessarily an indication for omitting the second dose of the vaccine—despite acute pancreatitis after the first vaccination, the patient received the second dose without triggering a severe response. However, such a decision should be taken carefully after a deep analysis of the patient’s observed adverse event and clinical condition.\n\nAuthor Contributions\n\nConceptualization, A.C. and K.K.; writing—original draft presentation, A.C. and K.K.; writing—review and editing, M.D., I.K.-K., A.C. and K.K.; visualization, A.C.; supervision, A.J., M.L. and K.K. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nDue to the case report nature of the manuscript, no ethical approval was required.\n\nInformed Consent Statement\n\nWritten informed consent has been obtained from the patient to publish this paper.\n\nData Availability Statement\n\nThe data presented in this study are available on request from the corresponding author.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Adverse effects observed after administration of COVID-19 vaccine.\n\nvaccines-09-00576-t001_Table 1 Table 1 Blood morphology of the patient, assessed on 9 January 2021.\n\nParameter [Unit] (Reference Values)\tResult\t\nWBC [109/L] (4.00–10.00)\t6.72\t\n%NEUT [%] (45.0–70.0)\t75.6 *\t\n%LYMPH [%] (20.0–45.0)\t16.1 *\t\n%MONO [%] (0.0–9.0)\t4.9\t\n%EOS [%] (0.0–5.0)\t1.3\t\n%BASO [%] (0.0–1.5)\t0.4\t\n%LUC [%] (0.0–4.0)\t1.7\t\n#NEUT [109/L] (1.80–7.00)\t5.08\t\n#LYMPH [109/L] (0.80–4.50)\t1.09\t\n#MONO [109/L] (0.00–0.90)\t0.33\t\n#EOS [109/L] (0.00–0.50)\t0.09\t\n#BASO [109/L] (0.00–0.15)\t0.03\t\n#LUC [109/L] (0.00–0.40)\t0.12\t\nRBC [1012/L] (4.00–5.00)\t4.29\t\nHGB [mmol/L] (7.45–10.00)\t8.50\t\nHCT [L/L] (0.36–0.47)\t0.39\t\nMCV [fL] (82–97)\t90\t\nMCH [fmol] (1.64–2.08)\t1.98\t\nMCHC [mmol/L] (20.00–22.00)\t22.01 *\t\nRDW [%] (11.00–15.00)\t12.60\t\nPLT [109/L] (130.0–390.0]\t161\t\nMPV [fL] (7.00–11.00]\t9.40\t\nPCT [L/L] (0.002–0.004)\t0.002\t\nPDW [%] (40.0–60.0)\t67.5 *\t\n* indicates results not in the reference range.\n\nvaccines-09-00576-t002_Table 2 Table 2 Results of biochemical analyses.\n\nParameter [Unit] (Reference Values)\t9 January 2021\t11 January 2021\t19 January 2021\t\nCRP [mg/L] (<5.0)\t128.0 *\t38.0 *\t2.2\t\nUrine amylase [U/L] (30–200)\t544 *\t208\t240\t\nSerum amylase [U/L] (25–115)\t51\t58\t64\t\nALAT [U/L] (<45)\t<7\t8\t8\t\nASPAT [U/L] (<35)\t15\t14\t13\t\nSerum creatinine [mg/dL] (0.50–0.90)\t0.68\t-\t0.83\t\nPotassium [mmol/L] (3.5–5.1)\t3.8\t-\t4.85\t\nSodium [mmol/L] (135.0–145.0)\t139.0\t-\t141.0\t\nFasting glucose [mg/dL] (70–99)\t-\t84\t89\t\nTotal bilirubin [mg/dL] (<1.20)\t-\t2.21 *\t1.24 *\t\nDirect bilirubin [mg/dL] (<0.3)\t-\t-\t0.40 *\t\nAlkaline phosphatase [U/L] (35–105)\t-\t61\t67\t\nGGT [U/L] (5–36)\t-\t12\t14\t\nTotal cholesterol [mg/dL] (<190)\t-\t174\t-\t\nHDL [mg/dL] (>45.0)\t-\t78\t-\t\n%HDL [%] (>20.0)\t-\t45\t-\t\nTriglycerides [mg/dL] (65–150)\t-\t45\t-\t\nIron [µg/dL] (37–145)\t-\t80\t-\t\nUIBC [µg/dL] (112–346)\t-\t224\t-\t\nTIBC (calculated) [µg/dL] (250–400)\t-\t304\t-\t\nTSAT (calculated) [%] (20–55)\t-\t26\t-\t\nCEA [ng/mL] (<5.0/<6.5 smoking/non-smoking)\t-\t0.88\t-\t\nCA [U/mL] (<39)\t-\t4.4\t-\t\n* indicates results not in reference range.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Worldometer COVID-19 Coronavirus Pandemic Available online: https://www.worldometers.info/coronavirus/?ref=tjournal.ru (accessed on 26 April 2021)\n2. Comirnaty Summary of Product Characteristics Available online: https://www.ema.europa.eu/documents/product-information/comirnaty-epar-product-information_en.pdf (accessed on 25 March 2021)\n3. COVID-19 Vaccine Moderna Summary of Product Characteristics Available online: https://www.ema.europa.eu/documents/product-information/covid-19-vaccine-moderna-epar-product-information_en.pdf (accessed on 25 March 2021)\n4. COVID-19 Vaccine (ChAdOx1-S [Recombinant]) Summary of Product Characteristics Available online: https://www.ema.europa.eu/documents/product-information/covid-19-vaccine-astrazeneca-epar-product-information_en.pdf (accessed on 25 March 2021)\n5. COVID-19 Vaccine (Ad26.COV2-S [Recombinant]) Summary of Product Characteristics Available online: https://www.ema.europa.eu/documents/product-information/covid-19-vaccine-janssen-epar-product-information_en.pdf (accessed on 25 March 2021)\n6. Chandak S. Mandal A. Singh A. Acute pancreatitis and pancreatic pseudocyst in a toddler following mumps, measles and rubella vaccine Clin. Pediatr. 2017 2 1 4 Available online: https://www.longdom.org/open-access/acute-pancreatitis-and-pancreatic-pseudocyst-in-a-toddler-followingmumps-measles-and-rubella-vaccine.pdf (accessed on 25 March 2021) 10.4172/2572-0775.1000117\n7. Shlomovitz E. Davies W. Cairns E. Brintnell W.C. Goldszmidt M. Dresser G.K. Severe necrotising pancreatitis following combined hepatitis A and B vaccination CMAJ 2007 176 339 342 10.1503/cmaj.060360 17261831\n8. Bizjak M. Bruck O. Praprotnik S. Dahan S. Shoenfeld Y. Pancreatitis after human papillomavirus vaccination: A matter of molecular mimicry Immunol. Res. 2017 65 164 167 10.1007/s12026-016-8823-9 27421720\n9. VRBPAC Briefing Document Pfizer-BioNTech COVID-19 Vaccine (BNT162, PF-07302048) Vaccines and Related Biological Products Advisory Committee. Briefing Document. Meeting Date: 10 December 2020. US Food and Drug Administration 2020:14 December. [Ref. ID 103835] Available online: https://www.fda.gov/media/144246/download (accessed on 8 April 2021)\n10. COVID-19 mRNA Pfizer-BioNTech Vaccine Analysis Print All UK Spontaneous Reports Received between 9/12/20 and 21/03/21 for mRNA Pfizer/BioNTech Vaccine Analysis Print Available online: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/975808/COVID-19_mRNA_Pfizer-BioNTech_Vaccine_Analysis_Print.pdf (accessed on 8 April 2021)\n11. Bogdanos D.P. Smith H. Ma Y. Baum H. Mieli-Vergani G. Vergani D. A study of molecular mimicry and immunological cross-reactivity between hepatitis B surface antigen and myelin mimics Clin. Dev. Immunol. 2005 12 217 224 10.1080/17402520500285247 16295528\n12. Vojdani A. Kharrazian D. Potential Antigenic Cross-Reactivity between SARS-CoV-2 and Human Tissue with a Possible Link to an Increase in Autoimmune Diseases Clin. Immunol. 2020 217 108480 Available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246018/ (accessed on 19 May 2021) 10.1016/j.clim.2020.108480 32461193\n13. Vojdani A. Vojdani E. Kharrazian D. Reaction of Human Monoclonal Antibodies to SARS-CoV-2 Proteins with Tissue Antigens: Implications for Autoimmune Diseases Front. Immunol. 2021 11 617089 Available online: https://www.frontiersin.org/articles/10.3389/fimmu.2020.617089/full#B23 (accessed on 19 May 2021) 10.3389/fimmu.2020.617089 33584709\n14. Kottanattu L. Lava S.A.G. Helbling R. Simonetti G.D. Bianchetti M.G. Milani G.P. Pancreatitis and cholecystitis in primary acute symptomatic Epstein-Barr virus infection - Systematic review of the literature J. Clin. Virol. 2016 82 51 55 10.1016/j.jcv.2016.06.017 27434148\n15. Rawla P. Bandaru S.S. Vellipuram A.R. Review of Infectious Etiology of Acute Pancreatitis Gastroenterol. Res. 2017 10 153 158 10.14740/gr858w 28725301\n16. Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. Liu L. Shan H. Lei C.L. Hui D.S.C. China Medical Treatment Expert Group for COVID-19. Clinical Characteristics of Coronavirus Disease 2019 in China N. Engl. J. Med. 2020 382 1708 1720 10.1056/NEJMoa2002032 32109013\n17. Perisetti A. Gajendran M. Boregowda U. Bansal P. Goyal H. COVID-19 and gastrointestinal endoscopies: Current insights and emergent strategies Dig. Endosc. 2020 32 715 722 10.1111/den.13693 32281689\n18. Wang F. Wang H. Fan J. Zhang Y. Wang H. Zhao Q. Pancreatic Injury Patterns in Patients with Coronavirus Disease 19 Pneumonia Gastroenterology 2020 159 367 370 10.1053/j.gastro.2020.03.055 32247022\n19. Patel K.P. Patel P.A. Vunnam R.R. Hewlett A.T. Jain R. Jing R. Vunnam S.R. Gastrointestinal, hepatobiliary, and pancreatic manifestations of COVID-19 J. Clin. Virol. 2020 128 104386 10.1016/j.jcv.2020.104386 32388469\n20. de-Madaria E. Capurso G. COVID-19 and acute pancreatitis: Examining the causality Nat. Rev. Gastroenterol. Hepatol. 2021 18 3 4 10.1038/s41575-020-00389-y 33203968\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2076-393X",
"issue": "9(6)",
"journal": "Vaccines",
"keywords": "COVID-19; COVID-19 mRNA vaccine; Comirnaty; coronavirus vaccine; pancreatic injury; pancreatitis",
"medline_ta": "Vaccines (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101629355",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34205898",
"pubdate": "2021-06-01",
"publication_types": "D002363:Case Reports",
"references": "33203968;32388469;27421720;17261831;33584709;32461193;32281689;32109013;32247022;16295528;28725301;27434148",
"title": "Pancreatic Injury after COVID-19 Vaccine-A Case Report.",
"title_normalized": "pancreatic injury after covid 19 vaccine a case report"
} | [
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"companynumb": "PL-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-304374",
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"activesubstancename": "ACETAMINOPHEN"
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"abstract": "BACKGROUND\nNeurological complications occur in 30-80% of patients following heart transplantation, and seizures account for 2-20% of these sequelae. The main risk factors are toxicity due to immunosuppression, infections, and brain lesions. We present 2 cases of grand mal type attacks that occurred on the 7th and 15th postoperative days. The origin of the attacks was an unusual interaction between 2 non-immunosuppressive drugs (metoclopramide and theophylline).\n\n\nMETHODS\nWe present 2 cases of seizure episodes during the early postoperative period in young heart transplant recipients (a 26-year-old female and a 33-year-old man). Grand mal type attacks occurred on the 7th and 15th postoperative day, respectively. Both patients were treated with standard triple immunosuppressive therapy including tacrolimus, mycophenolate mofetil, and steroids. Therapy with metoclopramide was started because the patients reported gastrointestinal disturbances. Theophylline was administered due to postoperative bradycardia. Serum theophylline levels were 33 and 34 mcg/ml, respectively. There were no neurological deficits noticed thereafter. The magnetic resonance imaging (MRI) was negative for stroke and central nervous system infection in both cases.\n\n\nCONCLUSIONS\nWe conclude that theophylline overdose combined with metoclopramide may provoke new-onset seizures, especially in young patients following heart transplantation.",
"affiliations": "Department of Cardiac Surgery and Transplantology, Chair of Cardio-Thoracic Surgery, Poznań University of Medical Sciences, Poznań, Poland.;Department of Cardiac Surgery and Transplantology, Chair of Cardio-Thoracic Surgery, Poznań University of Medical Sciences, Poznań, Poland.;Department of Cardiac Surgery and Transplantology, Chair of Cardio-Thoracic Surgery, Poznań University of Medical Sciences, Poznań, Poland.;Department of Cardiac Surgery and Transplantology, Chair of Cardio-Thoracic Surgery, Poznań University of Medical Sciences, Poznań, Poland.;Department of Cardiology, Poznań University of Medical Sciences, Poznań, Poland.;Department of Cardiology, Poznań University of Medical Sciences, Poznań, Poland.;Department of Cardiac Surgery and Transplantology, Chair of Cardio-Thoracic Surgery, Poznań University of Medical Sciences, Poznań, Poland.",
"authors": "Urbanowicz|Tomasz|T|;Pawłowska|Magdalena|M|;Buczkowski|Piotr|P|;Perek|Bartłomiej|B|;Baszyńska-Wachowiak|Hanna|H|;Straburzyńska-Migaj|Ewa|E|;Jemielity|Marek|M|",
"chemical_list": "D000932:Antiemetics; D065127:Dopamine D2 Receptor Antagonists; D010726:Phosphodiesterase Inhibitors; D013806:Theophylline; D008787:Metoclopramide",
"country": "United States",
"delete": false,
"doi": "10.12659/AOT.890743",
"fulltext": null,
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"issn_linking": "1425-9524",
"issue": "19()",
"journal": "Annals of transplantation",
"keywords": null,
"medline_ta": "Ann Transplant",
"mesh_terms": "D000328:Adult; D000932:Antiemetics; D001919:Bradycardia; D001921:Brain; D065127:Dopamine D2 Receptor Antagonists; D004347:Drug Interactions; D004830:Epilepsy, Tonic-Clonic; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008787:Metoclopramide; D010726:Phosphodiesterase Inhibitors; D011183:Postoperative Complications; D013806:Theophylline",
"nlm_unique_id": "9802544",
"other_id": null,
"pages": "417-20",
"pmc": null,
"pmid": "25152323",
"pubdate": "2014-08-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Seizures after heart transplantation--two cases of non-immunosuppressant drug interactions in young patients.",
"title_normalized": "seizures after heart transplantation two cases of non immunosuppressant drug interactions in young patients"
} | [
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"activesubstancename": "METOCLOPRAMIDE"
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"abstract": "Nalmefene, an opioid antagonist, has recently been approved for the treatment of alcohol dependence. We describe here the first case of a 52-year-old woman who developed a severe central sleep apnoea (CSA) 5 months after initiation of nalmefene. Scoring of ventilation during sleep recording revealed an apnoea-hypopnoea index of 67/h with 98.7% of central events and an apnoea index of 65/h. Nalmefene was withdrawn and a new polysomnography was performed which concluded that CSA has disappeared. Pathophysiology is still unclear but could involve the κ-opioid receptors. Physicians should be aware that CSA might affect patients treated with nalmefene. Further investigations are required to determine the pathophysiology, frequency, and treatment of CSA associated with nalmefene and other therapy for alcohol disorders.",
"affiliations": "Pharmacovigilance Unit, Grenoble Alps University Hospital, Grenoble, France.;Thorax and Vessel Division, Grenoble Alps University Hospital, Grenoble, France.;Pharmacovigilance Unit, Grenoble Alps University Hospital, Grenoble, France.;HP2 Laboratory, INSERM U1042, Grenoble Alps University, Grenoble, France.;HP2 Laboratory, INSERM U1042, Grenoble Alps University, Grenoble, France.",
"authors": "Khouri|Charles|C|0000-0002-8427-8573;Arbib|François|F|;Revol|Bruno|B|0000-0003-2931-2940;Pepin|Jean-Louis|JL|;Tamisier|Renaud|R|",
"chemical_list": "D009292:Narcotic Antagonists; D009271:Naltrexone; C038981:nalmefene",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.13547",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "84(5)",
"journal": "British journal of clinical pharmacology",
"keywords": "central sleep apnoea; drug safety; nalmefene",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D005260:Female; D006801:Humans; D008875:Middle Aged; D009271:Naltrexone; D009292:Narcotic Antagonists; D017286:Polysomnography; D020182:Sleep Apnea, Central",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "1075-1076",
"pmc": null,
"pmid": "29479731",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports",
"references": "29479731;28402252;27157226;16162728;24772053;12655322;27021234;23450252;25652768;29055040;23066376;10607087;12576394;29149325",
"title": "Severe central sleep apnoea associated with nalmefene: a case report.",
"title_normalized": "severe central sleep apnoea associated with nalmefene a case report"
} | [
{
"companynumb": "FR-TEVA-2019-FR-1081436",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIANSERIN"
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... |
{
"abstract": "A 91-year-old female presented with widespread skin sloughing and bullae clinically mimicking toxic epidermal necrolysis (TEN). The patient was on multiple antibiotics, including vancomycin and piperacillin/tazobactam. Histopathology and direct immunofluorescence were consistent with a diagnosis of linear IgA bullous disease (LABD). In a PubMed review of the literature from 1975 to the present, there have been 15 cases of LABD presenting as TEN clinically and with characteristic linear IgA deposits on direct immunofluorescence studies. Vancomycin and phenytoin were the most commonly implicated medications. Twelve patients saw a resolution or healing of skin lesions after discontinuation of the implicated medication. There were, however, 5 patients who died of complications related to their comorbidities. It is important to include LABD in the differential diagnosis when evaluating patients who clinically present with TEN.",
"affiliations": "Department of Dermatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.",
"authors": "Kakar|Rohit|R|;Paugh|Holly|H|;Jaworsky|Christine|C|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000353584",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-8665",
"issue": "227(3)",
"journal": "Dermatology (Basel, Switzerland)",
"keywords": null,
"medline_ta": "Dermatology",
"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D062027:Linear IgA Bullous Dermatosis; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "9203244",
"other_id": null,
"pages": "209-13",
"pmc": null,
"pmid": "24135381",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Linear IgA bullous disease presenting as toxic epidermal necrolysis: a case report and review of the literature.",
"title_normalized": "linear iga bullous disease presenting as toxic epidermal necrolysis a case report and review of the literature"
} | [
{
"companynumb": "US-RANBAXY-2014US-78909",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
"dru... |
{
"abstract": "Invasive vulvar Paget's disease with over-expression of the human epidermal growth factor receptor 2 (HER2) protein is potentially suitable for targeted therapy, especially in a metastatic setting where no effective treatments are available.\n\n\n\nFour consecutive patients with HER2 positive advanced vulvar Paget's disease, treated with weekly trastuzumab (loading dose 4 mg/kg, then 2 mg/kg) and paclitaxel (80 mg/m2) followed by 3-weekly trastuzumab maintenance (6 mg/kg), are reported.\n\n\n\nMedian age and follow-up of patients were 62.5 years (45-74) and 16 months (6-54), respectively. Complete or partial responses were observed in all patients. Median time to response was 3 months (range 2-4), while median duration of response was 10 months (range 2-34). Case 1 presented with pulmonary and lymph nodes involvement. She experienced a radiological complete response after 24 treatment administrations, and a progression-free survival of 36 months. At disease progression, treatment re-challenge achieved partial response. She is currently receiving treatment with trastuzumab-emtansine. Case 2 was a 74-year-old woman who developed pulmonary metastasis after first-line cisplatin treatment. She had a partial response and a progression-free survival of 10 months. Case 3 had inguinal and para-aortic lymphadenopathy in complete response after 18 treatment administrations. She developed brain metastasis while receiving trastuzumab maintenance. Case 4 was treated for locally advanced disease and experienced a subjective benefit with relief in perineal pain and itching. No unexpected treatment-related side effects were reported.\n\n\n\nAdvanced vulvar Paget's disease is a rare disorder and no standard treatment is available. In the sub-group of HER2 positive disease, weekly paclitaxel-trastuzumab appears to be active and safe, and may be considered a therapeutic option in these patients.",
"affiliations": "Department of Medicine, University of Udine, Udine, Italy michele.bartoletti@cro.it.;Department of Medicine, University of Udine, Udine, Italy.;Department of Medicine, University of Udine, Udine, Italy.;Unit of Gynecological Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Centro di Riferimento Oncologico, Aviano, Italy.;Department of Medicine, University of Udine, Udine, Italy.;Department of Medicine, University of Udine, Udine, Italy.;Unit of Molecular Oncology, Centro di Riferimento Oncologico, Aviano, Italy.;Department of Medical Oncology, Unit of Medical Oncology & Cancer Prevention, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.;Department of Oncology, ASUFC Udine University Hospital, Udine, Italy.;Department of Medical Oncology, Unit of Medical Oncology & Cancer Prevention, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.;Unit of Gynecological Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Centro di Riferimento Oncologico, Aviano, Italy.;Department of Medical Oncology, Unit of Medical Oncology & Cancer Prevention, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.;Department of Oncology, ASUFC Udine University Hospital, Udine, Italy.;Department of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy.;Department of Oncology, Ospedale San Bortolo, Azienda ULSS8 Berica, Vicenza, Italy.;Department of Oncology, ASUFC Udine University Hospital, Udine, Italy.;Unit of Gynecological Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Centro di Riferimento Oncologico, Aviano, Italy.;Department of Medicine, University of Udine, Udine, Italy.",
"authors": "Bartoletti|Michele|M|0000-0002-9631-5693;Mazzeo|Roberta|R|;De Scordilli|Marco|M|;Del Fabro|Anna|A|;Vitale|Maria Grazia|MG|;Bortot|Lucia|L|;Nicoloso|Milena Sabrina|MS|;Corsetti|Serena|S|;Bonotto|Marta|M|;Scalone|Simona|S|;Giorda|Giorgio|G|;Sorio|Roberto|R|;Andreetta|Claudia|C|;Meacci|Maria Luisa|ML|;De Vivo|Rocco|R|;Fasola|Gianpiero|G|;Sopracordevole|Francesco|F|;Puglisi|Fabio|F|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1136/ijgc-2020-001771",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1048-891X",
"issue": "30(11)",
"journal": "International journal of gynecological cancer : official journal of the International Gynecological Cancer Society",
"keywords": "extramammary; paget disease",
"medline_ta": "Int J Gynecol Cancer",
"mesh_terms": "D000328:Adult; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D056687:Off-Label Use; D017239:Paclitaxel; D010145:Paget Disease, Extramammary; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D014846:Vulvar Neoplasms",
"nlm_unique_id": "9111626",
"other_id": null,
"pages": "1672-1677",
"pmc": null,
"pmid": "32998859",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Human epidermal growth factor receptor-2 (HER2) is a potential therapeutic target in extramammary Paget's disease of the vulva.",
"title_normalized": "human epidermal growth factor receptor 2 her2 is a potential therapeutic target in extramammary paget s disease of the vulva"
} | [
{
"companynumb": "IT-TEVA-2020-IT-1849103",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nBupropion toxicity is characterized by central nervous system and cardiovascular toxicity. Intravenous lipid emulsion (ILE) has been suggested as a treatment by some for the treatment of refractory bupropion toxicity. This recommendation is based largely on published case reports and cases presented at scientific meetings. The objective of this study is to characterize the outcomes of patients with suspected bupropion toxicity in which ILE was administered and the indications for its use.\n\n\nMETHODS\nElectronic records from one regional poison center were searched for intentional bupropion ingestions from 1 January 2009 through 31 December 2015. Cases in which ILE was administered or death was listed as the outcome were further analyzed.\n\n\nRESULTS\nThere were 1274 cases of suspected bupropion ingestion reported during the study period with 14 reported deaths. Nine cases of ILE administration were identified. Of these, four patients expired and five survived. One of the survivors had neurologic sequelae necessitating placement in a long-term care facility. Patient complications after ILE administration were common and included continued hypotension in 7 cases, recurrent seizures in 3 patients, ARDS in two patients, and renal failure in one patient.\n\n\nCONCLUSIONS\nThe high mortality and complication rate after ILE in this study sample does not reflect the positive outcome benefit seen in previous published case reports. Further characterization of the efficacy and complications of ILE in bupropion toxicity is needed.",
"affiliations": "a Department of Emergency Medicine , Cook County Hospital (Stroger), Toxikon Consortium , Chicago , IL , USA.;b Illinois Poison Center , Chicago , IL , USA.;b Illinois Poison Center , Chicago , IL , USA.;a Department of Emergency Medicine , Cook County Hospital (Stroger), Toxikon Consortium , Chicago , IL , USA.",
"authors": "Chhabra|Neeraj|N|;DesLauriers|Carol|C|;Wahl|Michael|M|;Bryant|Sean M|SM|",
"chemical_list": "D005217:Fat Emulsions, Intravenous; D016642:Bupropion",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2017.1337909",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "56(1)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Poison Center; bupropion; fat emulsion; lipid emulsion; poisoning",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D016642:Bupropion; D005217:Fat Emulsions, Intravenous; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "51-54",
"pmc": null,
"pmid": "28644682",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Management of severe bupropion poisoning with intravenous lipid emulsion.",
"title_normalized": "management of severe bupropion poisoning with intravenous lipid emulsion"
} | [
{
