article dict | reports listlengths 1 3.97k |
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{
"abstract": "OBJECTIVE\nToxic epidermal necrolysis (TEN) is a rare, life-threatening, drug-induced, mucocutaneous disease, which can severely affect the ocular surface. The purpose of this study was to investigate the efficacy of plasmapheresis, human IV immunoglobulins (IVIg), and autologous serum (AS) eyedrops in the treatment of the severe acute ocular complications of TEN.\n\n\nMETHODS\nA retrospective chart review of all patients admitted to the Burn Unit, Azienda Ospedaliero-Universitaria-Sassari, Sassari, Italy, from 2009 to 2015, identified 9 patients (2 men, 7 women; mean age 63.8 ± 24.7 years) with TEN. Bilateral, acute ocular surface complications were observed in 7 (78%) patients; 3 showed catarrhal conjunctivitis, whereas 4 had severe pseudomembranous conjunctivitis and corneal ulcers.\n\n\nRESULTS\nAll patients with TEN were immediately treated with plasmapheresis and human IVIg, which produced a marked improvement in the patients' general condition. In the 3 with catarrhal conjunctivitis, preservative-free artificial tears and topical antibiotics were beneficial. In the 4 with severe pseudomembranous conjunctivitis and corneal ulcers, treatment with AS eyedrops resulted in corneal and conjunctival epithelium healing over 3-6 weeks. After a minimum follow-up of at least 12 months, there were minimal/mild residual signs and symptoms of dry eye.\n\n\nCONCLUSIONS\nPlasmapheresis and IVIg may be life-saving and contribute to reduce ocular surface inflammation in TEN. Autologous serum eyedrops, prepared after plasmapheresis completion and IVIg infusion, may be helpful in the management of the severe acute ocular complications of TEN.",
"affiliations": "1 Section of Ophthalmology, Department of Surgical, Microsurgical, and Medical Sciences, University of Sassari, Sassari - Italy.;1 Section of Ophthalmology, Department of Surgical, Microsurgical, and Medical Sciences, University of Sassari, Sassari - Italy.;1 Section of Ophthalmology, Department of Surgical, Microsurgical, and Medical Sciences, University of Sassari, Sassari - Italy.;3 Centro Ustioni, Azienda Ospedaliero-Universitaria-Sassari, Sassari - Italy.;1 Section of Ophthalmology, Department of Surgical, Microsurgical, and Medical Sciences, University of Sassari, Sassari - Italy.",
"authors": "Pinna|Antonio|A|;Nuvoli|Eleonora|E|;Blasetti|Francesco|F|;Posadinu|Maria Alma|MA|;Boscia|Francesco|F|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D009883:Ophthalmic Solutions",
"country": "United States",
"delete": false,
"doi": "10.5301/ejo.5000923",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": "27(6)",
"journal": "European journal of ophthalmology",
"keywords": "Acute ocular surface complications; Autologous serum eyedrops; Plasmapheresis; Toxic epidermal necrolysis",
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003231:Conjunctivitis; D003316:Corneal Diseases; D005141:Eyelid Diseases; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D008875:Middle Aged; D009883:Ophthalmic Solutions; D010956:Plasmapheresis; D012189:Retrospective Studies; D044967:Serum; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "658-663",
"pmc": null,
"pmid": "28362052",
"pubdate": "2017-11-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Plasmapheresis, Intravenous Immunoglobulins, and Autologous Serum Eyedrops in the Acute Eye Complications of Toxic Epidermal Necrolysis.",
"title_normalized": "plasmapheresis intravenous immunoglobulins and autologous serum eyedrops in the acute eye complications of toxic epidermal necrolysis"
} | [
{
"companynumb": "IT-TEVA-2018-IT-843679",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALLOPURINOL"
},
"drugadditional": "3",
... |
{
"abstract": "Despite limited evidence of efficacy, antipsychotics (APs) are commonly used to treat delirium. There has been little research on the long-term outcomes of patients who are started on APs in the hospital.\n\n\n\nUsing a previously described retrospective cohort of 300 elders (≥65 years old) who were newly prescribed APs while hospitalized between October 1, 2012 and September 31, 2013, we examined the 1-year outcomes of patients alive at the time of discharge. We examined number of readmissions, reasons for readmission, duration of AP therapy, use of other sedating medications, and incidence of readmission. We used the National Death Index to describe 1-year mortality and then created a multivariable model to identify predictors of 1-year mortality.\n\n\n\nThe 260 patients discharged alive from their index admissions had a 1-year mortality rate of 29% (75/260). Of the 146/260 patients discharged on APs, 60 (41%) patients experienced at least 1 readmission. At the time of first readmission, 65% of patients were still taking the same APs on which they had been discharged. Eighteen patients received new APs during the readmission hospitalizations. Predictors of death at 1 year included discharge to postacute facilities after index admission (odds ratio [OR]: 2.28; 95% confidence interval [CI]: 1.10-4.73, P = 0.03) and QT interval prolongation >500 ms during index admission (OR: 3.41; 95% CI: 1.34-8.67, P = 0.01).\n\n\n\nInitiating an AP in the hospital is likely to result in long-term use of these medications. Patients who received an AP during a hospitalization were at high risk of death in the following year. Journal of Hospital Medicine 2016;11:550-555. © 2016 Society of Hospital Medicine.",
"affiliations": "Division of Hematology/Oncology, James P. Wilmot Cancer Institute, University of Rochester/Strong Memorial Hospital, Rochester, New York.;Department of Medicine, Baystate Medical Center, Springfield, Massachusetts.;Division of Academic Affairs, Baystate Medical Center/Tufts University School of Medicine, Springfield, Massachusetts.;Department of Medicine, Baystate Medical Center, Springfield, Massachusetts.;Department of Medicine, Tufts University School of Medicine, Springfield, Massachusetts.;Department of Medicine, Baystate Medical Center, Springfield, Massachusetts.;Department of Medicine, Baystate Medical Center, Springfield, Massachusetts.",
"authors": "Loh|Kah Poh|KP|;Ramdass|Sheryl|S|;Garb|Jane L|JL|;Thim|Monica|M|;Brennan|Maura J|MJ|;Lindenauer|Peter K|PK|;Lagu|Tara|T|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "United States",
"delete": false,
"doi": "10.1002/jhm.2585",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1553-5592",
"issue": "11(8)",
"journal": "Journal of hospital medicine",
"keywords": null,
"medline_ta": "J Hosp Med",
"mesh_terms": "D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D005260:Female; D006760:Hospitalization; D006801:Humans; D015994:Incidence; D008297:Male; D009026:Mortality; D010351:Patient Discharge; D010359:Patient Readmission; D012189:Retrospective Studies; D018570:Risk Assessment; D013997:Time Factors",
"nlm_unique_id": "101271025",
"other_id": null,
"pages": "550-5",
"pmc": null,
"pmid": "27062675",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "10327941;10909946;16319382;16826866;16913993;17284125;17548409;19138567;20187598;21314654;21416025;22664311;22711077;23176020;23896958;23992774;24158020;24171946;24346382;25345721;25464932;25495432;25643002;25786075;8064651",
"title": "Long-term outcomes of elders discharged on antipsychotics.",
"title_normalized": "long term outcomes of elders discharged on antipsychotics"
} | [
{
"companynumb": "US-JNJFOC-20160614501",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "3",
... |
{
"abstract": "To present 5 cases of late choroidal detachment occurring spontaneously in pseudophakic glaucomatous eyes with previous trabeculectomy before cataract surgery. We discuss the causes, risk factors, frequency, diagnostic methods, differential diagnosis, and treatment of this disease.\n\n\n\nIn the presented 5 cases the choroidal effusion is proved by ophthalmoscopy and echography. Late choroidal detachment occurs after phacoemulsification 6 months at the earliest and 9 years at the latest (mean period 2.5 years) in glaucomatous eyes with previous trabeculectomy. To prove choroidal detachment we accomplished routine ophthalmological examination including medical history, visual acuity, tonometry, examination of anterior segment (AS) and fundus. We have done B-scan echography using А/В Ocular Ultrasound Aviso Quantel Medical.\n\n\n\nOne of the patients had hemorrhagic detachment confirmed by B-scan echography, the other four patients had serous detachment. The examined patients had the glaucomatous disease for 10.4±6.11 years (mean±SD). Mean age at the time of choroidal effusion diagnosis was 76.8±7.6 years (68-87 years). The period between the trabeculectomy and the following phacoemulsification was 6±3.08 years (from 1 to 9 years). All patients received anti-glaucomatous topical therapy, including carbonic anhydrase inhibitors, before the occurrence of the effusion. In all cases conservative treatment with corticosteroids and cycloplegics was enough to overcome the detachment and restore visual acuity.\n\n\n\nLate choroidal effusion after phacoemulsification in eyes with previous trabeculectomy is associated with an application of unjustified powerful hypotensive topical medications after cataract surgery associated with an additional reduction of intraocular pressure in most cases.",
"affiliations": "Medical University of Plovdiv, Plovdiv, Bulgaria.;Medical University of Plovdiv, Plovdiv, Bulgaria.;Medical University of Plovdiv, Plovdiv, Bulgaria.",
"authors": "Konareva-Kostianeva|Marieta|M|;Kostianeva-Zhelinska|Snezhina|S|;Stoyanova|Nina|N|",
"chemical_list": null,
"country": "Bulgaria",
"delete": false,
"doi": "10.3897/folmed.61.e48259",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0204-8043",
"issue": "61(4)",
"journal": "Folia medica",
"keywords": "choroidal effusion; glaucoma; phacoemulsification; trabeculectomy",
"medline_ta": "Folia Med (Plovdiv)",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000080324:Choroidal Effusions; D005260:Female; D005901:Glaucoma; D006801:Humans; D008297:Male; D018918:Phacoemulsification; D014130:Trabeculectomy",
"nlm_unique_id": "2984761R",
"other_id": null,
"pages": "506-511",
"pmc": null,
"pmid": "32337879",
"pubdate": "2019-12-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late Choroidal Effusion after Phacoemulsification in Eyes with Previous Trabeculectomy.",
"title_normalized": "late choroidal effusion after phacoemulsification in eyes with previous trabeculectomy"
} | [
{
"companynumb": "BG-MICRO LABS LIMITED-ML2020-02806",
"fulfillexpeditecriteria": "1",
"occurcountry": "BG",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DORZOLAMIDE\\TIMOLOL"
},
"drugadditi... |
{
"abstract": "Osteoporosis remains a chronic and common disease associated with high medical costs. Pharmacological therapy has shown to be a good strategy to significantly reduce fracture risk. While literary evidence for bone protection in the short and medium term is strongly in it's favor, there are concerns about long-term treatment with antiresorptive drugs. Increased risk of atypical femoral fractures (AFFs) have been demonstrated in several studies following the long-term use of bisphosphonate. Denosumab offers an alternative approach to the treatment of osteoporosis, however, it is also an antiresorptive drug. We present a case of simultaneous bilateral atypical femoral fractures in a patient with denosumab treatment. These findings highlight the need to reevaluate the optimal antiresorptive therapy duration, as well as the safety of transition from bisphosphonates to denosumab and the need for continued monitoring in the prevention of AFFs.",
"affiliations": null,
"authors": "Selga|J|J|;Nuñez|J H|JH|;Minguell|J|J|;Lalanza|M|M|;Garrido|M|M|",
"chemical_list": "D050071:Bone Density Conservation Agents; D000069448:Denosumab",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-015-3355-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-941X",
"issue": "27(2)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": null,
"medline_ta": "Osteoporos Int",
"mesh_terms": "D050071:Bone Density Conservation Agents; D000069448:Denosumab; D005260:Female; D005264:Femoral Fractures; D015775:Fractures, Stress; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal; D011859:Radiography",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "827-32",
"pmc": null,
"pmid": "26501556",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "26202488;24788502;21542743;21350886;24171686;23419776;23712442;25827453;20954650;22850908;21561306;9333131;23324969;18448990;21779886;21175240;24389366;16983459;24460109;24171676;24490096;19884427;23337161;19671655;22836783;23196269;24996528;22218417;26195566;21610533;21083387",
"title": "Simultaneous bilateral atypical femoral fracture in a patient receiving denosumab: case report and literature review.",
"title_normalized": "simultaneous bilateral atypical femoral fracture in a patient receiving denosumab case report and literature review"
} | [
{
"companynumb": "ES-AMGEN-ESPSP2016027062",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PARATHYROID HORMONE"
},
"drugadditional": nul... |
{
"abstract": "MELAS is a rare mitochondrial disorder. We report two cases in Irish males where the characteristics were evident, but the diagnosis not made for a considerable period of time. In one of the cases the symptoms were presumed secondary to prematurity. In the other the symptoms were presumed secondary to epilepsy and he had three respiratory arrests secondary to benzodiazepine administration. This report wishes to highlight MELAS as a differential diagnosis in paediatric patients who present with stroke.",
"affiliations": "Departments of Paediatrics, Neurology and Radiology, Childrens University Hospital, Temple St, Dublin 1.;Departments of Paediatrics, Neurology and Radiology, Childrens University Hospital, Temple St, Dublin 1.;Departments of Paediatrics, Neurology and Radiology, Childrens University Hospital, Temple St, Dublin 1.;Departments of Paediatrics, Neurology and Radiology, Childrens University Hospital, Temple St, Dublin 1.;Departments of Paediatrics, Neurology and Radiology, Childrens University Hospital, Temple St, Dublin 1.;Departments of Paediatrics, Neurology and Radiology, Childrens University Hospital, Temple St, Dublin 1.",
"authors": "Quinn|N M|NM|;Stone|G|G|;Brett|F|F|;Caro-Dominguez|P|P|;Neylon|O|O|;Lynch|B|B|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0332-3102",
"issue": "109(8)",
"journal": "Irish medical journal",
"keywords": null,
"medline_ta": "Ir Med J",
"mesh_terms": "D057210:Delayed Diagnosis; D003937:Diagnosis, Differential; D004827:Epilepsy; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D017241:MELAS Syndrome; D008297:Male",
"nlm_unique_id": "0430275",
"other_id": null,
"pages": "455",
"pmc": null,
"pmid": "28124854",
"pubdate": "2016-09-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke) - a Diagnosis Not to be Missed.",
"title_normalized": "melas mitochondrial encephalomyopathy lactic acidosis stroke a diagnosis not to be missed"
} | [
{
"companynumb": "AU-ROCHE-1857118",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIDAZOLAM HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nGastric cancer with peritoneal involvement has a poor prognosis. Intraperitoneal (IP) paclitaxel has shown promising results in these patients. However, this approach has only been studied in the Asian population, and in combination with S-1. We investigated the maximum tolerated dose of IP paclitaxel, with a standard chemotherapy combination, in the Australian population.\n\n\nMETHODS\nThe study of the population included metastatic human epidermal growth factor receptor 2 (HER2) negative gastric adenocarcinoma with peritoneal involvement. Treatment included six 21-day cycles of cisplatin (80 mg/m2 IV, day 1) plus capecitabine (1000 mg/m2 PO BD, days 1-14) plus IP paclitaxel (days 1 and 8). IP paclitaxel doses for cohort 1-3 were 10, 20, and 30 mg/m2 , respectively, in a 3 + 3 standard dose-escalation design.\n\n\nRESULTS\nFifteen patients were enrolled of which 6 were female and the median age was 63. Two patients developed dose-limiting toxicities. No grade 4/5 toxicities were recorded. The maximum tolerated dose was not reached. Therefore, as defined by the study protocol, the recommended phase-2 dose for IP paclitaxel was determined to be 30 mg/m2 . The 12-month survival rate was 46.7%, and the median survival was 11.5 months (interquartile range [IQR]: 15.3-6.9).\n\n\nCONCLUSIONS\nIP paclitaxel is safe in combination with cisplatin and capecitabine and the recommended phase-2 dose is 30 mg/m2 .",
"affiliations": "Department of Medical Oncology, Flinders Medical Centre, Bedford Park, Australia.;College of Medicine and Public Health, Flinders University, Adelaide, Australia.;Department of Medical Oncology, Flinders Medical Centre, Bedford Park, Australia.;Department of Medical Oncology, Flinders Medical Centre, Bedford Park, Australia.;College of Medicine and Public Health, Flinders University, Adelaide, Australia.;College of Medicine and Public Health, Flinders University, Adelaide, Australia.;Oesophago-Gastric Surgical Unit, Flinders Medical Centre, Bedford Park, Australia.;College of Medicine and Public Health, Flinders University, Adelaide, Australia.;Department of Medical Oncology, Flinders Medical Centre, Bedford Park, Australia.;Department of Medical Oncology, Flinders Medical Centre, Bedford Park, Australia.;Department of Medical Oncology, Flinders Medical Centre, Bedford Park, Australia.",
"authors": "Vatandoust|Sina|S|https://orcid.org/0000-0002-4815-0994;Bright|Tim|T|;Roy|Amitesh Chandra|AC|;Abbas|Muhammad Nazim|MN|https://orcid.org/0000-0002-1562-3708;Watson|David Ian|DI|;Gan|Susan|S|;Bull|Jeff|J|;Sorich|Michael|M|;Scott-Hoy|Alex|A|;Luu|Lee-Jen|LJ|https://orcid.org/0000-0003-3248-6597;Karapetis|Christos Stelios|CS|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/ajco.13659",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-7555",
"issue": null,
"journal": "Asia-Pacific journal of clinical oncology",
"keywords": "clinical trial; gastric cancer; intraperitoneal infusion; paclitaxel; peritoneal carcinomatosis; phase-1",
"medline_ta": "Asia Pac J Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101241430",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34811896",
"pubdate": "2021-11-23",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Phase 1 trial of intraperitoneal paclitaxel in combination with intravenous cisplatin and oral capecitabine in patients with advanced gastric cancer and peritoneal metastases (IPGP study).",
"title_normalized": "phase 1 trial of intraperitoneal paclitaxel in combination with intravenous cisplatin and oral capecitabine in patients with advanced gastric cancer and peritoneal metastases ipgp study"
} | [
{
"companynumb": "AU-ROCHE-2968467",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Sweet's syndrome, or acute febrile neutrophilic dermatosis, is characterized by fever, neutrophilia, and painful erythematous cutaneous plaques that contain a dense neutrophilic dermal infiltrate. Although the disorder is usually idiopathic, patients with drug-induced Sweet's syndrome have been described. We describe a 50-year-old woman with trimethoprim-sulfamethoxazole (TMP-SMX)--induced Sweet's syndrome and review the features of the 13 previously reported patients with drug-induced Sweet's syndrome. All patients had fever, painful skin lesions (most commonly on the upper extremities), and a biopsy-confirmed neutrophilic dermatosis. All patients also exhibited a temporal relationship between drug administration and clinical presentation and between drug withdrawal and healing. In patients with drug-induced Sweet's syndrome, neutrophilia is often absent.",
"affiliations": "Department of Dermatology, University of Texas-Houston Medical School 77030, USA.",
"authors": "Walker|D C|DC|;Cohen|P R|PR|",
"chemical_list": "D000890:Anti-Infective Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "United States",
"delete": false,
"doi": "10.1016/s0190-9622(96)90080-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": "34(5 Pt 2)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": null,
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000890:Anti-Infective Agents; D005260:Female; D006801:Humans; D008875:Middle Aged; D016463:Sweet Syndrome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "7907132",
"other_id": null,
"pages": "918-23",
"pmc": null,
"pmid": "8621829",
"pubdate": "1996-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet's syndrome.",
"title_normalized": "trimethoprim sulfamethoxazole associated acute febrile neutrophilic dermatosis case report and review of drug induced sweet s syndrome"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2017US-151066",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
... |
{
"abstract": "Histiocytic sarcoma (HS) is a rare, malignant, and aggressive subtype of histiocytosis. We present an unusual case of aggressive HS presenting in the gastrointestinal tract and gallbladder that progressed after several lines of chemotherapy with a leukemic phase. We review the clinical, pathological, and molecular characteristics of HS in this case and review the literature on HS involving the digestive system as well as on overt leukemic phase of this disease. HS is often diagnosed at an advanced stage, and mortality is high. We discuss the therapeutic approach to patients with HS. We highlight the role of overexpression and somatic alterations in the RAF-MEK-ERK pathway in the pathogenesis of HS and discuss potential targeted approaches to treat these rare tumors.",
"affiliations": "Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Surgical Division, Hillel Yaffe Medical Center, Affiliated with Rappaport Medical School, Technion, Hadera, Israel.;Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel, owolach@gmail.com.",
"authors": "Hofstetter|Liron|L|;Aranovich|David|D|;Bernstine|Hanna|H|;Hayman|Lucille|L|;Shahal-Zimra|Yael|Y|;Rabizadeh|Esther|E|;Cohen|Amos|A|;Lahav|Meir|M|;Raanani|Pia|P|;Wolach|Ofir|O|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000509723",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "144(2)",
"journal": "Acta haematologica",
"keywords": "Digestive system; Histiocytic sarcoma; Leukemic phase",
"medline_ta": "Acta Haematol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D049448:Cholangiopancreatography, Magnetic Resonance; D002763:Cholecystectomy; D005704:Gallbladder; D005770:Gastrointestinal Neoplasms; D054747:Histiocytic Sarcoma; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "229-235",
"pmc": null,
"pmid": "33017829",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Leukemic Phase of Histiocytic Sarcoma of the Digestive System: A Rare Manifestation of a Rare Disease.",
"title_normalized": "leukemic phase of histiocytic sarcoma of the digestive system a rare manifestation of a rare disease"
} | [
{
"companynumb": "IL-PFIZER INC-2021459610",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nWhile the frequency and importance of antipsychotic switching in patients with schizophrenia, there is insufficient evidence with regard to switching strategy. Quetiapine is one of the drugs of choice for switch because of its unique receptor profile. However, there were no data on the long-term clinical and neurocognitive effect of quetiapine in patients who had responded inadequately to prior antipsychotics. The purpose of this study is to examine the long-term efficacy and tolerability of quetiapine in patients with schizophrenia who switched from other antipsychotics because of inadequate therapeutic response. We hypothesized that quetiapine would show long-term effectiveness in broad symptom dimensions including negative and neurocognitive symptoms while having good tolerability.\n\n\nMETHODS\nTwenty-nine subjects with schizophrenia who did not respond to their current monotherapy of antipsychotic or who could not tolerate the treatment were switched to quetiapine and assessed at baseline and at 3, 6, and 12 months. The outcome measures included the brief assessment of cognition in schizophrenia (BACS), the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions Scale (CGI), the Schizophrenia Quality of Life Scale Japanese version (JSQLS), the Athens Insomnia Scale (AIS), and the Drug Attitude Inventory with 30 items (DAI-30). The Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS), HbA1c, prolactin (PRL), and body weight were also evaluated.\n\n\nRESULTS\nStatistically significant improvements were observed in all subscores of the PANSS, the GAF, and the symptoms and side effects subscale of the JSQLS, the DIEPSS, the AIS, and the PRL level, and nearly significant improvements were observed in the DAI-30. Quetiapine monotherapy was associated with significant improvement in the verbal memory test, even after controlling for the practice effect. Although quetiapine was well tolerated, three subjects dropped out because of the worsening of the psychotic symptoms and two additional subjects dropped out because of somnolence.\n\n\nCONCLUSIONS\nIn this open-label, single-arm study of 29 patients, quetiapine improved both the clinical symptoms and the neurocognitive impairment in chronic schizophrenia patients who failed to respond to prior antipsychotic treatment.",