"companynumb": "US-ZYDUS-018779",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Lamotrigine (LTG) is an anti-epileptic drug and mood-stabilizing agent, whose adverse effects include skin rash and dizziness. Interactions with the immune system are rare, and only a few cases linking hypogammaglobulinemia to LTG treatment have been previously described. In this report, we describe a case in which a patient developed hypogammaglobulinemia, and a subsequent immunoglobulin A (IgA) deficiency, following LTG treatment. As a result of her immunodeficiency, the patient presented with a severe urinary tract infection and required intravenous immunoglobulin. Serum levels of immunoglobulin G and M had recovered by seven months and one month after the discontinuation of LTG, respectively; however, IgA levels remained low (less than 4mg/dL) two years post-treatment. While previous reports have demonstrated IgA deficiencies in patients prescribed other antiepileptic drugs, this is the first case of an IgA deficiency following LTG administration.",
"affiliations": "Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan; Epilepsy Center, Kagoshima University Hospital, Japan. Electronic address: s-maru@m.kufm.kagoshima-u.ac.jp.;Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.;Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.;Epilepsy Center, Kagoshima University Hospital, Japan; Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.;Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.",
"authors": "Maruyama|Shinsuke|S|;Okamoto|Yasuhiro|Y|;Toyoshima|Mitsuo|M|;Hanaya|Ryosuke|R|;Kawano|Yoshifumi|Y|",
"chemical_list": "D000927:Anticonvulsants; D007070:Immunoglobulin A; D014227:Triazines; D000077213:Lamotrigine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.braindev.2016.06.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0387-7604",
"issue": "38(10)",
"journal": "Brain & development",
"keywords": "Hypogammaglobulinemia; IgA deficiency; Lamotrigine; Secondary",
"medline_ta": "Brain Dev",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D017074:Common Variable Immunodeficiency; D004827:Epilepsy; D005260:Female; D006801:Humans; D017098:IgA Deficiency; D007070:Immunoglobulin A; D000077213:Lamotrigine; D014227:Triazines",
"nlm_unique_id": "7909235",
"other_id": null,
"pages": "947-949",
"pmc": null,
"pmid": "27396372",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Immunoglobulin A deficiency following treatment with lamotrigine.",
"title_normalized": "immunoglobulin a deficiency following treatment with lamotrigine"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2016-05366",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditiona... |
{
"abstract": "OBJECTIVE\nThe effect of transcatheter arterial chemoembolization (TACE) therapy on hepatitis B virus (HBV) reactivation in hepatocellular carcinoma (HCC) patients with prior resolved hepatitis B is not fully understood.\n\n\nMETHODS\nFrom January 2006 to December 2010, 43 hepatitis B surface antigen (HBsAg)-negative/anti-hepatitis B core antigen (HBc) positive patients with newly diagnosed unresectable HCC were enrolled in the study. All underwent TACE therapy.\n\n\nRESULTS\nFour patients (9.3%) developed HBV reactivation with mild/moderate hepatitis. The median number of TACE cycles received was 3.5 (range 3-4 cycles). The median time interval between the occurrence of HBV reactivation and the completion of TACE therapy was 3 months (range 1-5 months) and their median HBV DNA level was 1.58 × 10(4) IU/mL (range, 1.65 × 10(3) -6.42 × 10(4) IU/mL). After the introduction of lamivudine at the occurrence of HBV reactivation, all had resolution of hepatitis. An exploratory analysis indicated that significant predictors of HBV reactivation included increased serum total bilirubin coexisting with cirrhosis and the total number of cycles of TACE received.\n\n\nCONCLUSIONS\nThe administration of TACE therapy may increase the risk of HBV reactivation in HBsAg-negative/anti-HBc-positive patients diagnosed with unresectable HCC. Further studies are warranted to explore the optimal management of HBV reactivation in patients with prior resolved hepatitis B.",
"affiliations": "Department of Medical Oncology, Zhongshan Hospital of Sun Yat-sen University, Zhongshan People's City Hospital, Zhongshan 528403, China.",
"authors": "Peng|Jie-Wen|JW|;Lin|Gui-Nan|GN|;Xiao|Jian-Jun|JJ|;Jiang|Xiao-Mei|XM|",
"chemical_list": "D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; C493949:hydroxycamptothecin polybutylcyanoacrylate; D016685:Mitomycin; D004998:Ethiodized Oil; D004659:Enbucrilate",
"country": "Australia",
"delete": false,
"doi": "10.1111/j.1743-7563.2012.01534.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-7555",
"issue": "8(4)",
"journal": "Asia-Pacific journal of clinical oncology",
"keywords": null,
"medline_ta": "Asia Pac J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D004659:Enbucrilate; D004998:Ethiodized Oil; D005260:Female; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D016685:Mitomycin; D012189:Retrospective Studies; D014775:Virus Activation",
"nlm_unique_id": "101241430",
"other_id": null,
"pages": "356-61",
"pmc": null,
"pmid": "22897940",
"pubdate": "2012-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hepatitis B virus reactivation in hepatocellular carcinoma patients undergoing transcatheter arterial chemoembolization therapy.",
"title_normalized": "hepatitis b virus reactivation in hepatocellular carcinoma patients undergoing transcatheter arterial chemoembolization therapy"
} | [
{
"companynumb": "CN-ACCORD-038090",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "10-HYDROXYCAMPTOTHECIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nVascular endothelial growth factor (VEGF)-mediated angiogenesis plays an important role in non-small cell lung cancer (NSCLC). Ramucirumab is a human immunoglobulin G1 monoclonal antibody that inhibits VEGF receptor 2. This phase 2 study investigated ramucirumab in combination with first-line pemetrexed and platinum chemotherapy in advanced/metastatic NSCLC.\n\n\nMETHODS\nEligible stage IV nonsquamous NSCLC patients with no prior chemotherapy for metastatic disease were randomized 1:1 to pemetrexed and carboplatin (or cisplatin) or ramucirumab (10 mg/kg) plus pemetrexed and carboplatin (or cisplatin) once every 3 weeks. Treatment was given for 4 to 6 cycles, and this was followed by a maintenance phase with pemetrexed or ramucirumab and pemetrexed. The primary endpoint was progression-free survival (PFS) with a sample size of sufficient power to detect an increase from 7 to 10.4 months.\n\n\nRESULTS\nFrom October 2010 to October 2011, 140 patients were randomized (pemetrexed-platinum arm, 71; ramucirumab-pemetrexed-platinum arm, 69), and most baseline characteristics were similar for the 2 treatment arms. The median PFS was 5.6 months for the pemetrexed-platinum arm and 7.2 months for the ramucirumab-pemetrexed-platinum arm (hazard ratio, 0.75; P = .132). The objective response rates were 38.0% and 49.3% for the pemetrexed-platinum and ramucirumab-pemetrexed-platinum arms, respectively (P = .180). The disease control rate was 70.4% for the pemetrexed-platinum arm and 85.5% for the ramucirumab-pemetrexed-platinum arm (P = .032). The grade 3 or higher adverse events occurring in 10% or more of patients were thrombocytopenia, neutropenia, fatigue, anemia, nausea, back pain, and hypertension.\n\n\nCONCLUSIONS\nThe primary endpoint of significant prolongation of PFS was not met; however, ramucirumab showed evidence of clinical activity in combination with pemetrexed and platinum in nonsquamous NSCLC patients. The addition of ramucirumab to pemetrexed and platinum did not result in new or unexpected safety findings.",
"affiliations": "University of Colorado Anschutz Medical Campus, Aurora, Colorado.",
"authors": "Doebele|Robert C|RC|;Spigel|David|D|;Tehfe|Mustapha|M|;Thomas|Sachdev|S|;Reck|Martin|M|;Verma|Sunil|S|;Eakle|Janice|J|;Bustin|Frederique|F|;Goldschmidt|Jerome|J|;Cao|Dachuang|D|;Alexandris|Ekaterine|E|;Yurasov|Sergey|S|;Camidge|D Ross|DR|;Bonomi|Philip|P|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D016190:Carboplatin; C543333:ramucirumab; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.29132",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "121(6)",
"journal": "Cancer",
"keywords": "non-small cell lung cancer (NSCLC); nonsquamous; pemetrexed; platinum; ramucirumab; vascular endothelial growth factor (VEGF)",
"medline_ta": "Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D002945:Cisplatin; D018572:Disease-Free Survival; D005260:Female; D005971:Glutamates; D006147:Guanine; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000068437:Pemetrexed; D055815:Young Adult",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "883-92",
"pmc": null,
"pmid": "25377507",
"pubdate": "2015-03-15",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase 2, randomized, open-label study of ramucirumab in combination with first-line pemetrexed and platinum chemotherapy in patients with nonsquamous, advanced/metastatic non-small cell lung cancer.",
"title_normalized": "phase 2 randomized open label study of ramucirumab in combination with first line pemetrexed and platinum chemotherapy in patients with nonsquamous advanced metastatic non small cell lung cancer"
} | [
{
"companynumb": "US-PFIZER INC-2011085387",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PEMETREXED"
},
"drugadditional": null,
... |
{
"abstract": "Rare cases of extrapulmonary involvement in Legionella spp. infections have been described, mostly in immunocompromised adults. We report a case of a 2-month old male with reticular dysgenesis variant of severe combined immune deficiency with multiple liver lesions. Core-needle biopsies of one liver lesion demonstrated Gram-negative bacilli and a broad-spectrum polymerase chain reaction assay detected Legionella pneumophila.",
"affiliations": null,
"authors": "Lapidot|Rotem|R|;Alawdah|Laila|L|;Köhler|J R|JR|;Paulson|Vera|V|;Levy|Ofer|O|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000001789",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "37(4)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D001706:Biopsy; D006505:Hepatitis; D006651:Histocytochemistry; D006801:Humans; D007223:Infant; D016952:Legionella pneumophila; D007877:Legionnaires' Disease; D008297:Male; D008853:Microscopy; D016133:Polymerase Chain Reaction; D016511:Severe Combined Immunodeficiency",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "356-358",
"pmc": null,
"pmid": "28938259",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatic Legionella pneumophila Infection in an Infant With Severe Combined Immunodeficiency.",
"title_normalized": "hepatic legionella pneumophila infection in an infant with severe combined immunodeficiency"
} | [
{
"companynumb": "US-BAYER-2018-088208",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "The standard antitubercular treatment (ATT), which consists of isoniazid (INH), rifampicin (RIF), ethambutol, and pyrazinamide (PZA), is the best available treatment for tuberculosis (TB). However, the hepatotoxicity of INH and PZA can be severe, and even after drug withdrawal, patients may require liver transplantation (LT). In these cases, the strategy for the treatment of TB is poorly defined. Between 1986 and 2008, 14 patients presented at our department with severe hepatitis secondary to INH and PZA treatment. Four of these patients were immunosuppressed: 2 after renal transplantation and 2 because of human immunodeficiency virus infection. In seven of the 14 patients an alternative ATT was begun on admission, which was well tolerated. Hepatitis improved spontaneously in 5 patients, and alternative ATT was continued for 9.3 ± 4.2 months; 1 patient deteriorated and underwent LT, and 1 patient died. ATT was stopped definitively in 2 patients. Six patients required urgent LT, and alternative ATT was started after transplantation and was successful. Five patients receiving RIF had an episode of acute rejection. In conclusion, hepatitis secondary to ATT can be successfully treated with alternative anti-TB regimens. The use of RIF in LT patients may lead to acute rejection. RIF should therefore be avoided in these patients.",
"affiliations": "Centre Hépato-BiliaireAP-HP Hôpital Paul Brousse, Villejuif, France. philippe.ichai@pbr.aphp.fr",
"authors": "Ichai|Philippe|P|;Saliba|Faouzi|F|;Antoun|Fadi|F|;Azoulay|Daniel|D|;Sebagh|Mylène|M|;Antonini|Teresa Maria|TM|;Escaut|Lélia|L|;Delvart|Valérie|V|;Castaing|Denis|D|;Samuel|Didier|D|",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid; D012293:Rifampin",
"country": "United States",
"delete": false,
"doi": "10.1002/lt.22125",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-6465",
"issue": "16(10)",
"journal": "Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society",
"keywords": null,
"medline_ta": "Liver Transpl",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents; D056486:Chemical and Drug Induced Liver Injury; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005602:France; D006084:Graft Rejection; D006801:Humans; D007538:Isoniazid; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012075:Remission, Spontaneous; D012293:Rifampin; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014376:Tuberculosis; D055815:Young Adult",
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"publication_types": "D016428:Journal Article",
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"title": "Acute liver failure due to antitubercular therapy: Strategy for antitubercular treatment before and after liver transplantation.",
"title_normalized": "acute liver failure due to antitubercular therapy strategy for antitubercular treatment before and after liver transplantation"
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"abstract": "The usual manifestation of brachial artery aneurysms is the incidental finding of a swelling of the arm, combined with paresthesia or pain in some cases. The etiology is often traumatic or secondary to drug abuse. Pathophysiology of brachial artery dilation in these cases is not completely clear. We herein describe a case of a 61-year-old male presenting with a giant, painful, pulsatile mass on his left arm. He was submitted to a cadaveric kidney transplant in 2005. He had a functioning arteriovenous fistula (AVF) on his right arm, and a spontaneously thrombosed radiocephalic AVF on his left arm. The aneurysm was surgically resected, sparing the median nerve that was totally entrapped and an inverted segment of the basilic vein interposed. At the follow-up, the patient did not present neurological or ischemic disturbs, and the vein graft maintained its patency.",
"affiliations": "Operative Unit of Vascular and Endovascular Surgery, University Federico II of Naples, Naples, Italy.;Operative Unit of Vascular and Endovascular Surgery, University Federico II of Naples, Naples, Italy.;Operative Unit of Vascular and Endovascular Surgery, University Federico II of Naples, Naples, Italy.;Operative Unit of Vascular and Endovascular Surgery, University Federico II of Naples, Naples, Italy.;Operative Unit of Vascular and Endovascular Surgery, University Federico II of Naples, Naples, Italy.;Operative Unit of Vascular and Endovascular Surgery, University Federico II of Naples, Naples, Italy.;Operative Unit of General Surgery, University Federico II of Naples, Naples, Italy.;Operative Unit of General Surgery & Transplants, University Federico II of Naples, Naples, Italy.;Operative Unit of Vascular and Endovascular Surgery, University Federico II of Naples, Naples, Italy.;Operative Unit of Vascular and Endovascular Surgery, University Federico II of Naples, Naples, Italy.",
"authors": "Ferrara|Doriana|D|;Di Filippo|Michele|M|;Spalla|Flavia|F|;Giribono|Anna Maria|AM|;Viviani|Emanuela|E|;Santagata|Annamaria|A|;Bracale|Umberto|U|;Santangelo|Michele|M|;Del Guercio|Luca|L|;Bracale|Umberto Marcello|UM|",
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"fulltext": "\n==== Front\nCase Rep Nephrol DialCase Rep Nephrol DialCNDCase Reports in Nephrology and Dialysis2296-9705S. 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.ch 10.1159/000452299cnd-0006-0128Case ReportGiant true Brachial Artery Aneurysm after Hemodialysis Fistula Closure in a Renal Transplant Patient Ferrara Doriana aDi Filippo Michele aSpalla Flavia aGiribono Anna Maria aViviani Emanuela aSantagata Annamaria aBracale Umberto bSantangelo Michele cdel Guercio Luca aBracale Umberto Marcello a*aOperative Unit of Vascular and Endovascular Surgery, University Federico II of Naples, Naples, ItalybOperative Unit of General Surgery, University Federico II of Naples, Naples, ItalycOperative Unit of General Surgery & Transplants, University Federico II of Naples, Naples, Italy*Umberto Marcello Bracale, MD, Operative Unit of Vascular and Endovascular Surgery, Department of Public Health, University Federico II of Naples, IT–80138 Naples (Italy), E-Mail umbertomarcello.bracale@unina.itSep-Dec 2016 1 11 2016 1 11 2016 6 3 128 132 8 8 2016 7 10 2016 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.The usual manifestation of brachial artery aneurysms is the incidental finding of a swelling of the arm, combined with paresthesia or pain in some cases. The etiology is often traumatic or secondary to drug abuse. Pathophysiology of brachial artery dilation in these cases is not completely clear. We herein describe a case of a 61-year-old male presenting with a giant, painful, pulsatile mass on his left arm. He was submitted to a cadaveric kidney transplant in 2005. He had a functioning arteriovenous fistula (AVF) on his right arm, and a spontaneously thrombosed radiocephalic AVF on his left arm. The aneurysm was surgically resected, sparing the median nerve that was totally entrapped and an inverted segment of the basilic vein interposed. At the follow-up, the patient did not present neurological or ischemic disturbs, and the vein graft maintained its patency.\n\nKeywords\nBrachial arteryAneurysmArteriovenous fistulaDialysisRenal transplantation\n==== Body\nIntroduction\nBrachial artery aneurysm (BAA) is a rare pathological arterial dilation that can lead to severe complications such as thrombosis and thromboembolic events. To date, etiology is not well defined, but one of the observed causes is the presence of a functioning or surgically closed arteriovenous fistula (AVF) for hemodialysis [1]. In this paper, we describe the surgical treatment of a giant BAA on the left arm several years after spontaneous closure of an ipsilateral radiocephalic hemodialysis AVF.\n\nCase Presentation\nA 61-year-old male was admitted to our department complaining of pain and paresthesia in the left upper limb associated with massive swelling. He was a heavy smoker and had a past medical history remarkable for hypertension and bilateral polycystic kidney disease. The patient started hemodialysis in 2003 from a distal radiocephalic AVF on the left arm. After spontaneous fistula thrombosis 1 year later, a new radiocephalic AVF for hemodialysis was created on the right arm. In 2005, he received a successful cadaveric kidney transplant in the right iliac fossa and since then had been administered with immunosuppressive drugs (cyclosporine 20 mg and mycophenolate mofetil 2,000 mg daily) and corticosteroids (methylprednisolone 4 mg daily) to avoid renal rejection. The patient lamented a small swelling of the left arm persisting for 2 years, which in the last 4 months went through an important increase in size, associated with mild paresthetic symptoms.\n\nThe patient's past medical history was negative for injective drug abuse, upper-limb trauma, and brachial artery access for endovascular procedures.\n\nOn physical examination, he had a left arm circumference of 41 cm, compared to the contralateral arm of 26 cm, with a pulsing ovoid swelling on the medial aspect, 3 cm above the medial epicondyle at the level of the armpit (Fig 1).\n\nThe mass resulted tight, pulsatile and incompressible, and painful on palpation along with mild distal edema. Bilaterally, the supraclavicular and axillary lymph nodes were not palpable. The right and left radial and ulnar pulses were both palpable. An ultrasound duplex scan of the left upper-limb arterial system revealed a giant true aneurysm of the brachial artery in presence of parietal thrombosis with turbulent flow seen along the vessel.\n\nThe patient underwent surgical treatment under general anesthesia. He was placed in the supine position with abducted left upper limb. An incision was made over the axilla, and the BAA was isolated with proximal and distal brachial artery control.\n\nThe aneurysm, entrapping the median nerve, was resected, and an interposition reversed basilic vein graft was used to restore the blood flow in the arm (Fig 2). Intraoperative ultrasound duplex scan examination of the vein graft showed patency and good functioning. The limb was warm with good capillary filling, the patient had relief of pain and numbness, and the radial and ulnar arteries were palpable distally. The patient was discharged 2 days after the operation, not presenting local or systemic complications.\n\nHistological findings on the surgical sample submitted to hematoxylin and eosin stain showed atherosclerotic wall degeneration with fibrous and calcific tissue and intraluminal thrombus (Fig 3).\n\nThe 1-month follow-up clinical examination revealed no pain or neurological deficit, but radial and ulnar pulses were still present. An ultrasound duplex scan showed patency of the vein graft.\n\nDiscussion\nBAAs are uncommon [2, 3, 4]; usually, they are caused by trauma, including iatrogenic ones, and drug abuse [5].\n\nThe usual manifestation of BAAs is an accidental finding of a pulsatile, painless, and asymptomatic mass. Complications include thrombosis of the sac, thromboembolic events with ischemia, and disruption causing profuse bleeding [6].\n\nAVFs determine the increase in the brachial and radial artery blood flow rate. Nitric oxide and reactive oxygen species released by the endothelium combine to produce peroxynitrite that upregulates matrix metalloproteinase production. This process results in a damage of the internal elastic lamina of the arterial wall followed by aneurysm formation, even after the AVF closure [1].\n\nLong-term steroid and immunosuppressive therapy has been reported as an accelerating factor of aneurysm development and rupture [7, 8]. Although the natural history of BAA is not well defined, management of complications such as hemorrhage, extremity venous edema, and neurological compression due to aneurysm enlargement is mandatory because of their life-threatening or disabling nature [4]. Duplex scan ultrasonography allows easy BAA detection combining accurate downstream vascularization study. Even though some authors propose digital subtraction angiography as diagnostic of choice, computed tomography angiography can offer detailed information about the extension of the aneurysm and its relationship with adjacent structures such as nerves, as in our case [9].\n\nTherapeutic options for true BAAs include the conservative treatment and either conventional or endovascular repair. As Kordzadeh et al. [10] describe in a recent review of 23 case reports from 1951 to 2014, open surgery is the treatment of choice for BAAs, with a preference of aneurysmectomy with interposition of the vein graft compared to polytetrafluoroethylene, with mean patency rates of 12 versus 6 months.\n\nWhen approaching giant BAAs with open surgery and a direct repair with an end-to-end arterial anastomosis is not feasible, vein grafts are preferred to the implantation of prosthetic material; usually the great saphenous vein is the conduit of choice, followed by the upper-limb veins, as suggested by Chemla et al. [11]. In the case presented, the patient had a moderate chronic venous insufficiency bilaterally, which did not allow using the saphenous vein for the graft. Therefore, the ipsilateral basilic vein was chosen. Only recently, Fendri et al. [12] described a successful case of arterial transposition using a superficial femoral artery to replace a BAA in complete absence of vein conduits for bypass or the possibility to position a prosthetic graft.\n\nAnother reason why the open repair was chosen was the risk of contrast-induced nephropathy. Contrast-induced nephropathy is characterized by the development of acute kidney injury after the administration of intravascular iodinated radiocontrast media, and the incidence ranges from 3 to 30%, depending on the preexisting risk factors, with higher incidence noted in the presence of diabetes mellitus, chronic kidney disease, and older age. The patient presented a mild alteration of the renal function (serum creatinine: 1.3 mg/dL and estimated glomerular filtration rate: 68 mL/min), and therefore an endovascular approach could have been an excessive risk for the patient. For the same reason, no contrast-enhanced computed tomography angiography scan was performed, since the ultrasound duplex scan had been sufficient in achieving preoperative information [13, 14].\n\nAlthough the endovascular techniques are constantly improving and widening their therapeutic possibilities on our experience, an open repair is at the moment the safest and most successful treatment for BAAs after AVFs for hemodialysis.\n\nConclusion\nAlthough BAA is a rare condition, the treatment is mandatory in order to avoid severe complications such as embolic or thrombotic events related to the risk of hand vascularization damaging or neurologic deficits due to nerve entrapment. Hemodynamic alterations in the brachial artery blood stream caused by hemodialysis AVF and its closure seem to be one of the major etiological factors of aneurysm growth. Open surgical repair with aneurysm resection and vein or prosthetic graft substitution offers good results in terms of patency and perioperative morbidity.\n\nStatement of Ethics\nConsent for publication was obtained from the patient.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFig. 1 Preoperative photograph of the patient's left arm.\n\nFig. 2 Intraoperative images showing the isolated brachial artery aneurysm (a) and interposition basilic vein graft after resection (b).\n\nFig. 3 Aneurysm specimen showing calcifications of the arterial wall (black arrow; a) and inflammatory cell infiltration (white arrow) as well as intraluminal thrombosis (black arrow; b).\n==== Refs\nReferences\n1 Basile C Antonelli M Libutti P Teutonico A Casucci F Lomonte C Is there a link between the late occurrence of a brachial artery aneurysm and the ligation of an arteriovenous fistula? Semin Dial 2011 24 341 342 20629969 \n2 Gray RJ Stone WM Fowl RJ Cherry KJ Bower TC Management of true aneurysms distal to the axillary artery J Vasc Surg 1998 28 606 610 9786253 \n3 Tetik O Ozcem B Calli AO Gurbuz A True brachial artery aneurysm Tex Heart Inst J 2010 37 618 619 20978587 \n4 Schunn CD Sullivan TM Brachial arteriomegaly and true aneurysmal degeneration: case report and literature review Vasc Med 2002 7 25 27 12083730 \n5 Hudorović N Lovricević I Brkić P Ahel Z Vicić-Hudorović V Renal replacement therapies after abdominal aortic aneurysm repair – a review Acta Clin Croat 2011 50 403 414 22384777 \n6 Dinoto E Bracale UM Vitale G Cacciatore M Pecoraro F Cassaro L Lo Monte AI Bajardi G Late, giant brachial artery aneurysm following hemodialysis fistula ligation in a renal transplant patient: case report and literature review Gen Thorac Cardiovasc Surg 2012 60 768 770 22627962 \n7 Sato O Atsuhiko T Tetsuro M Takayama Y Aortic aneurysm in patients with autoimmune disorders treated with corticosteroids Eur J Vasc Endovasc Surg 1995 10 366 369 7552541 \n8 Reilly JM Savage EB Brophy CM Tilson MD Hydrocortisone rapidly induces aortic rupture in a genetically susceptible mouse Arch Surg 1990 125 707 709 2346371 \n9 Yetkin U Gurbuz A Post-traumatic pseudoaneurysm of the brachial artery and its surgical treatment Tex Heart Inst J 2003 30 293 297 14677739 \n10 Kordzadeh A D'Espiney BRM Ahmad AS Hanif MA Panayiotopoulos YP Donor artery aneurysm formation following the ligation of haemodialysis arteriovenous fistula: a systematic review and case reports J Vasc Access 2015 16 5 12 25198824 \n11 Chemla E Nortley M Morsy M Brachial artery aneurysms associated with arteriovenous access for hemodyalisis Semin Dial 2010 23 440 444 20701723 \n12 Fendri J Palcau L Camelierie L Coffin O Felisaz A Gouicem D Dufranc J Laneelle D Berger L True brachial artery aneurysm after arteriovenous fistula for hemodyalisis: five cases and literature review Ann Vasc Surg 2016 Epub ahead of print \n13 Caruso M Balasus F Incalcaterra E Ruggieri A Evola S Fattouch K Bracale UM Amodio E Novo G Andolina G Novo S Contrast-induced nephropathy after percutaneous coronary intervention in simple lesions: risk factors and incidence are affected by the definition utilized Intern Med 2011 50 983 989 21532220 \n14 Haider M Yessayan L Venkat KK Goggins M Patel A Karthikeyan V Incidence of contrast-induced nephropathy in kidney transplant recipients Transplant Proc 2015 47 379 383 25769577\n\n",