"affiliations": "Department of Psychiatry, Hokkaido University Graduate School of Medicine, 060-8638, North 15, West 7, Kita-ku, Sapporo, Japan ; Child and Adolescent Psychiatry, Department of Psychiatry University of California, 401 Parnassus Ave, Box 0984-F, San Francisco, CA 94143 USA.;Department of Psychiatry, Hokkaido University Graduate School of Medicine, 060-8638, North 15, West 7, Kita-ku, Sapporo, Japan.;Honda Memorial Hospital, 061-1364, 619-1, Shimoshimamatsu Eniwa, Hokkaido, Japan.;Teine Hospital, 006-0816, 8-15, Maeda 6-jo 13-chome, Teine-ku, Sapporo, Japan.;Sapporo Hanazono Hospital, 064-0915, 1-30, South 15, West 15, Chuo-ku, Sapporo, Japan.;Teine Hospital, 006-0816, 8-15, Maeda 6-jo 13-chome, Teine-ku, Sapporo, Japan.;Teine Hospital, 006-0816, 8-15, Maeda 6-jo 13-chome, Teine-ku, Sapporo, Japan ; San-ai Hospital, 059-0463, 24-12, Nakanoboribetsu-cho Noboribetsu, Hokkaido, Japan.;Psychiatric Medical Center, Sapporo City General Hospital, 060-0011 1-1, North 11, West 13, Chuo-ku, Sapporo, Japan.;Department of Psychiatry, Hakodate Watanabe Hospital, 042-0932, 1-31-1, Yunokawa Hakodate, Hokkaido, Japan.;Oyachi Hospital, 004-0041, 7-10, Oyachi-higashi 5-chome, Atsubetsu, Sapporo, Japan.;Department of Psychiatry, Hokkaido University Graduate School of Medicine, 060-8638, North 15, West 7, Kita-ku, Sapporo, Japan.",
"authors": "Hashimoto|Naoki|N|;Toyomaki|Atsuhito|A|;Honda|Minoru|M|;Miyano|Satoru|S|;Nitta|Nobuyuki|N|;Sawayama|Hiroyuki|H|;Sugawara|Yasufumi|Y|;Uemura|Keiichi|K|;Tsukamoto|Noriko|N|;Koyama|Tsukasa|T|;Kusumi|Ichiro|I|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12991-014-0039-6",
"fulltext": "\n==== Front\nAnn Gen PsychiatryAnn Gen PsychiatryAnnals of General Psychiatry1744-859XBioMed Central London 256322933910.1186/s12991-014-0039-6Primary ResearchLong-term efficacy and tolerability of quetiapine in patients with schizophrenia who switched from other antipsychotics because of inadequate therapeutic response—a prospective open-label study Hashimoto Naoki hashinao@vega.ocn.ne.jp Toyomaki Atsuhito toyomaki@gmail.com Honda Minoru minosky9@honda-hospital.com Miyano Satoru tonukisaru.mm@gmail.com Nitta Nobuyuki nnnobu@jcom.home.ne.jp Sawayama Hiroyuki sawayama-5@nifty.com Sugawara Yasufumi sugawara@pd5.so-net.ne.jp Uemura Keiichi k1-uemura0827@nifty.com Tsukamoto Noriko ntsukamoto@hakodatewatanabe.or.jp Koyama Tsukasa koyama@ohyachi-hp.or.jp Kusumi Ichiro ikusumi@med.hokudai.ac.jp Department of Psychiatry, Hokkaido University Graduate School of Medicine, 060-8638, North 15, West 7, Kita-ku, Sapporo, Japan Child and Adolescent Psychiatry, Department of Psychiatry University of California, 401 Parnassus Ave, Box 0984-F, San Francisco, CA 94143 USA Honda Memorial Hospital, 061-1364, 619-1, Shimoshimamatsu Eniwa, Hokkaido, Japan Teine Hospital, 006-0816, 8-15, Maeda 6-jo 13-chome, Teine-ku, Sapporo, Japan Sapporo Hanazono Hospital, 064-0915, 1-30, South 15, West 15, Chuo-ku, Sapporo, Japan San-ai Hospital, 059-0463, 24-12, Nakanoboribetsu-cho Noboribetsu, Hokkaido, Japan Psychiatric Medical Center, Sapporo City General Hospital, 060-0011 1-1, North 11, West 13, Chuo-ku, Sapporo, Japan Department of Psychiatry, Hakodate Watanabe Hospital, 042-0932, 1-31-1, Yunokawa Hakodate, Hokkaido, Japan Oyachi Hospital, 004-0041, 7-10, Oyachi-higashi 5-chome, Atsubetsu, Sapporo, Japan 22 1 2015 22 1 2015 2015 14 130 6 2014 17 12 2014 © Hashimoto et al.; licensee BioMed Central. 2015This 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.Background\nWhile the frequency and importance of antipsychotic switching in patients with schizophrenia, there is insufficient evidence with regard to switching strategy. Quetiapine is one of the drugs of choice for switch because of its unique receptor profile. However, there were no data on the long-term clinical and neurocognitive effect of quetiapine in patients who had responded inadequately to prior antipsychotics. The purpose of this study is to examine the long-term efficacy and tolerability of quetiapine in patients with schizophrenia who switched from other antipsychotics because of inadequate therapeutic response. We hypothesized that quetiapine would show long-term effectiveness in broad symptom dimensions including negative and neurocognitive symptoms while having good tolerability.\n\nMethods\nTwenty-nine subjects with schizophrenia who did not respond to their current monotherapy of antipsychotic or who could not tolerate the treatment were switched to quetiapine and assessed at baseline and at 3, 6, and 12 months. The outcome measures included the brief assessment of cognition in schizophrenia (BACS), the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions Scale (CGI), the Schizophrenia Quality of Life Scale Japanese version (JSQLS), the Athens Insomnia Scale (AIS), and the Drug Attitude Inventory with 30 items (DAI-30). The Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS), HbA1c, prolactin (PRL), and body weight were also evaluated.\n\nResults\nStatistically significant improvements were observed in all subscores of the PANSS, the GAF, and the symptoms and side effects subscale of the JSQLS, the DIEPSS, the AIS, and the PRL level, and nearly significant improvements were observed in the DAI-30. Quetiapine monotherapy was associated with significant improvement in the verbal memory test, even after controlling for the practice effect. Although quetiapine was well tolerated, three subjects dropped out because of the worsening of the psychotic symptoms and two additional subjects dropped out because of somnolence.\n\nConclusion\nIn this open-label, single-arm study of 29 patients, quetiapine improved both the clinical symptoms and the neurocognitive impairment in chronic schizophrenia patients who failed to respond to prior antipsychotic treatment.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12991-014-0039-6) contains supplementary material, which is available to authorized users.\n\nKeywords\nSchizophreniaQuetiapineSwitchingAntipsychoticNegative symptomCognitive impairmentTreatment resistanceissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nThe antipsychotic medications have been a fundamental part of the treatment of schizophrenia. Although the benefit of antipsychotic treatment is evident especially about the psychotic symptoms, inadequate therapeutic response is common in this disorder [1,2]. If a patient does not respond well to the administered antipsychotic, and if the possibility of misdiagnosis or non-compliance is excluded, a switch of the currently prescribed antipsychotic is an often employed step [3]. In fact, it is estimated that switching because of suboptimal antipsychotic efficacy or tolerability occurs in 30%–50% of patients a year in outpatient clinic [4].\n\nAlthough little is known about the optimal clinical strategies for switching, it seems to be rational to choose a new compound with a different receptor binding profile [3]. From this point of view, quetiapine is one of the strong candidates for some patients because of its unique receptor profile. Quetiapine demonstrates a relatively high affinity for the 5HT2A receptor and relatively low affinity for the D2 receptor [5]. Such a low affinity for the D2 receptor is thought to be appropriate if the first compound was characterized by high affinities to dopamine receptors such as risperidone or first-generation antipsychotic (FGA) [3]. Furthermore, the high 5HT2A/D2 ratio leads to an overall increase in dopaminergic activity in the prefrontal cortex, and enhanced prefrontal activity is shown to be associated with the alleviation of negative symptoms and the improvement of cognitive function [6]. It is also important because the cognitive and negative symptoms are often refractory to antipsychotic treatment [7,8] and become the cause of inadequate response. Collectively, this evidence suggests that a study examining the long-term efficacy of quetiapine on negative as well as cognitive symptoms after switching from other antipsychotics might be quite valuable.\n\nThere were several studies that examined the long-term efficacy and tolerability of the quetiapine comparing with placebo [9] or risperidone [10-13]. Although the difference in the modes of dosage should be noted (oral risperidone [10,11] and risperidone long-acting injection [12,13], oral quetiapine immediate [11] and extended release [9,12]), in general, quetiapine showed long-term effectiveness similar to [11] or less than risperidone [10], a positive relapse prevention effect better than placebo [9] and equal to risperidone [12] except for its ability to achieve remission, which was less than risperidone [12,13]. When focused on studies that switched over to quetiapine, Larmo and his colleagues (2005) showed significant improvement in the Positive and Negative Syndrome Scale (PANSS) positive, negative, and general psychopathology subscales after switching to quetiapine in patients who were previously treated with low-dose haloperidol, risperidone, or olanzapine [14]. Recently, Chue et al. (2013) reported another open-label, prospective study to evaluate long-term clinical benefits of switching to quetiapine extended release from an oral antipsychotic in patients with schizophrenia. In this study, majority of the subjects switching from other antipsychotics to quetiapine due to insufficient efficacy or insufficient tolerability showed clinical benefits [15]. In all of these studies, quetiapine showed good long-term tolerability with little extrapyramidal side effects and hyperprolactinemia [10,14], and most common adverse events were somnolence and dizziness [11-15].\n\nWith regard to pharmacological treatment of the cognitive impairment, recent large sample naturalistic studies showed that the magnitude of cognitive improvement does not differ between first- and second-generation antipsychotics or between any two second-generation antipsychotics, if the dose of first-generation antipsychotics were appropriate [16-18]. However, in a randomized, double-blind 52-week comparison on neurocognitive function in early psychosis, quetiapine showed greater improvement than both olanzapine and risperidone on measures of verbal fluency and digit symbol coding test and than olanzapine on continuous performance test at Week 12 [19]. The superiority of quetiapine compared to other second-generation antipsychotics were also shown in a recent meta-analysis of two double-blind and one open-label studies [20]. However, there has been no data on the long-term neurocognitive effects of quetiapine in patients who had responded inadequately to prior antipsychotics.\n\nIn this study, we examined the long-term efficacy and tolerability of quetiapine in patients with schizophrenia who switched from other antipsychotics because of inadequate therapeutic response. We hypothesized that quetiapine would show long-term improvement in broad symptom dimensions including negative and neurocognitive symptoms while having good tolerability.\n\nMethod\nParticipants\nThis is a prospective, open-label study. The eligible subjects were schizophrenia patients aged 20 years or more, who need switch of antipsychotic because of an inadequate response (cognitive impairment, negative, positive, or general psychopathology symptoms) or intolerance for their current antipsychotic medication. The diagnosis according to the DSM-IV-TR and judgment about an inadequate response and/or poor tolerability were made by treating psychiatrists, who had at least 6 years of clinical experience. These eligible criteria are in consistent with the SPECTRUM trial [14]. Patients who had a history of seizure disorder, dementia, diabetes mellitus, history of substance misuse including alcohol abuse, or other significant laboratory results were excluded from the study. The subjects who were currently suicidal and women who were pregnant or breastfeeding were also excluded.\n\nThe study was conducted between January 2008 and December 2012 at nine clinical sites in Hokkaido, Japan (one university hospital, three general hospital, and five psychiatric hospitals). This study was approved by the ethics committees at Hokkaido University Hospital and has been carried out in accordance with the Declaration of Helsinki. We provided detailed explanations regarding the study procedures and the potential risk and benefits of pharmacotherapy to the eligible subjects. All participants voluntarily provided their written informed consent.\n\nProcedure\nThe trial began with a cross-titration period of 1 month to allow a gradual transition, followed by an 11-month follow-up phase during which quetiapine could be flexibly dosed. During the cross-titration period, a dose of quetiapine was titrated at a target dose of 400 mg/day, while the previous antipsychotic was gradually discontinued. During the follow-up period, the maximum dose of quetiapine was 750 mg/day. The concomitant use of psychotropics, such as anxiolytics, mood stabilizers, and antidepressants, was permitted, and the daily dosages of all psychotropics were recorded throughout the study. Hypnotics were tapered off if possible after the assessment at 6 months. The concomitant use of drugs for parkinsonism, which included anticholinergic agents, was permitted for the first 3 months, and it was also tapered off after the assessment at 3 months; continuous use was permitted if necessary. Non-psychoactive medications for stable conditions that were already taken by the subject before entry into the study were allowed to continue.\n\nClinical assessments\nThe assessments were performed at four points (baseline and 3, 6, and 12 months after entry). The baseline assessment had been done before cross-titration. Clinical improvement was examined using the Global Assessment of Functioning (GAF) and the PANSS [21]. Quality of life was assessed by the Schizophrenia Quality of Life Scale Japanese version (JSQLS) [22]. Vital signs and laboratory data, including prolactin and hemoglobin A1c (HbA1c), were checked at each assessment point. At every visit, adverse events were carefully checked via spontaneous reports from the patient and observation by the same treating psychiatrist. In addition, assessment of the extrapyramidal symptoms using the Drug-Induced Extrapyramidal Signs Scale (DIEPSS) [23] and sleep difficulty assessment using the Athens Insomnia Scale (AIS) [24] were done at each assessment.\n\nAssessment of neurocognition\nFor the neurocognitive assessment, we adopted the Brief Assessment of Cognition in Schizophrenia (BACS) [25,26], which is a brief set of tests designed to derive a composite score for neurocognitive functioning. The score from each test of the BACS was standardized by creating z score whereby the mean score of the healthy subjects were set to zero and the standard deviation was set to one. The composite score was then calculated by averaging all of the z scores of the six primary measures. The mean and standard deviation of normal Japanese individuals were derived from the published data of 709 normal Japanese subjects [27]. To compensate for practical effects, we recruited normal subjects and implemented the BACS four times at the same time interval as our schizophrenia subjects (baseline and 3, 6, and 12 months after). For the control group, ten subjects (five females) with no history of a DSM-IV Axis I disorder were recruited from the community. None of the control subjects had a neurological disorder or a first-degree relative with a DSM-IV Axis I disorder, nor were any of them receiving psychotropic medications. The mean age of the participants was 27.3 (SD = 2.3) years, and the duration of education was 18.2 (1.5) years. Both of which were significantly different from those of our schizophrenia subjects (age 50.7 (14.3), Wilcoxon test, P < 0.01; duration of education 12.9 (1.7), Wilcoxon test, P < 0.01) (Additional file 1).\n\nStatistical analyses\nWe compared the baseline categorical variables using χ2 or Fisher exact tests and examined the differences in the continuous variables among the follow-up time points using with repeated measure analysis of variance (rANOVA). Bonferroni correction was applied for multiple comparisons between each pair of subgroups. The last available assessment was carried forward if the actual data were not available (LOCF). Safety evaluations were based on all included patients treated with the studied medication except for three subjects who were omitted from all analyses because of incomplete data. Data were obtained from 28 subjects for PANSS and DIEPSS; 26 subjects for weight, HbA1c, GAF, and AIS; 25 subjects for BACS; 24 subjects for prolactin and DAI-30; and 24 subjects for JSQLS.\n\nFor the neurocognitive study, the baseline measures of the demographic data and the BACS z scores were compared between the schizophrenic subjects and the control group specifically recruited for the practice effect using the Wilcoxon test for continuous variables and the Fisher’s exact test for categorical variables. In the next step, analysis of covariance (ANCOVA) was used to detect the group (schizophrenia and normal subjects) x time (baseline to 3, 6, and 12 months) interaction, as well as the interaction as a factor of the baseline pretest score or age.\n\nAll comparison tests were two-tailed. Differences among groups were considered statistically significant if the P value was less than 0.05.\n\nResults\nPatient description and baseline demographics, severity of illness, and previous treatments\nA total of 32 patients signed the informed consent forms, but three of them were omitted from the analysis including safety analysis because of incomplete data and the remaining 29 patients were included. Seventeen subjects entered the study due to treatment resistance, six entered due to treatment intolerance, and six were recruited due to both treatment resistance and treatment intolerance. The subjects were medicated as follows: risperidone (n.16); haloperidol (n.8); olanzapine (n.3); aripiprazole (n.1); blonanserin (n.1). The mean chlorpromazine equivalent dosage for the previous treatment was 438.0 (s.d. 242.3) mg/day.\n\nTwenty-seven subjects completed the 3-month evaluation, 26 finished the 6-month assessment, and 22 reached the 12-month mark. Three patients dropped out because of worsening of psychotic symptoms, two dropped out because of somnolence, and one dropped out because of alopecia. Another one subject was discontinued due to a change of address. The last observation was carried forward for the analysis of patients who were dropped from the study. The baseline demographic data, the severity of illness, and previous treatment are shown in Table 1. There were no significant differences in the demographic and clinical profiles between the subjects who completed the study and those who did not.Table 1 \nBaseline demographic and clinical profiles\n\n\n\t\nCompleted (\nn \n= 22)\n\t\nWithdrawn (\nn \n= 7)\n\t\nP\na\n\t\nSex (male/female)\t10/12\t3/4\t0.59\t\nAge, year\t52.1 (14.4)\t46.5 (14.1)\t0.49\t\nClinical subtype\t\t\t0.49\t\n Paranoid\t18\t7\t\t\n Disorganized\t1\t0\t\t\n Catatonic\t1\t0\t\t\n Residual\t2\t0\t\t\nReason for switching\t\t\t0.60\t\n Treatment resistant\t13\t3\t\t\n Treatment intolerant\t5\t3\t\t\n Resistant and intolerant\t4\t1\t\t\nEducation, year\t\t\t\t\n Subject\t12.9 (1.8)\t13.0 (1.0)\t0.59\t\n Father\t12.3 (2.6)\t10.5 (1.9)\t0.28\t\n Mother\t12.0 (2.6)\t10.0 (1.7)\t0.25\t\nPrevious antipsychotics\t\t\t0.13\t\n Haloperidol\t5\t3\t\t\n Risperidone\t12\t4\t\t\n Others\t5\t0\t\t\nAverage dose of previous antipsychotics (mg/day)\t445.9 (230.6)\t409.2 (303.8)\t0.63\t\nValues are expressed as the mean (SD) unless otherwise indicated.\n\n\naDifferences in two groups with P values calculated by the Wilcoxon test or the χ\n2 test (sex, clinical subtype, reason for switching, and previous antipsychotics).\n\n\n\nEfficacy\nThe patients who switched to quetiapine had significant improvements in all subscores of the PANSS, the JSQLS score for symptoms and side effects, and GAF (Table 2). AIS score also improved significantly. The reason to switch (resistant vs intolerant) did not affect the change of PANSS positive (repeated ANOVA, effect of times x reason to switch, F(3,19) = 1.14, P = 0.36) and negative scores (repeated ANOVA, effect of times x reason to switch, F(3,19) = 1.00, P = 0.41).Table 2 \nChanges in clinical measurements\n\n\n\t\nBaseline\n\t\n3 months\n\t\n6 months\n\t\n12 months\n\t\nRepeated ANOVA\na\n\t\n\nF\n\t\nP\n\t\nAverage dose of QTP (mg/day)\t-\t379.6 (231.7)\t418.5 (243.4)\t438.6 (261.7)\t-\t-\t\nWeight (kg)\t56.9 (12.2)\t57.6 (12.4)\t57.0 (11.6)\t57.3 (10.7)\tF(3,75) = 0.44\t0.64\t\nHbA1C (%)\t4.97 (0.32)\t4.95 (0.37)\t4.98 (0.35)\t4.89 (0.32)\tF(3,75) = 1.32\t0.28\t\nPANSS\t\t\t\t\t\t\t\nPositive symptoms\t18.1 (4.7)\t15.7 (4.8)\t16.4 (54.2)\t15.3 (4.1)\tF(3,81) = 5.35\t<0.01\t\nNegative symptoms\t23.5 (5.2)\t21.5 (5.5)\t20.8 (6.2)\t19.6 (6.5)\tF(3,81) = 11.40\t<0.01\t\nGeneral pathological symptoms\t39.8 (10.2)\t36.8 (9.3)\t36.8 (10.5)\t34.7 (10.1)\tF(3,81) = 7.83\t<0.01\t\nGAF\t42.4 (14.7)\t50.3 (12.7)\t51.7 (14.0)\t51.6 (15.6)\tF(3,75) = 10.54\t<0.01\t\nAIS\t5.0 (3.1)\t4.9 (3.6)\t3.5 (2.9)\t3.7 (3.0)\tF(3,75) = 3.35\t0.04\t\nDIEPSS\t6.4 (4.9)\t3.9 (3.2)\t3.1 (2.8)\t3.0 (2.9)\tF(3,81) = 13.74\t<0.01\t\nProlactin (ng/ml)\t33.1 (26.2)\t17.8 (20.8)\t21.0 (27.0)\t19.9 (28.0)\tF(3,69) = 4.04\t0.02\t\nDAI-30\t−8.6 (3.2)\t−5.0 (7.1)\t−6.8 (5.2)\t−6.3 (5.9)\tF(3,69) = 2.78\t0.07\t\nJSQLS\t\t\t\t\t\t\t\nPsychosocial\t37.9 (13.5)\t37.2 (11.7)\t35.0 (11.6)\t35.3 (12.2)\tF(3,66) = 1.42\t0.25\t\nMotivation\t21.6 (2.9)\t20.2 (4.0)\t19.9 (2.8)\t19.7 (3.6)\tF(3,66) = 2.23\t0.11\t\nSymptoms and side effects\t16.7 (4.5)\t14.7 (4.3)\t14.4 (4.6)\t14.9 (5.4)\tF(3,66) = 3.20\t<0.05\t\nValues are expressed as the mean (SD) unless otherwise indicated.\n\n\na\nPost hoc analyses with Bonferroni correction: (pairs of comparison not specified here were all with P values of >0.05, BL baseline, 3 m 3 months, 6 m 6 months, 12 m 12 months) PANSS positive symptoms: BL vs 12 m (P = 0.02); PANSS negative symptoms: BL vs 3 m (P = 0.01), BL vs 6 m(P = 0.03), BL vs 12 m (P < 0.01), 3 m vs 12 m (P = 0.02); PANSS general pathological symptoms: BL vs 3 m (P = 0.02), BL vs 12 m (P < 0.01), 6 m vs 12 m (P = 0.03); GAF: BL vs 3 m (P < 0.01), BL vs 6 m (P < 0.01), BL vs 12 m (P < 0.01); Athens Insomnia Scale: BL vs 6 m (P = 0.03); DIEPSS: BL vs 3 m (P < 0.01), BL vs 6 m (P < 0.01), BL vs 12 m (P < 0.01); prolactin: BL vs 3 m (P < 0.01), BL vs 12 m (P < 0.01); JSQLS symptoms and side effects: BL vs 3 m (P = 0.03).\n\n\nHbA1c hemoglobin A1c, PANSS Positive and Negative Symptoms Scale, GAF Global Assessment of Functioning, AIS Athens Insomnia Scale, DIEPSS Drug-Induced Extrapyramidal Signs Scale, DAI-30 Drug Attitude Inventory with 30 dichotomous items, JSQLS Schizophrenia Quality of Life Scale Japanese version.\n\n\n\nSafety and tolerability\nQuetiapine significantly improved the DIEPSS score and the prolactin level throughout the study period. (Table 2) The weights and HbA1c did not increase during the treatment with quetiapine. The amelioration of the adverse events was also shown in the improvement of the symptoms and side effects subscale of the JSQLS. Three patients dropped out because of worsening of psychotic symptoms. Two additional patients were dropped out from the study because of somnolence. The DAI-30 score showed a trend for increase but did not reached statistical significance (P = 0.07).\n\nChanges in the neurocognitive battery test\nAdditional file 1 summarizes the demographic characteristics and BACS scores at the baseline of the patients and controls. There were significant differences in the age, the duration of education, and all the scores on the BACS. The z scores of the BACS in our schizophrenic subjects ranged from −2.78 (token motor test) to −1.18 (word fluency), which were similar to previous studies. In the next step, ANCOVA was implemented to detect the group (schizophrenia and normal subjects) x time (baseline to 3, 6, and 12 months) interaction, as well as the interaction as a factor of the baseline pretest score or age (Figure 1, Additional file 2). In this analysis, we found a significant effect of time on verbal memory, the token motor test, and the composite score. Furthermore, we found a significant interaction of time x group in the verbal memory test. Post hoc analyses using ANOVA with Bonferroni correction revealed that both normal subject group [F(3,27) = 3.67, (P = 0.03)] and schizophrenia subject group [F(3, 72) = 4.30, (P < 0.01)] showed significant increase of the score. The effect size (Cohen’s d) of the improvement between baseline and 12 months was 0.21 for normal subjects and 0.64 for schizophrenia subjects, which showed that the improvement of verbal memory by quetiapine therapy was greater than the practice effect of normal subjects.Figure 1 \nThe change of the scores of Brief Assessment of Cognition in Schizophrenia (BACS). Results of each test were standardized by setting the mean of the normal dataset to zero and the SD to one. BL baseline, 3 m 3 months, 6 m 6 months, 12 m 12 months. *P < 0.05, **P < 0.01, repeat ANOVA. Post hoc analyses were conducted with Bonferroni correction. Verbal memory: BL vs 6 m, P = 0.04, BL vs 12 m, P < 0.01; digit sequencing task: BL vs 12 m, P = 0.01; word fluency: BL vs 6 m, P = 0.03, BL vs 12 m, P < 0.01; symbol coding: BL vs 3 m, P = 0.02, BL vs 12 m, P < 0.01; Tower of London: BL vs 6 m, P = 0.01, BL vs 12 m, P < 0.01; composite score: BL vs 3 m, P = 0.43, BL vs 6 m, P < 0.01, BL vs 12 m, P < 0.01, 3 m vs 12 m, P = 0.04. P > 0.05 for all other paired comparisons.\n\n\n\nDiscussion\nThis study was a prospective, 1-year open-label study to evaluate the long-term effect of quetiapine on the clinical symptoms and cognitive performance in patients with schizophrenia who had an inadequate response or who poorly tolerated their previous antipsychotic medication. The total drop-out rate was 24.1% (7/29), which is consistent with prior open-label study [14,18]. Statistically significant improvements were observed on all subscales of the PANSS, the GAF, and the symptoms and side effects subscale of the JSQLS, the DIEPSS, the AIS, and the prolactin level, and nearly significant improvements were observed in the DAI-30. Regarding the neurocognitive performance, quetiapine therapy showed significant improvement in verbal memory test even after controlling the practice effect. Overall, as expected, quetiapine showed long-term improvement in broad symptom dimensions including negative and neurocognitive symptoms with good tolerability. To the best of our knowledge, this is the first study, albeit preliminary, showing long-term neurocognitive benefits of switching to quetiapine in patients that showed inadequate response to prior antipsychotics.\n\nIn this trial, the patients who switched to quetiapine had significant improvements of broad range of symptoms as demonstrated by the changes in the all subscores of the PANSS, the JSQLS score for symptoms and side effects, and GAF. A clinical benefit was also shown for insomnia reflected by the improvement of AIS score.\n\nIn concordance with our hypothesis, negative symptoms were ameliorated in addition to the positive and general pathological symptoms. In the study by Larmo and his colleagues, when quetiapine was switched from risperidone, the improvement of the negative and general psychopathological symptoms was more prominent than that of the positive symptom [14]. In our study, most patients had been treated by haloperidol (27.6%) or risperidone (51.7%) before registration for our study. By replacing these treatments with quetiapine, which has a much weaker affinity for the D2 receptor, we successfully achieved amelioration of the negative symptoms. This is consistent with the previous report which showed that higher postsynaptic D2 blockade could mimic certain negative symptoms [28].\n\nIn accordance with our other hypothesis, quetiapine therapy also showed significant improvement in verbal memory, even after controlling for practice effects. This improvement continued for a year. Impaired verbal memory is associated with poor community functioning and a poor response to psychosocial rehabilitation programs [29], and the improvement of verbal memory is particularly important for the cognitive remediation strategy [30]. However, we should evaluate this result with maximum caution because 1) a switch design study is not suitable for comparing the cognitive remediation effects of antipsychotics [8], 2) the improvement of cognitive disturbance may be due to the improvement of clinical symptoms and/or extrapyramidal side effects in part [31], and 3) there is a possibility of ceiling effect in the data of normal control.\n\nAbout the tolerability, switching to quetiapine induced a decrease in the prolactin levels, improvement of the extrapyramidal symptoms, and a decrease in the use of anticholinergics. At the baseline and at each time point, the number of the subjects who were prescribed with anticholinergics and the mean daily biperiden equivalent dose changed as follows: baseline [n.13, dose. 3.7 (SD = 2.2) mg/day]; 3 months [n.10, dose 3.3 (2.1) mg/day]; 6 months [n.7, dose 3.7 (2.4) mg/day]; 12 months [n.7, dose 3.7 (2.4) mg/day]. Weight gain and glucose intolerance were not apparent in our patients. Somnolence and worsening of the psychotic symptoms were noticeable adverse events, and this finding is consistent with previous studies [11,13-15]. However, the sedative effect of quetiapine improved the insomnia of our subjects, and this was reflected in the improvement of the AIS score. Tolerability findings were consistent with the trending improvement in DAI, although it did not reach statistical significance level. This may be due to the small sample size.\n\nThere are several limitations in our study. First, the small sample size of our study may limit the ability to detect moderate to small changes. As a consequence of the small sample size, we could not perform subgroup analyses, such as an analysis according to the prior antipsychotics. Second, because this was an open-label study with no control group except for the neurocognitive battery test, our study was prone to selection and observer bias. There was no indication of spontaneous recovery. Third, our normal control for the neurocognitive battery test was much younger and much longer educated than our schizophrenia subjects, and the score of the neurocognitive battery test was higher in the normal control group, though we used these factors as covariants in the statistical analysis. A younger age results in a better practice effect in general, and this age difference had never shown a favorable effect in the schizophrenia patient group. However, there is a possibility of ceiling effect in the score of our normal subject and the improvement of neurocognitive battery test in this study should be examined carefully, as we discussed above. Fourth, we did not have an objective measurement of treatment adherence, although the results of the DAI-30 indirectly suggested that their adherence was good throughout the study period.\n\nConclusion\nIn this open-label, single-arm study of 29 patients, we found that quetiapine improved both the clinical symptoms and the neurocognitive impairment in chronic schizophrenia patients who switched from other antipsychotics because of inadequate response. While the frequency and importance of antipsychotic are switching in patients with schizophrenia, there is insufficient evidence with regard to switching strategy. We hope that further studies seeking better antipsychotic switching strategies in clinical practice will be continued.\n\nAdditional files\nAdditional file 1: \nDemographic characteristics and BACS z scores of schizophrenic and normal subjects.\n\n\nAdditional file 2: \nChange of the BACS z scores and the results of ANCOVA controlled for age.\n\n\n\n\nAbbreviations\nAISAthens Insomnia Scale\n\nANCOVAanalysis of covariance\n\nBACSbrief assessment of cognition in schizophrenia\n\nCGIClinical Global Impressions Scale\n\nDAI-30Drug Attitude Inventory with 30 dichotomous items\n\nDIEPSSDrug-Induced Extrapyramidal Signs Scale\n\nHbA1chemoglobin A1c\n\nJSQLSSchizophrenia Quality of Life Scale Japanese version\n\nLOCFlast observation carried forward\n\nPANSSsPositive and Negative Syndrome Scales\n\nrANOVArepeated measure analysis of variance\n\nCompeting interests\n\nKI and NH received research grants from Astellas Pharma. For the remaining authors, none were declared.\n\nAuthors’ contributions\n\nKI and NH contributed substantially to the design and analysis of the study, as well as to development and critical revision of the manuscript. AT contributed substantially to the assessment and data analysis of BACS. TK contributed substantially to the critical revision of the manuscript. MH, SM, NN, HS, YS, KU, and NT contributed substantially to the recruitment and assessment of the subjects. All authors read and approved the final manuscript.\n\nAcknowledgement\nThe authors are grateful to Dr Yuki Omiya, Dr Tomoo Ogawa, Dr Susumu Oshibe, Dr Naomichi Kaji, Dr Yukie Kumazawa, Dr Kuniko Terae, Dr Shigetaka Nakae, and Dr Yuji Honma who entry the subjects to this study. We thank Fumiko Hoeft, MD, PhD, for editorial assistance. Their dedication made this study possible.\n==== Refs\nReferences\n1. Leucht S Arbter D Engel RR Kissling W Davis JM How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials Mol Psychiatry 2009 14 429 47 10.1038/sj.mp.4002136 18180760 \n2. Lieberman JA Stroup TS McEvoy JP Swartz MS Rosenheck RA Perkins DO Clinical Antipsychotic Trials of Intervention Effectiveness, Investigators Effectiveness of antipsychotic drugs in patients with chronic schizophrenia N Engl J Med 2005 353 1209 23 10.1056/NEJMoa051688 16172203 \n3. Dold M Leucht S Pharmacotherapy of treatment-resistant schizophrenia: a clinical perspective Evid Based Ment Health 2014 17 33 7 10.1136/eb-2014-101813 24713315 \n4. Weiden PJ Young AH Buckley PF The art and science of switching of antipsychotic medications, part 1 J Clin Psychiatry 2006 67 e15 10.4088/JCP.1106e15 17201045 \n5. Riedel M Muller N Strassnig M Spellmann I Severus E Moller HJ Quetiapine in the treatment of schizophrenia and related disorders Neuropsychiatr Dis Treat 2007 3 219 35 10.2147/nedt.2007.3.2.219 19300555 \n6. da Silva AF Figee M van Amelsvoort T Veltman D de Haan L The revised dopamine hypothesis of schizophrenia: evidence from pharmacological MRI studies with atypical antipsychotic medication Psychopharmacol Bull 2008 41 121 32 18362875 \n7. Kirkpatrick B Fenton WS Carpenter WT Jr Marder SR The NIMH-MATRICS consensus statement on negative symptoms Schizophr Bull 2006 32 214 9 10.1093/schbul/sbj053 16481659 \n8. Hill SK Bishop JR Palumbo D Sweeney JA Effect of second-generation antipsychotics on cognition: current issues and future challenges Expert Rev Neurother 2010 10 43 57 10.1586/ern.09.143 20021320 \n9. Peuskens J Trivedi J Malyarov S Brecher M Svensson O Miller F Prevention of schizophrenia relapse with extended release quetiapine fumarate dosed once daily: a randomized, placebo-controlled trial in clinically stable patients Psychiatry 2007 4 34 50 20428302 \n10. Liu J Sun J Shen X Guo W Zhi S Song G Randomized controlled trial comparing changes in serum prolactin and weight among female patients with first-episode schizophrenia over 12 months of treatment with risperidone or quetiapine Shanghai Arch Psychiatry 2014 26 88 94 25092954 \n11. Mullen J Jibson MD Sweitzer D A comparison of the relative safety, efficacy, and tolerability of quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: the quetiapine experience with safety and tolerability (QUEST) study Clin Ther 2001 23 1839 54 10.1016/S0149-2918(00)89080-3 11768836 \n12. Smeraldi E Cavallaro R Folnegovic-Smalc V Bidzan L Emin Ceylan M Schreiner A Long-term remission in schizophrenia and schizoaffective disorder: results from the risperidone long-acting injectable versus quetiapine relapse prevention trial (ConstaTRE) Ther Adv Psychopharmacol 2013 3 191 9 10.1177/2045125313479127 24167692 \n13. Gaebel W Schreiner A Bergmans P de Arce R Rouillon F Cordes J Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long-acting injectable vs quetiapine: results of a long-term, open-label, randomized clinical trial Neuropsychopharmacology 2010 35 2367 77 10.1038/npp.2010.111 20686456 \n14. Larmo I de Nayer A Windhager E Lindenbauer B Rittmannsberger H Platz T Efficacy and tolerability of quetiapine in patients with schizophrenia who switched from haloperidol, olanzapine or risperidone Hum Psychopharmacol 2005 20 573 81 10.1002/hup.723 16175656 \n15. Chue P Malla A Bouchard RH Lessard S Ganesan S Stip E The long-term clinical benefit and effectiveness of switching to once-daily quetiapine extended release in patients with schizophrenia Curr Med Res Opin 2013 29 227 39 10.1185/03007995.2012.762903 23281876 \n16. Keefe RS Bilder RM Davis SM Harvey PD Palmer BW Gold JM Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial Arch Gen Psychiatry 2007 64 633 47 10.1001/archpsyc.64.6.633 17548746 \n17. Davidson M Galderisi S Weiser M Werbeloff N Fleischhacker WW Keefe RS Cognitive effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: a randomized, open-label clinical trial (EUFEST) Am J Psychiatry 2009 166 675 82 10.1176/appi.ajp.2008.08060806 19369319 \n18. Guo X Zhai J Wei Q Twamley EW Jin H Fang M Early-stage Schizophrenia Outcome Study Investigators. Neurocognitive effects of first- and second-generation antipsychotic drugs in early-stage schizophrenia: a naturalistic 12-month follow-up study Neurosci Lett 2011 503 141 6 10.1016/j.neulet.2011.08.027 21888948 \n19. Keefe RS Sweeney JA Gu H Hamer RM Perkins DO McEvoy JP Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early psychosis: a randomized, double-blind 52-week comparison Am J Psychiatry 2007 164 1061 71 10.1176/ajp.2007.164.7.1061 17606658 \n20. Riedel M Schennach-Wolff R Musil R Dehning S Cerovecki A Opgen-Rhein M Neurocognition and its influencing factors in the treatment of schizophrenia-effects of aripiprazole, olanzapine, quetiapine and risperidone Hum Psychopharmacol 2010 25 116 25 10.1002/hup.1101 20196179 \n21. Kay SR Fiszbein A Opler LA The positive and negative syndrome scale (PANSS) for schizophrenia Schizophr Bull 1987 13 261 76 10.1093/schbul/13.2.261 3616518 \n22. Kaneda Y Imakura A Fujii A Ohmori T Schizophrenia Quality of Life Scale: validation of the Japanese version Psychiatry Res 2002 113 107 13 10.1016/S0165-1781(02)00240-8 12467950 \n23. Inada T Beasley CM Jr Tanaka Y Walker DJ Extrapyramidal symptom profiles assessed with the Drug-Induced Extrapyramidal Symptom Scale: comparison with Western scales in the clinical double-blind studies of schizophrenic patients treated with either olanzapine or haloperidol Int Clin Psychopharmacol 2003 18 39 48 10.1097/00004850-200301000-00007 12490774 \n24. Soldatos CR Dikeos DG Paparrigopoulos TJ Athens Insomnia Scale: validation of an instrument based on ICD-10 criteria J Psychosom Res 2000 48 555 60 10.1016/S0022-3999(00)00095-7 11033374 \n25. Keefe RS Goldberg TE Harvey PD Gold JM Poe MP Coughenour L The brief assessment of cognition in schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery Schizophr Res 2004 68 283 97 10.1016/j.schres.2003.09.011 15099610 \n26. Kaneda Y Sumiyoshi T Keefe R Ishimoto Y Numata S Ohmori T Brief assessment of cognition in schizophrenia: validation of the Japanese version Psychiatry Clin Neurosci 2007 61 602 9 10.1111/j.1440-1819.2007.01725.x 18081619 \n27. Kaneda Y Ohmori T Okahisa Y Sumiyoshi T Pu S Ueoka Y Measurement and treatment research to improve cognition in schizophrenia consensus cognitive battery: validation of the Japanese version Psychiatry Clin Neurosci 2013 67 182 8 10.1111/pcn.12029 23581870 \n28. Heinz A Knable MB Coppola R Gorey JG Jones DW Lee KS Psychomotor slowing, negative symptoms and dopamine receptor availability–an IBZM SPECT study in neuroleptic-treated and drug-free schizophrenic patients Schizophr Res 1998 31 19 26 10.1016/S0920-9964(98)00003-6 9633833 \n29. Green MF Kern RS Braff DL Mintz J Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the ‘right stuff’? Schizophr Bull 2000 26 119 36 10.1093/oxfordjournals.schbul.a033430 10755673 \n30. Hashimoto N Matsui M Kusumi I Toyomaki A Ito K Kako Y Effect of explicit instruction on Japanese verbal learning test in schizophrenia patients Psychiatry Res 2011 188 289 90 10.1016/j.psychres.2010.06.024 20630604 \n31. Stober G Ben-Shachar D Cardon M Falkai P Fonteh AN Gawlik M Schizophrenia: from the brain to peripheral markers. A consensus paper of the WFSBP task force on biological markers World J Biol Psychiatry 2009 10 127 55 10.1080/15622970902898980 19396704\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1744-859X",
"issue": "14(1)",
"journal": "Annals of general psychiatry",
"keywords": "Antipsychotic; Cognitive impairment; Negative symptom; Quetiapine; Schizophrenia; Switching; Treatment resistance",
"medline_ta": "Ann Gen Psychiatry",
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"pubdate": "2015",
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"title": "Long-term efficacy and tolerability of quetiapine in patients with schizophrenia who switched from other antipsychotics because of inadequate therapeutic response-a prospective open-label study.",
"title_normalized": "long term efficacy and tolerability of quetiapine in patients with schizophrenia who switched from other antipsychotics because of inadequate therapeutic response a prospective open label study"
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"abstract": "Available evidence supports the efficacy of pre-exposure prophylaxis (PrEP) in decreasing the incidence of human immunodeficiency virus (HIV) infection among high-risk individuals, especially when used in combination with other behavioural preventive methods. Safety concerns about PrEP present challenges in the implementation and use of PrEP. The aim of this review is to discuss safety concerns observed in completed clinical trials on the use of PrEP. We performed a literature search on PrEP in PubMed, global advocacy for HIV prevention (Aids Vaccine Advocacy Coalition) database, clinical trials registry \" http://www.clinicaltrials.gov \" and scholar.google, using combination search terms 'pre-exposure prophylaxis', 'safety concerns in the use of pre-exposure prophylaxis', 'truvada use as PrEP', 'guidelines for PrEP use', 'HIV pre-exposure prophylaxis' and 'tenofovir' to identify clinical trials and literature on PrEP. We present findings associated with safety issues on the use of PrEP based on a review of 11 clinical trials on PrEP with results on safety and efficacy as at April 2016. We also reviewed findings from routine real-life practice reports. The pharmacological intervention for PrEP was tenofovir disoproxil fumarate/emtricitabine in a combined form as Truvada® or tenofovir as a single entity. Both products are efficacious for PrEP and seem to have a good safety profile. Regular monitoring is recommended to prevent long-term toxic effects. The main adverse effects observed with PrEP are gastrointestinal related; basically mild to moderate nausea, vomiting and diarrhea. Other adverse drug effects worth monitoring are liver enzymes, renal function and bone mineral density. PrEP as an intervention to reduce HIV transmission appears to have a safe benefit-risk profile in clinical trials. It is recommended for widespread use but adherence monitoring and real-world safety surveillance are critical in the post-marketing phase to ensure that the benefits observed in clinical trials are maintained in real-world use.",
"affiliations": "Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. r_niiatetteh@yahoo.com.;School of Public Heath, Georgia State University, Atlanta, GA, USA.;World Health Organization Collaborating Centre for Advocacy and Training in Pharmacovigilance, Centre for Tropical Clinical Pharmacology and Therapeutics, School of Medicine and Dentistry, University of Ghana, Legon, Accra, Ghana.;Department of Medicine, School of Medicine and Dentistry, University of Ghana, Legon, Accra, Ghana.;Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.;World Health Organization Collaborating Centre for Advocacy and Training in Pharmacovigilance, Centre for Tropical Clinical Pharmacology and Therapeutics, School of Medicine and Dentistry, University of Ghana, Legon, Accra, Ghana.",
"authors": "Tetteh|Raymond A|RA|;Yankey|Barbara A|BA|;Nartey|Edmund T|ET|;Lartey|Margaret|M|;Leufkens|Hubert G M|HG|;Dodoo|Alexander N O|AN|",
"chemical_list": "D019380:Anti-HIV Agents; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D000068698:Tenofovir",
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"fulltext": "\n==== Front\nDrug SafDrug SafDrug Safety0114-59161179-1942Springer International Publishing Cham 50510.1007/s40264-017-0505-6Review ArticlePre-Exposure Prophylaxis for HIV Prevention: Safety Concerns Tetteh Raymond A. +233 244 279 857r_niiatetteh@yahoo.com 12Yankey Barbara A. 3Nartey Edmund T. 45Lartey Margaret 6Leufkens Hubert G. M. 17Dodoo Alexander N. O. 41 0000000120346234grid.5477.1Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands 2 0000 0004 0546 3805grid.415489.5Pharmacy Department, Korle-Bu Teaching Hospital, Korle-Bu, Mamprobi, MP 2362 Accra, Ghana 3 0000 0004 1936 7400grid.256304.6School of Public Heath, Georgia State University, Atlanta, GA USA 4 0000 0004 1937 1485grid.8652.9World Health Organization Collaborating Centre for Advocacy and Training in Pharmacovigilance, Centre for Tropical Clinical Pharmacology and Therapeutics, School of Medicine and Dentistry, University of Ghana, Legon, Accra, Ghana 5 0000 0004 1937 1485grid.8652.9Department of Epidemiology and Disease Control, School of Public Health, University of Ghana, Legon, Accra, Ghana 6 0000 0004 1937 1485grid.8652.9Department of Medicine, School of Medicine and Dentistry, University of Ghana, Legon, Accra, Ghana 7 Medicines Evaluation Board, Utrecht, The Netherlands 28 1 2017 28 1 2017 2017 40 4 273 283 © The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Available evidence supports the efficacy of pre-exposure prophylaxis (PrEP) in decreasing the incidence of human immunodeficiency virus (HIV) infection among high-risk individuals, especially when used in combination with other behavioural preventive methods. Safety concerns about PrEP present challenges in the implementation and use of PrEP. The aim of this review is to discuss safety concerns observed in completed clinical trials on the use of PrEP. We performed a literature search on PrEP in PubMed, global advocacy for HIV prevention (Aids Vaccine Advocacy Coalition) database, clinical trials registry “http://www.clinicaltrials.gov” and scholar.google, using combination search terms ‘pre-exposure prophylaxis’, ‘safety concerns in the use of pre-exposure prophylaxis’, ‘truvada use as PrEP’, ‘guidelines for PrEP use’, ‘HIV pre-exposure prophylaxis’ and ‘tenofovir’ to identify clinical trials and literature on PrEP. We present findings associated with safety issues on the use of PrEP based on a review of 11 clinical trials on PrEP with results on safety and efficacy as at April 2016. We also reviewed findings from routine real-life practice reports. The pharmacological intervention for PrEP was tenofovir disoproxil fumarate/emtricitabine in a combined form as Truvada® or tenofovir as a single entity. Both products are efficacious for PrEP and seem to have a good safety profile. Regular monitoring is recommended to prevent long-term toxic effects. The main adverse effects observed with PrEP are gastrointestinal related; basically mild to moderate nausea, vomiting and diarrhea. Other adverse drug effects worth monitoring are liver enzymes, renal function and bone mineral density. PrEP as an intervention to reduce HIV transmission appears to have a safe benefit-risk profile in clinical trials. It is recommended for widespread use but adherence monitoring and real-world safety surveillance are critical in the post-marketing phase to ensure that the benefits observed in clinical trials are maintained in real-world use.\n\nissue-copyright-statement© Springer International Publishing Switzerland 2017\n==== Body\nKey Points\n\nSafety concerns about pre-exposure prophylaxis pose challenges in use that should not be overlooked.\t\nBehavioural counselling and assurance of safety and efficacy are important components of pre-exposure prophylaxis.\t\nReal-world safety surveillance is critical in the post-marketing phase to ensure that the benefits observed in clinical trials are maintained.\t\n\n\n\nIntroduction\nAt the end of 2015, the World Health Organization established that 36.7 million people were living with human immunodeficiency virus (HIV) with about 2.1 million becoming newly infected in the year [1]. With this high prevalence of HIV/acquired immune deficiency syndrome in the world, the World Health Organization related the urgency and importance of novel, effective and safe interventions in the prevention of HIV infection. This became necessary in that preventive behavioural messages on abstinence, faithfulness and condom use presented useful but limited impact as primary prevention on the spread of HIV. This challenge is observed especially among people at high risk because these protective measures were not applied consistently [2].