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"issue": "6(3)",
"journal": "Case reports in nephrology and dialysis",
"keywords": "Aneurysm; Arteriovenous fistula; Brachial artery; Dialysis; Renal transplantation",
"medline_ta": "Case Rep Nephrol Dial",
"mesh_terms": null,
"nlm_unique_id": "101636294",
"other_id": null,
"pages": "128-132",
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"pmid": "27904865",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
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"title": "Giant true Brachial Artery Aneurysm after Hemodialysis Fistula Closure in a Renal Transplant Patient.",
"title_normalized": "giant true brachial artery aneurysm after hemodialysis fistula closure in a renal transplant patient"
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"abstract": "OBJECTIVE\nZolpidem, a nonbenzodiazepine hypnotic, is very effective and widely prescribed in clinical practice for the treatment of insomnia and is thought to have few adverse effects. However, zolpidem-induced adverse effects have begun to be reported in the literature, but few systemic descriptions of the adverse effects (especially for psychotic reactions) of zolpidem have been undertaken. In light of the accumulating reports of adverse reactions to zolpidem, we present 2 case reports of zolpidem-induced adverse effects and review the literature on this subject.\n\n\nMETHODS\nArticles were selected by the authors on the basis of our experience and by a PubMed search using the terms zolpidem or side effects or adverse effects or adverse reactions.\n\n\nMETHODS\nPublications relevant to the objective of this article were obtained (1992-2010), and some adverse neuropsychiatric reactions were summarized.\n\n\nRESULTS\nZolpidem has been associated with the development of adverse neuropsychiatric reactions, such as hallucinations/sensory distortion, amnesia, sleepwalking/somnambulism, and nocturnal eating. The following 4 variables should be considered when prescribing zolpidem: (1) gender: women have been found to have a significantly higher serum zolpidem concentration than men; (2) zolpidem dose: the adverse reactions that develop are dose dependent; (3) protein binding affinity: a high proportion of zolpidem is protein bound; therefore, low serum albumin results in a higher level of free zolpidem leading to adverse psychiatric reactions; and (4) cytochrome P450 (CYP) isoenzyme inhibition: concomitant administration of zolpidem and other drugs may cause interactions that lead to increased concentrations of zolpidem.\n\n\nCONCLUSIONS\nZolpidem is clinically very effective in treating insomnia. However, while rare, zolpidem-induced unusual complex behavior may develop. Primary care physicians should be alert to the possible unusual complex adverse effects of zolpidem.",
"affiliations": "Department of Psychology and Special Support Education, Shimane University, Shimane, Japan. inagaki@edu.shimane-u.ac.jp",
"authors": "Inagaki|Takuji|T|;Miyaoka|Tsuyoshi|T|;Tsuji|Seiichi|S|;Inami|Yasushi|Y|;Nishida|Akira|A|;Horiguchi|Jun|J|",
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"title": "Adverse reactions to zolpidem: case reports and a review of the literature.",
"title_normalized": "adverse reactions to zolpidem case reports and a review of the literature"
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"abstract": "Atezolizumab successfully reinvigorated JC virus immunity in a patient in Belgium with progressive multifocal leukoencephalopathy, as demonstrated by clinical, virologic, and radiologic response to treatment. However, the treatment also resulted in immune reconstitution inflammatory syndrome and life-threatening immune-related adverse events. These conditions were treated with corticosteroids, leading to treatment resistance.",
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"authors": "Lambert|Nicolas|N|;Dauby|Solène|S|;Dive|Dominique|D|;Sadzot|Bernard|B|;Maquet|Pierre|P|",
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"doi": "10.3201/eid2801.204809",
"fulltext": "\n==== Front\nEmerg Infect Dis\nEmerg Infect Dis\nEID\nEmerging Infectious Diseases\n1080-6040\n1080-6059\nCenters for Disease Control and Prevention\n\n34856110\n20-4809\n10.3201/eid2801.204809\nResearch Letter\nResearch Letter\nAtezolizumab Treatment for Progressive Multifocal Leukoencephalopathy\nAtezolizumab Treatment for Progressive Multifocal Leukoencephalopathy\nAtezolizumab Treatment for Progressive Multifocal Leukoencephalopathy\nLambert Nicolas\nDauby Solène\nDive Dominique\nSadzot Bernard\nMaquet Pierre\nUniversity Hospital of Liège, Liège, Belgium\nAddress for correspondence: Nicolas Lambert, Service de Neurologie, CHU de Liège, Avenue de l’Hopital, 1, 4000, Liège, Belgium; email: nicolas.lambert@chuliege.be\n1 2022\n28 1 253256\n2022\nhttps://creativecommons.org/licenses/by/4.0/ Emerging Infectious Diseases is a publication of the U.S. Government. This publication is in the public domain and is therefore without copyright. All text from this work may be reprinted freely. Use of these materials should be properly cited.\nAtezolizumab successfully reinvigorated JC virus immunity in a patient in Belgium with progressive multifocal leukoencephalopathy, as demonstrated by clinical, virologic, and radiologic response to treatment. However, the treatment also resulted in immune reconstitution inflammatory syndrome and life-threatening immune-related adverse events. These conditions were treated with corticosteroids, leading to treatment resistance.\n\nKeywords:\n\nprogressive multifocal leukoencephalopathy\nimmunotherapy\nJC virus\nimmune reconstitution inflammatory syndrome\nBelgium\nviruses\natezolizumab\n==== Body\npmcProgressive multifocal leukoencephalopathy (PML) is a devastating infectious disease of the brain that is caused by JC virus (JCV) in the context of cellular immunodeficiency. To date, no effective antiviral treatment for PML exists, and survival depends on the person’s ability to achieve timely immune reconstitution. Otherwise, the prognosis is particularly grim; the mortality rate is 90% for hematologic malignancy–associated PML (1). Immune checkpoints are costimulatory and coinhibitory molecules usually expressed on the surface of immune cells and modulating their activation. Several authors have reported successful PML treatment using immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD1), but whether ICIs targeting other proteins such as programmed death-ligand 1 (PD-L) could also treat PML is unknown (2).\n\nA 77-year-old woman living in Belgium and with medical history of asymptomatic interstitial lung disease and B-cell chronic lymphocytic leukemia treated with chlorambucil and obinutuzumab was admitted for aphasia, cerebellar ataxia, and cognitive decline that had progressed over 3 months. Complete blood count and flow cytometry revealed lymphopenia affecting all lymphocyte subsets (280 CD4+ cells/μL, 80 CD8+ cells/μL, 30 CD19+ cells/μL). Brain magnetic resonance imaging (MRI) showed T2-weighted hyperintense, nonenhancing, multifocal white matter lesions (Appendix Figure 1). Analysis of cerebrospinal fluid (CSF) revealed 733,845 JCV copies/mL, which enabled a definite diagnosis of PML (3). To treat PML, we administered atezolizumab, an anti–PD-L1 humanized monoclonal antibody, at 1,200 mg every 3 weeks. Clinical follow-up consisted of daily physical and neurologic examinations. To monitor immune exhaustion, we performed immunophenotyping on blood specimens by using multicolor flow cytometry the day before and 5 weeks after treatment initiation.\n\nOne week after treatment initiation, we noted improvement of aphasia and cognitive function. The next week, the patient experienced abdominal pain, psoriasis-like skin lesions, an episode of transient third-degree atrioventricular block, and a right hemicorporeal clonic seizure, after which mental status was persistently altered. JCV load in the CSF was considerably reduced to 945 copies/mL (Figure). Brain MRI showed progression of lesions visualized on T2 and fluid-attenuated inversion recovery sequences and an increased apparent diffusion coefficient signal, compatible with vasogenic edema (Appendix Figure 1). Despite the absence of classical immune reconstitution inflammatory syndrome (IRIS) features, including gadolinium enhancement, we considered these radiologic characteristics, together with a paradoxical clinical deterioration in viral clearance, to be markers of immune reconstitution. Suspecting IRIS and skin, cardiac, and enteral immune-related adverse events (IRAEs), we administrated intravenous methylprednisolone (1 g/d for 10 d), followed by oral taper over 6 weeks. This regimen resulted in a substantial improvement of her mental status, decrease of the edema seen on brain MRI, and resolution of all other systemic complications. However, 3 weeks after corticosteroid initiation, the patient demonstrated progressive decrease of alertness, new rise of viral load in the CSF, and expansion of PML lesions as shown on brain MRI (Figure). She died of aspiration pneumonia 3 weeks later.\n\nFigure Clinical course and evolution of JC virus load in CSF of 77-year-old patient undergoing atezolizumab therapy for progressive multifocal leukoencephalopathy. CSF, cerebrospinal fluid; IRAEs, immune-related adverse events; JCV, JC virus.\n\nIn parallel, atezolizumab treatment was associated with a decrease in detection of PD1 on CD8+ T cells in peripheral blood, but its expression on CD4+ cells remained unchanged (Appendix Figure 2). We observed no substantial change in CD3+, CD4+, and CD8+ cell counts after treatment.\n\nIn this case, atezolizumab successfully counteracted immune exhaustion to reinvigorate JCV immunity as reflected by several elements: the initial clinical improvement, the reduction of PD1 expression on blood CD8+ T cells, the marked JCV load reduction in CSF, and the development of a clinical IRIS. However, the clinical IRIS and the severe life-threatening IRAEs required administration of high-dose corticosteroids. Because corticosteroids impair JCV-specific T-cell response and mitigate beneficial ICIs effects (4,5), methylprednisolone likely resulted in treatment resistance, which led to PML progression and, ultimately, death.\n\nEvidence is growing that immune exhaustion, and notably the PD1 pathway, is involved in PML pathophysiology (6). PD1-expressing lymphocytes colocalize with PD-L1+ macrophages in PML lesions, thereby indicating they might function as T-cell partners in immune exhaustion (7). Considering the history of interstitial lung disease in our patient, we chose to target PD-L1 to leave intact the interaction between PD1 and its alternative ligand, PD-L2, which had the theoretical benefit of promoting self-tolerance in the lungs, where the PD1/PDL-2 pathway plays a role in regulating inflammation (8). Accordingly, despite a striking systemic inflammatory response, our patient did not experience pulmonary IRAE.\n\nTreating PML with ICIs targeting proteins other than PD1 opens the way to a new therapeutic strategy: reinvigorating JCV immunity by using combinations of ICIs. In cancer therapy, compensatory upregulation of alternative immune checkpoints is 1 of the mechanisms of ICI resistance, and PD1/PD-L1 pathway blockade is already combined with inhibition of cytotoxic T lymphocyte antigen 4 to treat metastatic melanoma. Moreover, novel ICIs are being developed, and their combination with current ICIs is already considered a possibility (9). Because upregulation of alternative immune checkpoints has been observed in unsuccessful PML treatment with anti-PD1 antibodies (10), patients with PML might also benefit from these promising synergic therapeutic combinations.\n\nAppendix\n\nAdditional information about atezolizumab treatment for progressive multifocal leukoencephalopathy\n\nAcknowledgments\n\nWe thank the patient’s family for their understanding and support.\n\nWe thank Majdouline El Moussaoui (Department of Infectious Diseases, University Hospital of Liège, Belgium) for providing general advice and review of the manuscript. We also thank Andrée Rorive and Pierre Freres (Department of Oncology, University Hospital of Liège, Belgium) for their help for the patient care. Finally, we thank Joseph Jorssen and Christophe Desmet (Laboratory of Cellular and Molecular Immunology, GIGA Institute, Liège University, Belgium) for technical support.\n\nAtezolizumab was supplied by Roche (https://www.roche.com) on a compassionate use basis. S.D. received travel grants from Merck and Sanofi. D.D. received travel grants and institutional payments for participation in advisory boards and meetings from Bayer, Biogen, Merck, Celgene, Novartis, Sanofi, Teva, and Roche.\n\nDr. Lambert is a resident medical doctor in the Department of Neurology at the University Hospital of Liège. He specializes in neuroinfectious and neuroinflammatory diseases.\n\nSuggested citation for this article: Lambert N, Dauby S, Dive D, Sadzot B, Maquet P. Atezolizumab treatment for progressive multifocal leukoencephalopathy. Emerg Infect Dis. 2022 Jan [date cited]. https://doi.org/10.3201/eid2801.204809\n==== Refs\nReferences\n\n1. Cortese I, Reich DS, Nath A. Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease. Nat Rev Neurol. 2021;17 :37–51. 10.1038/s41582-020-00427-y 33219338\n2. Beck ES, Cortese I. Checkpoint inhibitors for the treatment of JC virus-related progressive multifocal leukoencephalopathy. Curr Opin Virol. 2020;40 :19–27. 10.1016/j.coviro.2020.02.005 32279025\n3. Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ, Sejvar JJ, et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology. 2013;80 :1430–8. 10.1212/WNL.0b013e31828c2fa1 23568998\n4. Antoniol C, Jilek S, Schluep M, Mercier N, Canales M, Le Goff G, et al. Impairment of JCV-specific T-cell response by corticotherapy: effect on PML-IRIS management? Neurology. 2012;79 :2258–64. 10.1212/WNL.0b013e3182768983 23175722\n5. Tokunaga A, Sugiyama D, Maeda Y, Warner AB, Panageas KS, Ito S, et al. Selective inhibition of low-affinity memory CD8+ T cells by corticosteroids. J Exp Med. 2019;216 :2701–13. 10.1084/jem.20190738 31537643\n6. Tan CS, Bord E, Broge TA Jr, Glotzbecker B, Mills H, Gheuens S, et al. Increased program cell death-1 expression on T lymphocytes of patients with progressive multifocal leukoencephalopathy. J Acquir Immune Defic Syndr. 2012;60 :244–8. 10.1097/QAI.0b013e31825a313c 22549384\n7. Audemard-Verger A, Gasnault J, Faisant M, Besse MC, Martin-Silva N, Berra M, et al. Sustained response and rationale of programmed cell death-1-targeting for progressive multifocal leukoencephalopathy. Open Forum Infect Dis. 2019;6 :ofz374. 10.1093/ofid/ofz374 31660340\n8. Akbari O, Stock P, Singh AK, Lombardi V, Lee WL, Freeman GJ, et al. PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions. Mucosal Immunol. 2010;3 :81–91. 10.1038/mi.2009.112 19741598\n9. Kon E, Benhar I. Immune checkpoint inhibitor combinations: Current efforts and important aspects for success. Drug Resist Updat. 2019;45 :13–29. 10.1016/j.drup.2019.07.004 31382144\n10. Medrano C, Vergez F, Mengelle C, Faguer S, Kamar N, Del Bello A. Effectiveness of immune checkpoint inhibitors in transplant recipients with progressive multifocal leukoencephalopathy. Emerg Infect Dis. 2019;25 :2145–7. 10.3201/eid2511.190705 31625858\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1080-6040",
"issue": "28(1)",
"journal": "Emerging infectious diseases",
"keywords": "Belgium; JC virus; atezolizumab; immune reconstitution inflammatory syndrome; immunotherapy; progressive multifocal leukoencephalopathy; viruses",
"medline_ta": "Emerg Infect Dis",
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"nlm_unique_id": "9508155",
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"pubdate": "2021-12-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Atezolizumab Treatment for Progressive Multifocal Leukoencephalopathy.",
"title_normalized": "atezolizumab treatment for progressive multifocal leukoencephalopathy"
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"abstract": "Pulmonary Arterial Hypertension (PAH) and cancer share growth factor and protein kinase signaling pathways that result in smooth muscle cell proliferation and vasculopathy. There is little known about the impact of Lapatinib on the pulmonary vasculature. After reporting a case of Lapatinib-induced PAH we investigated the association of Lapatinib with the development of PAH in our institution.\n\n\n\nWe reviewed charts for all patients treated with Lapatinib at our institution between 2008 and 2013. Patients who had undergone 2D-echocardiogram both prior to and after treatment were included in the analysis. Increase in Pulmonary artery systolic pressure (PASP) was assessed. Patients were also evaluated in terms of risk factors for non-Group 1 PAH.\n\n\n\nA total of 27 patients were found to have 2-D echo done before and after starting treatment with Lapatinib. Six patients were found to have significant increase in their PASP after starting treatment. Right heart catheterization before and after stopping the medication was available in three patient, confirming the diagnosis of PAH with complete resolution after stopping the medication. The median pre-treatment and post treatment PASP in those 6 patients was 29 mmHg and 65.5 mmHg respectively (N = 6; p = 0.027).\n\n\n\nLapatinib might be associated with the development of PAH. PASP should be evaluated in patients who become short of breath while on treatment, and stopping the drug in cases where no other reasons are identified could be associated with reversibility of the elevated pulmonary artery pressure.",
"affiliations": "Division of Hematology/Oncology, Henry Ford Hospital/Wayne State University, USA. Electronic address: Yalkhat1@hfhs.org.;Division of Cardiology, Tulane University, USA.;Division of Pulmonary and Critical Care, Deaconess Health System, USA.;Division of Pulmonary and Critical Care, Henry Ford Hospital/Wayne State University, USA.",
"authors": "Alkhatib|Yaser|Y|;Albashaireh|Derar|D|;Al-Aqtash|Tameem|T|;Awdish|Rana|R|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077341:Lapatinib",
"country": "England",
"delete": false,
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"issn_linking": "1094-5539",
"issue": "37()",
"journal": "Pulmonary pharmacology & therapeutics",
"keywords": "Lapatinib; Pulmonary hypertension; Tyrosine kinase inhibitors",
"medline_ta": "Pulm Pharmacol Ther",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D006328:Cardiac Catheterization; D004452:Echocardiography; D006801:Humans; D006976:Hypertension, Pulmonary; D000077341:Lapatinib; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "9715279",
"other_id": null,
"pages": "81-4",
"pmc": null,
"pmid": "26965087",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The role of tyrosine kinase inhibitor \"Lapatinib\" in pulmonary hypertension.",
"title_normalized": "the role of tyrosine kinase inhibitor lapatinib in pulmonary hypertension"
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"abstract": "The treatment of depression during pregnancy can be challenging for patients and providers alike. An increasing attention to perinatal mood disorders has led to an expanding literature that is often difficult for providers to navigate. It can be a challenge for providers to feel comfortable reviewing the broad scope of the risks and benefits of treatments in the context of the limitations of the literature. Women who are depressed during pregnancy have been found to have an elevated risk of poor obstetrical outcomes, although studies of the relationship between depression and outcomes are limited. Women who are treated with antidepressants during pregnancy are also at risk for a host of poor obstetrical and fetal outcomes. The risks for these outcomes are often confused by confounding factors and study design limitations. Understanding the current data and their limitations will allow providers to guide their patients in choosing treatment options. Consistent and simple strategies should be used when discussing the risk-benefit analysis with the patient.",
"affiliations": "Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, NY USA. linda_chaudron@urmc.rochester.edu",
"authors": "Chaudron|Linda H|LH|",
"chemical_list": "D000928:Antidepressive Agents; D020280:Sertraline",
"country": "United States",
"delete": false,
"doi": "10.1176/appi.ajp.2012.12040440",
"fulltext": null,
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"issn_linking": "0002-953X",
"issue": "170(1)",
"journal": "The American journal of psychiatry",
"keywords": null,
"medline_ta": "Am J Psychiatry",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000928:Antidepressive Agents; D003131:Combined Modality Therapy; D003866:Depressive Disorder; D003865:Depressive Disorder, Major; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011613:Psychotherapy; D012008:Recurrence; D018570:Risk Assessment; D020280:Sertraline",
"nlm_unique_id": "0370512",
"other_id": null,
"pages": "12-20",
"pmc": null,
"pmid": "23288385",
"pubdate": "2013-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Complex challenges in treating depression during pregnancy.",
"title_normalized": "complex challenges in treating depression during pregnancy"
} | [
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"companynumb": "US-CIPLA LTD.-2016US04742",
"fulfillexpeditecriteria": "1",
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"abstract": "The aim of the study was to identify practices of gastroenterologists screening for adrenal insufficiency (AI) and report prevalence of AI in children with eosinophilic esophagitis (EoE) treated with topical corticosteroids (TCS); compare serum dehydroepiandrosterone sulfate (DHEA-S) levels to morning serum cortisol (MSC) levels as screening tool for AI.\n\n\n\nA multipart study was conducted. In part 1, a survey about screening practices for AI in children with EoE on TCS was sent to gastroenterologists belonging to a PedsGI listserv and to EoE consortia. In part 2, children with EoE on TCS for ≥6 months were prospectively screened for AI with MSC levels. For subjects with a MSC level of <10 μg/dL, a repeat MSC level and/or confirmatory adrenocorticotropic hormone (ACTH) stimulation testing was offered. AI was defined by peak serum cortisol level <18 μg/dL. In part 3, DHEA-S levels were drawn with MSC levels.\n\n\n\nSeven percent (16/238) of gastroenterologists screened for AI. Providers in EoE consortia were more likely to screen than nonconsortia providers [9/21(43%) vs 7/217(3%); P = 0.0001]. Thirty-seven children were prospectively screened for AI, and 51% (19/37) had a low MSC level. Ten patients had a low-dose ACTH stimulation test (LDST) after 1 or more low MSC levels. Five percent (2/37) of patients were diagnosed with AI. DHEA-S and MSC levels had a moderate correlation (rs = 0.44, P = 0.03).\n\n\n\nGastroenterologists belonging to EoE consortia were more likely to screen for AI. Prevalence of AI in our prospective cohort was 5%. DHEA-S has a moderate correlation with MSC levels, but more data is required to assess utility as a screening tool for AI.",