\n\nHuman immunodeficiency virus continues to be a major public health problem and it has claimed more than 35 million lives so far. In 2015 alone, 1.1 million died from HIV-related causes worldwide [1]. The various management options for HIV including treatment, post-exposure prophylaxis and prevention of mother-to-child transmission have been integral in lowering HIV incidence, but reaching out to individuals at substantial risk owing to lifestyle practices required newer specific preventive approaches. Pre-exposure prophylaxis (PrEP) is a powerful tool in curbing the transmission of HIV infection [3], and it involves taking an antiretroviral (ARV) pill daily in addition to other preventive behavioural measures to prevent HIV infection. This is a protective mechanism used for individuals not diagnosed with HIV but who may be at substantial risk of becoming infected because of their lifestyle or as a partner in a sero-discordant relationship.\n\nResults from clinical trials demonstrate the efficacy of PrEP, either used alone or in combination with other behavioural preventive methods, where it has been shown that PrEP can reduce the incidence of HIV by up to 86% [4, 5] or even more with strict adherence. Based on results and evidence from PrEP trials, the US Food and Drug Administration (FDA) on 16 July, 2012 approved Truvada® [tenofovir (TDF) 300 mg/emtricitabine (FTC) 200 mg] (Gilead Sciences Inc., Foster City, CA, USA) as an effective medication for the prevention of HIV that could be sexually acquired [6, 7] and in all other types of possible HIV infection including injectable drug use. This was followed with guidelines for the provision of PrEP in clinical settings issued by the US Centers for Disease Control (CDC) and recently the World Health Organization also issued similar guidelines recommending PrEP as a prevention option for individuals at substantial risk for acquiring HIV [8, 9].\n\nIn the 2014 CDC guidelines, TDF alone based on positive results of substantial efficacy and safety in clinical trials with injectable drug use and heterosexual active adults was recommended as an alternative regimen for these populations, but not for men who have sex with men (MSM) because no efficacy studies were concluded as yet in the group. Again, the use of other antiretroviral medications for PrEP, either in place of or in addition to TDF/FTC or TDF alone is not recommended and finally the use of oral PrEP for sex activity-timed or noncontinuous daily use is also not recommended [8]. The CDC also recommend in addition to regular follow-up testing for changes in HIV-negative status and adverse drug monitoring including renal function before the initiation of PrEP and regularly while on preventive therapy. Routine bone mineral density (BMD) monitoring was not recommended by the CDC [8].\n\nThere are several challenges in the implementation and use of PrEP. These concerns include high costs, safety screening, toxicity arising from continuous use, adverse drug reactions, poor adherence, possible abuse and the fear of decreased condom use as an additional protective method [10, 11]. Poor adherence during PrEP is especially an important factor that may reduce effectiveness and lead to an increase in HIV infection rate with a possible development of HIV-resistant strains and subsequent transfer among the population. Factors that can affect adherence include adverse drug reactions (at regular doses) or toxicity (adverse drug reactions at probable high, intolerant doses or long-term use).\n\nThe ARV drugs presently recommended for oral PrEP are TDF or a combination of TDF/FTC. These medications have proven to be potent [12–14], have a favourable resistance profile and are claimed to have limited adverse effects, thus rendering them efficacious and safe for PrEP [14–17]. Some studies have also assessed the efficacy of a 1% vaginal gel formulation of TDF and found it to be effective in reducing HIV transmission by 39% [18]. Essential factors to be considered before using PrEP include a confirmed HIV-negative status with a normal renal function, a negative hepatitis B status, and absence of reduced BMD or a history of bone fractures, bone loss and osteoporosis [19, 20]. Recipients of PrEP also need to be tested on a minimum of a quarterly basis during follow-up to ensure they remain HIV negative, do not present with decreased estimated creatinine clearance levels or reductions in BMD [21]. The aim of this review is to describe and discuss safety concerns on the use of PrEP in the literature. Results from this review will contribute to the growing knowledge on the safety profile or use of PrEP.\n\nMethods\nWe performed a search of the literature on PrEP in PubMed (search date: 10 May, 2016), scholar.google (search date: 11 May, 2016), global advocacy for HIV prevention (Aids Vaccine Advocacy Coalition) database (search date: 12 May, 2016) and the clinical trials, “http://www.clinicaltrials.gov” (search date: 13 May, 2016), using combination search terms ‘pre-exposure prophylaxis’, ‘safety concerns in the use of pre-exposure prophylaxis’, ‘truvada use as PrEP’, ‘guidelines for PrEP use’, ‘HIV pre-exposure prophylaxis’ and ‘tenofovir’ to identify literature on PrEP safety trials and issues. The coverage dates were from January 2001 to April 2016. We limited the search to articles in English, which were completed with results available and based on the safety or efficacy of TDF, FTC and TDF/FTC. We profiled our findings on safety concerns of PrEP. Information on clinical trials was extracted from PubMed, Aids Vaccine Advocacy Coalition and clinicaltrials.gov based on completed studies (Fig. 1).Fig. 1 Chart of search strategy for clinical trials on pre-exposure prophylaxis based on tenofovir (TDF), emtricitabine (FTC) and a TDF/FTC combination. AVAC Aids Vaccine Advocacy Coalition\n\n\n\n\nIn the clinical trials database, studies that were enrolling or incomplete at the time of this review were excluded. Seventy-two cases were retrieved. We modified the search for closed and completed studies and reduced the number to 42. Further modification with emphasis on the drugs of interest reduced the trials to 23. We then isolated nine studies that were complete with results and enough data for our review (Fig. 1).\n\nIn PubMed, we obtained 938 articles after the initial search. We then limited the search to only clinical trials and obtained 79. We then modified to include only trials involving TDF/FTC and TDF and got 35 articles. From here, we isolated 29 articles that were completed and had results. We then focused on efficacy and safety, and retrieved nine articles.\n\nFor AVAC, the initial search on PrEP and then clinical trials and product development yielded 38 articles; we then selected completed studies and obtained 14 articles. We then modified to focus on efficacy and safety and isolated eight articles. We then isolated 11 studies that appeared in all three search engines that satisfied our review requirements and used these for our review and discussion (Fig. 1).\n\nResults\nClinical Trials Supporting the Use of PrEP\nNumerous trials involving both humans and animals have tested oral and vaginal routes of administration of PrEP and have been found efficacious in preventing HIV. The basis for PrEP stems from results of clinical and epidemiological research [22–25]. We reviewed 11 clinical trials on PrEP among different risk groups conducted from 2005 to 2015. These trials had results at the time of our study and allowed for review. Results from literature on PrEP studies are not necessarily universal. The efficacy ranges from lack of protection to protection levels of as high as 96%, attesting to the complex nature of PrEP implementation [26]. Aside from the effectiveness of PrEP in most of the studies cited, the Vaginal and Oral Interventions to Control the Epidemic (VOICE) [27] and Preexposure Prophylaxis Trial for HIV Prevention among African Women (FEM-PrEP) [28] studies were terminated ahead of time because the analysis failed to demonstrate efficacy attributed to poor adherence. Results for the VOICE study differ with findings in three other placebo-controlled vaginal PrEP trials [Partners PrEP [14], TDF2 [17], Iniciativa Profilaxis Pre-Exposicion (iPrEx) and [16] one placebo-controlled vaginal gel trial [Centre for AIDS program of Research in South Africa (CAPRISA 004)] [18]. Partners PrEP [14] studied Truvada® and TDF alone in HIV-discordant committed African couples, TDF2 [17] studied heterosexual African women and men, iPrEx [16] studied gay and bisexual men on four continents and CAPRISA 004 [18] studied South African women. Poor adherence as in FEM-PrEP was the main reason for failure in all three VOICE arms. Among 334 women who became infected with HIV, 22 entered the trial with acute HIV infection. With their exclusion, HIV incidence was 5.7 per 100 person-years, meaning about 6 in every 100 women got infected in every 12 months. HIV incidence rates per 100 person-years were 6.3 and 4.2 for oral TDF vs. placebo, 4.7 and 4.6 for Truvada® vs. placebo, and 5.9 and 6.8 for TDF gel vs. placebo; therefore, none of the three strategies worked as hazard ratios (HRs) was for oral TDF: HR 1.49 [95% confidence interval (CI) 0.97–2.29], oral Truvada®: HR 1.04 (95% CI 0.73–1.49) and TDF gel: HR 0.85 (95% CI 0.6–1.2). In all cases, women reported 90–91% adherence with return data suggesting the same, but TDF concentrations in plasma told another story: 30% or fewer women in all three treatment arms had detectable concentrations in plasma: 30% in oral TDF, 29% in oral Truvada® and 25% using TDF gel. In all three again, 50% or more women never had detectable blood in any sample. Three factors predicted detectable TDF in plasma: first, being married (adjusted odds ratio = 2.24 [95% CI, 1.12–4.49]), the second being older than 25 years (adjusted odds ratio = 1.62 [95% CI, 1.12–2.34]), and the third being multiparous (adjusted odds ratio = 1.84 [95% CI, 1.26–2.69]).\n\nThe FEM-PrEP [28] study of 2120 participants reported 56 new HIV infections 14 months after initiation of the study with the infections equally distributed between Truvada® and placebo groups (28 in each arm), clearly indicating the lack of protection in the use of Truvada®. Overall adherence (based on participants self-report) was 95% with no clear difference in adherence between the two arms.\n\nThese two results revealed that “products that are long acting and require minimum daily adherence may be more suitable for the population under study” contrary to positive results posted by the other findings, which suggest that young, sexually active, single people can be motivated to take oral Truvada® or TDF gel regularly enough to protect themselves from HIV. However, the CAPRISA 004 trial [18] differed from the FEM-PrEP [28] and VOICE [27] studies by determining a 65% protection against HIV at a TDF concentration of >100 ng/mL and up to 76% with a TDF concentration of >1000 ng/mL. Results from Pre-exposure Prophylaxis to Prevent the Acquisition of HIV-1 Infection (PROUD) [29] in the UK and Intervention Preventive de l’Exposition aux Risques avec Risques avec et pour les Gays (Ipergay) [5] in France both showed that PrEP reduced infections among gay men by 86%. None of the participants on PrEP involved in these studies acquired HIV. PrEP was also found to be effective for heterosexual men and women: a study in East Africa (Partners) [14] reduced possible HIV infection within couples in which one partner was positive by 75%. The iPrEx study also found that the HIV infection rate in HIV-negative gay men who were given a daily pill containing Truvada® was reduced by 44%, compared with men given placebo. Those who confirmed adherence at 90% had a reduction rate of up to 73%. The TDF2 trial in Botswana gave a reduction rate of 63% against placebo and 77.9% after secondary analysis; therefore, confirming the obvious benefit in the use of PrEP. The Bangkok Tenofovir Study [30] focused on men and women who inject drugs and found that the risk of acquiring HIV reduced by 49% and up to 79% in those who adhered consistently to their medication. The study also found that participants taking TDF were more likely to experience nausea and or/vomiting than those in the placebo group. No indication of elevated creatinine or renal impairment in the TDF group was reported.\n\nThe PrEP study in USA with 373 participants with 186 taking TDF and 187 taking placebo was successful with [31] only four on placebo and three among the delayed-arm participants seroconverting. Estimated adherence by pill load was 92% and by medication event monitoring system was 77%. Oral TDF was well tolerated with no significant renal concerns, while adverse drug events reported did not differ significantly between TDF and placebo arms.\n\nSensitivity analysis on oral PrEP demonstrated that both TDF/FTC and TDF are efficacious in the prevention of HIV infection for a variety of high-risk populations irrespective of country [32, 33]. Both daily and intermittent dosing of PrEP have proven effective and safe [15]. Pharmacokinetic modelling of the pre-exposure prophylaxis initiative (iPrEx) data revealed that a PrEP dose regimen of 7 days in the week dosing could achieve as high as 99% efficacy in the prevention of HIV infection among MSM. Additionally, an intermittent dosing of 4 days in the week could result in 96% efficacy [15]. In a laboratory analysis, detectable blood concentrations of medications used for PrEP were consistently associated with a protective effect against HIV acquisition [16].\n\nSafety Concerns\nAdverse reactions to medications used for any intervention are undoubtedly a primary safety concern irrespective of the duration of use. A qualitative study of gay and bisexual sero-discordant male couples assessed the concerns for adoption of PrEP and revealed that the main concerns and probable barriers to adoption of PrEP were short- and long-term side effects or adverse effects due to intermittent dosing or early termination of drug use aside from cost and accessibility of the drugs [34]. In this review, we acknowledge that the trials discussed are short term and do not give the opportunity to assess the long-term, real-world safety profile of the products used for PrEP. Pre-exposure prophylaxis is premised on ARV medications that have been used by people living with HIV and AIDS for quite some time now, since the inception of ARVs. We would expect based on current evidence that the long-term safety profile will be within acceptable limits with favourable benefit-risk profiles, considering the impact of PrEP on HIV prevention. Nonetheless, established adverse drug events such as renal impairment, reduction in BMD, and gastrointestinal (GI) disturbances captured in scientific literature concerning the use of TDF should be considered and monitoring is recommended in PrEP use. An earlier study by the same authors on the association between the occurrence of adverse drug events and the modification of first-line highly active antiretroviral therapy in Ghanaian patients established that adverse drug events play a major role in treatment modification and could be used as a predictor for possible therapy modification [35].\n\nOther concerns on the use and implementation of PrEP include resistance to PrEP medications, feasibility, acceptability and very importantly adherence to PrEP regimens. Because of the importance of PrEP in reducing the spread of HIV, it is critical that these concerns are addressed and fears alleviated to allow for the promising potential of PrEP. The US Public Health Service recommended guidelines for the use of PrEP in 2014 [21] and the CDC has interim guidelines for clinicians on the use of PrEP [36]. Essential factors to be considered before using PrEP include a confirmed HIV-negative status with a normal renal function and a negative hepatitis B status [19, 20]. Recipients of PrEP should be at high risk for HIV infection, receive behavioural and adherence counselling, and need to be tested on a minimum of a quarterly basis during follow-up to ensure they remain HIV negative [21, 36].\n\nAdverse Effects\nThe TDF/FTC (Truvada®) combination or TDF alone used for PrEP generally shows a tolerable profile. In most studies, the experienced side effects did not differ significantly from rates among participants taking placebo. The side effects or adverse events are basically of GIT origin and more prevalent at the start of use, but subside within a month of use. The GIT disturbances are generally upset abdominal pain, nausea, vomiting or diarrhoea. Other reported adverses events not of GIT origin are dizziness, headache, fatigue, weight loss, shortness of breath, cough, anxiety, fever or joint and muscle pain. In most studies, these side effects or adverse events did not differ significantly from rates among participants taking placebo.\n\nRisk factors in long-term use include age, duration of treatment with TDF, elevated baseline creatinine levels, and treatment with a protease inhibitor boosted with ritonavir combinations and among persons with African descent as against Caucasians [37]. Side effects considered potentially serious in the daily use of Truvada® or TDF for PrEP are liver function problems, kidney damage, hypophosphatamia, proteinaemia or glucosuria, pancreatitis, bone thinning and lactic acidosis. Flu-like symptoms, hypertriglyceridemia, increased creatinine phosphokinase, unusual dreams and hyperpigmentation are associated with the use of FTC. The Partners PrEP safety trial [14], the iPrEx [16] and the Bangkok Tenofovir studies [30] all recorded increased serum creatinine levels but analyses indicated that they were statistically insignificant compared with placebo. However, changes in estimated glomerular filtration rate were associated with a small but statistically significant decline in the estimated glomerular filtration rate, which was non-progressive and resolved with TDF discontinuation. The use of TDF alone is also associated with liver and pancreatic problems as well as depression [38]. The iPrEx study found a modest effect on BMD reduction in men who participated in the study. The study compared changes in BMD between placebo group and study participants with blood concentrations of tenofovir diphosphate associated with 90% efficacy and use of two to three tablets per week. There was a decline of 1% in the hip and 1.8% in the spine by the end of the study in those with optimal TDF diphosphate concentrations but this reduced to normal levels after 1.5 years of stopping PrEP [16]. The loss of BMD could lead to potential bone fractures and is a problem for TDF-based PrEP. This could be because of phosphate wasting. TDF/FTC was well tolerated with some nausea but little difference was observed between participants and those taking placebo (9 vs. 5%). No differences in severe (grade 3) or life-threatening (grade 4) adverse laboratory events were observed between the active and placebo groups [8].\n\nIn the CAPRISA 004 study [18], hepatic flare (defined as an event with an abrupt rise of alanine aminotransferase levels to more than five times the upper limit of normal) during chronic hepatitis B virus infection and considered to be the result of a human leukocyte antigen-1 restricted, cytotoxic T lymphocyte-mediated immune response against hepatitis B virus [39] was observed for two hepatitis B carriers but this did not result in drug discontinuation. In the Partners-PrEP study [14], there were no significant differences across the study arms with respect to serious adverse effects including the total of 1% deaths per arm.\n\nThe US MSM safety trial [31] presented no marked difference in the overall frequency of adverse events between TDF and placebo groups, but in a subset of men at a San Francisco site (n = 184), the use of TDF was associated with a small but statistically significant decrease in BMD at the femoral neck (1.1%) and total hip (0.8% decrease) but no bone fractures were detected. Rates of nausea and vomiting were higher among the TDF than among placebo recipients in the first 2 months in the Bangkok Tenofovir Study [30] but not thereafter. The rates of adverse drug events, deaths or elevated creatinine were not different between the TDF and the placebo groups [30].\n\nConcerning the trials with questionable efficacy, the FEM-PrEP trial [28] presented adverse drug events of nausea and vomiting, which were transient, and a mild elevation of liver enzymes was much more common with the TDF/FTC group than that of placebo group. No change in renal function was reported in either group. In the VOICE study [27], a confirmed increase in creatinine levels was observed in the oral TDF/FTC group than in the oral placebo group. There were no significant differences between the active products and placebo groups for other safety outcomes [27].\n\nResistance\nGenerally, resistance to PrEP is rarely observed in seroconverters who are infected with HIV after randomisation. Participants who show resistance are more likely to be the result of circulating resistance and not necessarily, PrEP induced. In the PROUD trial, no one acquired resistance to TDF [29]. Resistant virus reported in studies include one with TDF-resistant virus (K65R mutation) in a participant randomised to TDF and one with FTC-resistant virus (M184V mutation) in a participant randomised to FTC/TDF from the Partners-PrEP trial [14]. They were found to be infected at randomisation. A rare TDF resistance mutation (K65N) was however reported in the TDF arm of the Partners-PrEP study after randomisation [14]. In the TDF2 study, K65R, M184V and A62V resistance mutations occurred in one participant in the TDF/FTC group. The participant was later found to have had HIV infection at enrolment. The iPrEx study presented two of two men in the active group and one of eight in the placebo group with FTC-resistant virus. TDF/FTC resistant virus was detected in five women (one in the placebo group and four in the TDF/FTC group) in the FEM-PrEP study [28]. Two women from the TDF/FTC group who were determined after enrolment to have had acute HIV infection at baseline had the virus with the M1841/V mutation associated with FTC resistance. One other woman also had the M1841/V mutation but acquired the HIV infection after enrolment. The development of a resistant mutation seems to be more common with FTC than TDF. Additional care must be deployed to ensure that PrEP use is not approved during the acute infection stage to prevent the development of resistance strains. An abstract authored by Knox et al. presented at the CROI 2016 conference in Boston, MA, USA titled “HIV-1 infection with multiclass resistance despite PrEP” provided evidence of breakthrough HIV infection irrespective of long-term adherence to FTC/TDF (monitored via clinical and pharmacokinetic data) and described a resistant strain irrespective of long-term adherence [40]. It is described as the first such report and more efforts would be deployed to closely monitor the use of PrEP following this report.\n\nThe other area of concern is sexual and reproductive health because women of childbearing age are prone to HIV infection and the use of PrEP in discordant relationships could be useful. The Partners PrEP and the FEM-PrEP studies showed that TDF based PrEP does not affect the effectiveness of hormonal contraception and neither does hormonal contraception affect PrEP efficacy [14, 28]. There were not significant differences in pregnancy related and infant adverse reaction including premature births, congenital anomalies and growth throughout the early years of life for infants born to women who received PrEP as against placebo in the Partners PrEP study. Therefore, PrEP is relatively safe to be used by women of child-bearing age [14] though, like all medicines, its benefits should be weighed against any risks that it may pose in specific individuals.\n\nFeasibility and Acceptability\nSome research on behavioural tendencies has helped to determine adherence to PrEP, but few studies have assessed the acceptability and use of PrEP. Factors associated with intentions to use PrEP in a sample of men who have sex with men (MSM) in USA included the efficacy, costs and potential side effects of PrEP [41]. Preliminary findings from the PrEP Safety trial showed that MSM attending the STD clinic in San Francisco had a high interest in taking PrEP. This trial also demonstrated feasibility of including PrEP in busy clinical settings, indicating that PrEP can be accessed at clinics providing HIV care management [42]. Project PrEP, a study on the acceptability and feasibility of PrEP among young men who have sex with men, reported of high feasibility and acceptability of PrEP [43]. The PROUD study also affirmed the feasibility of incorporating PrEP in routine activities of clinical settings [29]. Acceptability of PrEP as demonstrated in a study among MSM and female sex workers in Nairobi and Mtwapa, Kenya, was also rated as high [44]. Suggestions proposed in this study included how best to improve the pill characteristics to make it easy to take, how to reduce stigma and discrimination from other family members, certain barriers and facilitators to adhering to PrEP regimens such as lifestyles, dosing regimen and side effects were identified. Enhanced counselling and commitment to using the products also improved their ability to adhere to the regimens despite the challenges.\n\nParticipants in all the listed studies were receptive to monthly HIV testing and counselling, risk reduction counselling, physical examinations and group-based intervention sessions. Participants were more likely to accept a daily pill compared with multiple daily pills administration, especially if they knew their partner was not infected [43]. The Ipergay trial demonstrated that high-risk MSM who do not use condoms consistently, accepted on demand PrEP as a practical alternative to daily PrEP if its effective [5]. A substudy of The Alternative Dosing to Augment Pre-Exposure Prophylaxis Pill Taking [45] study involving 37 men in Harlem revealed scepticism and distrust by male partners and sometimes resulted in unwillingness of partners to engage in sex after learning about their PrEP use, thus pointing out how stigma and social barriers may impede adherence and therefore acceptability.\n\nAdherence\nSix clinical trials yielded PrEP efficacy estimates of 0–75% mostly because of differences in adherence among the studies [14, 16, 17]. Self-reported adherence to PrEP is unreliable as the initial clinical trials quickly established that blood drug concentrations sharply differ from perceived adherence claims. Effective counselling and other support measures are required in all persons who desire to use PrEP for HIV prevention.\n\nThe iPrEx study [16] clearly illustrated how adherence produced different outcomes in HIV-negative gay men who were given a daily pill of TDF and FDC and achieved a reduction rate of 44% as against men given a placebo. It was realised that subjects who by self-report and pill count took the drugs more than 90% of the time reduced the infection rate by 73% [16]. Meanwhile, another interesting finding of the trial indicated that while 93% of trial subjects reported complete compliance, only 51% actually complied effectively when drug concentrations in blood were determined [16]. The investigators concluded through calculations that a reduction in the risk of HIV infection could have been as much as 92% compared with placebo if the study subjects had complied totally [16]. This confirms the importance of adherence as a major tool to be deployed in PrEP. The FEM-PrEP trial [28], which was halted for futility, reported adherence by self-report and pill count as high, but plasma drug concentrations showed that only 15–26% of samples from HIV seroconverters had detectable concentrations of serum TDF and only 26–38% of non-seroconverting controls. This low level of adherence was recorded as 37% (Table 1) by the researchers and this may have resulted in the inability to assess the protective effect of Truvada® in FEM-PrEP trial. This again points to the importance of ensuring adherence in PrEP management.Table 1 Abstract on clinical trials on pre-exposure prophylactic agents (tenofovir and emtricitabine)\n\nStudy\tYear\tStudy design\tStudy population\tSample size\tAgent used\tObjective\tOutcome/results\t\niPrEx trial [16]\t2010\tPlacebo-controlled RCT\tMSM\t2499\tTDF/FTC\tEffectiveness\t44%\t\nSafety\tNausea; ↑serum creatinine\t\nAdherence\t51%\t\nTDF2 [17]\t2012\tPlacebo-controlled RCT\tHeterosexual adults\t1219\tTDF/FTC\tEffectiveness\t62%\t\nSafety\tDizziness; nausea; vomiting; ↓bone mineral density\t\nAdherence\t84%\t\nPartners PrEP [14]\t2012\tPlacebo-controlled RCT\tHeterosexual couples\t1013\tTDF vs. TDF/FTC\tEffectiveness\t67% (TDF); 75% (TDF/FTC)\t\nSafety\tGIT; fatigue; neutropaenia; ↑serum creatinine; ↓phosphorous\t\nAdherence\t82%\t\nVOICE [27]\t2015\tPlacebo-controlled RCT\tWomen of reproductive age\t3019\tTDF vs. TDF/FTC\tEffectiveness\t−49% (TDF); −4% (TDF/FTC)\t\nSafety\t↑Serum creatinine\t\nAdherence\t28–29%\t\nFEM-PrEP [28]\t2012\tPlacebo-controlled RCT\tHigh-risk women\t2120\tTDF/FTC\tEffectiveness\t6%\t\nSafety\tNausea; vomiting; ↑ALT; hepatic and renal abnormalities\t\nAdherence\t37%\t\nPROUD [29]\t2016\tPlacebo-controlled RCT\tMSM\t545\tTDF/FTC\tEffectiveness\t86%\t\nSafety\tNausea; diarrhoea; abdominal pains; fatigue; headache; flu-like illness; sleep disturbance; ↑creatinine clearance\t\nAdherence\t86%\t\nIpergay [5]\t2015\tPlacebo-controlled RCT\tMSM\t400\tTDF/FTC\tEffectiveness\t86%\t\nSafety\tAbdominal pains; nausea; vomiting; diarrhoea\t\nAdherence\t43% optimal use; 25% suboptimal use by ACASI\t\nADAPT [45]\t2015\tPlacebo-controlled RCT\tMSM; TGW\t179\tTDF/FTC\tEffectiveness\tNR\t\nSafety\tNausea; unintentional weight loss; ↑serum creatinine\t\nAdherence\tDaily, 79%; time driven, 63%; event driven, 53%\t\nThe Bangkok Tenofovir study [30]\t2013\tPlacebo-controlled RCT\tDrug injectors\t2413\tTDF\tEffectiveness\t48.9%\t\nSafety\tNausea; vomiting\t\nAdherence\t83.8%\t\nCAPRISA 004 trial [18]\t2013\tPlacebo-controlled RCT\tWomen of reproductive age\t889\tTDF\tEffectiveness\t39%\t\nSafety\t↑Serum creatinine; anaemia; diarrhoea\t\nAdherence\tNR\t\nPrEP safety trial [31]\t2013\tPlacebo-controlled RCT\tMSM\t400\tTDF\tEffectiveness\tNR\t\nSafety\tBack pain; ↓in bone mass density; Hypophosphatemia\t\nAdherence\t92% (pill count); 77% (MEMS)\t\n\nACASI Audio Computer-Assisted Self-Interview Software, ADAPT Alternative Dosing to Augment Pre-Exposure Prophylaxis Pill Taking, ALT alanine transaminase, CAPRISA Centre for AIDS program of Research in South Africa, FEM PrEP Preexposure Prophylaxis Trial for HIV Prevention among African Women, FTC emtricitabine, Ipergay Intervention Preventive de l’Exposition aux Risques avec Risques avec et pour les Gays, iPrEX Iniciativa Profilaxis Pre-Exposicion, MEMS medication event monitoring system, MSM men who have sex with men, NR not reported, PrEP pre-exposure prophylaxis, PROUD Pre-exposure Prophylaxis to Prevent the Acquisition of HIV-1 Infection, RCT randomised controlled trial, TDF tenofovir, TGW trans-gender women, VOICE Vaginal and Oral Interventions to Control the Epidemic, ↑ increased, ↓ decreased\n\n\n\n\nLiu et al. [42], examined self-reported medication-taking experiences, facilitators and barriers of medication adherence among a geographically diverse online sample of HIV-uninfected MSM in US. Their multivariable analyses showed that age and sex were likely associated with adherence. In this study, 1480 men having sex with other men were surveyed, 806 (54%) of participants indicated regular taking of medicines, 80% of this number reported taking medicines for treatment whilst 55% said they take medicines for preventive purposes. The study also realised that men aged older than 25 years were more likely to report excellent adherence together with those who did not report any adherence barriers. Willingness to use PrEP was also associated with high likelihood of reporting perfect 30-day adherence. They listed factors that improved medication adherence as establishing a routine, keeping medication visible and using a pill-box. Forgetfulness, changes in usual routine, and being busy or away from home were listed as barriers to adherence [42]. Counselling strategies to build pill-taking routines can help improve adherence to PrEP. Daily dosing are much more associated with a high level of adherence than post-coital use of PrEP, which is generally low [15].\n\nFollowing the approval of the use of PrEP in USA and Europe, reports on adherence have been claimed to be higher in recent trials and open label extensions as compared with the initial clinical trials. Explanations provided include available evidence of PrEP efficacy and individual motivations and reasons for taking PrEP [46].\n\nDiscussion\nThe advent of PrEP is a promising turning point in the prevention of HIV among at-risk groups. TDF-based PrEP is recommended to prevent HIV infection in tandem with other preventive measures. From the trials reviewed, it is evident that PrEP is highly effective against HIV infection when taken as required. Most importantly, PrEP seems to be characterised by low adverse effects. Our current review shows a favourable pattern of adverse events for PrEP among eligible populations. Side effects can lead to a lack of compliance, resulting in low levels of adherence (frequency of medicine intake) to pill use. Some reported symptoms associated with the start of PrEP gradually resolve. Generally, even for some side effects listed as serious, such as kidney dysfunction, observed increases in the serum creatinine level return to normal after the discontinuation of PrEP. Tubular renal toxicity from PrEP is rare and active screening is not recommended. The same applies to the reduction of BMD after cessation in the use of TDF and therefore current evidence does not support constant X-ray monitoring at baseline before initiating PrEP and while taking TDF/FTC.\n\nLiver toxicity mentioned earlier in the findings was reported by the D.A.D. study, which looked at the use of antiretroviral therapy and the risk of end-stage liver disease and hepatocellular carcinoma in HIV-positive persons. It concluded among that alongside other antiretroviral agents, TDF is associated with an increased risk of end-stage liver disease among HIV-positive patients on long-term therapy. It also indicated that the unexpected viral hepatitis independent TDF association should be investigated further [47]. The use of TDF-based PrEP is yet to present any case report involving serious hepatic complications. However, the regular monitoring of liver enzymes in PrEP uses would be helpful in preventing possible toxicities.\n\nThe correspondent decrease in sexual risk behaviour among participants in the course of PrEP is very encouraging. This is attributed to behavioural intervention including sexual health counselling and the provision of condoms across the studies where applicable. Undoubtedly, behavioural interventions should be an integral part of PrEP.\n\nBecause PrEP is meant for HIV-negative individuals, an important aspect of PrEP is the identification of people who are seroconverting [14]. Preliminary testing methods, for example polymerase chain reaction that can diagnose people who are recently infected with HIV, are thus important but expensive. This will enable provision of treatment options instead of preventive interventions.\n\nExclusion criteria that run across trials were the low level of creatinine clearance below 50 mL/min, some cases of hepatitis and evidence of bone fractures. People who do not qualify for PrEP but are at risk for HIV should be encouraged to adhere to good evidence-based sexual behavioural prevention practices including regular condom use. The reduction in rates of sex without condoms from 27 to 9% after 24 months of the Partners-PrEP trial [14] is encouraging and shows that counselling and education on good sexual practices is complementary on HIV prevention. Several other studies [48–51], including studies conducted in West African women with TDF, also demonstrate a reduction in high-risk sexual behaviour with counselling during PrEP [52]. TDF/FTC is the only medication with a label indication as PrEP against HIV infection, but new PrEP drugs and formulations are being considered for future trials (Maraviroc, intravaginal rings containing dapivirine and TDF) and long-acting injectables (rilpivirine, carbotegravir). These newer agents also present a good safety profile when used for the treatment of HIV infection, but use for PrEP purposes in HIV-uninfected persons is unknown as efficacy and clinical safety is yet to be established [37]. A new formulation, tenofovir alafenamide that provides 90% lower plasma levels of TDF concentrations compared with standard TDF, has recently being approved by the FDA. It is claimed to have favourable renal and bone safety profile better than original TDF, unfortunately as at the time of this review efficacy and safety in PrEP has not been established in HIV-negative populations [37].\n\nConclusion\nThe medications currently studied for PrEP (TDF and FTC) are efficacious and seem to have a good safety profile within the average short period of 3 years studied. Emphasis on the use of additional prevention methods should be made alongside. The main adverse effects observed with PrEP are GI related and graded below 2 for severity. These are basically mild to moderate nausea, vomiting and diarrhea. Major concerns are renal, hepatic and bone toxicity, but these are transient and non-progressive and quickly resolved after discontinuation of TDF. Overall, the benefit-risk profiles of the products used for PrEP appear favourable.\n\nPrEP as an intervention to reduce HIV transmission appears to have a safe benefit-risk profile in clinical trials. It is recommended for widespread use but adherence monitoring and real-world safety surveillance are critical in the post-marketing phase to ensure that the benefits observed in clinical trials are maintained in real-world use. Behavioural counselling and assurance of safety and efficacy are important components of PrEP. Other factors of PrEP implementation that have been suggested include improving access, averting stigma, cost effectiveness, and education on PrEP to improve knowledge and assure people of the efficacy profile of products used for PrEP. Further studies must ultimately look at how safe and beneficial PrEP could be for pregnant women and women seeking to get pregnant.\n\nAuthors’ contributions\nThe authors, RAT, ANOD, BAY and ETN worked on the conception, study design and the final article composition. RAT, ETN, BAY, ML, HGML and ANOD contributed to the methods, results and its continuous critical review. BAY, RAT, ETN, ML, ANOD and HGML worked on the data analysis, discussions and critical revisions. All the authors read and approved the final manuscript.\n\nCompliance with Ethical Standards\nFunding\nNo sources of funding were used to assist in the preparation of this review.\n\nConflict of interest\nRaymond A. Tetteh, Barbara A. Yankey, Edmund T. Nartey, Margaret Lartey, Hubert G.M. Leufkens, and Alexander N.O. Dodoo have no conflicts of interest that are directly relevant to the content of this review.\n\nEthics approval\nEthical approval for the study was not obtained as it was a review of published work.\n==== Refs\nReferences\n1. UNAIDS. 2015 facts sheet. Geneva: WHO; 2016. http://www.unaids.org/sites/default/files/media_asset/20150901_FactSheet_2015_en.pdf. Accessed 3 June 2016.\n2. Weinhardt LS Carey MP Johnson BT Bickham NL Effects of HIV counseling and testing on sexual risk behavior: a meta-analytic review of published research, 1985–1997 Am J Public Health 1999 89 9 1397 1405 10.2105/AJPH.89.9.1397 10474559 \n3. Castilla J Del Romero J Hernando V Effectiveness of highly active antiretroviral therapy in reducing heterosexual transmission of HIV J Acquir Immune Defic Syndr 2005 40 1 96 101 10.1097/01.qai.0000157389.78374.45 16123689 \n4. Kirby T Thornber-Dunwell M Uptake of PrEP for HIV slow among MSM Lancet 2014 383 9915 399 400 10.1016/S0140-6736(14)60137-9 24494225 \n5. Molina JM Capitant C Spire B On-demand preexposure prophylaxis in men at high risk for HIV-1 infection N Engl J Med 2015 373 23 2237 2246 10.1056/NEJMoa1506273 26624850 \n6. Holmes D FDA paves the way for pre-exposure HIV prophylaxis Lancet 2012 380 9839 325 10.1016/S0140-6736(12)61235-5 22852138 \n7. US Food and Drug Administration. FDA approves first drug for reducing the risk of sexually acquired HIV infection. Silver Spring, Maryland: US Food and Drug Administration. 2012.\n8. Centres for Disease Control and Prevention. Preexposure prophylaxis for the prevention of HIV infection in the United States. Atlanta, Georgia: Centres for Disease Control and Prevention. 2014.\n9. World Health Organization. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. Geneva: World Health Organization; 2015. ISBN: 9789241509565. http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/. Accessed 6 June 2016.\n10. Underhill K Operario D Skeer M Packaging PrEP to prevent HIV: an integrated framework to plan for pre-exposure prophylaxis implementation in clinical practice J Acquir Immune Defic Syndr 2010 55 1 8 10.1097/QAI.0b013e3181e8efe4 21423876 \n11. Arnold EA Hazelton P Lane T A qualitative study of provider thoughts on implementing pre-exposure prophylaxis (PrEP) in clinical settings to prevent HIV infection PLoS One 2012 7 7 e40603 10.1371/journal.pone.0040603 22792384 \n12. Louissaint NA Cao Y-J Skipper PL Single dose pharmacokinetics of oral tenofovir in plasma, peripheral blood mononuclear cells, colonic tissue, and vaginal tissue AIDS Res Hum Retrovir 2013 29 11 1443 1450 10.1089/aid.2013.0044 23600365 \n13. Anderson PL Kiser JJ Gardner EM Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection J Antimicrob Chemother 2011 66 2 240 250 10.1093/jac/dkq447 21118913 \n14. Baeten JM Donnell D Ndase P Antiretroviral prophylaxis for HIV prevention in heterosexual men and women N Engl J Med 2012 367 5 399 410 10.1056/NEJMoa1108524 22784037 \n15. Kibengo FM Ruzagira E Katende D Safety, adherence and acceptability of intermittent tenofovir/emtricitabine as HIV pre-exposure prophylaxis (PrEP) among HIV-uninfected Ugandan volunteers living in HIV-serodiscordant relationships: a randomized, clinical trial PLoS One 2013 8 9 e74314 10.1371/journal.pone.0074314 24086333 \n16. Grant RM Lama JR Anderson PL Preexposure chemoprophylaxis for HIV prevention in men who have sex with men N Engl J Med 2010 363 27 2587 2599 10.1056/NEJMoa1011205 21091279 \n17. Thigpen MC Kebaabetswe PM Paxton LA Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana N Engl J Med 2012 367 5 423 434 10.1056/NEJMoa1110711 22784038 \n18. Sokal DC Karim QA Sibeko S Safety of tenofovir gel, a vaginal microbicide, in South African women: results of the CAPRISA 004 trial Antivir Ther. 2013 18 3 301 310 10.3851/IMP2311 22914267 \n19. Smith DK Thigpen MC Nesheim SR Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults MMWR Morb Mortal Wkly Rep 2012 61 31 586 589 22874836 \n20. Smith D Grant R Weidle P Interim guidance: preexposure prophylaxis for the prevention of HIV infection in men who have sex with men MMWR Morb Mortal Wkly Rep 2011 60 3 65 68 21270743 \n21. CDC. Control CfD, prevention. Preexposure prophylaxis for the prevention of HIV infection in the United States–2014: a clinical practice guideline. Atlanta (GA): CDC; 2014.\n22. Celum CL Robinson NJ Cohen MS Potential effect of HIV type 1 antiretroviral and herpes simplex virus type 2 antiviral therapy on transmission and acquisition of HIV type 1 infection J Infect Dis 2005 191 Suppl. 1 S107 S114 10.1086/425272 15627220 \n23. Derdelinckx I Wainberg MA Lange JM Criteria for drugs used in pre-exposure prophylaxis trials against HIV infection PLoS Med. 2006 3 11 e454 10.1371/journal.pmed.0030454 17090213 \n24. Liu AY Grant RM Buchbinder SP Preexposure prophylaxis for HIV: unproven promise and potential pitfalls JAMA 2006 296 7 863 865 10.1001/jama.296.7.863 16905792 \n25. Cardo DM Culver DH Ciesielski CA A case-control study of HIV seroconversion in health care workers after percutaneous exposure N Engl J Med 1997 337 21 1485 1490 10.1056/NEJM199711203372101 9366579 \n26. Cohen MS Baden LR Preexposure prophylaxis for HIV: where do we go from here? N Engl J Med 2012 367 5 459 461 10.1056/NEJMe1207438 22784041 \n27. Marrazzo JM Ramjee G Richardson BA Tenofovir-based preexposure prophylaxis for HIV infection among African women N Engl J Med 2015 372 6 509 518 10.1056/NEJMoa1402269 25651245 \n28. Van Damme L Corneli A Ahmed K Preexposure prophylaxis for HIV infection among African women N Engl J Med 2012 367 5 411 422 10.1056/NEJMoa1202614 22784040 \n29. McCormack S Dunn DT Desai M Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial Lancet 2016 387 10013 53 60 10.1016/S0140-6736(15)00056-2 26364263 \n30. Choopanya K Martin M Suntharasamai P Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial Lancet 2013 381 9883 2083 2090 10.1016/S0140-6736(13)61127-7 23769234 \n31. Grohskopf LA Chillag KL Gvetadze R Randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate among HIV-uninfected men who have sex with men in the United States J Acquir Immune Defic Syndr 2013 64 1 79 86 10.1097/QAI.0b013e31828ece33 23466649 \n32. Paltiel AD Freedberg KA Scott CA HIV preexposure prophylaxis in the United States: impact on lifetime infection risk, clinical outcomes, and cost-effectiveness Clin Infect Dis 2009 48 6 806 815 10.1086/597095 19193111 \n33. Van der Straten A Van Damme L Haberer JE Bangsberg DR Unraveling the divergent results of pre-exposure prophylaxis trials for HIV prevention AIDS. 2012 26 7 F13 F19 10.1097/QAD.0b013e3283522272 22333749 \n34. Brooks RA Kaplan RL Lieber E Motivators, concerns, and barriers to adoption of preexposure prophylaxis for HIV prevention among gay and bisexual men in HIV-serodiscordant male relationships AIDS Care. 2011 23 9 1136 1145 10.1080/09540121.2011.554528 21476147 \n35. Tetteh RA Nartey ET Lartey M Association between the occurrence of adverse drug events and modification of first-line highly active antiretroviral therapy in Ghanaian HIV patients Drug Saf 2016 39 11 1139 1149 10.1007/s40264-016-0460-7 27638659 \n36. Smith DK Thigpen MC Nesheim SR Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults Morb Mortal Wkly Rep 2012 61 31 586 589 \n37. Mugwanya KK Baeten JM Safety of oral tenofovir disoproxil fumarate-based pre-exposure prophylaxis for HIV prevention Exp Opin Drug Saf. 2016 15 2 265 273 10.1517/14740338.2016.1128412 \n38. Grant RM, van Griensven F. The ADAPT Study: A Phase II, Randomised, Open-Label, Pharmacokinetic and Behavioural Study of the Use of Intermittent Oral Emtricitabine/Tenofovir Disoproxil Fumarate Pre-Exposure Prophylaxis (PrEP). United States: DAIDS. 2011.\n39. Chang ML Liaw YF Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management J Hepatol 2014 61 6 1407 1417 10.1016/j.jhep.2014.08.033 25178562 \n40. Knox D, Tan D, Harrigan R, Anderson P, editors. HIV-1 infection with multiclass resistance despite pre-exposure prophylaxis (PrEP). CROI Conference: Boston (MA); 22–25 Feb 2016.\n41. Mimiaga MJ Case P Johnson CV Preexposure antiretroviral prophylaxis attitudes in high-risk Boston area men who report having sex with men: limited knowledge and experience but potential for increased utilization after education J Acquir Immune Defic Syndr 2009 50 1 77 83 10.1097/QAI.0b013e31818d5a27 19295337 \n42. Liu A Cohen S Follansbee S Cohan D Early experiences implementing pre-exposure prophylaxis (PrEP) for HIV prevention in San Francisco PLoS Med. 2014 11 3 e1001613 10.1371/journal.pmed.1001613 24595035 \n43. Hosek S, Siberry G, Bell M, et al. Project PrEPare (ATN082): the acceptability and feasibility of an HIV pre-exposure prophylaxis (PrEP) trial with young men who have sex with men (YMSM). J Acquir Immune Defic Syndr. 2013;62(4). doi:10.1097/QAI.0b013e3182801081.\n44. Van der Elst EM Mbogua J Operario D High acceptability of HIV pre-exposure prophylaxis but challenges in adherence and use: qualitative insights from a phase I trial of intermittent and daily PrEP in at-risk populations in Kenya AIDS Behav 2013 17 6 2162 2172 10.1007/s10461-012-0317-8 23080358 \n45. Bekker J, Hughes J, Amico R, et al. HPTN 067/ADAPT Cape Town: a comparison of daily and nondaily PrEP dosing in African women. CROI 2015. Seattle (WA): The HIV Prevention Trials Network; 2015.\n46. Haberrer JE Current concepts for PrEP adherence in the PrEP revolution: from clinical trials to routine practice Curr Opin HIV AIDS. 2016 11 1 10 17 10.1097/COH.0000000000000220 26633638 \n47. Ryom L Lundgren JD De Wit S Use of antiretroviral therapy and risk of end-stage liver disease and hepatocellular carcinoma in HIV-positive persons AIDS. 2016 30 11 1731 1743 10.1097/QAD.0000000000001018 26752282 \n48. Marcus JL Glidden DV Mayer KH No evidence of sexual risk compensation in the iPrEx trial of daily oral HIV preexposure prophylaxis PLoS One 2013 8 12 e81997 10.1371/journal.pone.0081997 24367497 \n49. Guest G Shattuck D Johnson L Changes in sexual risk behavior among participants in a PrEP HIV prevention trial Sex Transm Dis 2008 35 12 1002 1008 19051397 \n50. Brooks RA Landovitz RJ Kaplan RL Sexual risk behaviors and acceptability of HIV pre-exposure prophylaxis among HIV-negative gay and bisexual men in serodiscordant relationships: a mixed methods study AIDS Patient Care STDS. 2012 26 2 87 94 10.1089/apc.2011.0283 22149764 \n51. Mimiaga MJ Case P Johnson CV Preexposure antiretroviral prophylaxis attitudes in high-risk Boston area men who report having sex with men: limited knowledge and experience but potential for increased utilization after education J Acquir Immun Defic Syndr. 2009 50 1 77 83 10.1097/QAI.0b013e31818d5a27 \n52. Peterson L Taylor D Roddy R Tenofovir disoproxil fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, placebo-controlled trial PLoS Clin Trials. 2007 2 5 e27 10.1371/journal.pctr.0020027 17525796\n\n",