"affiliations": "Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Indiana University School of Medicine/Riley Hospital for Children Indianapolis, IN.;Department of Pediatric Gastroenterology- Digestive Health, Ascension St. John Hospital and Medical Center, Detroit, MI.;Division of Pediatric Endocrinology and Diabetology, Department of Pediatrics, Indiana University School of Medicine/Riley Hospital for Children Indianapolis, IN.;Indiana University Department of Statistics Bloomington, IN (at the time of her contribution), Cook Research, Inc., West Lafayette, IN (current).;Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Indiana University School of Medicine/Riley Hospital for Children Indianapolis, IN.;Department of Pediatric Allergy and Immunology, Gastrointestinal Eosinophilic Diseases Program, University of Colorado School of Medicine/Children's Hospital Colorado Aurora, CO.;Department of Pediatric Gastroenterology, Hepatology, and Nutrition/Digestive Health Institute, Gastrointestinal Eosinophilic Diseases Program, University of Colorado School of Medicine/Children's Hospital Colorado, Aurora, CO.;Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Illinois College of Medicine/Children's Hospital of Illinois, Peoria, IL.",
"authors": "Bose|Paroma|P|;Kumar|Sanjay|S|;Nebesio|Todd D|TD|;Li|Chuwen|C|;Hon|Emily C|EC|;Atkins|Dan|D|;Furuta|Glenn T|GT|;Gupta|Sandeep K|SK|",
"chemical_list": "D019314:Dehydroepiandrosterone Sulfate; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone",
"country": "United States",
"delete": false,
"doi": "10.1097/MPG.0000000000002537",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-2116",
"issue": "70(3)",
"journal": "Journal of pediatric gastroenterology and nutrition",
"keywords": null,
"medline_ta": "J Pediatr Gastroenterol Nutr",
"mesh_terms": "D000309:Adrenal Insufficiency; D000324:Adrenocorticotropic Hormone; D002648:Child; D019314:Dehydroepiandrosterone Sulfate; D057765:Eosinophilic Esophagitis; D006801:Humans; D006854:Hydrocortisone; D011446:Prospective Studies",
"nlm_unique_id": "8211545",
"other_id": null,
"pages": "324-329",
"pmc": null,
"pmid": "31688699",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Adrenal Insufficiency in Children With Eosinophilic Esophagitis Treated With Topical Corticosteroids.",
"title_normalized": "adrenal insufficiency in children with eosinophilic esophagitis treated with topical corticosteroids"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP026250",
"fulfillexpeditecriteria": "2",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditio... |
{
"abstract": "OBJECTIVE\nTo report a case of an adolescent with autism with clinically significant hypersexual behaviors in whom a trial of low-dose propranolol led to major clinical improvement.\n\n\nMETHODS\nThis case report describes a 13-year-old boy with a history of autism who presented to the outpatient psychiatric clinic for hypersexual behaviors that started at the onset of puberty. The behaviors affected his functioning both at school and home. A trial of low-dose propranolol, 0.3 mg/kg/d (10 mg twice a day), targeting hypersexual behavior led to remarkable clinical improvement. The behaviors remained stable on this dose of propranolol for 1 year.\n\n\nCONCLUSIONS\nHypersexual behavior exhibited by adolescent patients with autism can be a big challenge to manage. The literature on pharmacological options to manage these behaviors in children and adolescents with autism is limited. Clinical data of propranolol use are novel.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first case report of low-dose propranolol leading to clinically significant improvement in hypersexual behaviors in an adolescent with autism. Propranolol use may expand the choice of treatment option in this patient population.",
"affiliations": "University of Arkansas for Medical Sciences, Little Rock, AR, USA ddeepmala@uams.edu.;University of Arkansas for Medical Sciences, Little Rock, AR, USA.",
"authors": "Deepmala|||;Agrawal|Mayank|M|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D013565:Sympatholytics; D011433:Propranolol",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028014541630",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "48(10)",
"journal": "The Annals of pharmacotherapy",
"keywords": "adolescent; autism; hypersexual behaviors; propranolol",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000293:Adolescent; D000319:Adrenergic beta-Antagonists; D001321:Autistic Disorder; D006801:Humans; D008297:Male; D011433:Propranolol; D012725:Sexual Behavior; D020018:Sexual Dysfunctions, Psychological; D013565:Sympatholytics",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1385-8",
"pmc": null,
"pmid": "24965689",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of propranolol for hypersexual behavior in an adolescent with autism.",
"title_normalized": "use of propranolol for hypersexual behavior in an adolescent with autism"
} | [
{
"companynumb": "US-ROXANE LABORATORIES, INC.-2014-RO-01662RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
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{
"abstract": "Introduction: We performed a chart review study in our castration-resistant prostate cancer (CRPC) patients who received Abiraterone acetate (AA) treatment after docetaxel and identified clinical markers which can predict treatment outcome. Materials and Methods: From 2012 to 2016, 64 patients who received docetaxel after CRPC followed by AA treatment were included. Clinical parameters were recorded and analysis was performed to identify associations between pre-treatment variables and treatment outcome. Results: Thirty three patients (51.6%) achieved a decrease in PSA of 50%. The median PSA progression-free survival and overall survival in the total cohort of 64 patients were 6.6 and 24 months, respectively. Adverse events (AEs) in all grades developed in 35.9% (23/64) patients and mostly were grade 1 or 2. The most common AEs were gastric upset, hypokalemia and elevated liver function tests. Of the eight variables analyzed, first line androgen deprivation therapy (ADT) duration showed positive association to progression free survival (HR 0.98, 95% CI [0.96-0.99], p = 0.012) and overall survival (HR 0.97, 95% CI [0.94-0.99], p = 0.019). Pre-AA PSA and PSA progression ratio showed negative association only to progression free survival (HR 1.0, 95% CI [1.000-1.002], p = 0.025, HR 1.01, 95% CI [1.00-1.01], p < 0.001, respectively). Conclusion: First line ADT duration was positively associated with AA treatment efficacy in progression free survival and overall survival. It can be used as a pre-treatment predictor.",
"affiliations": "Division of Urology, Department of Surgery, Taichung Veterans General HospitalTaichung, Taiwan; Institute of Medicine, Chung Shan Medical UniversityTaichung, Taiwan; Department of Medicine and Nursing, Hungkuang UniversityTaichung, Taiwan.;Division of Urology, Department of Surgery, Taichung Veterans General HospitalTaichung, Taiwan; Institute of Medicine, Chung Shan Medical UniversityTaichung, Taiwan; Department of Applied Chemistry, National Chi Nan UniversityNantou, Taiwan.;Division of Urology, Department of Surgery, Taichung Veterans General Hospital Taichung, Taiwan.;Division of Urology, Department of Surgery, Taichung Veterans General HospitalTaichung, Taiwan; Institute of Medicine, Chung Shan Medical UniversityTaichung, Taiwan.;Division of Urology, Department of Surgery, Taichung Veterans General Hospital Taichung, Taiwan.;Division of Urology, Department of Surgery, Taichung Veterans General HospitalTaichung, Taiwan; Department of Applied Chemistry, National Chi Nan UniversityNantou, Taiwan.;Division of Urology, Department of Surgery, Taichung Veterans General Hospital Taichung, Taiwan.;Division of Urology, Department of Surgery, Taichung Veterans General HospitalTaichung, Taiwan; Institute of Medicine, Chung Shan Medical UniversityTaichung, Taiwan.;Department of Urology, China Medical University Hospital Taichung, Taiwan.;Division of Urology, Department of Surgery, Taichung Veterans General Hospital Taichung, Taiwan.;Division of Urology, Department of Surgery, Taichung Veterans General Hospital Taichung, Taiwan.;Division of Urology, Department of Surgery, Taichung Veterans General Hospital Taichung, Taiwan.;Division of Urology, Department of Surgery, Taichung Veterans General HospitalTaichung, Taiwan; Institute of Medicine, Chung Shan Medical UniversityTaichung, Taiwan; Department of Medical Research, Taichung Veterans General HospitalTaichung, Taiwan.",
"authors": "Li|Jian-Ri|JR|;Wang|Shian-Shiang|SS|;Yang|Cheng-Kuang|CK|;Chen|Chuan-Su|CS|;Ho|Hao-Chung|HC|;Chiu|Kun-Yuan|KY|;Hung|Chi-Feng|CF|;Cheng|Chen-Li|CL|;Yang|Chi-Rei|CR|;Chen|Cheng-Che|CC|;Wang|Shu-Chi|SC|;Lin|Chia-Yen|CY|;Ou|Yen-Chuan|YC|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fphar.2017.00055",
"fulltext": "\n==== Front\nFront PharmacolFront PharmacolFront. Pharmacol.Frontiers in Pharmacology1663-9812Frontiers Media S.A. 10.3389/fphar.2017.00055PharmacologyOriginal ResearchFirst Line Androgen Deprivation Therapy Duration Is Associated with the Efficacy of Abiraterone Acetate Treated Metastatic Castration-Resistant Prostate Cancer after Docetaxel Li Jian-Ri 123Wang Shian-Shiang 124Yang Cheng-Kuang 1Chen Chuan-Su 12Ho Hao-Chung 1Chiu Kun-Yuan 14Hung Chi-Feng 1Cheng Chen-Li 12Yang Chi-Rei 5Chen Cheng-Che 1Wang Shu-Chi 1Lin Chia-Yen 1Ou Yen-Chuan 126*1Division of Urology, Department of Surgery, Taichung Veterans General HospitalTaichung, Taiwan2Institute of Medicine, Chung Shan Medical UniversityTaichung, Taiwan3Department of Medicine and Nursing, Hungkuang UniversityTaichung, Taiwan4Department of Applied Chemistry, National Chi Nan UniversityNantou, Taiwan5Department of Urology, China Medical University HospitalTaichung, Taiwan6Department of Medical Research, Taichung Veterans General HospitalTaichung, TaiwanEdited by: Jean-Paul Deslypere, Proclin Therapeutic Research Pte Ltd, Singapore\n\nReviewed by: Amit D. Raval, Healthcore, Inc., USA; Chao Zhu, Eli Lilly and Company, China\n\n*Correspondence: Yen-Chuan Ou, ycou@vghtc.gov.twThis article was submitted to Pharmaceutical Medicine and Outcomes Research, a section of the journal Frontiers in Pharmacology\n\n13 2 2017 2017 8 5513 7 2016 25 1 2017 Copyright © 2017 Li, Wang, Yang, Chen, Ho, Chiu, Hung, Cheng, Yang, Chen, Wang, Lin and Ou.2017Li, Wang, Yang, Chen, Ho, Chiu, Hung, Cheng, Yang, Chen, Wang, Lin and OuThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Introduction: We performed a chart review study in our castration-resistant prostate cancer (CRPC) patients who received Abiraterone acetate (AA) treatment after docetaxel and identified clinical markers which can predict treatment outcome.\n\nMaterials and Methods: From 2012 to 2016, 64 patients who received docetaxel after CRPC followed by AA treatment were included. Clinical parameters were recorded and analysis was performed to identify associations between pre-treatment variables and treatment outcome.\n\nResults: Thirty three patients (51.6%) achieved a decrease in PSA of 50%. The median PSA progression-free survival and overall survival in the total cohort of 64 patients were 6.6 and 24 months, respectively. Adverse events (AEs) in all grades developed in 35.9% (23/64) patients and mostly were grade 1 or 2. The most common AEs were gastric upset, hypokalemia and elevated liver function tests. Of the eight variables analyzed, first line androgen deprivation therapy (ADT) duration showed positive association to progression free survival (HR 0.98, 95% CI [0.96–0.99], p = 0.012) and overall survival (HR 0.97, 95% CI [0.94–0.99], p = 0.019). Pre-AA PSA and PSA progression ratio showed negative association only to progression free survival (HR 1.0, 95% CI [1.000–1.002], p = 0.025, HR 1.01, 95% CI [1.00–1.01], p < 0.001, respectively).\n\nConclusion: First line ADT duration was positively associated with AA treatment efficacy in progression free survival and overall survival. It can be used as a pre-treatment predictor.\n\nabiraterone acetateandrogen deprivation therapycastration-resistant prostate cancerdocetaxelPSA\n==== Body\nIntroduction\nAbiraterone acetate (AA) has been shown to be effective in prolonging progression-free survival and overall survival in metastatic castration-resistant prostate cancer (MCRPC) after docetaxel chemotherapy (de Bono et al., 2011). Although the recent COU-AA-302 (Cougar Biotechnology, AA) study showed a clinical benefit of AA in a chemo-naïve setting, it still have more clinical applications using the post-chemotherapy model for advanced prostate cancer patients in Asian countries. In the subgroup analysis of the COU-AA-301 trial, AA showed an equivalent efficacy in the Asian group compared with data from Western countries with progression-free survival (Fizazi et al., 2012; Kwak et al., 2014). Various parameters were used for prediction of patient outcome during AA treatment, but still controversial (Azad et al., 2015; Houede et al., 2015; Xu et al., 2015; Bellmunt et al., 2016; Chi et al., 2016; Facchini et al., 2016; Rescigno et al., 2016). Herein, we conducted a clinical investigation of AA in CRPC patients after chemotherapy and validated several clinical factors correlated with progression-free survival and overall survival before AA treatment.\n\nMaterials and Methods\nPatients\nThis was a retrospective chart-review study which analyzed metastatic castration prostate cancer patients after chemotherapy using AA between 2012 and 2016. Of the 71 consecutive patients, 7 were excluded because of incomplete data or loss of follow-up and were also excluded. All included patients received informed consent before treatment according to the certification of the institute review board of Taichung Veterans General Hospital, number CE13240A-2. The rest 64 patients all had bone metastases and were included in this analysis. All patients received AA 1000 mg with prednisolone 5 mg or 10 mg per day. Patients received proper pain control with opioid medication or palliative radiation therapy according to clinical requirements.\n\nStudy Assessment\nThe primary patient characteristics were age at start of AA treatment, serum PSA level at MCRPC, PSA at chemotherapy, PSA at AA treatment, first-line chemotherapy cycles, second-line cycles, first-line androgen deprivation therapy (ADT) duration, chemotherapy duration, PSA progression velocity before AA, PSA progression ratio before AA treatment, follow-up duration, progression-free survival of AA treatment, overall survival of AA treatment and survival status. Maximal effect period was recorded as the time period required to the lowest PSA level after AA treatment. The adverse events (AEs) developed during treatment were also recorded.\n\nThe first-line ADT duration was defined as the months between the date of ADT beginning and the date of CRPC. First-line ADT included surgical castration (orchiectomy) or medical castration using LH-RH agonists or antagonists. The chemotherapy cycles were defined according to the standard 3-week docetaxel treatment. In our practice, 2-week and 4-week courses of chemotherapy were performed. We transferred the 2-week cycles into standard 3-week cycle counts. PSA progression was defined according to the Prostate Cancer Working Group second publication (PCWG2) criteria (Scher et al., 2008). Some patients also received bone scan and evaluation symptoms to better define their progression. Although the clinical management did not completely match the definition criteria, such as delayed or early chemotherapy at the time of PSA progression, we still recorded the date of treatment. Chemotherapy duration was defined as the months between the date of AA treatment beginning and the date of chemotherapy beginning. PSA progression velocity before AA was defined as the PSA change between the pre-AA treatment and the CRPC divided by the time interval. PSA progression ratio was defined as PSA before AA treatment divided by the CRPC PSA level.\n\nStatistical Analysis\nThe differences between continuous values were analyzed by Mann–Whitney U test and Fisher’s exact test t-test for continuous variables. χ2 test was used for categorical variables. The progression-free survival and overall survival curves were plotted using the Kaplan–Meier method with statistical significance examined by the log-rank test. Univariate and multivariate Cox hazard regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for association between variables and progression-free and overall survival. All statistical analyses were performed using SAS software version 9.2 (SAS Institute, Inc., Cary, NC, USA). A p-value of < 0.05 was considered statistically significant.\n\nResult\nThirty-three patients (51.6%, 33/64) met the criteria of PSA decline greater than 50% after AA treatment. Table 1 shows the basic characteristics among all 64 patients. During the median 7.9 months follow-up period, 43 patients (67.2%) were still alive. The median first line ADT duration was 26.9 months and the median fist line chemotherapy used was seven cycles. Twenty-five patients (39.1%) received second line chemotherapy with cabazitaxel with a median of four cycles. The overall chemotherapy duration before AA treatment was 17.1 months.\n\nTable 1 Basic characteristics of patients receiving Abiraterone acetate treatment.\n\n\tMedian\tRange\t\nAge at AA treatment (years; n = 64)\t72\t49–89\t\nReceived radical prostatectomy (n, %)\t15\t23.4%\t\nStart 1st line ADT age (months; n = 64)\t66.0\t46–87\t\n1st line ADT duration (months; n = 63)\t26.9\t2.3–144.5\t\nCRPC PSA (n = 63)\t5.3\t2–354\t\n1st line chemo cycles (n = 63)\t7.0\t1–33\t\n2nd line chemo cycles (n = 25)\t4.0\t3–12\t\nChemotherapy period (months; n = 63)\t17.1\t2.7–71\t\nPre-AA PSA (n = 64)\t42.7\t4–1941\t\nPSA response (n, %)\t33\t51.6%\t\nPSA decline % (n = 64)\t80.3\t-269–99.9\t\nTotal follow-up period (months; n = 64)\t7.9\t0.9–46.5\t\nMaximal effect period (months; n = 37)\t3.6\t0.5–11.7\t\nProgress-free survival (months; n = 64)\t4.1\t0.8–25.2\t\nPSA velocity (PSA/months; n = 63)\t1.0\t-23.2–78.1\t\nPSA ratio (n = 63)\t6.5\t0.3–447.3\t\nSurvival (n, %)\t\t\t\nAlive\t43\t67.2%\t\nDeath\t21\t32.8%\t\n\t\nAA, abiraterone acetate; ADT, androgen deprivation therapy; CRPC, castration-resistant prostate cancer. PSA decline, (Pre-AA PSA subtract Lowest PSA after AA) divided by Pre-AA PSA. PSA velocity before AA, (Pre-AA PSA subtract CRPC PSA) divided by (Date start AA subtract Date CRPC). PSA ratio, Pre-AA PSA divided by CRPC PSA.The median progression free survival expected using the Log-rank test was 6.6 months and the overall survival was 24 months (Figures 1 and 2).\n\nFIGURE 1 Progression-free survival in total 64 patients.\n\nFIGURE 2 Overall survival in total 64 patients.\n\nTable 2 shows the development of AEs during AA treatment. The development percentage of grade 1/2 and grade 3/4 AE was 31.3% (20/64) and 4.7% (3/64), respectively. However, one case of hyperkalemia developed in the PSA non-responder group and resulted in patient death. Two patients experienced elevated glutamate oxaloacetate transaminase (GOP) and glutamate pyruvate transaminase (GPT). They received temporary suspension of AA; one of them recovered after 1 week and was kept on treatment without tapering dosage and the other had PSA progression.\n\nTable 2 Adverse events during abiraterone acetate treatment.\n\n\tPatients (n = 64)\t\n\t\t\n\tGrade 1/2\tGrade 3/4\t\nSubjects with AE, n (%)\t20 (31.3)\t3 (4.7)\t\nGeneral AE, n (%)\t\t\t\nDiarrhea\t1 (1.6)\t0\t\nHypokalemia\t3 (4.7)\t0\t\nHyperkalemia\t1 (1.6)\t1 (1.6)\t\nFatigue\t2 (3.1)\t0\t\nVertigo\t1 (1.6)\t0\t\nStasis dermatitis\t2 (3.1)\t0\t\nLeg edema\t4 (6.3)\t0\t\nPuffing face\t1 (1.6)\t0\t\nGastric upset\t4 (6.3)\t0\t\nElevated liver function\t1 (1.6)\t2 (3.1)\t\n\t\nIn univariate Cox regression analysis, first-line ADT duration showed a positive association to better progression free survival; pre-AA PSA, and PSA progression ratio showed a negative association to longer progression free survival. After adjustment, all three factors were considered predictors of PSA progression before AA treatment (Table 3). In the analysis of overall survival, only first line ADT duration reached the statistical significance (p = 0.019) (Table 4).\n\nTable 3 Predictive variables of progression-free survival.\n\n\tUnivariate analysis\tMultivariate analysis\t\n\t\t\t\n\tHR\t95% CI\tP-value\tHR\t95% CI\tP-value\t\nAge at AA treatment\t0.99\t(0.95–1.03)\t0.476\t\t\t\t\n1st line ADT duration (months)\t0.98\t(0.96–0.99)\t0.011∗\t0.98\t(0.96–0.99)\t0.012∗a\t\nCRPC PSA\t1.00\t(1.00–1.01)\t0.163\t\t\t\t\nPre-chemo PSA\t1.00\t(1.00–1.00)\t0.544\t\t\t\t\n1st line chemo cycles\t0.99\t(0.94–1.03)\t0.597\t\t\t\t\nPre-AA PSA\t1.00\t(1.00–1.00)\t0.023∗\t1.00\t(1.000–1.002)\t0.025∗a\t\nPSA velocity before AA (PSA/month)\t1.01\t(1.00–1.02)\t0.138\t\t\t\t\nPSA progression ratio\t1.00\t(1.00–1.01)\t0.001∗\t1.01\t(1.00–1.01)\t<0.001∗b\t\n\t\nCox regression. HR, hazard ratio. aAdjusted for 1st line ADT duration (months), Pre-AA PSA, bAdjusted for 1st line ADT duration (months), PSA progression ratio. ∗P < 0.05.Table 4 Predictive variables of overall survival.\n\n\tUnivariate analysis\t\n\t\t\n\tHR\t95% CI\tp-value\t\nAge at AA treatment\t1.01\t(0.96–1.07)\t0.695\t\n1st line ADT duration (months)\t0.97\t(0.94–0.99)\t0.019∗\t\nCRPC PSA\t1.00\t(0.99–1.01)\t0.924\t\nPRE-chemo PSA\t1.00\t(1.00–1.01)\t0.428\t\n1st line chemo cycles\t0.96\t(0.89–1.03)\t0.289\t\nChemo period (month)\t0.98\t(0.94–1.02)\t0.255\t\nPre-AA PSA\t1.00\t(1.00–1.00)\t0.186\t\nPSA velocity before AA (PSA/month)\t1.01\t(1.00–1.03)\t0.069\t\nPSA progression ratio\t1.00\t(1.00–1.01)\t0.270\t\n\t\nCox regression. HR, hazard ratio. aAdjusted for 1st line ADT duration (month).∗p < 0.05.Discussion\nOur study provided the evidence that clinical, non-laboratory parameters can also predict patient outcome using AA treatment in post-docetaxel MCRPC. Several clinical factors had been used as outcome predictors. Chi et al. (2016) used database from COU-AA-301 study and found serum lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group Performance Status (ECOG PS), liver metastases, serum albumin, serum alkaline phosphatase (ALP) and first line ADT duration could act as a cumulative scoring system to predict AA treatment efficacy. Our data corresponded to their finding on the ADT treatment duration. However, lack of most of lab blood tests or image study results makes our finding limited. Facchini et al. (2016) reported early PSA response could predict the overall survival after AA treatment which was a post-treatment prediction. Our study is the first to show pre-treatment clinical markers such as first-line ADT duration, pre-AA PSA level, and PSA progression ratio may correspond to progression-free survival and may serve as a simpler tool for predicting AA treatment outcome.\n\nMolecular factors such as androgen-receptor splice variant seven messenger RNA (AR-V7) has been well studied in the prediction of the efficacy of second-line hormone therapy, especially AA and enzalutamide (Antonarakis et al., 2014). AR-V7 not only explained the possible drug-resistant mechanism, it may have value as a predictive tool before second-line hormone therapy.\n\nThe overall PSA response rate was 51.6% (33/64) in our study which was better than the 29.5% response rate found in the COU-AA-301 trial. Our data were similar to the findings of a previous Korean and Taiwanese small group study which showed a PSA response rate of 43% (Kwak et al., 2014). However, our results showed the median PSA progression-free survival was only 6.6 months which was shorter than the duration of 8.5 months in the COU-AA-301 trial. This is because the definition of treatment failure in our series was only based on PSA progression. Interestingly, our median overall survival was 24 months which was longer than the duration of 15.8 months in the COU-AA-301 trial. This is the result of some patients who experienced longer overall survival (longest follow-up 46.5 months) in our database which made survival prediction right shift.\n\nThe median time to maximal PSA response was 3.6 months which implied most patients who were sensitive to AA treatment would experience early PSA response in about 3 months period. This finding corresponded to Facchini’s results in the post-treatment observation. However, one patient did not reach lowest PSA decline until 9.3 months. This patient did have early PSA decline about 55% after 6 months, he received prednisolone shift to dexamethasone and experienced more PSA decline to 90%. Similar findings were reported by Lorente et al. (2014).\n\nOur data showed most patients tolerated AA well and only 4.7% (3/64) had grade 3/4 AEs. One of them developed severe hyperkalemia and died of shock. The precise etiology was unknown but a latent infection which induced septic shock and acute renal failure was suspected. Some patients developed leg and facial edema and symptoms similar to metabolic syndrome in previous reports (Logothetis et al., 2012).