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"mesh_terms": "D000818:Animals; D019380:Anti-HIV Agents; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D015658:HIV Infections; D006801:Humans; D065129:Pre-Exposure Prophylaxis; D000068698:Tenofovir",
"nlm_unique_id": "9002928",
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"pubdate": "2017-04",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "22874836;21270743;26364263;23080358;9366579;24135734;19295337;22784038;22784037;24494225;22784040;26633638;15627220;25178562;16905792;16123689;24595035;24367497;22784041;23769234;22792384;26752282;19051397;26634852;10474559;25651245;21091279;26624850;17090213;22149764;23466649;21423876;22852138;17525796;22333749;24086333;21476147;27638659;21118913;22914267;19193111;23600365",
"title": "Pre-Exposure Prophylaxis for HIV Prevention: Safety Concerns.",
"title_normalized": "pre exposure prophylaxis for hiv prevention safety concerns"
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"abstract": "A 67-year-old man who was hospitalized at a mental hospital because of schizophrenia was admitted to our hospital with a complaint of dysphagia and vomiting. He was found to have advanced cancer in the middle thoracic esophagus. With the cooperation of a radiologist, a psychiatrist, and a nurse, we successfully performed chemoradiation therapy with S-1 and CDDP. The patient had adverse events of esophagitis and anuria during chemoradiation therapy. However, such adverse events were well controlled through the cooperation with a palliative care team and a urologist. Finally, we were able to enforce chemoradiation therapy with S-1 and CDDP without interruption.",
"affiliations": "Dept. of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Science, Kagoshima University.",
"authors": "Tsuruda|Yusuke|Y|;Okumura|Hiroshi|H|;Uchikado|Yasuto|Y|;Megumi|Koichi|K|;Urata|Masakazu|M|;Kawagoe|Kousuke|K|;Satake|Souichi|S|;Kita|Yoshiaki|Y|;Uenosono|Yoshikazu|Y|;Arigami|Takaaki|T|;Mori|Shinichiro|S|;Baba|Kenji|K|;Ishigami|Sumiya|S|;Owaki|Tetsuhiro|T|;Natsugoe|Shoji|S|",
"chemical_list": "D002945:Cisplatin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
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"issue": "42(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D002945:Cisplatin; D004938:Esophageal Neoplasms; D005472:Fluorouracil; D006801:Humans; D008297:Male; D012559:Schizophrenia",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1923-5",
"pmc": null,
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"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A Case of Advanced Esophageal Cancer Patient with Schizophrenia Successfully Treated with Chemoradiation Therapy with S-1 and CDDP.",
"title_normalized": "a case of advanced esophageal cancer patient with schizophrenia successfully treated with chemoradiation therapy with s 1 and cddp"
} | [
{
"companynumb": "JP-ACCORD-037793",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "CISPLATIN"
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{
"abstract": "BACKGROUND\nSpontaneous hemorrhage into a thyroid nodule occurs exceedingly rare and rarely a neck hematoma can develop. We report a case of syncope due to spontaneous hemorrhage into a thyroid nodule during anticoagulant and antithrombotic therapy.\n\n\nMETHODS\nA 64-year-old man was transferred to the emergency department of our hospital because of syncope. His physical examination revealed a 7 x 5 cm hard and painless mass at the left neck region. The neck MRI confirmed a heterogeneous, hyperintense mass in the left lobe of thyroid compressing the trachea and left common carotid artery, internal jugular vein, and vagus nerve bundle. He did not require a surgery in the follow-up. As the hematoma underwent subtotal shrinkage, he remained well without syncope.\n\n\nCONCLUSIONS\nHemorrhage into a thyroid nodule should always be considered in patients presenting with neurally mediated syncope.",
"affiliations": "> Department of Endocrinology and Metabolism Disease, Recep Tayyip Erdogan University Medical School, Rize, Turkey.;Department of Internal Medicine, Recep Tayyip Erdogan University Medical School, Rize, Turkey.;Department of Radiology, Recep Tayyip Erdogan University Medical School, Rize, Turkey.;Department of Internal Medicine, Recep Tayyip Erdogan University Medical School, Rize, Turkey.;Department of Internal Medicine, Recep Tayyip Erdogan University Medical School, Rize, Turkey.",
"authors": "Sahin|Sb|S|;Belice|T|T|;Ogullar|S|S|;Ayaz|T|T|;Cure|E|E|",
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"country": "Greece",
"delete": false,
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"issn_linking": "1108-4189",
"issue": "18(2)",
"journal": "Hippokratia",
"keywords": "Syncope; hemorrhage; thyroidnodule",
"medline_ta": "Hippokratia",
"mesh_terms": null,
"nlm_unique_id": "101296613",
"other_id": null,
"pages": "177-9",
"pmc": null,
"pmid": "25336885",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports",
"references": "23024949;23975614;17486567;3887580;16275409;16044935;21873852;13159772;12180243;19713422;16772204;18397159;20843443;16481831",
"title": "Syncope in a patient with spontaneous hemorrhage into a thyroid nodule.",
"title_normalized": "syncope in a patient with spontaneous hemorrhage into a thyroid nodule"
} | [
{
"companynumb": "CHPA2014TR013534",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASPIRIN"
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"abstract": "Granulomatous amebic encephalitis is a rare necrotizing infection of the CNS that occurs most commonly in immunocompromised individuals and is usually fatal. It is difficult to diagnose as the clinical symptoms and radiographic findings are often mistaken for other bacterial, viral, fungal, or protozoan infections. Herein, we present the case of a 69-year-old heart transplant recipient who suffered fulminant neurological decline ∼5 months after transplant. Extensive radiographic and laboratory testing did not provide a definite anatomic diagnosis and, despite aggressive clinical treatment, he died. An autopsy examination demonstrated numerous brain abscesses which contained amebic trophozoites and cysts. An indirect immunofluorescence assay performed at the Centers for Disease Control confirmed the presence of Acanthamoeba species. To the best of our knowledge, only 13 other cases of Acanthamoeba amebic encephalitis have been reported in patients who have received solid organ transplants and this is the second case reported in a heart transplant recipient. This case emphasizes that amebic encephalitis should be in the differential diagnosis for immunocompromised patients with new brain lesions found on radiographic imaging.",
"affiliations": "Department of Pathology, Duke University Medical Center, Durham, North Carolina.;Department of Pathology, Duke University Medical Center, Durham, North Carolina.;Department of Pathology, Duke University Medical Center, Durham, North Carolina.",
"authors": "Harrison|William T|WT|;Lecky|Bruce|B|;Hulette|Christine M|CM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jnen/nly089",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3069",
"issue": "77(11)",
"journal": "Journal of neuropathology and experimental neurology",
"keywords": null,
"medline_ta": "J Neuropathol Exp Neurol",
"mesh_terms": "D000048:Acanthamoeba; D000368:Aged; D001344:Autopsy; D020808:Central Nervous System Protozoal Infections; D017809:Fatal Outcome; D016027:Heart Transplantation; D006801:Humans; D000069544:Infectious Encephalitis; D008279:Magnetic Resonance Imaging; D008297:Male",
"nlm_unique_id": "2985192R",
"other_id": null,
"pages": "1001-1004",
"pmc": null,
"pmid": "30295806",
"pubdate": "2018-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal Granulomatous Amebic Encephalitis in a Heart Transplant Patient: Clinical, Radiographic, and Autopsy Findings.",
"title_normalized": "fatal granulomatous amebic encephalitis in a heart transplant patient clinical radiographic and autopsy findings"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2019-05312",
"fulfillexpeditecriteria": "1",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
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{
"abstract": "Listeria monocytogenes is an uncommon cause of brain abscesses. Immunocompromised hosts, pregnant women and patients at extremes of age are especially susceptible. We discuss the successful management of a woman with autoimmune hepatitis on prednisone and azathioprine therapy with a L. monocytogenes brain abscess. Previously thought to be a rare cause of central nervous system (CNS) infection, the incidence of CNS listeriosis has increased due to a rise in organ and bone marrow transplantation requiring immunosuppressive medications. L. monocytogenes brain abscesses are now more frequently described and are associated with high rates of concomitant bacteremia suggesting a hematogenous route of infection.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, United States.;Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, United States.;Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, United States.;Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, United States.",
"authors": "Trachuk|Polina|P|;Marin Saquicela|Tania|T|;Levi|Michael|M|;Khedimi|Rabea|R|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2019.e00569",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(19)30058-710.1016/j.idcr.2019.e00569e00569ArticleListeria brain abscess in a patient with autoimmune hepatitis Trachuk Polina aMarin Saquicela Tania bLevi Michael cKhedimi Rabea rkhedimi@montefiore.orga⁎a Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, United Statesb Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, United Statesc Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, United States⁎ Corresponding author at: Department of Medicine, Division of Infectious Diseases, Montefiore Medical Center, The University Hospital for Albert Einstein College of Medicine, 3230 Bainbridge Ave, Suite D, Bronx, NY 10467, United States. rkhedimi@montefiore.org31 5 2019 2019 31 5 2019 17 e0056922 3 2019 24 5 2019 24 5 2019 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Listeria monocytogenes is an uncommon cause of brain abscesses. Immunocompromised hosts, pregnant women and patients at extremes of age are especially susceptible. We discuss the successful management of a woman with autoimmune hepatitis on prednisone and azathioprine therapy with a L. monocytogenes brain abscess. Previously thought to be a rare cause of central nervous system (CNS) infection, the incidence of CNS listeriosis has increased due to a rise in organ and bone marrow transplantation requiring immunosuppressive medications. L. monocytogenes brain abscesses are now more frequently described and are associated with high rates of concomitant bacteremia suggesting a hematogenous route of infection.\n\nKeywords\nListeria monocytogenesBrain abscessAutoimmune hepatitisAzathioprine\n==== Body\nIntroduction\nListeria monocytogenes is a gram positive bacillus most commonly isolated in immunocompromised hosts, pregnant women and patients at extremes of age. It was first described as a new species in 1926, when isolated in laboratory rabbits [1]. In humans, it was first reported as a blood stream infection in a 17-year-old boy [2]. Subsequent reports have described both asymptomatic carriage, as well as invasive disease [2,3]. In this report, we discuss the successful management of a woman with autoimmune hepatitis on prednisone and azathioprine therapy who was found to have a L. monocytogenes brain abscess.\n\nCase report\nA 56-year-old woman presented to our institution with two days of acute onset right arm and leg weakness, which progressed to right hemiparesis. Her medical history was significant for autoimmune hepatitis diagnosed 3 months prior, for which she was prescribed prednisone 20 mg daily and azathioprine 100 mg daily. Prior to presentation, the patient had experienced chills, frontal headache and rhinorrhea. She denied fevers, night sweats, blurry vision, abdominal pain, nausea, emesis, diarrhea or rash. She denied recent travel, consumption of unpasteurized cheese or changes in diet.\n\nOn presentation to the emergency room, vital signs were within normal limits. Physical exam was significant for decreased strength in the right upper and lower extremities, right patellar hyperreflexia and preserved sensation. The remainder of the exam was unremarkable. Her initial basic metabolic panel, complete blood count, erythrocyte sedimentation rate and C-reactive protein were all within normal limits. A computed tomography (CT) of the head without contrast revealed a left frontal mass with vasogenic edema. Magnetic resonance imaging (MRI) of the brain with and without contrast revealed two dominant left-sided peripherally enhancing brain lesions measuring 2.1 cm and 1.2 cm in size, with surrounding vasogenic edema and local mass effect.\n\nOn hospital day 3, she was febrile to 100.4 °F and her white blood cell count increased to 11.8 k/uL. Chest x-ray demonstrated no infiltrates. There was no evidence of urinary tract infection on urinalysis. She was started on empiric antimicrobial coverage with ceftriaxone, metronidazole and vancomycin for a suspected brain abscess. A lumbar puncture showed 48 cells/uL white blood cells with 89% neutrophils, 125 mg/dL protein and 63 mg/dL glucose. Her blood cultures grew gram positive rods (Fig. 1), rapidly identified via matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF) as L. monocytogenes, and her antimicrobial regimen was switched to ampicillin and gentamicin. Over the next two days, a total of three sets of blood cultures grew L. monocytogenes. On hospital day 5, she underwent an MRI-guided stereotactic aspiration of the left frontoparietal brain abscess with drainage of 2 mL of purulent material. The Gram stain was positive for gram positive rods and the bacterial culture also grew L. monocytogenes (Fig. 2). The patient clinically improved after drainage, and subsequent blood cultures were negative. She was discharged to an acute rehabilitation center with a plan to complete two weeks of gentamicin and six weeks of ampicillin. Four months later, she reported significant improvement in strength in her right upper and right lower extremities, however still required assistance with household activities.Fig. 1 Gram stain of blood culture showing gram positive rods (arrow).\n\nFig. 1Fig. 2 Gram stain of brain abscess fluid showing gram positive rods (arrow).\n\nFig. 2\n\nDiscussion\nThe genus Listeria consists of 7 species, including L. monocytogenes, L. innocua, L. welshimeri, L. grayi, L. seeligeri, L. ivanovii and L. marthii. L. monocytogenes is most commonly associated with human disease. It is a gram-positive bacillus that grows readily on blood agar, producing a narrow band of beta-hemolysis. It possesses peritrichous flagella, which give it characteristic tumbling motility, occurring only in a narrow temperature range, between 20 and 25 °C. L. monocytogenes is acquired via ingestion of contaminated food, and the majority of human infections occur in those with weakened cellular immunity. Once ingested, L. monocytogenes crosses the mucosal barrier and invades into the blood stream. Once phagocytosis within circulating leukocytes has occurred, the organism uses actin filaments to move to adjacent cells without being exposed to antibodies, thereby bypassing the humoral immune system and allowing for hematogenous dissemination. L. monocytogenes has a specific affinity for the central nervous system, especially cell mediated immunodeficient individuals [4,5]. Infection of the central nervous system may occur via hematogenous spread, as a consequence of direct bacterial dissemination to and from the brain parenchyma or via retrograde axonal migration along the axons of cranial nerves [6]. In the past, lengthy culture-based techniques were used for identification of Listeria, requiring the organism to multiply at cooler temperatures. Recently, the use of MALDI-TOF MS has allowed for a more rapid and reliable identification of Listeria in patients with infection [7,8].\n\nPreviously thought to be a rare cause of central nervous system (CNS) infection, the reported incidence of CNS listeriosis has increased with the increased frequency of organ and bone marrow transplantation requiring the use of immunosuppressant medications. Since host defense against L. monocytogenes is predominantly cell-mediated, patients with physiologic or medication-induced defects in cell-mediated immunity, such as those on prednisone or azathioprine, are particularly vulnerable to infection. Corticosteroids such as prednisone are frequently used as immunosuppressive therapy, and can cause immunosuppression in a variety of ways, including the inhibition of phagocytosis and intracellular killing of pathogens [9]. Mice treated with corticosteroids and inoculated with L. monocytogenes showed prolonged fecal shedding of bacteria, as well as its persistence in the liver and spleen [10]. Azathioprine is an immunosuppressant agent that is FDA approved for renal transplant recipients and patients with rheumatoid arthritis. It is also used off-label for the treatment of autoimmune disorders, including autoimmune hepatitis. It is an antagonist of purine metabolism and functions by reducing intracellular purine synthesis, thereby suppressing cellular immunity and thus predisposing patients to infections [11]. Multiple experiments in mice have demonstrated that azathioprine prolonged the survival of Listeria inoculum and that those infected with a sublethal dose of L. monocytogenes while on azathioprine have a suppressed immune response, allowing for the growth of the organism in vivo [12,13].\n\nThough still an uncommon presentation, L. monocytogenes brain abscesses have become more frequently described as well, with a high rate of concomitant bacteremia supporting the notion that the development is secondary to hematogenous spread [14]. Ampicillin has historically been the treatment of choice, with both in vivo and in vitro studies documenting a synergistic effect with the combination of an aminoglycoside, especially in cases of meningitis and endocarditis [15]. Intravenous trimethoprim-sulfamethoxazole has been used to successfully treat a 55 year old woman with an orthotopic liver transplant on azathioprine who was found to have L. monocytogenes bacteremia, and developed facial rash and urticaria while on oxacillin [16].\n\nAt our institution, we saw 9 cases of L. monocytogenes bacteremia in the previous 4 years. Though the number of yearly cases has remained steady, the use of MALDI-TOF allowed for earlier diagnosis when compared to previous methods. Our patient presented with symptoms concerning for a neoplasm, as she had no systemic signs of infection. She became febrile on the third day of hospitalization, and the blood cultures drawn at the time of fever allowed for rapid identification via MALDI-TOF. This represents a crucial step in the ultimate diagnosis of a L. monocytogenes brain abscess. Previously, L. monocytogenes brain abscesses have been described in immunosuppressed transplant patients, as well as a patient with autoimmune hepatitis on prednisolone [14,17]. Meningitis in a patient with autoimmune hepatitis on azathioprine has also been described, as well as cases in patients with autoimmune hepatitis who were post-transplant or on a medication other than azathioprine [18,19]. To our knowledge this is the first case of a L. monocytogenes brain abscess in a patient with autoimmune hepatitis on prednisone and azathioprine as the primary risk factors for infection.\n\nDeclarations of interest\nNone.\n\nAcknowledgements\nThe authors would like to thank Dr. Priya Nori and Dr. Liise-anne Pirofski for their critical review of the manuscript.\n==== Refs\nReferences\n1 Murray E.G.D. Webb R.A. Swann M.B.R. A disease of rabbits characterised by a large mononuclear leucocytosis, caused by a hitherto undescribed bacillus Bacterium monocytogenes (n.sp.) J Pathol Bacteriol 29 4 1926 407 439 \n2 Kaplan M.M. Listerellosis N Engl J Med 232 26 1945 755 759 \n3 Nyfeldt A. Aetiology of Infective Mono-nucleosis Compte rendu des seances de la Societe de biologie 101 1929 590 592 \n4 Farber J.M. Peterkin P.I. Listeria monocytogenes, a food-borne pathogen Microbiol Rev 55 3 1991 476 511 1943998 \n5 Lorber B. Listeriosis Clin Infect Dis 24 1 1997 1 9 quiz 10-1 8994747 \n6 Disson O. Lecuit M. Targeting of the central nervous system by Listeria monocytogenes Virulence 3 2 2012 213 221 22460636 \n7 Barbuddhe S.B. Maier T. Schwarz G. Kostrzewa M. Hof H. Domann E. Rapid identification and typing of listeria species by matrix-assisted laser desorption ionization-time of flight mass spectrometry Appl Environ Microbiol 74 17 2008 5402 5407 18606788 \n8 Jadhav S. Bhave M. Palombo E.A. Methods used for the detection and subtyping of Listeria monocytogenes J Microbiol Methods 88 3 2012 327 341 22261140 \n9 Klein N.C. Go C.H. Cunha B.A. Infections associated with steroid use Infect Dis Clin North Am 15 2 2001 423 432 viii 11447704 \n10 Prats N. Lopez S. Domingo M. Briones V. Garcia J.A. Dominguez L. Prolonged persistence of Listeria monocytogenes after intragastric infection in corticosteroid-treated mice Vet Microbiol 58 1 1997 79 85 9451464 \n11 Trotter J.L. Rodey G.E. Gebel H.M. Azathioprine decreases suppressor T cells in patients with multiple sclerosis N Engl J Med 306 6 1982 365 366 \n12 Tripathy S.P. Mackaness G.B. The effect of cytotoxic agents on the primary immune response to Listeria monocytogenes J Exp Med 130 1 1969 1 16 4978231 \n13 Walencka M. Bloch M. Goscicka T. Effect of cyclosporine A (CsA), cyclophosphamide (Cy) and azathioprine (Aza) on the survival of Listeria innocua in mice Arch Immunol Ther Exp (Warsz) 42 4 1994 275 279 7487366 \n14 Eckburg P.B. Montoya J.G. Vosti K.L. Brain abscess due to Listeria monocytogenes: five cases and a review of the literature Medicine (Baltimore) 80 4 2001 223 235 11470983 \n15 Mylonakis E. Hohmann E.L. Calderwood S.B. Central nervous system infection with Listeria monocytogenes. 33 years’ experience at a general hospital and review of 776 episodes from the literature Medicine (Baltimore) 77 5 1998 313 336 9772921 \n16 Spitzer P.G. Hammer S.M. Karchmer A.W. Treatment of Listeria monocytogenes infection with trimethoprim-sulfamethoxazole: case report and review of the literature Rev Infect Dis 8 3 1986 427 430 3523699 \n17 Limmahakhun S. Chayakulkeeree M. Listeria monocytogenes brain abscess: two cases and review of the literature Southeast Asian J Trop Med Public Health 44 3 2013 468 478 24050079 \n18 Tseng J. Strasfeld L.M. Orloff S.L. An unusual presentation of altered mental status after orthotopic liver transplantation: listeria brain abscess Transplantation 95 12 2013 e72 3 23774775 \n19 Gaini S. Listeria monocytogenes meningitis in an immunosuppressed patient with autoimmune hepatitis and IgG4 subclass deficiency Case Rep Infect Dis 2015 2015 102451\n\n",
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"title": "Listeria brain abscess in a patient with autoimmune hepatitis.",
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"abstract": "A 3-year-old African American girl taking sirolimus and tacrolimus for a small bowel transplantation presented with hypopigmented macules and papules throughout her trunk. A biopsy diagnosed epidermodysplasia verruciformis (EV) that was found to be associated with human papillomavirus (HPV) type 14 according to polymerase chain reaction analysis. There are few cases of acquired EV in the setting of organ transplantation. Although there is no standardized treatment for acquired EV, prevention and surveillance for transformation to squamous cell carcinoma are primary concerns.",