\n\nThe treatment strategy of MCRPC has been discussed in the literature in recent years (Sonpavde et al., 2015; van Dodewaard-de Jong et al., 2015; van Soest et al., 2015). In our study, 29.7% (19/64) patients received cabazitaxel before AA in the early period. After AA was insurance reimbursed, no patients received cabazitaxel before AA. Ten patients received docetaxel after AA failure which showed no obvious survival benefit as previous reports (Zhang et al., 2015).\n\nThere were several limitations in our study. First, this is a retrospective chart review study. PSA check-up schedules and many variables were not well controlled. Second, PSA was the only parameter to define treatment outcome in our study. It is now considered PCWG3 consensus as a recommended evaluations in CRPC studies (Scher et al., 2016). There would be outcome variations in such different standards. Third, six patients in the PSA responder group received prednisolone shift to dexamethasone after PSA mild elevation. All of them experienced PSA decline after shifting and it was regarded as treatment continuing in our study. Although this design might influence progression free survival, there should be no differences in the overall survival comparison. Fourth, our sample size was too small and the HR seemed no such great impact even reaching statistical significance.\n\nConclusion\nOur real-world patient data showed that pre-treatment predictors of AA in PSA progression-free survival included first-line ADT duration, pre-AA PSA, and PSA progression ratio. For overall survival, first-line ADT duration can also serve as a pre-treatment predictor. PSA response itself can be applied as post-treatment predictors for PSA progression-free survival and overall survival after prescription.\n\nEthics Statement\nThis is a retrospective case analysis in a single institute.\n\nAuthor Contributions\nCase collection: J-RL, S-SW, C-KY, C-SC, H-CH, K-YC, C-FH, C-LC, C-RY, C-CC, S-CW, C-YL, Y-CO. Manuscript writing: J-RL.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nWe would like to thank the Biostatistics Task Force of Taichung Veterans General Hospital for their assistance with the statistical analyses.\n==== Refs\nReferences\nAntonarakis E. S. Lu C. Wang H. Luber B. Nakazawa M. Roeser J. C. (2014 ). AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. \nN. Engl. J. Med. \n371 \n1028 –1038 . 10.1056/NEJMoa1315815 25184630 \nAzad A. A. Eigl B. J. Leibowitz-Amit R. Lester R. Kollmannsberger C. Murray N. (2015 ). Outcomes with abiraterone acetate in metastatic castration-resistant prostate cancer patients who have poor performance status. \nEur. Urol. \n67 \n441 –447 . 10.1016/j.eururo.2014.01.030 24508071 \nBellmunt J. Kheoh T. Yu M. K. Smith M. R. Small E. J. Mulders P. F. (2016 ). Prior Endocrine therapy impact on abiraterone acetate clinical efficacy in metastatic castration-resistant prostate cancer: post-hoc analysis of randomised phase 3 studies. \nEur. Urol. \n69 \n924 –932 . 10.1016/j.eururo.2015.10.021 26508309 \nChi K. N. Kheoh T. Ryan C. J. Molina A. Bellmunt J. Vogelzang N. J. (2016 ). A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel. \nAnn. Oncol. \n27 \n454 –460 . 10.1093/annonc/mdv594 26685010 \nde Bono J. S. Logothetis C. J. Molina A. Fizazi K. North S. Chu L. (2011 ). Abiraterone and increased survival in metastatic prostate cancer. \nN. Engl. J. Med. \n364 \n1995 –2005 . 10.1056/NEJMoa1014618 21612468 \nFacchini G. Caffo O. Ortega C. D’aniello C. Di Napoli M. Cecere S. C. (2016 ). Very early PSA response to abiraterone in mCRPC patients: a novel prognostic factor predicting overall survival. \nFront. Pharmacol. \n7 :123 \n10.3389/fphar.2016.00123 \nFizazi K. Scher H. I. Molina A. Logothetis C. J. Chi K. N. Jones R. J. (2012 ). Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. \nLancet Oncol. \n13 \n983 –992 . 10.1016/S1470-2045(12)70379-0 22995653 \nHouede N. Beuzeboc P. Gourgou S. Tosi D. Moise L. Gravis G. (2015 ). Abiraterone acetate in patients with metastatic castration-resistant prostate cancer: long term outcome of the Temporary Authorization for Use programme in France. \nBMC Cancer \n15 :222 \n10.1186/s12885-015-1257-2 \nKwak C. Wu T. T. Lee H. M. Wu H. C. Hong S. J. Ou Y. C. (2014 ). Abiraterone acetate and prednisolone for metastatic castration-resistant prostate cancer failing androgen deprivation and docetaxel-based chemotherapy: a phase II bridging study in Korean and Taiwanese patients. \nInt. J. Urol. \n21 \n1239 –1244 . 10.1111/iju.12589 25099185 \nLogothetis C. J. Basch E. Molina A. Fizazi K. North S. A. Chi K. N. (2012 ). Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. \nLancet Oncol. \n13 \n1210 –1217 .23142059 \nLorente D. Omlin A. Ferraldeschi R. Pezaro C. Perez R. Mateo J. (2014 ). Tumour responses following a steroid switch from prednisone to dexamethasone in castration-resistant prostate cancer patients progressing on abiraterone. \nBr. J. Cancer \n111 \n2248 –2253 . 10.1038/bjc.2014.531 25314055 \nRescigno P. Lorente D. Bianchini D. Ferraldeschi R. Kolinsky M. P. Sideris S. (2016 ). Prostate-specific antigen decline after 4 weeks of treatment with abiraterone acetate and overall survival in patients with metastatic castration-resistant prostate cancer. \nEur. Urol. \n70 \n724 –731 . 10.1016/j.eururo.2016.02.055 26965561 \nScher H. I. Halabi S. Tannock I. Morris M. Sternberg C. N. Carducci M. A. (2008 ). Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. \nJ. Clin. Oncol. \n26 \n1148 –1159 . 10.1200/JCO.2007.12.4487 18309951 \nScher H. I. Morris M. J. Stadler W. M. Higano C. Basch E. Fizazi K. (2016 ). Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3. \nJ. Clin. Oncol. \n34 \n1402 –1418 . 10.1200/JCO.2015.64.2702 26903579 \nSonpavde G. Bhor M. Hennessy D. Bhowmik D. Shen L. Nicacio L. (2015 ). Sequencing of cabazitaxel and abiraterone acetate after docetaxel in metastatic castration-resistant prostate cancer: treatment patterns and clinical outcomes in multicenter community-based US oncology practices. \nClin. Genitourin. Cancer \n13 \n309 –318 . 10.1016/j.clgc.2014.12.019 25743206 \nvan Dodewaard-de Jong J. M. Verheul H. M. Bloemendal H. J. De Klerk J. M. Carducci M. A. Van Den Eertwegh A. J. (2015 ). New treatment options for patients with metastatic prostate cancer: what is the optimal sequence? \nClin. Genitourin. Cancer \n13 \n271 –279 . 10.1016/j.clgc.2015.01.008 25704270 \nvan Soest R. J. De Morree E. S. Kweldam C. F. De Ridder C. M. Wiemer E. A. Mathijssen R. H. (2015 ). Targeting the androgen receptor confers in vivo cross-resistance between enzalutamide and docetaxel, but not cabazitaxel, in castration-resistant prostate cancer. \nEur. Urol. \n67 \n981 –985 .25484141 \nXu X. S. Ryan C. J. Stuyckens K. Smith M. R. Saad F. Griffin T. W. (2015 ). Correlation between prostate-specific antigen kinetics and overall survival in abiraterone acetate-treated castration-resistant prostate cancer patients. \nClin. Cancer Res. \n21 \n3170 –3177 . 10.1158/1078-0432.CCR-14-1549 25829400 \nZhang T. Dhawan M. S. Healy P. George D. J. Harrison M. R. Oldan J. (2015 ). Exploring the clinical benefit of docetaxel or enzalutamide after disease progression during abiraterone acetate and prednisone treatment in men with metastatic castration-resistant prostate cancer. \nClin. Genitourin. Cancer \n13 \n392 –399 . 10.1016/j.clgc.2015.01.004 25708161\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1663-9812",
"issue": "8()",
"journal": "Frontiers in pharmacology",
"keywords": "PSA; abiraterone acetate; androgen deprivation therapy; castration-resistant prostate cancer; docetaxel",
"medline_ta": "Front Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "101548923",
"other_id": null,
"pages": "55",
"pmc": null,
"pmid": "28243202",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "26965561;25708161;26685010;18309951;24508071;26508309;25743206;25484141;25184630;25829400;22995653;25314055;25099185;25884302;27242530;21612468;25704270;23142059;26903579",
"title": "First Line Androgen Deprivation Therapy Duration Is Associated with the Efficacy of Abiraterone Acetate Treated Metastatic Castration-Resistant Prostate Cancer after Docetaxel.",
"title_normalized": "first line androgen deprivation therapy duration is associated with the efficacy of abiraterone acetate treated metastatic castration resistant prostate cancer after docetaxel"
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"companynumb": "TW-JNJFOC-20170308811",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
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"activesubstance": {
"activesubstancename": "PREDNISOLONE"
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{
"abstract": "Long-term bisphosphonate (BP) therapy in adults with osteoporosis is associated with atypical femoral fractures, caused by increased material bone density and prolonged suppression of bone remodeling which may reduce fracture toughness. In children with osteogenesis imperfecta (OI), long-term intravenous BP therapy improves bone structure and mass without further increasing the already hypermineralized bone matrix, and is generally regarded as safe. Here we report a teenage girl with OI type IV, who was started on cyclical intravenous pamidronate therapy at age 6 years because of recurrent fractures. Transiliac bone biopsy revealed classical structural features of OI but unusually low bone resorption surfaces. She made substantial improvements in functional ability, bone mass, and fracture rate. However, after 5 years of pamidronate therapy she started to develop recurrent, bilateral, nontraumatic, and proximal femur fractures, which satisfied the case definition for atypical femur fractures. Some fractures were preceded by periosteal reactions and prodromal pain. Pamidronate was discontinued after 7 years of therapy, following which she sustained two further nontraumatic femur fractures, and continued to show delayed tibial osteotomy healing. Despite rodding surgery, and very much in contrast to her affected, untreated, and normally mobile mother, she remains wheelchair-dependent. The case of this girl raises questions about the long-term safety of BP therapy in some children, in particular about the risk of oversuppressed bone remodeling with the potential for microcrack accumulation, delayed healing, and increased stiffness. The principal concern is whether there is point at which benefit from BP therapy could turn into harm, where fracture risk increases again. This case should stimulate debate whether current adult atypical femoral fracture guidance should apply to children, and whether low-frequency, low-dose cyclical, intermittent, or oral treatment maintenance regimens should be considered on a case-by-case basis. © 2016 American Society for Bone and Mineral Research.",
"affiliations": "Department of Endocrinology and Diabetes, Birmingham Children's Hospital, Birmingham, UK.;Department of Orthopaedics, Norfolk and Norwich University Hospital, Norwich, UK.;Department of Human Metabolism, Sheffield Children's Hospital, Sheffield, UK.;Department of Endocrinology and Diabetes, Birmingham Children's Hospital, Birmingham, UK.",
"authors": "Vasanwala|Rashida F|RF|;Sanghrajka|Anish|A|;Bishop|Nicholas J|NJ|;Högler|Wolfgang|W|",
"chemical_list": "D004164:Diphosphonates; D000077268:Pamidronate",
"country": "United States",
"delete": false,
"doi": "10.1002/jbmr.2805",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0884-0431",
"issue": "31(7)",
"journal": "Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research",
"keywords": "ATYPICAL FEMUR FRACTURE; BISPHOSPHONATE; OSTEOGENESIS IMPERFECTA; REMODELING; STRESS FRACTURE",
"medline_ta": "J Bone Miner Res",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D006801:Humans; D010013:Osteogenesis Imperfecta; D000077268:Pamidronate",
"nlm_unique_id": "8610640",
"other_id": null,
"pages": "1449-54",
"pmc": null,
"pmid": "26845496",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent Proximal Femur Fractures in a Teenager With Osteogenesis Imperfecta on Continuous Bisphosphonate Therapy: Are We Overtreating?",
"title_normalized": "recurrent proximal femur fractures in a teenager with osteogenesis imperfecta on continuous bisphosphonate therapy are we overtreating"
} | [
{
"companynumb": "GB-FRESENIUS KABI-FK201605365",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PAMIDRONATE DISODIUM"
},
"drugadditional... |
{
"abstract": "Small-vessel vasculitis is an uncommon diagnosis associated with many causes, including certain medication. Characteristic findings are immune complex deposition, vessel wall damage, and erythrocyte extravasation. We present a case of a 77-year-old man with advanced hepatocellular carcinoma who was treated with sorafenib. Twenty days post introduction to sorafenib, the patient experienced high fever and painful purpura on the lower limbs. The results of the skin biopsy confirmed the diagnosis. More extensive diagnostics was undertaken, which excluded other possible causes of vasculitis and infectious disease. Following a full recovery, after the steroid treatment was completed, sorafenib has been continued until the progression of the carcinoma. This is the second described case of hepatocellular carcinoma associated with sorafenib treatment and leukocytoclastic vasculitis. Sorafenib is a potential cause of vasculitis, and clinicians should bear in mind to differentiate it from hand-foot skin reaction, which is a common side effect of multikinase inhibitors. The result of our assessment is important considering that vasculitis requires more specific diagnostic procedures, treatment, and often drug discontinuation.",
"affiliations": "Department of Oncology.;Department of Oncology.;Department of Oncology.;Department of Medical Oncology and Hematology, Pula General Hospital, Pula, Croatia.;Department of Pathology, University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Oncology.",
"authors": "Prejac|Juraj|J|;Kekez|Domina|D|;Belev|Borislav|B|;Kocić|Lidija|L|;Bulimbašić|Stela|S|;Pleština|Stjepko|S|",
"chemical_list": "D000970:Antineoplastic Agents; D000077157:Sorafenib",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000840",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "31(1)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D006528:Carcinoma, Hepatocellular; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D000077157:Sorafenib; D018366:Vasculitis, Leukocytoclastic, Cutaneous",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "76-79",
"pmc": null,
"pmid": "31567309",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Leukocytoclastic vasculitis associated with sorafenib treatment for hepatocellular carcinoma.",
"title_normalized": "leukocytoclastic vasculitis associated with sorafenib treatment for hepatocellular carcinoma"
} | [
{
"companynumb": "HR-BAYER-2019-184709",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": "1",
"dr... |
{
"abstract": "Purpose: Coronavirus Disease 2019 (COVID-19) can cause conjunctivitis in up to 31.6% of patients. Additionally, retinal findings compatible with retinal microvascular ischemia have also been associated with coronavirus disease in asymptomatic patients. We describe a case of bilateral retinal changes compatible with microangiopathy occurring during the late phase of COVID-19.Case report: A 50-year-old man with bilateral pneumonia and positive polymerase chain reaction for SARS-CoV-2 developed an arcuate visual field defect in his left eye. Funduscopy revealed multiple, bilateral cotton-wool spots without haemorraghes. OCT-angiography revealed multifocal areas of retinal microvascular ischemia in the superficial plexus, the largest of which corresponded to the arcuate scotoma observed in the automated perimetry.Conclusion: Visual field defects due to retinal microangiopathy can occur during the late phase of COVID-19. Vascular changes observed in the retina may mimic what may be happening in other, less-accessible organs.",
"affiliations": "Ophthalmology Department, Hospital Universitario Ramon y Cajal, IRYCIS, Madrid, Spain.;Ophthalmology Department, Hospital Universitario Ramon y Cajal, IRYCIS, Madrid, Spain.;Ophthalmology Department, Hospital Universitario Ramon y Cajal, IRYCIS, Madrid, Spain.",
"authors": "Gonzalez-Lopez|Julio J|JJ|0000-0001-7210-7809;Felix Espinar|Beatriz|B|;Ye-Zhu|Cristina|C|0000-0003-1785-1226",
"chemical_list": "D012367:RNA, Viral",
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2020.1852260",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": "29(4)",
"journal": "Ocular immunology and inflammation",
"keywords": "Communicable diseases; Covid-19; ophthalmology; retina; uveitis",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000086382:COVID-19; D002196:Capillaries; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D006801:Humans; D008297:Male; D008875:Middle Aged; D009887:Ophthalmoscopy; D012367:RNA, Viral; D012164:Retinal Diseases; D012171:Retinal Vessels; D000086402:SARS-CoV-2; D041623:Tomography, Optical Coherence",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "642-644",
"pmc": null,
"pmid": "33284032",
"pubdate": "2021-05-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Symptomatic Retinal Microangiopathy in a Patient with Coronavirus Disease 2019 (COVID-19): Single Case Report.",
"title_normalized": "symptomatic retinal microangiopathy in a patient with coronavirus disease 2019 covid 19 single case report"
} | [
{
"companynumb": "ES-LUPIN PHARMACEUTICALS INC.-2022-01898",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
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{
"abstract": "BACKGROUND\nEpilepsy with progressive cortical volume loss is described secondary to energy failure such as mitochondrial disorders, infectious, or inflammatory etiologies and associated with temporal lobe epilepsy. Postmortem studies do not support that spontaneous seizures even if present for prolonged periods universally result in cortical volume loss.\n\n\nRESULTS\nWe describe two children with extratemporal pharmacoresistent epilepsy, slowly progressive gray matter volume loss over several years, and evidence of central nervous system inflammation. Brain magnetic resonance imaging changes and antibody profiles were not typical of a well-defined, antibody-mediated central nervous system syndrome such as N-methyl-D-aspartate receptor encephalitis.\n\n\nCONCLUSIONS\nThese patients illustrate a novel presentation of a subacute inflammatory central nervous system process with epilepsy and progressive cortical volume loss, supporting the role of sequential brain imaging in children with epilepsy.",
"affiliations": "Pediatric Neurology, Children's Hospital and Research Center, Oakland, California. Electronic address: rkuperman@mail.cho.org.;Pediatric Radiology, Children's Hospital and Research Center, Oakland, California.",
"authors": "Kuperman|Rachel A|RA|;Martin|Kenneth W|KW|",
"chemical_list": "D000927:Anticonvulsants; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-8994",
"issue": "53(1)",
"journal": "Pediatric neurology",
"keywords": "Poliodystrophy; Rassmusen encephalitis; autoimmune encephalitis; paraneoplastic encephalitis; pharmacoresistant epilepsy",
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D000927:Anticonvulsants; D020274:Autoimmune Diseases of the Nervous System; D001921:Brain; D002648:Child; D002675:Child, Preschool; D004828:Epilepsies, Partial; D005260:Female; D066128:Gray Matter; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D008279:Magnetic Resonance Imaging; D008297:Male; D009929:Organ Size",
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "83-7",
"pmc": null,
"pmid": "25937386",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pharmacoresistent Partial Epilepsy Secondary to Progressive Inflammatory Poliodystrophy.",
"title_normalized": "pharmacoresistent partial epilepsy secondary to progressive inflammatory poliodystrophy"
} | [
{
"companynumb": "US-APOTEX-2017AP019345",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "OXCARBAZEPINE"
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... |
{
"abstract": "Mass vaccination campaigns are being run all over the globe to combat the ongoing COVID-19 pandemic. There have been several reports of immune thrombocytopenic purpura (ITP) occurrence following COVID-19 vaccination. However, ITP due to the Pfizer-BioNTech vaccine has been rarely reported, and a causal link has not been identified. The pathophysiology behind immune thrombocytopenia is similar to heparin-induced thrombocytopenia. The management is also similar to other secondary immune thrombocytopenia. We present a case of a 67-year old female diagnosed with immune thrombocytopenia following Pfizer-BioNTech vaccination. The treatment was resistant to high-dose steroids, intravenous immunoglobulin (IVIG), and rituximab and eventually responded to a thrombopoietin-stimulating agent.",
"affiliations": "Department of Internal Medicine, Mount Sinai Hospital, Chicago, USA.;Department of Internal Medicine, Mount Sinai Hospital, Chicago, USA.;Department of Emergency Medicine, Palpa Hospital, Palpa, NPL.;Department of Hematology and Oncology, Mount Sinai Hospital, Chicago, USA.",
"authors": "Jasaraj|Ranjit B|RB|;Shrestha|Dhan B|DB|;Gaire|Suman|S|;Kassem|Mohammed|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.16871",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.16871\nInternal Medicine\nAllergy/Immunology\nInfectious Disease\nImmune Thrombocytopenic Purpura Following Pfizer-BioNTech COVID-19 Vaccine in an Elderly Female\nMuacevic Alexander\nAdler John R\nJasaraj Ranjit B 1\nShrestha Dhan B 1\nGaire Suman 2\nKassem Mohammed 3\n1 Department of Internal Medicine, Mount Sinai Hospital, Chicago, USA\n2 Department of Emergency Medicine, Palpa Hospital, Palpa, NPL\n3 Department of Hematology and Oncology, Mount Sinai Hospital, Chicago, USA\nDhan B. Shrestha medhan75@gmail.com\n4 8 2021\n8 2021\n13 8 e168714 8 2021\nCopyright © 2021, Jasaraj et al.\n2021\nJasaraj et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/65828-immune-thrombocytopenic-purpura-following-pfizer-biontech-covid-19-vaccine-in-an-elderly-female\nMass vaccination campaigns are being run all over the globe to combat the ongoing COVID-19 pandemic. There have been several reports of immune thrombocytopenic purpura (ITP) occurrence following COVID-19 vaccination. However, ITP due to the Pfizer-BioNTech vaccine has been rarely reported, and a causal link has not been identified. The pathophysiology behind immune thrombocytopenia is similar to heparin-induced thrombocytopenia. The management is also similar to other secondary immune thrombocytopenia. We present a case of a 67-year old female diagnosed with immune thrombocytopenia following Pfizer-BioNTech vaccination. The treatment was resistant to high-dose steroids, intravenous immunoglobulin (IVIG), and rituximab and eventually responded to a thrombopoietin-stimulating agent.\n\ncovid-19 vaccine\nmrna vaccines\npfizer-biontech\nimmune thrombocytopenia\ncovid-19\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\npmcIntroduction\n\nCoronavirus disease-2019 (COVID-19) was declared a pandemic on March 11, 2020, by the WHO. As of July 10, 2021, there have been 33,604,986 total reported cases and 603,958 deaths in the United States [1]. Mass vaccination campaigns are being run all over the world to combat the pandemic. The U.S. Food and Drug Administration (US-FDA) has approved the Pfizer-BioNTech, Moderna, and Janssen COVID-19 vaccines, under Emergency Use Authorization (EUA). The US-FDA gave the Pfizer-BioNTech COVID-19 Vaccine EUA on December 11, 2020, for individuals 16 years or older. The EUA was expanded to include adolescents between 12 and 15 years on May 10, 2021 [2]. As of July 10, 2021, 184,469,317 Pfizer-BioNTech COVID-19 vaccines and a total of 332,966,409 vaccines have been administered in the US [1]. The Pfizer-BioNTech vaccine is an mRNA vaccine coated in a lipid that encodes the severe acute respiratory syndrome-coronavirus-2 (SARS-COV-2) spike glycoprotein.\n\nImmune thrombocytopenic purpura (ITP) is an immune-mediated disease defined by isolated thrombocytopenia (peripheral blood platelet count < 100,000/uL) [3]. When other causes or diseases that have led to the condition are not identified, it is termed primary ITP. In contrast, secondary ITP refers to immune thrombocytopenia due to underlying conditions or drugs [3]. Various viral diseases like the human immunodeficiency virus (HIV), Varicella-Zoster virus, cytomegalovirus (CMV), Zika virus, and various autoimmune diseases like systemic Lupus Erythematosus have been associated with secondary ITP. The annual incidence of adult immune thrombocytopenia is around 3.3 per 100,000 in the US [4].\n\nWe present a case of a 67-year-old female who presented with ITP following the second dose of the Pfizer-BioNTech vaccine.\n\nCase presentation\n\nA 67-year-old Hispanic female with a past medical history of hypertension, type 2 diabetes mellitus, hypothyroidism, depression, vitamin B12 deficiency, and chronic cluster headaches was referred to our hospital from the clinic after she was found to have low platelet levels. Past medical records have shown that she had a normal platelet count two months before presentation. She was under regular medication for the aforementioned comorbidities with no recent changes in the regimen.\n\nThe patient had received the first dose of the Pfizer Bio-NTech COVID-19 vaccine about two months before hospitalization. She developed mild petechial rashes on her legs and chest after two weeks of the first dose of the vaccine. Rashes were insidious in onset and were non-pruritic. She denies any other adverse effects after her first dose of the vaccine. However, two days after her second dose of the vaccine, the patient noticed a rapid rash progression throughout her body without resolution of the rash (Figure 1). She also noticed bleeding in her gums when brushing her teeth and had an episode of epistaxis that resolved spontaneously. In addition, she developed a subconjunctival hemorrhage in the right eye (Figure 2) and hemorrhagic lesions of the tongue and buccal mucosa. On a subsequent clinic follow-up, her platelet count was found to be 3,000/µL, and she was referred to our hospital.\n\nFigure 1 Ecchymosis over bilateral legs\n\nFigure 2 Subconjunctival hemorrhage\n\nUpon admission, the patient complained of a constant right-sided headache. She did not have fever, chills, night sweats, vomiting, weight loss, lymphadenopathy, or any focal neurological deficits on presentation. She denied hemoptysis, hematemesis, melena, hematochezia, or hematuria. She reported a history of duodenal ulcers treated long back. Her vaccinations were up to date. She was diagnosed with hypertensive urgency, which was managed with antihypertensives. Laboratory investigations showed a hemoglobin level of 10.3 mg/dl and a platelet count of <3,000/µL. White blood cell count, coagulation studies, fibrinogen level, liver function tests (LFTs), lactate dehydrogenase (LDH), haptoglobin, and reticulocyte counts were normal. A CT scan of the head was negative for any acute intracranial hemorrhage. She tested negative for hepatitis B, C, HIV, Ebstein Bar virus, and CMV. She also tested negative for COVID-19. An ultrasound of the abdomen was negative for organomegaly.\n\nThe patient was immediately started on oral Prednisone at 1 mg/kg body weight and intravenous immunoglobulin (IVIG) at 400 mg/kg/day. However, her platelet counts did not improve, and she was transfused with 1 unit of platelets, given the high risk of bleeding. She was found to have a decline in her hemoglobin count, with her hemolytic lab panel being negative for hemolysis. Since she continued to develop large, ecchymotic patches on her arms, suggesting soft tissue bleed from each lab draw. She was started on aminocaproic acid at a loading dose of 5 g and continued on a maintenance dose of 1 g twice daily. She tolerated the treatment well, and her platelet level rose slowly to 10,000-15,000. She received three days of treatment with IVIG along with high-dose steroids, with her platelet count peaking at 10,000/µL. \n\nUpon further investigation, her autoimmune workup with anti-nuclear antibody (ANA), dsDNA, and complement levels was normal. Her rheumatoid factor was elevated to a level of 87 IU/mL, which eventually normalized. Her serum protein electrophoresis was normal. A bone marrow biopsy and aspirate were done, and pathology reported adequate megakaryocytes with trilineage hematopoiesis without evidence of myelodysplasia. She was discharged on day 14 with a platelet count of 6,000/µL. While closely following up in a Hematology/Oncology clinic, she received four doses of Rituximab. At this time, her petechial rashes and subconjunctival hemorrhage were starting to resolve. Since her platelet counts continued to stay below 10,000/µL, she was treated with a TPO agent (Eltrombopag). This eventually helped to increase her platelet count and maintain it over 200,000/µL over the next two months. Subsequently, her platelet counts have maintained above 200,000-250,000/fL, off of all medications.\n\nDiscussion\n\nWe have presented a case of ITP occurrence following Pfizer-BioNTech vaccination. In the randomized, double-blinded, placebo-controlled trial of the Pfizer-BioNTech vaccine with 43,548 patients; only four severe adverse events were reported. The reported severe adverse events were shoulder injury related to vaccine administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia. Additionally, two deaths were reported - one caused by arteriosclerosis and the other by cardiac arrest. All other adverse effects were mild [5].\n\nPrior evidence has suggested that ITP occurrence may be seen after immunization with various vaccines. A direct, cause-effect relation between ITP and the measles mumps rubella (MMR) vaccine has been established [6]. Although a causal relationship has not been identified in many cases, ITP has been reported following several immunizations, including varicella live vaccine, human papilloma vaccine, Hemophilus influenza vaccine, hepatitis B, the polio vaccine, and the diphtheria-tetanus-pertussis vaccine [7].\n\nCovid-19 may be associated with secondary ITP, which can be attributed to several mechanisms like immune dysregulation, molecular mimicry, expression of cryptic antigen on platelets, etc. [8]. Furthermore, thrombocytopenia may worsen in patients already suffering from chronic ITP following COVID-19 vaccine administration [9].\n\nSeveral case reports of immune thrombocytopenia have been reported after the COVID-19 vaccination. In addition, reports have indicated vaccine-induced immune thrombocytopenia with the adenoviral vaccine, ChAdOx1, and the Janssen Covid-19 vaccine [10,11]. The pathogenesis behind vaccine-induced immune thrombocytopenia is similar to heparin-induced thrombocytopenia. Antibodies against platelet-activating factor 4 have been implicated, which causes massive platelet activation by widespread binding to the Fc receptor. This leads to platelet consumption with thrombosis and thrombocytopenia [10].\n\nCases of immune thrombocytopenia following the Pfizer Bio-NTech Covid-19 vaccine have not been as widely reported. There are reports of 35 possible cases of central nervous system thrombosis following vaccination [12] and two cases of deep vein thrombosis [13,14]. In addition, there have been some cases of thrombocytopenia following vaccination reported in the Vaccine Adverse Events Reporting System (VAERS). However, there are not enough cases to attribute to safety concerns following mRNA vaccines [15].\n\nVaccine-induced thrombocytopenia occurs 4 to 16 days after exposure to the vaccine [16]. However, in cases of earlier exposure to the immunogenic agent or the presence of naturally occurring antibodies, it can manifest earlier [17]. Our patient presented with ITP following the second dose of the Pfizer Bio-NTech Covid-19 vaccine. She also had developed some symptoms following the first dose. This could have caused a relatively earlier presentation in our patient.\n\nIVIG and glucocorticoids are considered the first line in the management of ITP; accordingly, our patient was treated with. Our patient did not improve and had severe thrombocytopenia. She finally recovered after Rituximab and Eltrombopag therapies, which helped to raise her platelet counts. After three months of treatment, her platelet counts have stabilized, and she is off of all therapies.\n\nConclusions\n\nImmune thrombocytopenia occurrence after the Pfizer-BioNTech Covid-19 vaccine is rare and a causal relationship of the vaccine to ITP has not been established. In cases with prior exposure, ITP can be seen within hours to days of vaccine administration. We presented a case with severe thrombocytopenia, unresponsive to high-dose steroids, IVIG, and Rituximab. Subsequently, responding to thrombopoietin stimulating agent, Eltrombopag.\n\nHuman Ethics\n\nWe would like to acknowledge our patient without whom this report would not have been possible. Additionally, we would like to thank all the treating healthcare personal who were involved in patient care.\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 COVID data tracker 72021 2021 https://covid.cdc.gov/covid-data-tracker/\n2 Coronavirus (COVID-19) update: FDA Authorizes Pfizer-BioNTech COVID-19 vaccine for emergency use in adolescents in another important action in fight against pandemic | FDA 72021 2021 https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-pfizer-biontech-covid-19-vaccine-emergency-use\n3 Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group Blood Rodeghiero F Stasi R Gernsheimer T 2386 2393 113 2009 19005182\n4 The incidence of immune thrombocytopenic purpura in children and adults: a critical review of published reports Am J Hematol Terrell DR Beebe LA Vesely SK Neas BR Segal JB George JN 174 180 85 2010 20131303\n5 Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine N Engl J Med Polack FP Thomas SJ Kitchin N 2603 2615 383 2020 33301246\n6 Vaccine administration and the development of immune thrombocytopenic purpura in children Hum Vaccin Immunother Cecinati V Principi N Brescia L Giordano P Esposito S 1158 1162 9 2013 23324619\n7 Thrombocytopenia after vaccination: case reports to the US Vaccine Adverse Event Reporting System, 1990-2008 Vaccine Woo EJ Wise RP Menschik D 1319 1323 29 2011 21126606\n8 Immune Thrombocytopenia Secondary to COVID-19: a Systematic Review SN Compr Clin Med Bhattacharjee S Banerjee M 1 11 2 2020\n9 Exacerbation of immune thrombocytopenia following COVID-19 vaccination [PREPRINT] Br J Haematol Kuter DJ 2021\n10 Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination N Engl J Med Greinacher A Thiele T Warkentin TE Weisser K Kyrle PA Eichinger S 2092 2101 384 2021 33835769\n11 Joint CDC and FDA statement on Johnson & Johnson COVID-19 vaccine Research : media statement : for 82021 Schuchat A Marks P 2021 13 2021 https://www.fda.gov/news-events/press-announcements/joint-cdc-and-fda-statement-johnson-johnson-covid-19-vaccine\n12 SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia N Engl J Med Cines DB Bussel JB 2254 2256 384 2021 33861524\n13 A 59-year-old woman with extensive deep vein thrombosis and pulmonary thromboembolism 7 days following a first dose of the Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine Am J Case Rep Al-Maqbali JS Al Rasbi S Kashoub MS Al Hinaai AM Farhan H Al Rawahi B Al Alawi AM 0 22 2021\n14 Deep vein thrombosis (DVT) occurring shortly after the second dose of mRNA SARS-CoV-2 vaccine Intern Emerg Med Carli G Nichele I Ruggeri M Barra S Tosetto A 803 804 16 2021 33687691\n15 Thrombocytopenia including immune thrombocytopenia after receipt of mRNA COVID-19 vaccines reported to the Vaccine Adverse Event Reporting System (VAERS) Vaccine Welsh KJ Baumblatt J Chege W Goud R Nair N 3329 3332 39 2021 34006408\n16 Diagnosis and management of vaccine-related thrombosis following AstraZeneca COVID-19 vaccination: guidance statement from the GTH Hamostaseologie Oldenburg J Klamroth R Langer F 184 189 41 2021 33822348\n17 Drug-induced thrombocytopenia Arch Pathol Lab Med Kenney B Stack G 309 314 133 2009 19195976\n\n",
"fulltext_license": "CC BY",
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"issue": "13(8)",
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"medline_ta": "Cureus",
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"pages": "e16871",
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"publication_types": "D002363:Case Reports",
"references": "33687691;19005182;21126606;33861524;33822348;20131303;34006408;33835769;23324619;33301246;19195976;34117206;32984764;34075578",
"title": "Immune Thrombocytopenic Purpura Following Pfizer-BioNTech COVID-19 Vaccine in an Elderly Female.",
"title_normalized": "immune thrombocytopenic purpura following pfizer biontech covid 19 vaccine in an elderly female"
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"abstract": "Non-steroidal anti-inflammatory drugs are suspected to cause drug hypersensitivity very frequently in paediatric patients. In this article, we describe the first case of anaphylaxis to flurbiprofen in a child and provide insight into the possibility of severe reactions and even anaphylaxis to over-the-counter flurbiprofen. Finally, the importance of a rigorous allergy work-up in reaching a confident diagnosis and providing the patient with a safe alternative is shown.",
"affiliations": "Allergy Unit, Department of Pediatrics, Anna Meyer Children's University Hospital, Florence, Italy.",
"authors": "Giovannini|Mattia|M|;Sarti|Lucrezia|L|;Barni|Simona|S|;Pucci|Neri|N|;Novembre|Elio|E|;Mori|Francesca|F|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004366:Nonprescription Drugs; D005480:Flurbiprofen",
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"issn_linking": "0031-7012",
"issue": "99(3-4)",
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"medline_ta": "Pharmacology",
"mesh_terms": "D000707:Anaphylaxis; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002648:Child; D005260:Female; D005480:Flurbiprofen; D006801:Humans; D004366:Nonprescription Drugs",
"nlm_unique_id": "0152016",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anaphylaxis to Over-the-Counter Flurbiprofen in a Child.",
"title_normalized": "anaphylaxis to over the counter flurbiprofen in a child"
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"companynumb": "IT-GLAXOSMITHKLINE-IT2016GSK185315",
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"activesubstancename": "IBUPROFEN"
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"abstract": "A 9-month-old infant experienced severe chloramphenicol toxicity associated with high serum levels (313 micrograms/ml). Cardiovascular collapse with cardiomyopathic changes and impaired left ventricular function was documented by echocardiography. Serial echocardiographic evaluation showed resolution of the cardiomyopathic findings as the chloramphenicol levels were spontaneously cleared. Clinical course was complicated by the development of liver disease and coagulopathy compatible with disseminated intravascular consumption. Patient's recovery was complete and uneventful, nevertheless, chloramphenicol toxicity in childhood is associated with a significant mortality rate of 40%. The related impaired cardiac function, although reversible, appears to play a major role in the pathogenesis and eventual outcome in this syndrome.",
"affiliations": "Department of Pediatrics, Loyola University Medical Center, Maywood, IL 60153.",
"authors": "Suarez|C R|CR|;Ow|E P|EP|",
"chemical_list": "D002701:Chloramphenicol",
"country": "United States",
"delete": false,
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"issn_linking": "0172-0643",
"issue": "13(1)",
"journal": "Pediatric cardiology",
"keywords": null,
"medline_ta": "Pediatr Cardiol",
"mesh_terms": "D002701:Chloramphenicol; D003490:Cyanosis; D006331:Heart Diseases; D006801:Humans; D007022:Hypotension; D007223:Infant; D008297:Male; D013577:Syndrome; D016277:Ventricular Function, Left",
"nlm_unique_id": "8003849",
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"pmc": null,
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"pubdate": "1992-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "4825630;6886920;7310593;13649107;6338466;7277114;6886919;6985658;7350295;7229771",
"title": "Chloramphenicol toxicity associated with severe cardiac dysfunction.",
"title_normalized": "chloramphenicol toxicity associated with severe cardiac dysfunction"
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"actiondrug": "1",
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"activesubstancename": "CHLORAMPHENICOL SODIUM SUCCINATE"
},
"drugaddi... |
{
"abstract": "The new anti-arrhythmic agent, amiodarone, is increasingly recognized as a cause of pulmonary toxicity (APT). In the present series, 11 of 171 patients (6.4%) receiving the drug had APT develop. Clinical symptoms varied from mild cough and dyspnea to acute respiratory failure. Chest x-rays demonstrated alveolar and/or interstitial opacities in all 11 patients. The microscopic appearance of APT resembled that seen in lung injury from other drugs. The features were those of diffuse alveolar damage, ranging from the early acute to the organizing phase. Mural and intraalveolar foam cells were a prominent component. The epithelial origin of these cells was confirmed by positive immunoperoxidase staining for carcinoembryonic antigen. They were further identified as type II pneumocytes by electron microscopic examination. These findings support the concept that amiodarone is responsible for a drug-induced phospholipidosis. APT was clinically reversible in all patients; however, five patients (45%) died of arrhythmia shortly after discontinuation of amiodarone.",
"affiliations": null,
"authors": "Dean|P J|PJ|;Groshart|K D|KD|;Porterfield|J G|JG|;Iansmith|D H|DH|;Golden|E B|EB|",
"chemical_list": "D002272:Carcinoembryonic Antigen; D000638:Amiodarone",
"country": "England",
"delete": false,
"doi": "10.1093/ajcp/87.1.7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9173",
"issue": "87(1)",
"journal": "American journal of clinical pathology",
"keywords": null,
"medline_ta": "Am J Clin Pathol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000638:Amiodarone; D002272:Carcinoembryonic Antigen; D004848:Epithelium; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D008171:Lung Diseases; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D011650:Pulmonary Alveoli",
"nlm_unique_id": "0370470",
"other_id": null,
"pages": "7-13",
"pmc": null,
"pmid": "3799544",
"pubdate": "1987-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Amiodarone-associated pulmonary toxicity. A clinical and pathologic study of eleven cases.",
"title_normalized": "amiodarone associated pulmonary toxicity a clinical and pathologic study of eleven cases"
} | [
{
"companynumb": "US-PFIZER INC-HQWYE303312MAY06",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMIODARONE HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "We compared thrombophilia in 67 cases (59 men and 8 women) with thrombotic events after starting testosterone therapy (TT) versus 111 patient controls having unprovoked venous thrombotic events without TT. In the 67 patients, thrombosis (47 deep venous thrombosis-pulmonary embolism, 16 osteonecrosis, and 4 ocular thrombosis) occurred 6 months (median) after starting TT. Cases differed from controls for factor V Leiden heterozygosity (16 of the 67 [24%] vs 13 [12%] of the 111, P = .038) and for lupus anticoagulant (9 [14%] of the 64 vs 4 [4%] of the 106, P = .019). After a first thrombotic event and continuing TT, 11 cases had a second thrombotic event, despite adequate anticoagulation, 6 of whom, still anticoagulated, had a third thrombosis. Screening for thrombophilia before starting TT should identify men and women at high risk for thrombotic events with an adverse risk-benefit ratio for TT. When TT is given to patients with familial and acquired thrombophilia, thrombosis may occur and recur in thrombophilic men despite anticoagulation.",
"affiliations": "Cholesterol, Metabolism, and Thrombosis Center, Jewish Hospital of Cincinnati, Cincinnati, OH, USA cjglueck@mercy.com.;Cholesterol, Metabolism, and Thrombosis Center, Jewish Hospital of Cincinnati, Cincinnati, OH, USA.;Cholesterol, Metabolism, and Thrombosis Center, Jewish Hospital of Cincinnati, Cincinnati, OH, USA.;Cholesterol, Metabolism, and Thrombosis Center, Jewish Hospital of Cincinnati, Cincinnati, OH, USA.;Cholesterol, Metabolism, and Thrombosis Center, Jewish Hospital of Cincinnati, Cincinnati, OH, USA.;Cholesterol, Metabolism, and Thrombosis Center, Jewish Hospital of Cincinnati, Cincinnati, OH, USA.;Cholesterol, Metabolism, and Thrombosis Center, Jewish Hospital of Cincinnati, Cincinnati, OH, USA.",
"authors": "Glueck|Charles J|CJ|;Prince|Marloe|M|;Patel|Niravkumar|N|;Patel|Jaykumar|J|;Shah|Parth|P|;Mehta|Nishi|N|;Wang|Ping|P|",
"chemical_list": "D016682:Lupus Coagulation Inhibitor; D013739:Testosterone; D005165:Factor V",
"country": "United States",
"delete": false,
"doi": "10.1177/1076029615619486",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1076-0296",
"issue": "22(6)",
"journal": "Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis",
"keywords": "anticoagulation; deep venous thrombosis; estradiol; factor V Leiden; human chorionic gonadotropin; lupus anticoagulant; pulmonary embolus; testosterone; venous thromboembolism",
"medline_ta": "Clin Appl Thromb Hemost",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005165:Factor V; D005260:Female; D006801:Humans; D016682:Lupus Coagulation Inhibitor; D008297:Male; D008875:Middle Aged; D018570:Risk Assessment; D012307:Risk Factors; D013739:Testosterone; D019851:Thrombophilia; D013927:Thrombosis; D054556:Venous Thromboembolism",
"nlm_unique_id": "9508125",
"other_id": null,
"pages": "548-53",
"pmc": null,
"pmid": "26620418",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thrombophilia in 67 Patients With Thrombotic Events After Starting Testosterone Therapy.",
"title_normalized": "thrombophilia in 67 patients with thrombotic events after starting testosterone therapy"
} | [
{
"companynumb": "US-ENDO PHARMACEUTICALS INC-2016-005377",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TESTOSTERONE ENANTHATE"
},
"dru... |
{
"abstract": "We report an unusual case of systemic anaplastic large cell lymphoma (ALCL), ALK positive with leukemic involvement in a 57-year-old woman. The patient presented with a fulminant respiratory infection unresponsive to treatment requiring intensive care and ventilatory support. The CT scan demonstrated mediastinal and bilateral lymphadenopathy. On peripheral smear a few atypical lymphocytes were visualized. Based on the increasing number of atypical lymphocytes in the daily peripheral bloodsmears, the diagnosis ALCL was suggested. Definitive diagnosis was made on a bone marrow biopsy, with lymphocytes being immunoreactive for CD30, EMA, and ALK. Leukemic peripheral blood involvement in ALCL is an uncommon clinicopathologic entity with unfavorable prognosis. The case we present is perhaps unusual in that a complete respons was achieved, highlighting the importance of prompt diagnosis and judicious management.",
"affiliations": "a Medical Student , UZ Leuven , Leuven , Belgium.;b Department of Hematology , AZ Sint Maarten , Mechelen-Duffel , Belgium.;c Department of Pneumology , AZ Sint Maarten , Mechelen-Duffel , Belgium.;d Department of Pathology , AZ Sint Maarten , Mechelen-Duffel , Belgium.;e Department of Radiology , AZ Sint Maarten , Mechelen-Duffel , Belgium.;f Department of Laboratory Medicine , UZ Leuven , Leuven , Belgium.;g Department of Laboratory Medicine , AZ Sint Maarten , Mechelen-Duffel , Belgium.",
"authors": "Al-Ahmad|Selma|S|;Maertens|Vincent|V|;Libeer|Christophe|C|http://orcid.org/0000-0001-7595-9329;Schelfhout|Vera|V|;Vanhoenacker|Filip|F|;Boeckx|Nancy|N|;Vandevenne|Marleen|M|",
"chemical_list": "C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases",
"country": "England",
"delete": false,
"doi": "10.1080/17843286.2017.1312057",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "72(6)",
"journal": "Acta clinica Belgica",
"keywords": "ALK positive; Anaplastic large cell lymphoma; Leukemic involvement; Respiratory failure",
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000077548:Anaplastic Lymphoma Kinase; D005260:Female; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic; D008875:Middle Aged; D020794:Receptor Protein-Tyrosine Kinases; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "454-460",
"pmc": null,
"pmid": "28441913",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "The masquerading presentation of a systemic anaplastic large cell lymphoma, ALK positive: a case report and review of the literature.",
"title_normalized": "the masquerading presentation of a systemic anaplastic large cell lymphoma alk positive a case report and review of the literature"
} | [
{
"companynumb": "BE-TEVA-2018-BE-861127",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "In the implementation of American Society for Apheresis national guidelines, the decision for therapeutic plasma exchange may be confounded by a clinical presentation that fits both a Category I and IV designation. We report the case of a 45-year-old female who presented with concern for a Category IV disorder, gemcitabine-induced thrombotic microangiopathy, and was ultimately diagnosed with a Category I disorder, idiopathic thrombotic thrombocytopenic purpura. This case highlights the importance of ruling out idiopathic TTP by a thorough evaluation for ADAMTS13 activity and inhibitor, even when an alternate thrombotic microangiopathy diagnosis may be likely.",
"affiliations": "Duke University School of Medicine, Durham, North Carolina.;Department of Medicine, Duke University Medical Center, Durham, North Carolina.;Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.",
"authors": "Bittar|Peter G|PG|http://orcid.org/0000-0001-8243-4408;Nickolich|Myles S|MS|;Onwuemene|Oluwatoyosi A|OA|http://orcid.org/0000-0001-7266-7101",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1002/jca.21590",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-2459",
"issue": "33(3)",
"journal": "Journal of clinical apheresis",
"keywords": "ASFA national guidelines; TMA; TTP; therapeutic plasma exchange",
"medline_ta": "J Clin Apher",
"mesh_terms": "D000071120:ADAMTS13 Protein; D003841:Deoxycytidine; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008875:Middle Aged; D010951:Plasma Exchange; D017410:Practice Guidelines as Topic; D011697:Purpura, Thrombotic Thrombocytopenic; D013921:Thrombocytopenia; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "8216305",
"other_id": null,
"pages": "423-426",
"pmc": null,
"pmid": "28940604",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports",
"references": "25943718;16968717;17613425;15790464;15340761;10223245;27322218;24091354;15197810;10070921;24237646;19203505;14727262;27743743",
"title": "ASFA Category IV becomes Category I: Idiopathic thrombotic thrombocytopenic purpura in a patient with presumed gemcitabine-induced thrombotic microangiopathy.",