"affiliations": "Graduate Medical Education Department, McLaren Bay Region, Bay City, Michigan.;Department of Dermatology, University Hospitals Case Medical Center, Cleveland, Ohio.;Center for Clinical Studies, University of Texas Health Science Center, Houston, Texas.;Center for Clinical Studies, University of Texas Health Science Center, Houston, Texas.;Department of Dermatology, University Hospitals Case Medical Center, Cleveland, Ohio.;Department of Dermatology, University Hospitals Case Medical Center, Cleveland, Ohio.",
"authors": "Hirschman|Derek|D|;Tacastacas|Joselin|J|;Rady|Peter L|PL|;Tyring|Stephen K|SK|;Cooper|Kevin|K|;Honda|Kord|K|",
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"title": "Acquired Epidermodysplasia Verruciformis Associated with Human Papilloma Virus Type 14 in a Small Bowel Transplanted Child--A Case Report.",
"title_normalized": "acquired epidermodysplasia verruciformis associated with human papilloma virus type 14 in a small bowel transplanted child a case report"
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"abstract": "Acquired aplastic anemia (AA) is a life-threatening bone marrow failure caused by an autoimmune cytotoxic T lymphocyte attack on hematopoietic stem and progenitor cells. Factors contributing to aberrant autoimmune activation in AA include a deficit of T regulatory cells and high levels of inflammatory cytokines. Several acquired conditions of immune dysregulation and genetic polymorphisms in inflammatory cytokines and human leukocyte antigen genes have been linked to an increased risk of AA. However, AA has not been reported in patients with Mendelian disorders of immune regulation. Here we report a patient with familial common variable immunodeficiency (CVID) caused by a pathogenic variant in NFKB1, who developed AA as an adult. The patient had a difficult clinical course and was unable to tolerate standard AA therapy with cyclosporine A and eltrombopag, with complications attributed in part to the effect of cyclosporine A on NF-κB signaling. Our case suggests a novel link between genetic disorders of immune regulation and AA and highlights the importance of recognizing inherited autoimmunity syndromes in AA patients for the selection of optimal therapy and prognostic counseling.",
"affiliations": "Cooper Medical School of Rowan University, Camden, New Jersey 08103, USA.;Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.;Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania 19131, USA.;GeneDx, Gaithersburg, Maryland 20877, USA.;Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.;Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.",
"authors": "Sklarz|Tammarah|T|;Hurwitz|Stephanie N|SN|0000-0002-6975-9168;Stanley|Natasha L|NL|;Juusola|Jane|J|0000-0002-4476-1309;Bagg|Adam|A|0000-0002-1669-468X;Babushok|Daria|D|",
"chemical_list": "D001565:Benzoates; D006834:Hydrazines; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D011720:Pyrazoles; D016572:Cyclosporine; C520809:eltrombopag",
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"fulltext": "\n==== Front\nCold Spring Harb Mol Case Stud\nCold Spring Harb Mol Case Stud\ncshmcs\ncshmcs\ncshmcs\nCold Spring Harbor Molecular Case Studies\n2373-2873 Cold Spring Harbor Laboratory Press \n\n32972988\n10.1101/mcs.a005769\nMCS005769Skl\nResearch Report\nAplastic anemia in a patient with CVID due to NFKB1 haploinsufficiency\nAplastic anemia in an NFKB1-mutated CVID patientAplastic anemia in an NFKB1-mutated CVID patientSklarz Tammarah 1 http://orcid.org/0000-0002-6975-9168Hurwitz Stephanie N. 2 Stanley Natasha L. 345 http://orcid.org/0000-0002-4476-1309Juusola Jane 6 http://orcid.org/0000-0002-1669-468XBagg Adam 2 Babushok Daria 45 1 Cooper Medical School of Rowan University, Camden, New Jersey 08103, USA;\n2 Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;\n3 Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania 19131, USA;\n4 Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;\n5 Comprehensive Bone Marrow Failure Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;\n6 GeneDx, Gaithersburg, Maryland 20877, USA\nCorresponding author: daria.babushok@pennmedicine.upenn.edu\n12 2020 \n6 6 a00576923 7 2020 4 9 2020 © 2020 Sklarz et al.; Published by Cold Spring Harbor Laboratory Press2020This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.Acquired aplastic anemia (AA) is a life-threatening bone marrow failure caused by an autoimmune cytotoxic T lymphocyte attack on hematopoietic stem and progenitor cells. Factors contributing to aberrant autoimmune activation in AA include a deficit of T regulatory cells and high levels of inflammatory cytokines. Several acquired conditions of immune dysregulation and genetic polymorphisms in inflammatory cytokines and human leukocyte antigen genes have been linked to an increased risk of AA. However, AA has not been reported in patients with Mendelian disorders of immune regulation. Here we report a patient with familial common variable immunodeficiency (CVID) caused by a pathogenic variant in NFKB1, who developed AA as an adult. The patient had a difficult clinical course and was unable to tolerate standard AA therapy with cyclosporine A and eltrombopag, with complications attributed in part to the effect of cyclosporine A on NF-κB signaling. Our case suggests a novel link between genetic disorders of immune regulation and AA and highlights the importance of recognizing inherited autoimmunity syndromes in AA patients for the selection of optimal therapy and prognostic counseling.\n\naplastic anemiabone marrow hypocellularitydefective production of NFKB1-dependent cytokinesimmune dysregulationK08 HL132101\n==== Body\nINTRODUCTION\nAcquired aplastic anemia (AA) is a rare life-threatening blood disease characterized pathologically by pancytopenia and a hypocellular bone marrow due to the immune-mediated destruction of early hematopoietic cells by cytotoxic T lymphocytes (Young 2018). Specific triggers of autoimmunity or the identities of autoantigens immunologically targeted in AA remain unknown. Several acquired conditions involving immune dysregulation have been linked to AA, such as Hodgkin lymphoma (Linaburg et al. 2019), immune checkpoint inhibitor therapy (Davis et al. 2019), thymoma (Gendron et al. 2020), autoimmune hepatitis (Brown et al. 1997), and eosinophilic fasciitis (de Masson et al. 2013). Additionally, a number of polymorphisms associated with overproduction of inflammatory cytokines (e.g., interferon-γ [Dufour et al. 2004]) and certain human leukocyte antigen genes (Nakao et al. 1994; Babushok et al. 2017; Zaimoku et al. 2017) have been linked to an increased risk of AA. However, AA has not been previously reported in patients with inherited diseases of immune dysregulation. Here, we report a patient with common variable immune deficiency (CVID) caused by a pathogenic variant in the NF-κB1 gene (NFKB1), who developed AA during her adult life and clinically rapidly declined despite attempts at standard AA therapy. Our patient's case suggests a new connection between the immune dysregulation seen in primary immunodeficiencies and AA. Furthermore, we propose that alterations in NF-κB signaling as well as the more general complications associated with CVID, including liver dysfunction and enteropathy, may present unique challenges in the management of AA with currently available therapeutics.\n\nRESULTS\nClinical Presentation and Family History\nA 50-yr-old female was referred for an evaluation of suspected AA. Her past medical history was notable for CVID, which was diagnosed at the age of 12 yr, after having frequent upper respiratory infections as a child, and was managed with monthly intravenous immunoglobulin (IVIG). The patient's CVID-associated complications included a remote history of autoimmune hemolytic anemia, currently in remission, which was diagnosed in the patient's 20s and was managed with a variety of immunosuppressants and splenectomy. In her 30s, the patient was diagnosed with Plummer–Vinson syndrome, a classical triad of iron deficiency, esophageal webs, and dysphagia, which has been associated with autoimmune disorders and carries an increased risk of squamous cell carcinoma of the oropharynx (Chisholm 1974; Messmann 2001). At the age of 38 yr, the patient developed a squamous cell carcinoma of the tongue, which was cured with surgical resection. She was subsequently well over the following 10 years, until 2 years prior to her current presentation when she developed anemia. Her initial evaluation was notable for a low reticulocyte count and a hypocellular marrow with an absence of erythroid precursors, consistent with acquired red cell aplasia. She was treated with corticosteroids and low-dose cyclosporine without response and eventually progressed to aplastic anemia.\n\nThe patient's family history was notable for Northern European and English ancestry, two healthy sisters who were monozygotic twins, a mother who died from glioblastoma at the age of 68 yr, and a maternal aunt with multiple sclerosis.\n\nOn physical exam, the patient was a thin middle-aged woman, weighing 106 lbs at a height of 5′7′′. Physical exam was notable for a well-healed partial glossectomy without evidence of tongue carcinoma recurrence and no oral lesions or leukoplakia. Sclera were icteric. Cardiopulmonary exam was normal. There was no lymphadenopathy or hepatosplenomegaly. Skin exam showed no rashes, café-au-lait spots, or hypo- or hyperpigmented lesions. There was no nail dystrophy. Musculoskeletal exam was normal, with no thumb or radial anomalies.\n\nLaboratory studies revealed a white blood cell count of 4 × 109 cells/L with a normal leukocyte differential, normocytic anemia (hemoglobin of 7 g/dL; mean corpuscular volume of 88 fL), a low reticulocyte count of 22 × 109 cells/L, and severe thrombocytopenia (19 × 109 platelets/L). A bone marrow biopsy revealed a severely hypocellular bone marrow with marked trilineage hypoplasia and scattered lymphohistiocytic aggregates, consistent with AA (Fig. 1). Cytogenetic examination of the bone marrow demonstrated a normal karyotype and targeted massively parallel sequencing of genes commonly mutated in hematologic malignancies showed no clinically significant variants. Consistent with an immunodominant antigen-driven autoimmune process in AA, polymerase chain reaction (PCR) analysis of the T-cell receptor gamma chain gene revealed a monoclonal rearrangement within a much more prominent polyclonal background (Risitano et al. 2004). There was no immunophenotypic evidence of clonal lymphoproliferative disorder or pan-T-cell antigen loss. Flow cytometry for paroxysmal nocturnal hemoglobinuria (PNH) revealed a subclinical (0.39%) PNH clone in granulocytes. Extensive evaluation for alternative etiologies of the patient's bone marrow failure, including underlying viral infection or nutritional deficiency was unrevealing (Supplemental Table S1). Chromosome breakage of the patient's peripheral blood lymphocytes in the presence of mitomycin C and diepoxybutane was normal. Telomere testing showed low median lymphocyte telomere lengths between the first and fifth percentile for age in total lymphocytes as well as in the naive and memory T-cell and natural killer (NK)-cell subsets. The low telomere length was interpreted to likely reflect telomere attrition because of the underlying autoimmunity; however, to exclude an atypical telomeropathy or another occult inherited marrow failure syndrome, whole-exome sequencing was requested. Given the clinical urgency, the patient was started on treatment with cyclosporine and eltrombopag for a presumed diagnosis of AA, while awaiting genetic testing results to determine more definitive therapy. An evaluation for allogeneic hematopoietic stem cell transplant was initiated. Unexpectedly, the patient was not able to tolerate cyclosporine at therapeutic doses, with an unusual degree of complications including progressive failure to thrive, >10 lb weight loss (∼10% body weight), fatigue, generalized pain and weakness, and septicemia within 2–3 wk of therapeutic cyclosporine dosing, requiring hospitalization. Cyclosporine was discontinued. Progressive liver dysfunction with rising hyperbilirubinemia and ascites precluded therapy with eltrombopag. Whole-exome sequencing revealed no disease-associated variants in genes associated with inherited bone marrow failure but identified a heterozygous variant in NFKB1 (Fig. 2; Table 1). Unfortunately, the patient continued to have a progressively deteriorating course and died within 4 mo of AA diagnosis from multiple complications, including recurrent neutropenic sepsis, severe malnutrition due to CVID-related enteropathy, and hepatic dysfunction.\n\nFigure 1. Bone marrow biopsy demonstrating hematopoietic trilineage hypoplasia. Hematoxylin and eosin (H&E)-stained sections at (A) 5× and (B) 20× magnification illustrate a profoundly hypocellular marrow (5%–10% cellularity). Scattered interstitial lymphohistiocytic aggregates account for the majority of cellularity. (C) A concurrent bone marrow aspirate is hypocellular and composed predominantly of small lymphocytes and occasional left-shifted myeloid precursors, with virtually absent erythroid cells and megakaryocytes.\n\nFigure 2. The pathogenic variant in the NFKB1 gene (c.702delC; p.V235WfsX17) identified in a patient with CVID who developed AA as an adult. (A) Screenshot from Integrative Genome Viewer (IGV) showing a single-nucleotide deletion in the NFKB1 gene (c.702delC; black arrow). (B) Confirmatory Sanger sequencing demonstrating the region containing the frameshift mutation (black arrow; region is shown in reverse complement).\n\nVariant Interpretation\nA constellation of a congenital immune deficiency, short lymphocyte telomere lengths, malnutrition, and progressive bone marrow failure was suspicious for an underlying inherited bone marrow failure syndrome. To screen the patient for an inherited etiology of her bone marrow failure, we performed whole-exome sequencing including sequencing of mitochondrial DNA. One heterozygous pathogenic variant in exon 8 of the NFKB1 gene (p.V235Wfs*17, c.702delC) was identified (Fig. 2). There were two additional variants in a gene associated with bone marrow failure and immunologic disorders (Supplemental Table S2); however, these were determined not to contribute to the patient's phenotype. Two variants in the DOCK8 gene, linked to autosomal recessive hyper IgE syndrome, were located in cis in the same allele and the patient lacked clinical features of hyper IgE syndrome with no eosinophilia, eczema, or recurrent viral infections. The identified pathogenic variant in NFKB1 is predicted to lead to NFKB1 haploinsufficiency because of protein truncation or nonsense-mediated mRNA decay. It has not been previously reported in association with CVID and has not been previously identified in population databases (Genomes Project Consortium et al. 2015; Lek et al. 2016; Exome Variant Server, Genome aggregation database [gnomAD]). Although germline status of the NFKB1 variant in our patient was not formally verified in paired nonhematopoietic tissue, NFKB1 is not a known cancer gene (Sondka et al. 2018), and NFKB1 mutations have not been described in age-related clonal hematopoiesis (Genovese et al. 2014; Jaiswal et al. 2014). The patient's clinical presentation (Table 2), together with a pathogenic heterozygous variant in NFKB1 detected in the patient's peripheral blood, is most consistent with autosomal dominant CVID caused by a germline NFKB1 variant. The patient's sisters (monozygotic twins) were negative for the variant, and the other family members were not tested. Given the family history of glioblastoma in the patient's mother and multiple sclerosis in the maternal aunt, two conditions linked to NF-κB dysregulation (Rajaraman et al. 2009; Mieczkowski et al. 2015; Cartwright et al. 2016; Kina et al. 2019; Zhou et al. 2020), the patient's NFKB1 variant could have been inherited from the maternal side of her family; alternatively, the variant may have emerged de novo.\n\nTable 1. Genomic findings\n\nGene\tDisease\tMode of inheritance\tVariant\tCoding DNA\tZygosity\tInherited from\tVariant classification\t\nNFKB1\tCommon variable immunodeficiency\tAutosomal dominant\tp.V235Wfs*17\tc.702delC\tHeterozygous\tUnknown\tPathogenic\t\nTable 2. Clinical findings in autosomal dominant NFKB1 deficiency\n\nClinical features\tPatient\t\nAutosomal dominant inheritance\tYes\t\nRespiratory system\t\n Upper respiratory tract infections (83.0%)\tYes\t\n Pneumonia (59.0%)\t\t\n Bronchiectasis (25.6%)\t\t\n Granulomatous lymphocytic interstitial lung disease (GLILD) (7.4%)\t\t\nGastrointestinal complications\t\t\n Gastrointestinal infections (28.6%)\t\t\n Autoimmune enteropathy (13.9%)\tYes\t\n Celiac-like disease (9.3%)\t\t\n IBD-like disease (5.6%)\t\t\n Diarrhea of unknown etiology (8.3%)\t\t\n Atrophic gastritis (4.6%)\t\t\nLiver\t\t\n Hepatomegaly (24.7%)\t\t\n Liver disease (19.5%)\tYes\t\nMalignancies (16.8%)\t\t\n Lymphoma (11.1%)\t\t\n Solid organ cancer (4.6%)\tYes\t\nSpleen\t\t\n Splenomegaly (48.5%)\t\t\n Splenectomy (11.9%)\tYes\t\nBone marrow\t\t\n Antibody deficiency (88.9%)\tYes\t\n Low IgA (87.4%)\tYes\t\n Low IgG (74.4%)\tYes\t\n Low IgM (70.9%)\tYes\t\n Cytopenia (43.9%)\tYes\t\nNovel clinical features\t\t\n Acquired aplastic anemia\tYes\t\nSkin\t\t\n Skin infections (37.7%)\t\t\n Rosacea\t\t\n Autoimmune (14.9%)\t\t\n Psoriasis\t\t\n Eczema\t\t\n Necrotizing fasciitis\t\t\nAlopecia\t\t\nThyroiditis (6.5%)\t\t\nCardiovascular system\t\t\n Cardiovascular complications (17.8%)\t\t\n Behçet disease (5.6%)\t\t\n Vasculitis (4.6%)\t\t\nBone/Joints\t\t\n Osteopenia (12.9%)\t\t\n Arthritis (10.3%)\t\t\n Enthesiopathy\t\t\nAphthous ulcerations (17.8%)\t\t\nNeurological complications (13.9%)\t\t\nNoninfectious fever (12.0%)\t\t\nLymphoproliferation\t\t\n Lymphadenopathy (35.3%)\t\t\nThe summary of clinical features is adapted from Lorenzini et al. 2020.\n\nDISCUSSION\nIn this report, we present a patient with familial NFKB1-associated CVID syndrome who developed AA in adulthood. Although CVID can be associated with a variety of autoimmune complications, including autoimmune cytopenias such as immune thrombocytopenia (ITP), hemolytic anemia, Evans syndrome, and autoimmune neutropenia (Podjasek and Abraham 2012), neither immune-mediated bone marrow failure nor AA have been previously reported. The patient was unable to tolerate standard AA therapies and rapidly declined. Our case highlights the importance of recognizing inherited syndromes of immune dysregulation such as CVID in AA patients, because of their unique complications and the potential implications for AA therapy, including the use of calcineurin inhibitors and timing and donor selection for hematopoietic stem cell transplantation.\n\nCVID is the most common primary immunodeficiency caused by a failure of B-cell differentiation into functional plasma cells leading to immunoglobulin deficiency and recurrent sinopulmonary infections. Some CVID patients also have autoimmune and inflammatory manifestations (Table 1; Patuzzo et al. 2016; Lorenzini et al. 2020). In up to 20% of CVID patients, a genetic cause can be identified. Monoallelic loss-of-function mutations in NFKB1 are found in 4% of CVID patients and are the most common cause of familial CVID (Kaustio et al. 2017; Tuijnenburg et al. 2018; Lorenzini et al. 2020). NF-κB proteins are a family of five transcription factors (p50/p105, p52/p100, RelA, RelB, and c-Rel) characterized by a conserved DNA-binding domain (Rel homology domain). Dimers of NF-κB proteins direct transcriptional regulation of genes involved in various cellular processes including immune and inflammatory responses (Karin and Lin 2002; Lougaris et al. 2017). Intact NF-κB signaling contributes to proper B-cell maturation, survival, differentiation, and T-cell-independent antibody class switching (Vallabhapurapu and Karin 2009; Gerondakis and Siebenlist 2010; Kaileh and Sen 2012).\n\nAlthough immune-mediated bone marrow failure has not been previously reported in CVID patients, the association of NFKB1-mutated CVID with other autoimmune disorders suggests that the cooccurrence of AA and CVID in our patient was not coincidental. In fact, NFKB1 was previously found to have a critical role for maintaining a resting state of dendritic cells (DCs), induction of T-cell tolerance, and CD8+ lymphocyte cytotoxicity (Dissanayake et al. 2011). When pulsed with self-antigens, unstimulated DCs lacking NFKB1 may activate CD8+ T lymphocytes, leading to autoimmunity (Dissanayake et al. 2011). The absence of NFKB1 in resting antigen-presenting cells is associated with poor induction of T-cell tolerance and higher granzyme B expression in cytotoxic T cells, pointing to the role of dendritic cell defects in the establishment of autoimmunity in NKFB1-deficient patients (Dissanayake et al. 2011). Additionally, CVID patients were previously found to have lower numbers of T regulatory cells, which may also contribute to the development of AA (Fevang et al. 2007). Further studies are needed to better evaluate the role of NFKB1 and other genetic variants of immune regulation in the development of AA.\n\nAfter the development of AA, our patient experienced rapid decline, further complicated by the difficulty in tolerating standard aplastic anemia therapy. Within days of starting therapeutic doses of cyclosporine, the patient experienced generalized failure to thrive, weight loss, hepatic dysfunction, and recurrent infections. The patient also recalled that during her previous treatment with low-dose cyclosporine, she also subjectively felt that “cyclosporine did not agree with her.” Notably, cyclosporine is a potent inhibitor of T-cell activation and has multiple cellular functions, the best known of which is inhibition of calcineurin. Intracellular calcium release and its regulation by calcineurin were also found to be critical for NF-κB activation (Frantz et al. 1994; Steffan et al. 1995; Chan et al. 2013), and treatment with calcineurin inhibitors cyclosporine and tacrolimus has been shown to suppress NF-κB signaling (Venkataraman et al. 1995; Marienfeld et al. 1997; Meyer et al. 1997; Jin et al. 2015). We suspect that the use of cyclosporine in the context of NFKB1 haploinsufficiency may have led to enhanced toxicity as a result of further inhibition of NF-κB-dependent processes. Other CVID-related complications contributing to the poor outcome in our patient include recurrent infections, CVID enteropathy, and hepatic dysfunction.\n\nIn summary, in this report we expand the spectrum of hematologic complications of CVID to include AA and establish a novel link between genetic disorders of immune regulation and AA. Our case highlights potential challenges in managing AA in patients with CVID because of the underlying immune dysregulation, chronic complications of CVID, and what appears to be an epistatic interaction of calcineurin inhibitors in patients with genetic alterations of the NF-κB pathway. Increased recognition of immune-mediated bone marrow failure as a potential etiology of cytopenias in patients with CVID may improve outcomes by intervening at earlier stages of the disease and by anticipating potential complications. Allogeneic stem cell transplantation can be considered in selected patients; however, historical outcomes in CVID patients treated with bone marrow transplant have been poor, because of the high rates of treatment-refractory graft-versus-host disease and poor immune reconstitution leading to infectious complications (Wehr et al. 2015). Future studies are needed to determine optimal immunosuppressive therapies and transplant approaches in this difficult-to-treat patient population.\n\nMethods\nPatient Recruitment and Regulatory Approval\nThe patient was enrolled into Penn–CHOP Bone Marrow Failure cohort, a bone marrow failure registry study approved by the Institutional Review Boards of Children's Hospital of Philadelphia and the University of Pennsylvania (IRB # 10-007569). Informed consent from the patient was obtained in accordance with the Declaration of Helsinki. The diagnosis of aplastic anemia was established using standard criteria (International Agranulocytosis and Aplastic Anemia Study 1987; Wilson et al. 2014).\n\nWhole-Exome Sequencing\nWhole-exome sequencing was performed on patient's genomic DNA extracted from peripheral blood by paired-end massively parallel sequencing at the CLIA-approved commercial genetic testing laboratory (XomeDxPlus test, GeneDx). The exonic regions and flanking splice junctions were captured using a GeneDx proprietary system and sequenced at a mean depth of coverage of 158×, with 98.7% of the captured regions covered by at least 10 sequence reads. Reads were aligned to human genome build GRCh37/UCSC hg19 and analyzed using a custom-developed analysis tool (XomeAnalyzer, GeneDx). Capillary sequencing was used to confirm all potentially reportable variants (Fig. 2).\n\nHematopathology and Ancillary Studies\nBone marrow histology was evaluated by a hematopathologist prior to the study enrollment. Cytogenetic analysis was performed by standard karyotyping techniques. Analysis of somatic mutations in genes associated with hematologic malignancies was performed at the University of Pennsylvania Center for Personalized Diagnostics as previously described (Fox et al. 2016), with the following 68 genes analyzed (ABL1, ASXL1, ATM, BCOR, BCORL1, BIRC3, BRAF, CALR, CBL, CDKN2A, CEBPA, CSF1R, CSF3R, DDX3X, DNMT3A, ETV6, EZH2, FAM5C, FBXW7, FLT3, GATA2, GNAS, HNRNPK, IDH1, IDH2, IL7R, JAK2, KIT, KLHL6, KRAS, MAP2K1, MAPK1, MIR142, MPL, MYC, MYCN, MYD88, NF1, NOTCH1, NOTCH2, NPM1, NRAS, PDGFRA, PHF6, POT1, PRPF40B, PTEN, PTPN11, RAD21, RIT1, RUNX1, SETBP1, SF1, SF3A1, SF3B1, SMC1A, SRSF2, STAG2, TBL1XR1, TET2, TP53, TPMT, U2AF1, U2AF2, WT1, XPO1, ZMYM3, ZRSR2). TRG gene rearrangements were analyzed by PCR-based amplification using consensus V and J primers and capillary electrophoresis at the Penn Molecular Diagnostics Laboratory.\n\nTelomere Length Measurement and Chromosome Breakage Testing\nFlow-FISH telomere length measurements were performed on the lymphocyte subsets total lymphocytes, CD45RA positive naive T cells, CD45RA negative memory T cells, and CD57 positive NK cells at the CLIA-certified clinical telomere length testing center (Repeat Diagnostics, Inc.). Chromosome breakage testing in the presence or absence of mitomycin C and diepoxybutane with appropriate controls was performed on patient's lymphocytes at the Comprehensive Center for Fanconi Anemia.\n\nADDITIONAL INFORMATION\nData Deposition and Access\nThe patient's NFKB1 variant NM_003998.4(NFKB1):c.702del (p.Val235fs) was deposited to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) under the accession number VCV000450428.2, variation ID: 450428. Patient consent was not granted to deposit WES data.\n\nEthics Statement\nThe patient was enrolled into the Penn–CHOP Bone Marrow Failure cohort, a bone marrow failure registry study approved by the Institutional Review Boards of Children's Hospital of Philadelphia and the University of Pennsylvania (IRB # 10-007569). Informed consent from the patient was obtained in accordance with the Declaration of Helsinki.\n\nAcknowledgments\nThe authors thank the patient for participation in this study and Dr. Monica Bessler and members of the Penn–CHOP Bone Marrow Failure Center for critical discussions.\n\nAuthor Contributions\nT.S. and D.B. performed the clinical review, analyzed the literature, and wrote and edited the manuscript. J.J. performed genetic sequencing analysis. S.N.H. and A.B. reviewed histopathology and ancillary studies. N.L.S. performed clinical chart review and prepared laboratory data tables. 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"fulltext_license": "CC BY-NC",