"title_normalized": "asfa category iv becomes category i idiopathic thrombotic thrombocytopenic purpura in a patient with presumed gemcitabine induced thrombotic microangiopathy"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201809440",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "This is a report of a case with mucous membrane pemphigoid (MMP) with severe eye involvement and concurrent COVID-19 treated successfully using simultaneous high dose intravenous immunoglobulin (IVIg) and anti-viral treatment as hydroxychloroquine, lopinavir/ritonavir, and ribavirin. He had finished a 2-g cycle of rituximab (RTX) in late January. He was receiving mycophenolate mofetil (MMF) for one month and 30 mg prednisolone for three months until his hospitalization. Prednisolone was tapered to 15 mg when current COVID-19 was suspected, considering his recent cough, dyspnea, and fever.",
"affiliations": "Department of Dermatology, Autoimmune Bullous Diseases Research Center, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Department of Infectious Diseases, Autoimmune Bullous Diseases Research Center, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Department of Dermatology, Autoimmune Bullous Diseases Research Center, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Department of Dermatology, Autoimmune Bullous Diseases Research Center, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Daneshpazhooh|Maryam|M|http://orcid.org/0000-0003-1020-8895;Soori|Tahereh|T|;Isazade|Ahdie|A|;Noormohammadpour|Pedram|P|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D004338:Drug Combinations; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; C558899:lopinavir-ritonavir drug combination; D053139:Oseltamivir; D061466:Lopinavir; D000069283:Rituximab; D011239:Prednisolone; D009173:Mycophenolic Acid; D019438:Ritonavir",
"country": "England",
"delete": false,
"doi": "10.1080/09546634.2020.1764472",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6634",
"issue": "31(5)",
"journal": "The Journal of dermatological treatment",
"keywords": "COVID-19; IVIg; Mucous membrane pemphigoid",
"medline_ta": "J Dermatolog Treat",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D000069340:Deprescriptions; D003924:Diabetes Mellitus, Type 2; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D006801:Humans; D006973:Hypertension; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D007492:Iran; D061466:Lopinavir; D008297:Male; D009173:Mycophenolic Acid; D053139:Oseltamivir; D058873:Pandemics; D010390:Pemphigoid, Benign Mucous Membrane; D011024:Pneumonia, Viral; D011239:Prednisolone; D019438:Ritonavir; D000069283:Rituximab; D000086402:SARS-CoV-2; D036542:Tomography, Spiral Computed",
"nlm_unique_id": "8918133",
"other_id": null,
"pages": "446-447",
"pmc": null,
"pmid": "32363963",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mucous membrane pemphigoid and COVID-19 treated with high-dose intravenous immunoglobulins: a case report.",
"title_normalized": "mucous membrane pemphigoid and covid 19 treated with high dose intravenous immunoglobulins a case report"
} | [
{
"companynumb": "IR-BAUSCH-BL-2020-016515",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Background: Euglycemic diabetic ketoacidosis (euDKA) is a potential side effect associated with inhibitors of the sodium-glucose cotransporter 2 (SGLT-2). This effect is most often recognized during physiologic stress (i.e., sepsis) or in patients who undergo surgery. Case presentations: Case 1: A 66-year-old woman underwent distal pancreatectomy with en bloc splenectomy after presenting with a biopsy-proven pancreatic adenocarcinoma in the body of the pancreas noted incidentally on a screening magnetic resonance imaging for an ovarian mass. The patient had a history of type 2 diabetes mellitus (T2DM) and used canagliflozin, which she was instructed to hold 24 h before surgery. Case 2: A 75-year-old man underwent a pylorus-preserving pancreaticoduodenectomy after presenting with obstructive jaundice. This patient also had a history of T2DM and was on dapagliflozin, which he was also instructed to hold 24 h before surgery. Postoperatively, both patients were diagnosed with euDKA, which was suspected primarily because of intraoperative and postoperative polyuria. Conclusions: SGLT-2 inhibitors are associated with euDKA that can be potentiated in patients who undergo surgery. This medication side effect can be easily unrecognized and potentially lead to significant morbidity.",
"affiliations": "Department of Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.;Department of Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.;Department of Pharmacy, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Department of Pharmacy, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Department of Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.",
"authors": "Pace|Devon J|DJ|;Dukleska|Katerina|K|;Phillips|Samantha|S|;Gleason|Vanessa|V|;Yeo|Charles J|CJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/pancan.2018.0016",
"fulltext": "\n==== Front\nJ Pancreat CancerJ Pancreat CancerpancanJournal of Pancreatic Cancer2475-3246Mary Ann Liebert, Inc., publishers 140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA 10.1089/pancan.2018.001610.1089/pancan.2018.0016Case ReportEuglycemic Diabetic Ketoacidosis Due to Sodium–Glucose Cotransporter 2 Inhibitor Use in Two Patients Undergoing Pancreatectomy Pace Devon J. 1Dukleska Katerina 1Phillips Samantha 2Gleason Vanessa 2Yeo Charles J. 1,*1 Department of Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.2 Department of Pharmacy, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.* Address correspondence to: Charles J. Yeo, MD, Department of Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, 1015 Walnut Street, Curtis Building, Suite 620, Philadelphia, PA 19107, charles.yeo@jefferson.edu15 11 2018 2018 15 11 2018 4 1 95 99 © Devon J. Pace et al. 2018; Published by Mary Ann Liebert, Inc.2018This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract\nBackground: Euglycemic diabetic ketoacidosis (euDKA) is a potential side effect associated with inhibitors of the sodium–glucose cotransporter 2 (SGLT-2). This effect is most often recognized during physiologic stress (i.e., sepsis) or in patients who undergo surgery.\n\nCase presentations: Case 1: A 66-year-old woman underwent distal pancreatectomy with en bloc splenectomy after presenting with a biopsy-proven pancreatic adenocarcinoma in the body of the pancreas noted incidentally on a screening magnetic resonance imaging for an ovarian mass. The patient had a history of type 2 diabetes mellitus (T2DM) and used canagliflozin, which she was instructed to hold 24 h before surgery. Case 2: A 75-year-old man underwent a pylorus-preserving pancreaticoduodenectomy after presenting with obstructive jaundice. This patient also had a history of T2DM and was on dapagliflozin, which he was also instructed to hold 24 h before surgery. Postoperatively, both patients were diagnosed with euDKA, which was suspected primarily because of intraoperative and postoperative polyuria.\n\nConclusions: SGLT-2 inhibitors are associated with euDKA that can be potentiated in patients who undergo surgery. This medication side effect can be easily unrecognized and potentially lead to significant morbidity.\n\nKeywords: \ncanagliflozindapagliflozindistal pancreatectomyeuglycemic DKApancreatic cancerpancreaticoduodenectomySGLT-2 inhibitor\n==== Body\nIntroduction\nEuglycemic diabetic ketoacidosis (euDKA) is an underrecognized phenomenon associated with the use of SGLT-2 inhibitors in the perioperative period.1 Sodium–glucose cotransporter 2 (SGLT-2) inhibitors are oral hypoglycemic agents that promote glucosuria by inhibiting the renal glucose reabsorption in the proximal convoluted tubule.2 They are approved and indicated for use in patients with type 2 diabetes mellitus (T2DM) as adjunctive therapies to improve glycemic control.3 In this study, we present two patients who underwent a pancreatectomy for pancreatic adenocarcinoma complicated by the development of euDKA because of preoperative use of SGLT-2 inhibitors.\n\nCase Presentations\nCase 1\nThe patient is a 66-year-old woman who initially presented with an incidental finding of a body of pancreas mass on magnetic resonance imaging for follow-up of a stable ovarian cyst. Computed tomography redemonstrated a hypodense mass in the body of the pancreas (Fig. 1). Fine-needle aspiration biopsies returned positive for pancreatic adenocarcinoma. There was no evidence of dissemination, and baseline tumor markers were within normal range. Her medical history was notable for T2DM on canagliflozin and sitagliptin. Her preoperative hemoglobin A1c (HbA1c) was 8.2%. The patient was offered surgical resection and was instructed to hold all oral hypoglycemic agents 24 h before surgery.\n\nFIG. 1. Relevant imaging for case 1: select CT imaging demonstrating a hypoattenuating and hypoenhancing lesion in the body of the pancreas (red arrow). CT, computed tomography.\n\nShe underwent an uncomplicated distal pancreatectomy with en bloc splenectomy. Over the first 12 h after surgery, it was noted that the patient had polyuria (urine output range: 100–325 mL/h). On routinely obtained serial laboratory analyses, the serum bicarbonate level was noted to be consistently low in the setting of anion gap and absence of lactic acidosis (Table 1).\n\nTable 1. Overview of Laboratory Trends in 6 h Increments Postoperatively for Case 1: Euglycemic Diabetic Ketoacidosis was Suspected 16 h Postoperatively\n\n \t0 h\t6 h\t12 h\t18 h\t24 h\t30 h\t\nSerum carbon dioxide (reference range: 24–32 mmol/L)\t20\t16\t14\t15\t20\t20\t\nAnion gap (reference range: 4–16 mmol/L)\t16\t19\t20\t19\t10\t9\t\nβ-Hydroxybutyrate (reference range: 0.2–2.8 mg/dL)\tn/a\tn/a\tn/a\t48.1\t7.7\t3.4\t\nGlucose (reference range: 70–100 mg/dL)\t159\t165\t155\t224\t143\t153\t\nUrinalysis (reference ranges: ketone—negative)\tn/a\tn/a\tn/a\t2+ Ketone bodies\t1+ Ketone bodies\tTrace ketone bodies\t\nn/a, not available.\n\nThere was suspicion that the patient may be developing euDKA because of her use of canagliflozin. A serum β-hydroxybutyrate was obtained and it was markedly elevated at 48.1 mg/dL (reference range: 0.2–2.8 mg/dL). A urinalysis was performed that demonstrated glucosuria and ketonuria. Up to this point, the patient's serum glucose level was only modestly elevated (range: 155–224 mg/dL).\n\nAfter the recognition of euDKA, an intravenous insulin infusion was initiated and the patient was fluid resuscitated. Within 10 h after such treatment, there was improvement in the β-hydroxybutyrate levels, the anion gap normalized, and the urinalysis only demonstrated trace ketone bodies (Table 1). The remainder of the patient's postoperative course was uncomplicated and she was discharged on postoperative day 5 (POD 5).\n\nHer final pathology revealed poorly differentiated invasive ductal carcinoma, with 2 of 13 specimen lymph nodes containing metastatic cancer. The patient was educated regarding the benefit of postoperative adjuvant chemotherapy.\n\nCase 2\nThe patient is a 75-year-old man who initially presented with obstructive jaundice and elevated liver function tests. He underwent an endoscopic ultrasound, which demonstrated a mass in the head of the pancreas with an associated bile duct stricture. Endoscopic retrograde cholangiography was performed, with biliary endoprosthesis placement. He had no evidence of metastatic disease on axial imaging, and although there was no identifiable pancreatic mass, the patient did have a double duct sign (Fig. 2). His medical history was notable for T2DM on dapagliflozin, glipizide, metformin, and liraglutide. His preoperative HbA1c was 7.3%.\n\nFIG. 2. Relevant imaging for case 2: select contrast-enhanced CT imaging demonstrating a double duct sign (red arrow) where both the common bile duct and main pancreatic duct are simultaneously visualized and dilated.\n\nThe patient was offered surgical resection and was instructed to hold all oral hypoglycemic agents 24 h before surgery. He underwent an uncomplicated pylorus preserving pancreaticoduodenectomy. Over the first 12 h after surgery, it was noted that the patient had polyuria (urine output range: 150–300 mL/h). On routinely obtained serial laboratory analysis, the serum bicarbonate level was noted to be consistently low in the setting of a normal anion gap and absence of a lactic acidosis (Table 2).\n\nTable 2. Overview of Laboratory Trends in 6 h Increments Postoperatively for Case 2: Euglycemic Diabetic Ketoacidosis was Suspected 16 h Postoperatively\n\n \t0 h\t6 h\t12 h\t18 h\t24 h\t30 h\t\nSerum carbon dioxide (reference range: 24–32 mmol/L)\t17\t16\t15\t16\t15\t22\t\nAnion gap (reference range: 4–16 mmol/L)\t15\t15\t14\t19\t14\t9\t\nβ-Hydroxybutyrate (reference range: 0.2–2.8 mg/dL)\t31.8\t36.2\t42.8\t50.8\t14.3\t8.9\t\nGlucose (reference range: 70–100 mg/dL)\t158\t173\t169\t225\t182\t164\t\nUrinalysis (reference range: ketone—negative)\tn/a\tn/a\tn/a\t3+ Ketone bodies\t1+ Ketone bodies\tNegative for ketone bodies\t\nRetrospectively obtained β-hydroxybutyrate levels were elevated immediately postoperatively, despite a normal anion gap.\n\nThere was suspicion that the patient may be developing euDKA because of his use of dapagliflozin. A serum β-hydroxybutyrate was obtained and it was markedly elevated at 50.8 mg/dL (reference range: 0.2–2.8 mg/dL). It was only at that time that the patient had an abnormal anion gap of 19 mmol/L. A urinalysis was performed that demonstrated glucosuria and ketonuria. Up to this point, the patient's serum glucose level was only modestly elevated (range: 158–225 mg/dL). β-Hydroxybutyrate levels were retrospectively obtained on POD 1 by analyzing samples that were routinely collected on POD 0, which demonstrated that they were consistently elevated postoperatively in the setting of a normal anion gap.\n\nAfter the recognition of euDKA, an intravenous insulin infusion was initiated and the patient was fluid resuscitated. Within 12 h after such treatment, there was improvement in the β-hydroxybutyrate levels, the anion gap normalized, and the urinalysis was negative for ketone bodies. The remainder of the patient's postoperative course was uncomplicated and he was discharged on POD 6.\n\nHis final pathology revealed moderately differentiated pancreatic ductal adenocarcinoma, with metastatic carcinoma identified in 2 of 14 specimen lymph nodes. He was also educated regarding the benefits of postoperative adjuvant chemotherapy.\n\nConclusions\nPancreatectomy is a complex abdominal procedure associated with numerous complications in up to 50% of patients, and mortality in 0.5–5% of patients. Common complications of pancreatectomy include delayed gastric emptying, pancreatic fistula formation, hemorrhage, intraabdominal abscess, and many others.4 Uncommon findings of postpancreatectomy are polyuria, glucosuria, ketonuria, and acidosis. Therefore, when present, these findings should alert clinicians to investigate the causes unrelated to surgery. The two patients discussed previously manifested these uncommon postpancreatectomy findings and, to our knowledge, these are the first reports to describe euDKA in patients who underwent pancreatectomy as a consequence of SGLT-2 inhibitor use.\n\neuDKA was first described in 1973 in a report that described a series of 37 episodes of severe ketosis in patients with normal or modestly elevated serum glucose levels.5 This condition continues to be a diagnostic challenge because the euglycemia oftentimes obscures the underlying ketosis. SGLT-2 inhibitors are a class of oral hypoglycemics that have been shown to improve glycemic control in patients with T2DM.3 However, in 2015, the Food and Drug Administration released a communication describing the risk of euDKA associated with SGLT-2 inhibitors.1 This risk is increased in the setting of physiologic stress and surgery that has resulted in the recommendation for these medications to be held 24–72 h preoperatively.2,6 Ketosis and particularly euDKA seems to specifically be associated with dual SGLT-1/2 inhibitors and SLGT-2 inhibitors. To our knowledge, none of the other patients' home medications or other oral hypoglycemics have been reported to be associated with euDKA. Of importance, other oral hypoglycemics such as glucagon-like peptide-1 receptor agonists or dipeptidyl peptidase-4 inhibitors have been associated with pancreatitis and heart failure, respectively.7,8 Therefore, it is important for clinicians to be aware of these rare but important serious medication side effects.\n\nThe mechanism of action for SGLT-2-induced euDKA is attributed to increased lipolysis and fatty acid oxidation because of a reduced plasma insulin-to-glucagon ratio, resulting in increased ketone body production and increased ketone body reabsorption in the kidney (Fig. 3).2,9 This, along with the metabolic stress of surgery combined with prolonged fasting, increases the risk of SGLT-2-induced euDKA.2,10 In this case series, we present two patients with euDKA associated with canagliflozin and dapagliflozin use, and a delay in recognition. In part, this delay was because of normal glucose levels and in the second case, an initially normal anion gap.\n\nFIG. 3. Proposed mechanism for the development of euglycemic diabetic ketoacidosis in patients exposed to SGLT-2 inhibitors. SGLT-2, sodium–glucose cotransporter 2.\n\nTo avoid this complication, we recommended that SGLT-2 inhibitors be held at least 5 days preoperatively. Based upon the relatively long half-life of these medications (11–13 h), the drug effect should be absent after 5 days and the risk of euDKA should be reduced. Clinicians must also be mindful that the half-life of SGLT-2 inhibitors can be prolonged in patients with diminished renal function, and the drug effect in this instance may still be present even after the medication is held for 5 days.2 These cases underscore the importance of a having a high clinical suspicion for euDKA in patients who are taking SGLT-2 inhibitors who undergo surgery, even in the absence of an anion gap.\n\nAuthor Disclosure Statement\nNo competing financial interests exist.\n\n\nCite this article as: Pace DJ, Dukleska K, Phillips S, Gleason V, Yeo CJ (2018) Euglycemic diabetic ketoacidosis due to sodium–glucose cotransporter 2 inhibitor use in two patients undergoing pancreatectomy, Journal of Pancreatic Cancer 4:1, 95–99, DOI: 10.1089/pancan.2018.0016.\n\nAbbreviations Used\nCTcomputed tomography\n\neuDKAeuglycemic diabetic ketoacidosis\n\nHbA1chemoglobin A1c\n\nSGLT-2sodium-glucose cotransporter 2\n\nT2DMtype 2 diabetes mellitus\n==== Refs\nReferences\n1 Food and Drug Administration (FDA) . FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood . Issued \n5 \n15 , 2015 .\n2 Milder DA , Milder TY , Kam PCA \nSodium-glucose co-transporter type-2 inhibitors: pharmacology and peri-operative considerations . Anaesthesia . 2018 ;73 :1008 –1018 29529345 \n3 Molugulu N , Yee LS , Ye YT , et al. \nSystematic review of metformin monotherapy and dual therapy with sodium glucose co-transporter 2 inhibitor (SGLT-2) in treatment of type 2 diabetes mellitus . Diabetes Res Clin Pract . 2017 ;132 :157 –168 28797524 \n4 Winter JM , Cameron JL , Campbell KA , et al. \n1423 pancreaticoduodenectomies for pancreatic cancer: a single-institution experience . J Gastrointest Surg . 2006 ;10 :1199 –1210 ; discussion 1210–1211. 17114007 \n5 Munro JF , Campbell IW , McCuish AC , et al. \nEuglycaemic diabetic ketoacidosis . Br Med J . 1973 ;2 :578 –580 4197425 \n6 Handelsman Y , Henry RR , Bloomgarden ZT , et al. \nAmerican Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis . Endocr Pract . 2016 ;22 :753 –762 27082665 \n7 Egan AG , Blind E , Dunder K , et al. \nPancreatic safety of incretin-based drugs—FDA and EMA assessment . N Engl J Med . 2014 ;370 :794 –797 24571751 \n8 Food and Drug Administration (FDA) . FDA drug safety communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin . 2016 \n9 Qiu H , Novikov A , Vallon V \nKetosis and diabetic ketoacidosis in response to SGLT2 inhibitors: basic mechanisms and therapeutic perspectives . Diabetes Metab Res Rev . 2017 ;33 :e2886 \n10 Blau JE , Tella SH , Taylor SI , et al. \nKetoacidosis associated with SGLT2 inhibitor treatment: analysis of FAERS data . Diabetes Metab Res Rev . 2017 ;33 . doi:10.1002/dmrr.2924\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2475-3246",
"issue": "4(1)",
"journal": "Journal of pancreatic cancer",
"keywords": "SGLT-2 inhibitor; canagliflozin; dapagliflozin; distal pancreatectomy; euglycemic DKA; pancreatic cancer; pancreaticoduodenectomy",
"medline_ta": "J Pancreat Cancer",
"mesh_terms": null,
"nlm_unique_id": "101703452",
"other_id": null,
"pages": "95-99",
"pmc": null,
"pmid": "30631862",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "17114007;24571751;27082665;28099783;28736981;28797524;29529345;4197425",
"title": "Euglycemic Diabetic Ketoacidosis Due to Sodium-Glucose Cotransporter 2 Inhibitor Use in Two Patients Undergoing Pancreatectomy.",
"title_normalized": "euglycemic diabetic ketoacidosis due to sodium glucose cotransporter 2 inhibitor use in two patients undergoing pancreatectomy"
} | [
{
"companynumb": "US-JNJFOC-20181204862",
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"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CANAGLIFLOZIN"
},
"drugadditional": "3",
... |
{
"abstract": "Although several chemotherapeutic agents have been proven to be safe for the fetus after the organogenesis period, there is limited information on their use during the first trimester of pregnancy. We here report the first case of a patient with lung cancer who was treated with platinum-based chemotherapy from the first trimester of an unrecognized pregnancy. A 35-year-old woman was diagnosed with stage IV non-small cell lung cancer with brain metastasis. Since she recalled the date of her last menstrual period at about 20 days prior to consult, we did not consider the possibility of conception at the time of diagnosis. With an object of controlling the increased intracranial pressure, we initially performed a craniotomy with tumor removal, followed by whole brain irradiation. Without our knowledge of her pregnancy, she received a palliative chemotherapy with docetaxel and cisplatin followed by gemcitabine and cisplatin as the second-line chemotherapeutic agents between weeks 9 and 22 of gestation. Follow-up computed tomographic scans performed 2 months after the last chemotherapy showed a fetus in the patient's abdomen. Cesarean section was performed at 33 weeks of gestation, delivering a 1490 g female newborn with no evidence of congenital malformations.",
"affiliations": "Division of Hematology and Oncology, Department of Internal Medicine, Hallym University College of Medicine, Seoul, Republic of Korea. harricil@hotmail.com",
"authors": "Kim|Jung Han|JH|;Kim|Hyeong Su|HS|;Sung|Chong Won|CW|;Kim|Keong Ju|KJ|;Kim|Chang Hyun|CH|;Lee|Keun Young|KY|",
"chemical_list": "D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D011838:Radiation-Sensitizing Agents; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C056507:gemcitabine; D012264:Ribonucleotide Reductases; D002945:Cisplatin",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2007.06.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "59(2)",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": null,
"medline_ta": "Lung Cancer",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D001932:Brain Neoplasms; D002289:Carcinoma, Non-Small-Cell Lung; D002945:Cisplatin; D003841:Deoxycytidine; D003937:Diagnosis, Differential; D000077143:Docetaxel; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D008175:Lung Neoplasms; D009367:Neoplasm Staging; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First; D011262:Pregnancy Trimester, Second; D011838:Radiation-Sensitizing Agents; D012264:Ribonucleotide Reductases; D043823:Taxoids; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "270-3",
"pmc": null,
"pmid": "17688967",
"pubdate": "2008-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Docetaxel, gemcitabine, and cisplatin administered for non-small cell lung cancer during the first and second trimester of an unrecognized pregnancy.",
"title_normalized": "docetaxel gemcitabine and cisplatin administered for non small cell lung cancer during the first and second trimester of an unrecognized pregnancy"
} | [
{
"companynumb": "KR-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-112886",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
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"druga... |
{
"abstract": "Background Anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) combined with mTOR inhibitors, like everolimus, result in significant responses and prolonged progression-free survival (PFS) among patients with renal cell carcinoma (RCC) [1]. However, everolimus doses >5 mg are often not tolerated when combined with other TKIs2,3. Vorolanib (X-82), an oral anti-VEGFR/platelet derived growth factor receptor (PDGFR)/colony stimulating factor 1 receptor (CSF1R) multitarget TKI, has a short half-life and limited tissue accumulation. We conducted a Phase 1 study of vorolanib with everolimus (10 mg daily) in patients with solid tumors. Methods A 3 + 3 dose escalation design was utilized to determine dose limiting toxicities (DLT) and recommended Phase 2 dose (RP2D) of vorolanib/everolimus. Oral vorolanib at 100, 150, 200, 300, or 400 mg was combined with 10 mg oral everolimus daily. The phase 2 portion was terminated after enrolling two patients due to funding. Results Eighteen patients were evaluable for DLT among 22 treated subjects. Observed DLTs were grade 3 fatigue, hypophosphatemia, and mucositis. The RP2D is vorolanib 300 mg with everolimus 10 mg daily. In 15 patients evaluable for response, three had partial response (PR; 2 RCC, 1 neuroendocrine tumor [NET]) and eight had stable disease (SD; 2 RCC, 6 NET). Conclusions Vorolanib can safely be combined with everolimus. Encouraging activity is seen in RCC and NET. Further studies are warranted. Trial Registration Number: NCT01784861.",
"affiliations": "Division of Oncology, Washington University, St. Louis, MO, USA.;Division of Oncology, Washington University, St. Louis, MO, USA.;Division of Oncology, Washington University, St. Louis, MO, USA.;Division of Medical Oncology, University of Miami, Miami, FL, USA.;Division of Oncology, Washington University, St. Louis, MO, USA.;Division of Public Health Sciences, Washington University, St. Louis, MO, USA.;Division of Oncology, Washington University, St. Louis, MO, USA.;Division of Oncology, Vanderbilt University, Nashville, TN, USA.;Division of Oncology, Washington University, St. Louis, MO, USA.;Xcovery, Palm Beach Gardens, FL, USA.;Division of Oncology, Washington University, St. Louis, MO, USA.;Division of Oncology, Washington University, St. Louis, MO, USA. btan@wustl.edu.",
"authors": "Pedersen|Katrina S|KS|http://orcid.org/0000-0003-2793-6901;Grierson|Patrick M|PM|;Picus|Joel|J|;Lockhart|A Craig|AC|;Roth|Bruce J|BJ|;Liu|Jingxia|J|;Morton|Ashley|A|;Chan|Emily|E|;Huffman|Jesse|J|;Liang|Chris|C|;Wang-Gillam|Andrea|A|;Tan|Benjamin|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-021-01093-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6997",
"issue": "39(5)",
"journal": "Investigational new drugs",
"keywords": "Everolimus; Neuroendocrine carcinoma; Phase 1; Renal cell carcinoma; Vorolanib; X-82",
"medline_ta": "Invest New Drugs",
"mesh_terms": null,
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "1298-1305",
"pmc": null,
"pmid": "33738668",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "26482279;19293676;12861060;16226705;18323556;18936475;20368553;15728109;28283069;18653228;27621394;30478190;21898375;24685058;25488966;25426617;32335374",
"title": "Vorolanib (X-82), an oral anti-VEGFR/PDGFR/CSF1R tyrosine kinase inhibitor, with everolimus in solid tumors: results of a phase I study.",
"title_normalized": "vorolanib x 82 an oral anti vegfr pdgfr csf1r tyrosine kinase inhibitor with everolimus in solid tumors results of a phase i study"
} | [
{
"companynumb": "US-NOVARTISPH-NVSC2022US015913",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Percutaneous transluminal coronary angioplasty with metal stent placement has become a well-developed treatment modality for coronary stenotic lesions. Although infection involving implanted stents is rare, it can, however, occur with high morbidity and mortality. We describe herein a case of an inserted coronary stent that was infected and complicated with recurrent stent thrombosis, pseudoaneurysm formation and severe sepsis. Despite repeated intervention and bypass surgery, the patient died from severe sepsis.",
"affiliations": "Division of Interventional Cardiology, Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.;Division of Cardiovascular Surgery, Department of Surgery, Feng Yuan Hospital, Taichung, Taiwan, R.O.C.;Division of Interventional Cardiology, Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.;Division of Interventional Cardiology, Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C. wcchangvghtc@gmail.com.",
"authors": "Lai|Chih Hung|CH|;Lin|Yung Kai|YK|;Lee|Wen Lieng|WL|;Chang|Wei Chun|WC|",
"chemical_list": "D008670:Metals",
"country": "Korea (South)",
"delete": false,
"doi": "10.3349/ymj.2017.58.2.458",
"fulltext": "\n==== Front\nYonsei Med JYonsei Med. JYMJYonsei Medical Journal0513-57961976-2437Yonsei University College of Medicine 2812058010.3349/ymj.2017.58.2.458Case ReportOncologyCoronary Stent Infection Presented as Recurrent Stent Thrombosis Lai Chih-Hung 12Lin Yung-Kai 3Lee Wen-Lieng 12Chang Wei-Chun 11 Division of Interventional Cardiology, Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.2 School of Medicine, National Yang-Ming University, Taipei, Taiwan, R.O.C.3 Division of Cardiovascular Surgery, Department of Surgery, Feng Yuan Hospital, Taichung, Taiwan, R.O.C.\nCorresponding author: Dr. Wei-Chun Chang, Division of Interventional Cardiology, Cardiovascular Center, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung, Taiwan 40705, R.O.C. Tel: 886-4-23592525, Fax: 886-4-23595046, wcchangvghtc@gmail.com01 3 2017 16 1 2017 58 2 458 461 28 7 2015 04 12 2015 17 12 2015 © Copyright: Yonsei University College of Medicine 20172017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Percutaneous transluminal coronary angioplasty with metal stent placement has become a well-developed treatment modality for coronary stenotic lesions. Although infection involving implanted stents is rare, it can, however, occur with high morbidity and mortality. We describe herein a case of an inserted coronary stent that was infected and complicated with recurrent stent thrombosis, pseudoaneurysm formation and severe sepsis. Despite repeated intervention and bypass surgery, the patient died from severe sepsis.\n\nStent infectionpseudoaneurysmstent thrombosisgraft stentacute myocardial infarction\n==== Body\nINTRODUCTION\nPercutaneous transluminal coronary angioplasty (PTCA) with metal stent placement has become a well-developed treatment modality for coronary stenotic lesions. Although infection involving implanted stent is rare, it can, however, occur with high morbidity and mortality.1 We describe an inserted coronary stent that was infected and complicated with recurrent stent thrombosis, pseudoaneurysm formation and severe sepsis. In an effort to raise awareness of the possible fatal outcome of this situation, we herein report our experience.\n\nCASE REPORT\nA 69-year-old male with a history of hypertension, type 2 diabetes mellitus, and ischemic heart failure (ejection fraction: 32%), was admitted to our hospital to receive transurethral resection of prostate (TURP) for benign prostatic hyperplasia with prophylactic antibiotic with intravenous cefazolin. Before operation, there was no symptom of heart failure and the radiography of chest revealed no pulmonary congestion or edema. After TURP, non-ST elevation myocardial infarction with acute pulmonary edema and respiratory failure developed and, for this reason, intubation was performed. Echocardiography showed hypokinesia in inferior and anterior wall with severe left ventricle systolic dysfunction (ejection fraction: 36%), and electrocardiogram revealed sinus rhythm with premature ventricle beat and left ventricle hypertrophy. Aspirin and clopidogrel were given for myocardial infarction, diuretic agents were given for heart failure, and adequate antibiotic (Piperacillin-tazobactam) was given for superimposed pneumonia. After these therapies, there was no fever and C-reactive protein level decreased apparently, suggesting that the infection was under control, however, pulmonary edema still had poor response to diuretic. Nevertheless, because of severe cardiac dysfunction with difficulty weaning off the ventilator, coronary angiography was done 2 weeks later and revealed triple vessels disease, mainly with distal left main (LM) stenosis and chronic total occlusion of the distal right coronary artery (RCA) (Fig. 1A and B) (Supplementary Video 1, only online). Because of high surgical mortality, the patient refused coronary bypass surgery (CABG), and staged PTCA was planned instead. It was done with two drug eluting stents (DES) (Everolimus-eluting stents: Promus element 2.5×38 mm and Promus element 3.0×38 mm, Boston Scientific, Natick, MA, USA) being inserted in the distal RCA (Fig. 1C). One week later, PTCA of the left side was done, with one bare metal stent (Liberte 2.5×20 mm, Boston Scientific) being put in the middle left circumflex artery (LCX), one DES (Promus element 2.75×32 mm, Boston Scientific) in the middle left anterior coronary artery (LAD), and the other DES (Promus element 3.5×20 mm, Boston Scientific) in the LM to the proximal LAD (Fig. 1D, E, and F) (Supplementary Video 2, only online). After the PTCA, the patient's condition improved, and he was successfully weaned from the ventilator and continually received dual antiplatelet medications with aspirin and clopidogrel. However, a fever developed 4 days later. One week after the procedure, chest pain and acute ST elevation myocardial infarction developed. Emergent angiography revealed subacute stent thrombosis and pseudoaneurysm formation at the distal LM stent (Fig. 2A and B) (Supplementary Video 3, only online). Manual thrombus aspiration was performed and some pus-like debris was noted (Fig. 2C). Bacterial culture of the debris was also done. After the PTCA, the flow was restored and the intravenous glycoprotein IIb/IIIa inhibitor (tirofiban hydrochloride) and heparin (350 U/hour) were also given, accompanied with dual anti-platelet medications, but concurrent fever and persisting bacteremia were also noted. Methicillin-resistant Staphylococcus aureus (MRSA) was observed in both the blood culture and bacterial culture of pus-like debris. By the suggestion of infection specialist, antibiotic with Tigecycline (initial dose 100 mg, followed by 50 mg every 12 hours) was given. One day after the emergent PTCA, chest pain and recurrent ST elevation myocardial infarction developed again. A repeated angiography revealed recurrent stent thrombosis and progression of LM pseudoaneurysm (Fig. 2D) (Supplementary Video 4, only online). Mycotic pseudoaneurysm was diagnosed, and emergent CABG was performed with one great saphenous venous graft from aortic root to distal LAD and the other saphenous venous graft from aortic root to first obtuse marginal branch of LCX. However, the infected DES was not removed by surgeon due to high mortality risk. One day after the CABG, graft stents (GraftMaster 3.0×19 mm and 3.5×19 mm, Abbott, Santa Clara, CA, USA) were been put in the LM to the proximal LAD in case of rupture of the pseudoaneurysm (Fig. 2E to F). Despite the above aggressive therapy, intermittent fever persisted and the patient died due to severe sepsis with multiple organ failure ten days later.\n\nDISCUSSION\nIn a recent review by Bosman et al. in 2014, 77 cases of metal stent infections (including coronary and peripheral stents) were reported and only 29 of them were found to have coronary stent infection.1 Despite the combined efforts of medical and surgical therapy, the mortality rate has been reported to be 38.9%.1 Therefore, infections involving an inserted stent are quite rare, nevertheless, the outcome is highly fatal. Even though stent infection is rare, we still need to pay close attention to its possibility.\n\nThe exact mechanism of stent infections remains unclear: is it a result of infection at the time of stent placement, or subsequent in stent balloon angioplasty, or of a hematogenous spread from another source of bacteremia? However, with the popular use of DES, the reports of stent infection have increased. It seems that the inhibition of neointimal growth may lead to the metallic stent remaining uncovered intraluminally, thereby forming a nidus for the adhesion of bacteria, especially in late stent infection.2 In addition to patient and stent-related risk factors, it is generally believed that risk factors of procedure–including imperfect sterility of procedure, prolonged use of indwelling catheter, and extensive changing of wires–also play an important role in early stent infection.1\n\nMore than half (57%) of PTCA cases have been reported to present with symptoms within the first month after stent placement,1 with the most common symptoms and signs being fever (93%), chills (41%), and local pain/chest pain (51.7%). Furthermore, almost 80% of image study in coronary stent infections revealed pseudoaneurysm.1 To our best knowledge, this is the first report of a PTCA patient presenting as recurrent stent thrombosis, showing that the occlusions might be caused by septic emboli or infection-related hypercoagulopathy, or both. Physicians should be aware that the stent thrombosis could be caused by stent infection, if it comes with signs of infection.\n\nThe majority of patients received emergency surgical therapy (62%) and ninety four percent (94%) of these cases also had their stents removed.1 However, the outcome was poor: the mortality in the surgery group was the lowest (38.9%), followed by the endovascular-treated group (50%) and the intravenous antibiotic only group (63.3%). The antibiotic-only therapy carries an overly high mortality. Therefore, if there are other treatment options, we recommend their combination with antibiotics. To the best of our knowledge, there have been only two case reports on endovascular therapy, and one patient succumbed to sudden death after discharge.34 In the present case of recurrent acute stent thrombosis and persistent septic shock, the cover stent or prolongation inflation might have solved the problem of perforation, perhaps even preventing further stent thrombosis. However, it could not control the progression of sepsis, because of the residual infection from the remained infected stent. Furthermore, cover stent carries risks of in-stent restenosis and possible stent thrombosis in the future. For similar cases in the future, we would suggest that surgical therapy with the removal of stent probably is the best choice. If this is not possible, however, endovascular therapy with cover stent and adequate antibiotic and anti-platelet, even anti-coagulant, may be the most reasonable second choice.\n\nThe authors have no financial conflicts of interest.\n\nSUPPLEMENTARY DATA\nVideo 1\nCoronary angiography of left coronary artery.\n\n Video 2\nAfter stenting of all lesions in left coronary artery.\n\n Video 3\nOne week after angioplasty, the emergent angiography shows stent thrombosis in the proximal LAD stent and coronary pseudoaneurysm in the distal LM.\n\n Video 4\nSecond time emergent angiography reveals recurrent stent thrombosis and rapid progression of LM pseudoaneurysm.\n\n Fig. 1 Serial angiography of first time intervention. (A) Right oblique caudal view of left coronary artery shows severe stenosis of distal left main (LM, arrow) and proximal left circumflex artery. (B) Diffuse stenosis and distal total occlusion of right coronary artery (RCA). (C) Angiography of RCA after stenting. (D) Stent deployed from LM to proximal left anterior descending artery (arrow). (E) Right oblique caudal view of left coronary artery after stenting (arrow: LM stenting). (F) Spider view of left coronary artery after stenting.\nFig. 2 (A, B, and C) Emergent angioplasty for first time stent thrombosis. (D) Emergent angioplasty for second time stent thrombosis. (E and F) Putting a graft stent. (A) Right oblique cranial view of left coronary artery shows stent thrombosis in proximal LAD (arrowheads) and pseudoaneurysm in distal LM (arrow). (B) Spider view of left coronary artery shows coronary pseudoaneurysm in distal LM (arrow). (C) Material from manual thrombus aspirator reveals thrombi with pus like material (arrow). (D) One day later, emergent angiography shows recurrent in stent thrombosis (arrowheads) and progression of coronary pseudoaneurysm in distal LM (arrow). (E) Graft stent being inserted from LM to proximal LAD (stent margin marked as arrowheads) to cover coronary pseudoaneurysm (arrow). (F) After inserting graft stent, angiography of left coronary artery reveals complete jailing of LCX. LAD, left anterior descending artery; LM, left main; LCX, left circumflex artery.\n==== Refs\n1 Bosman WM Borger van der Burg BL Schuttevaer HM Thoma S Hedeman Joosten PP Infections of intravascular bare metal stents: a case report and review of literature Eur J Vasc Endovasc Surg 2014 47 87 99 24239103 \n2 Roubelakis A Rawlins J Baliulis G Olsen S Corbett S Kaarne M Coronary artery rupture caused by stent infection: a rare complication Circulation 2015 131 1302 1303 25847982 \n3 Wu EB Chan WW Yu CM Left main stem rupture caused by methicillin resistant Staphylococcus aureus infection of left main stent treated by covered stenting Int J Cardiol 2010 144 e39 e41 19176250 \n4 Garg RK Sear JE Hockstad ES Spontaneous coronary artery perforation secondary to a sirolimus-eluting stent infection J Invasive Cardiol 2007 19 E303 E306 17906356\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0513-5796",
"issue": "58(2)",
"journal": "Yonsei medical journal",
"keywords": "Stent infection; acute myocardial infarction; graft stent; pseudoaneurysm; stent thrombosis",
"medline_ta": "Yonsei Med J",
"mesh_terms": "D015906:Angioplasty, Balloon, Coronary; D023921:Coronary Stenosis; D017809:Fatal Outcome; D006801:Humans; D008670:Metals; D012008:Recurrence; D018805:Sepsis; D015607:Stents; D013927:Thrombosis; D016896:Treatment Outcome",
"nlm_unique_id": "0414003",
"other_id": null,
"pages": "458-461",
"pmc": null,
"pmid": "28120580",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports",
"references": "17906356;19176250;24239103;25847982",
"title": "Coronary Stent Infection Presented as Recurrent Stent Thrombosis.",
"title_normalized": "coronary stent infection presented as recurrent stent thrombosis"
} | [
{
"companynumb": "TW-PFIZER INC-2017094411",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TIGECYCLINE"
},
"drugadditional": "3",
... |
{
"abstract": "A previously high-functioning woman presents with clinical and CT features of a subacute ischaemic stroke. Her medical history is relevant for refractory giant cell arteritis on long-term high-dose prednisolone and recent commencement of tocilizumab (interleukin-6 monoclonal antibody). The potential for stroke mimic is considered and a magnetic resonance brain scan is requested. She rapidly deteriorates within 24 hours of admission and unexpectantly dies. An autopsy reveals that she has bilateral pulmonary emboli with lower limb deep vein thrombosis and Pseudomonas meningoencephalitis with frank pus on the brain. We discuss the potential risks of immunosuppression and the role of imaging in the diagnosis of stroke.",
"affiliations": "Royal Melbourne Hospital, Parkville, Victoria, Australia.;Austin Health, Heidelberg, Victoria, Australia.;Box Hill Hospital, Box Hill, Victoria, Australia.",
"authors": "Williams|Cameron J|CJ|http://orcid.org/0000-0003-4952-8896;Foote|Andrew|A|;Choi|Philip|P|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227296",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(1)",
"journal": "BMJ case reports",
"keywords": "biological agents; neuroimaging; stroke",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D001921:Brain; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008590:Meningoencephalitis; D011552:Pseudomonas Infections; D011655:Pulmonary Embolism; D020521:Stroke; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D020246:Venous Thrombosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30696642",
"pubdate": "2019-01-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23449259;28745999;20625171;9707216;28485026",
"title": "Pseudomonas meningoencephalitis masquerading as a stroke in a patient on tocilizumab.",
"title_normalized": "pseudomonas meningoencephalitis masquerading as a stroke in a patient on tocilizumab"
} | [
{
"companynumb": "AU-BAUSCH-BL-2019-005644",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": null,
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthori... |
{
"abstract": "Merkel cell carcinoma (MCC) is a rare, aggressive primary neuroendocrine carcinoma of the skin that can present in immunocompromised patients. Kaposi sarcoma (KS) is an indolent angioproliferative tumor associated with human herpesvirus 8 (HHV8). The concurrence of both MCC and KS is rare, and there have been limited cases reported in the literature. We present a rare case of concurrent MCC and KS in an immunocompromised patient. To our knowledge, this is the first report of MCC and KS described in the same histopathological specimen. A 37-year-old Black male with a history of recurrent AIDS-related KS involving bilateral lower extremities was evaluated for a tender nodule on the left posterior leg. A punch biopsy was consistent with MCC. Magnetic resonance imaging brain and full-body positron emission tomography/computed tomography (PET/CT) scan were without evidence of distant metastasis. The patient underwent wide local excision with negative margins and completed postoperative radiation therapy. However, he later developed cutaneous metastasis of MCC to the left medial thigh and excision revealed residual MCC with adjacent KS. Treatment is still ongoing with pembrolizumab for both KS and MCC.",
"affiliations": "Dell Medical School, University of Texas at Austin, Austin, Texas, USA.;Department of Internal Medicine, Division of Dermatology and Dermatologic Surgery, Dell Medical School, University of Texas at Austin, Austin, Texas, USA.;Department of Surgery and Perioperative Care, Dell Medical School, University of Texas at Austin, Austin, Texas, USA.;Department of Internal Medicine, Division of Dermatology and Dermatologic Surgery, Dell Medical School, University of Texas at Austin, Austin, Texas, USA.;Department of Internal Medicine, Division of Dermatology and Dermatologic Surgery, Dell Medical School, University of Texas at Austin, Austin, Texas, USA.",
"authors": "Schiele|Kristan|K|https://orcid.org/0000-0002-4265-7081;Kojder|Priscilla Ly|PL|;Haynes|Alex B|AB|;Soldano|Anthony|A|;Jambusaria-Pahlajani|Anokhi|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/cup.14146",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-6987",
"issue": null,
"journal": "Journal of cutaneous pathology",
"keywords": "AIDS-related opportunistic infections; Kaposi; Merkel cell; carcinoma; cutaneous metastases; immunosuppression; sarcoma",
"medline_ta": "J Cutan Pathol",
"mesh_terms": null,
"nlm_unique_id": "0425124",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34622465",
"pubdate": "2021-10-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Merkel cell carcinoma in a young man with AIDS-related Kaposi sarcoma.",
"title_normalized": "merkel cell carcinoma in a young man with aids related kaposi sarcoma"
} | [
{
"companynumb": "US-009507513-2111USA003203",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "4",
... |
{
"abstract": "Electrophysiologic procedures in the young engender concern about the potential long-term effects of radiation exposure. This concern is manifold if such procedures are contemplated during pregnancy. Catheter ablations in pregnancy are indicated only in the presence of an unstable tachycardia that cannot be controlled by antiarrhythmic agents. This report describes the case of an 18-year-old pregnant woman and our stratagem to minimize irradiation of the mother and the fetus.",
"affiliations": null,
"authors": "Raman|Ajay Sundara|AS|;Sharma|Saumya|S|;Hariharan|Ramesh|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14503/THIJ-14-4173",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0730-2347",
"issue": "42(2)",
"journal": "Texas Heart Institute journal",
"keywords": "Catheter ablation/adverse effects; electrophysiologic techniques, cardiac/standards; pregnancy complications, cardiovascular/radiation effects/therapy; puncture, transseptal; radiography/adverse effects; risk factors; tachycardia, supraventricular/therapy",
"medline_ta": "Tex Heart Inst J",
"mesh_terms": "D000293:Adolescent; D017115:Catheter Ablation; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D005333:Fetus; D005471:Fluoroscopy; D006801:Humans; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D000069079:Radiation Exposure; D013617:Tachycardia, Supraventricular",
"nlm_unique_id": "8214622",
"other_id": null,
"pages": "152-4",
"pmc": null,
"pmid": "25873828",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8745100;2678486;7171162;16690631;19188321;14563598",
"title": "Minimal use of fluoroscopy to reduce fetal radiation exposure during radiofrequency catheter ablation of maternal supraventricular tachycardia.",
"title_normalized": "minimal use of fluoroscopy to reduce fetal radiation exposure during radiofrequency catheter ablation of maternal supraventricular tachycardia"
} | [
{
"companynumb": "US-BAYER-2015-213404",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "► Cytomegalovirus is an uncommon infectious agent in gynecologic cancer patients. ► Viral causes should be considered in women on chemotherapy with persistent fever.",
"affiliations": "Division of Gynecologic Oncology and Reproductive Medicine, Department of Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.;Division of Infectious Disease, Department of Internal Medicine, Weill Cornell Medical College, The Methodist Hospital, Houston, Texas, USA.;Division of Gynecologic Oncology and Reproductive Medicine, Department of Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.",
"authors": "Schlumbrecht|Matthew|M|;Grimes|Kevin|K|;Brown|Jubilee|J|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.gynor.2011.08.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-338X",
"issue": "1(1)",
"journal": "Gynecologic oncology case reports",
"keywords": "Chemotherapy; Cytomegalovirus; Fever of unknown origin",
"medline_ta": "Gynecol Oncol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101599306",
"other_id": null,
"pages": "22-3",
"pmc": null,
"pmid": "24371595",
"pubdate": "2011",
"publication_types": "D016428:Journal Article",
"references": "14738558;18070129;21328386;20924616;17013817;20426575;20513085",
"title": "Cytomegalovirus reactivation following chemoradiation for invasive cervical carcinoma.",
"title_normalized": "cytomegalovirus reactivation following chemoradiation for invasive cervical carcinoma"
} | [
{
"companynumb": "US-MYLANLABS-2016M1045632",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
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