"issn_linking": "2373-2873",
"issue": "6(6)",
"journal": "Cold Spring Harbor molecular case studies",
"keywords": "aplastic anemia; bone marrow hypocellularity; defective production of NFKB1-dependent cytokines; immune dysregulation",
"medline_ta": "Cold Spring Harb Mol Case Stud",
"mesh_terms": "D000741:Anemia, Aplastic; D001565:Benzoates; D001853:Bone Marrow; D017074:Common Variable Immunodeficiency; D016572:Cyclosporine; D005260:Female; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D006801:Humans; D006834:Hydrazines; D008875:Middle Aged; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011720:Pyrazoles; D015398:Signal Transduction; D000073359:Whole Exome Sequencing",
"nlm_unique_id": "101660017",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32972988",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "28232583;30819785;15276395;7532676;23429351;8112299;28971166;15327519;17302902;26663363;3676511;32278790;7594468;25426838;28115215;24888387;27684276;30293088;27535533;26427514;19302050;30951562;4449772;27923702;31727769;22435560;11875461;30354958;7994040;27392505;11355914;29477724;26432245;30450997;22837758;22081022;9247567;25426837;32265906;19423540;24204950;9091802;9280312;20452952;25595268;25980752",
"title": "Aplastic anemia in a patient with CVID due to NFKB1 haploinsufficiency.",
"title_normalized": "aplastic anemia in a patient with cvid due to nfkb1 haploinsufficiency"
} | [
{
"companynumb": "US-TEVA-2020-US-1843845",
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"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "ELTROMBOPAG"
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{
"abstract": "Rheumatoid arthritis (RA) patients have increased risk of lymphoma which seems associated mainly with high inflammatory state and disease activity, but also with immunosuppressive agents or Epstein-Barr virus (EBV) infection. Many case reports describe lymphoproliferative lesions arising during methotrexate therapy, often EBV positive with possible regression after methotrexate withdrawal. The authors report the case of an 85-year-old patient with erosive and seronegative RA, in remission under methotrexate who developed a midfacial destructive lesion with epistaxis and local inflammatory signs. The magnetic resonance imaging showed a large nasal septum defect. Anti-neutrophil cytoplasmic antibodies titres and angiotensin converting enzyme were normal. Biopsies of the lesion identified a NK/ T nasal type lymphoma. EBV latent membrane protein research on the lesion was negative. Polymerase chain reaction analysis of the bone marrow aspirate showed EBV DNA positivity. Withdrawal of methotrexate was performed without tumour regression. The authors described the single case of a patient with RA in stable remission under methotrexate who presented a rare type of lymphoma, a nasal type NK/T. EBV active replication was found in the bone marrow.",
"affiliations": null,
"authors": "Terroso|G|G|;Aleixo|J|J|;Bernardes|M|M|;Mariz|E|E|;Fonseca|E|E|;Costa|L|L|",
"chemical_list": "D018501:Antirheumatic Agents; D008727:Methotrexate",
"country": "Portugal",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-464X",
"issue": "39(1)",
"journal": "Acta reumatologica portuguesa",
"keywords": null,
"medline_ta": "Acta Reumatol Port",
"mesh_terms": "D000369:Aged, 80 and over; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D006801:Humans; D054391:Lymphoma, Extranodal NK-T-Cell; D008297:Male; D008727:Methotrexate; D009669:Nose Neoplasms",
"nlm_unique_id": "0431702",
"other_id": null,
"pages": "77-81",
"pmc": null,
"pmid": "24811465",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nasal type extranodal NK/T cell lymphoma diagnosed in a patient with rheumatoid arthritis under methotrexate.",
"title_normalized": "nasal type extranodal nk t cell lymphoma diagnosed in a patient with rheumatoid arthritis under methotrexate"
} | [
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"companynumb": "PHHY2014PT065225",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
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"activesubstancename": "GENTAMICIN"
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{
"abstract": "Thrombotic thrombocytopenic purpura (TTP) is a rare, dangerous, life-threatening disease characterized by microangiopathic hemolytic anemia and thrombocytopenia, along with organ dysfunction due to microangiopathy-related ischemia. Plasma exchange and steroids are used for initial treatment, and rituximab is often used in refractive patients. Caplacizumab, cyclophosphamide, and splenectomy are among other treatment options. It has been reported that bortezomib, a proteasome inhibitor, can be used in the management of refractory acquired TTP. Herein, we present a 16-year-old female patient who was monitored for acquired TTP and treated with high-dose steroids, plasma exchange, rituximab, cyclophosphamide, and N-acetylcysteine but developed renal, cardiac, gastrointestinal, and neurologic complications. The girl was then successfully treated with bortezomib, and she has been monitored in remission for 6 months. We consider that bortezomib is a beneficial treatment, especially in patients with refractory TTP.",
"affiliations": "Division of Pediatric Critical Care Medicine.;Division of Pediatric Critical Care Medicine.;Divion of Pediatric Hematology and Oncology.;Division of Pediatric Hematology and Oncology, Kirikklale University Faculty of Medicine, Kirikkale, Turkey.;Division of Pediatric Neurology, Dr Sami Ulus Maternity and Children's Training and Research Hospital, Ankara.;Divion of Pediatric Hematology and Oncology.",
"authors": "Azapağasi|Ebru|E|;Uysal Yazici|Mutlu|M|;Eroğlu|Nilgün|N|;Albayrak|Meryem|M|;Kucur|Özge|Ö|;Fettah|Ali|A|",
"chemical_list": "D061988:Proteasome Inhibitors; D000069286:Bortezomib",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000002026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "43(4)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000069286:Bortezomib; D005260:Female; D006801:Humans; D010951:Plasma Exchange; D061988:Proteasome Inhibitors; D011697:Purpura, Thrombotic Thrombocytopenic; D016896:Treatment Outcome",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e587-e591",
"pmc": null,
"pmid": "33306607",
"pubdate": "2021-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment With Bortezomib for Refractory and Complicated Acquired Thrombotic Thrombocytopenic Purpura in an Adolescent Girl.",
"title_normalized": "successful treatment with bortezomib for refractory and complicated acquired thrombotic thrombocytopenic purpura in an adolescent girl"
} | [
{
"companynumb": "TR-LUPIN PHARMACEUTICALS INC.-2021-20524",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugad... |
{
"abstract": "Metastasis to bone (BM) is an uncommon manifestation of advanced endometrial cancer (EC). The present study will review the clinicopathologic features of a cohort of patients with EC and BM. We conducted a multi-center retrospective review of patients with EC and BM. Demographic and clinical information was extracted from the medical records. Survival outcomes were determined using Kaplan-Meier Curves. Final analysis included 10 patients. The median age was 65 years (range 31-71). 80% had FIGO stage III/IV disease. The most common site of BM was the spine (66%). All patients presented with extraosseous dissemination at the time of diagnosis of BM and 70% were found to have multiple sites of BM. 80% of patients were diagnosed with BM in the recurrent setting. The median time to diagnosis of bone recurrence was 14 months (range: 0-44). Median survival after diagnosis of BM was 11 months (range: 1-22 months). Patients with endometrioid histology and single site of bone metastasis experienced improved survival (p = 0.04 and p = 0.05, respectively). Eight patients had immunohistochemistry or molecular tumor profiles available for review. Seven of these patients (87.5%) were found to have microsatellite instability (MSI). The most common mutation was hypermethylation of MLH-1 (43%). To our knowledge, this is the first report demonstrating a correlation between MSI and metastasis to bone. The identification of BM in EC is uncommon, but will alter treatment strategies and dramatically impact prognosis. Molecular tumor profiling should be performed to identify targeted therapy options and optimize adjuvant treatment strategies.",
"affiliations": "Division of Gynecologic Oncology, SUNY Downstate Medical Center, Brooklyn, NY, United States.;Division of Gynecologic Oncology, Good Samaritan Hospital Medical Center, West Islip, NY, United States.;Division of Gynecologic Oncology, New York Presbyterian - Brooklyn Methodist Hospital, Brooklyn, NY, United States.;Division of Gynecologic Oncology, New York Presbyterian - Brooklyn Methodist Hospital, Brooklyn, NY, United States.;Division of Gynecologic Oncology, New York Presbyterian - Brooklyn Methodist Hospital, Brooklyn, NY, United States.;Division of Gynecologic Oncology, SUNY Downstate Medical Center, Brooklyn, NY, United States.;Division of Gynecologic Oncology, New York Presbyterian - Brooklyn Methodist Hospital, Brooklyn, NY, United States.",
"authors": "McEachron|Jennifer|J|;Chatterton|Carolyn|C|;Hastings|Victoria|V|;Gorelick|Constantine|C|;Economos|Katherine|K|;Lee|Yi-Chun|YC|;Kanis|Marguax J|MJ|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.gore.2020.100549",
"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(20)30015-110.1016/j.gore.2020.100549100549Case SeriesA clinicopathologic study of endometrial cancer metastatic to bone: Identification of microsatellite instability improves treatment strategies McEachron Jennifer Jennifer.McEachron@downstate.edua⁎Chatterton Carolyn bHastings Victoria cGorelick Constantine cEconomos Katherine cLee Yi-Chun aKanis Marguax J. ca Division of Gynecologic Oncology, SUNY Downstate Medical Center, Brooklyn, NY, United Statesb Division of Gynecologic Oncology, Good Samaritan Hospital Medical Center, West Islip, NY, United Statesc Division of Gynecologic Oncology, New York Presbyterian – Brooklyn Methodist Hospital, Brooklyn, NY, United States⁎ Corresponding author at: Department of Gynecologic Oncology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, United States. Jennifer.McEachron@downstate.edu10 2 2020 5 2020 10 2 2020 32 10054926 11 2019 2 2 2020 4 2 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Metastasis of endometrial cancer (EC) to bone is rare, occurring in <1.0% of cases.\n\n• The most common sites of bone metastasis in EC are the spine and hip.\n\n• Diagnosis of bone metastasis is associated with widely metastatic disease and poor prognosis.\n\n• The median overall survival following a diagnosis of bone metastasis was 11 months in our series.\n\n• 87.5% of patients with bone metastasis were found to have microsatellite instability.\n\n\n\nMetastasis to bone (BM) is an uncommon manifestation of advanced endometrial cancer (EC). The present study will review the clinicopathologic features of a cohort of patients with EC and BM. We conducted a multi-center retrospective review of patients with EC and BM. Demographic and clinical information was extracted from the medical records. Survival outcomes were determined using Kaplan-Meier Curves. Final analysis included 10 patients. The median age was 65 years (range 31–71). 80% had FIGO stage III/IV disease. The most common site of BM was the spine (66%). All patients presented with extraosseous dissemination at the time of diagnosis of BM and 70% were found to have multiple sites of BM. 80% of patients were diagnosed with BM in the recurrent setting. The median time to diagnosis of bone recurrence was 14 months (range: 0–44). Median survival after diagnosis of BM was 11 months (range: 1–22 months). Patients with endometrioid histology and single site of bone metastasis experienced improved survival (p = 0.04 and p = 0.05, respectively). Eight patients had immunohistochemistry or molecular tumor profiles available for review. Seven of these patients (87.5%) were found to have microsatellite instability (MSI). The most common mutation was hypermethylation of MLH-1 (43%). To our knowledge, this is the first report demonstrating a correlation between MSI and metastasis to bone. The identification of BM in EC is uncommon, but will alter treatment strategies and dramatically impact prognosis. Molecular tumor profiling should be performed to identify targeted therapy options and optimize adjuvant treatment strategies.\n\nKeywords\nEndometrial cancerMicrosatellite instabilityBone metastasis\n==== Body\n1 Introduction\nEndometrial cancer (EC) represents the most common gynecologic malignancy in the United States, affecting 63,230 patients in 2018 (National Institutes of Health, 2018). The majority of EC is diagnosed at early stage with an overall good prognosis. However, approximately one-third of patients are diagnosed with advanced disease (Siegel et al., 2018, NCCN Guidelines, 2019). Despite excellent outcomes in early stage disease, patients presenting with advanced stage or with aggressive histologic subtypes have a higher incidence of recurrence and subsequently shorter survival. The reported 5-year overall survival (OS) of stage IV disease is a dismal 0–18% (Miller et al., 2012, Goff et al., 1994, Bristow et al., 2000). EC most commonly metastasizes by direct extension or lymphatic spread, and as a result, the majority of recurrences occur locally with in the pelvis and abdomen. Hematogenous spread occurs less frequently and most commonly manifests as lung and liver metastasis (Uccella et al., 2013, Mariani et al., 2001).\n\nAlthough rare in EC, hematogenous spread to bone is a common feature of many non-gynecologic tumors. In fact, it is the most common site of distant metastasis in both breast and prostate cancer (Kennecke et al., 2010, Bubendorf et al., 2000). The true incidence of bony metastasis (BM) of EC is unknown, however several small series in the literature report an incidence of <1.0% (Uccella et al., 2013). At present, there is little known about the risk factors and pathologic mechanisms leading to development of BM in EC. The majority of affected patients initially present with advanced stage disease and high-grade histology, however most patients meeting these criteria do not go on to develop BM and instead will experience abdominopelvic failure. The present study will review the clinicopathologic features of a cohort of patients with EC metastatic to bone.\n\n2 Methods\nThis is a multi-center retrospective review of patients with EC metastatic to bone. Institutional Review Board approval was obtained by each site. Tumor board registries from each institution were queried for cases of EC with BM. Inclusion criteria were patients with confirmed histologic diagnosis of primary EC and BM at initial presentation or recurrence. BM were diagnosed on the basis of radiographic or histologic confirmation. Demographic and clinical information extracted from the medical records of eligible patients included age, body mass index (BMI), race, stage, histology, grade, location of bony metastasis, time to bony recurrence, sites of metastatic disease, CA-125 level, treatments and survival status. Pathology reports were reviewed for microsatellite instability (MSI), based on absence of mismatch repair (MMR) genes by immunohistochemistry (IHC). Additionally, when available, molecular tumor profiles were reviewed. Descriptive statistics were employed to detail individual patient outcomes. Survival outcomes were determined using Kaplan-Meier Curves. Statistical significance was defined as P < 0.05. Analyses were performed using SPSS, Version 22.0. (IBM, USA).\n\n3 Results\nFrom 2012 to 2019, there were 1085 patients diagnosed with EC. Ten patients (0.09%) were diagnosed with BM in either the upfront or recurrent setting. There was a total of 32 osseous metastases (range 1–8 per patient). The median age was 65 years (range 31–71). Histology included 70% endometrioid and 30% serous carcinoma. All patients with endometrioid histology had moderately or poorly differentiated tumors. Eighty percent of the patients presented at advanced stage at initial diagnosis, defined as FIGO stage III/IV disease. The remaining two patients presented with FIGO stage I disease. In two patients, the diagnosis of BM was made at time of presentation of EC. In the remaining eight patients, BM were diagnosed at time of recurrence with a mean time of 14.4 months (range: 0–44 months) (Table 1). In five patients, diagnosis was confirmed by bone biopsy and histologic examination consistent with primary endometrial tumor. The remaining five patients were diagnosed on the basis of radiographic findings. 90% of patients presented with bone-related symptoms which prompted a further work up. There was only one incidental diagnosis of bone metastasis that were identified during simulation for adjuvant radiation therapy, after completion of 3 cycles of systemic chemotherapy (Table 2, Patient B). In this patient, bone lesions were not present on pre-operative CT scan, confirming that BM developed during chemotherapy.Table 1 Patient characteristics (N = 10).\n\nCharacteristic\tN (%)X\t\nAge, median (range), years\t65 (31–71)\t\nBody mass index, median (range)\t33 (24–48)\t\nFIGO Stage at Initial Diagnosis\t\n I\t2 (20)\t\n II\t–\t\n III\t5 (50)\t\n IV\t3 (30)\t\nHistology\t\t\n Endometrioid\t7 (70)\t\n Serous\t3 (30)\t\nFIGO grade*\t\n I\t–\t\n II\t2 (29)\t\n III\t5 (71)\t\nBone metastasis at diagnosis\t2 (20)\t\nBone metastasis at recurrence\t8 (80)\t\nMean time from diagnosis to bone metastasis (months)\t14.4 (0–44)\t\nExtent of bone metastasis\t\n Single\t3 (30)\t\n Multiple\t7 (70)\t\nConcurrent extraosseous metastases\t10 (100)\t\nTreatment of bone metastasis\t\n Radiation\t3 (3)\t\n Chemotherapy\t1 (10)\t\n Chemotherapy + radiation\t2 (20)\t\n Concurrent chemoradiation, followed by chemotherapy\t1 (10)\t\n Chemotherapy + radiation, followed by immunotherapy\t1 (10)\t\n Chemotherapy + anti-angiogenesis\t1 (10)\t\n Immunotherapy\t1 (10)\t\n Overall survival, median (range), months\t11 (1–22)\t\n Presence of microsatellite instability**\t7 (87.5)\t\n* Endometrioid histology only, all other histologies represent high-grade disease.\n\n** N = 8 patients with immunohistochemistry or molecular tumor profiles available for review.\n\nX Values are number (percentage) unless indicated otherwise.\n\nTable 2 Patient characteristics and treatment.\n\n\tAge\tStage*\tHistology/Grade**\tInitial Treatment***\tTime from Diagnosis to BM (months)\tSite of BM\tOther Sites of Metastatic Disease\tMolecular Tumor/IHC Profile\tCA 125 Level at Diagnosis of BM (u/mL)\tSurvival Status after BM\t\nA\t59\tIIIC1\tEM/G3\tRA TH BSO PPALND; CT 3C; EBRT + VBT; CT 1C\t9\tSpine: T10-L3\tBL pelvic LN\tMSI-high (MLH1 absent); ER, PR positive\t8.4\tDOD, 13 months\t\nB\t65\tIIIC2\tEM/G3\tELAP TAH BSO PPALND; CT 3C\t4\tR sacrum, T3, T11, L3\tL pelvic LN & PA LN, lung\tMSI-high (MSH6 absent)\t5.1\tAlive, with disease at 7 months\t\nC\t31\tIA\tEM/G3\tTAH BS ovarian transposition PPALND\t44\tL acetabulum\tL pelvic sidewall mass\tNA\t5.3\tAlive, NED at 22 months\t\nD\t70\tIVB\tEM/G2\tCT 5C, EBRT to L hip; RA TLH BSO PPALND\t0\tR iliac & hemisacrum, L femoral neck\tR parametria, BL pelvic LN\tMSI-high (MLH1 absent); ER, PR positive\t8.2\tAlive, with disease at 9 months\t\nE\t67\tIIIC1\tEM/G2\tTAH BSO PPALND; CT 3C; EBRT; CT 3C\t13\tL iliac\tL pelvic LN, vagina\tMSI-high (MLH1 absent)\t10.3\tDOD, 17 months\t\nF\t66\tIVB\tS\tCT 2C; palliative EBRT to T6; anastrozole\t0\tL iliac, T6\tUpper abdomen\tMSI-high; BRCA positive\t151\tDOD, 6 months\t\nG\t59\tIIIB\tEM/G3\tELAP TH BSO PPALND; EBRT; CT 6C\t10\tR iliac, L3-4\tR parametria, liver\tMSI-high (MSH 6 absent)\t22.7\tDOD, 11 months\t\nH\t71\tIIIC2\tS\tELAP TH BSO PPALND; CT 3C; EBRT; VBT; CT 3C\t12\tL iliac, T7-10, L1, L4, sternum\tBL pelvic and PA LN\tHER2/neu positive\t15.6\tDOD, 11 months\t\nI\t63\tIB\tS\tELAP RH BSO; refused adjuvant treatment\t12\tT11\tR pelvic LN, vaginal cuff\tNA\tNA\tAlive, with disease at 3 months\t\nJ\t64\tIVB\tEM/G2\tELAP TH BSO PPALND omentectomy, CT 4C, PLD 6C\t40\tL1, L3, R 7th rib\tSupraclavicular LN, PA & L pelvic LN, lung\tMSI-high\t75.3\tAlive, with disease at 3 months\t\nBL: bilateral; BM: Bone metastasis BSO: bilateral salpingoophorectomy; C: cycles of chemotherapy; CT: carboplatin paclitaxel; DOD: died of disease; EBRT: external beam radiation therapy; ELAP: exploratory laparotomy; EM: Endometrioid; IHC: immunohistochemistry; L: left; NA: not available; NED: no evidence of disease; PA: paraaortic; PLD: Pegylated liposomal doxorubicin. PPALND: pelvic and paraaortic lymphadenectomy; R: right; RH: radical hysterectomy; TH: total hysterectomy; S: serous; VBT: vaginal brachytherapy.\n\n* Staging based on FIGO 2009 staging system.\n\n** Endometrioid only, other histologies all represent high grade disease.\n\n*** Treatment modalities listed in sequence of treatment.\n\n\n\nThe most common sites of bony metastasis were the spine (66%) and the hip (22%). Six patients (60%) presented with distant bony failure, defined as bone metastasis outside of the pelvic bones or lumbar spine (Fig. 1). All patients presented with extraosseous dissemination at the time of diagnosis of bony metastasis. Multiple bony metastasis were identified in 7 (70%) patients. CA-125 level was elevated in only 2 (20%) patients. Of the eight patients presenting with BM in the recurrent setting, five were treated with platinum-based therapy in the upfront setting and all were resistant or refractory to platinum. Of these five patients, two were found to be platinum resistant with a mean time of 4.5 months from chemotherapy completion to the development of bone disease. The remaining three developed BM during platinum-based treatment.Fig. 1 Location of bone metastasis (N = 32).\n\n\n\nMedian overall survival (OS) after diagnosis of BM was 11 months (range: 1–22 months). Four patients are currently alive, all undergoing treatment, and one is alive with no evidence of disease. There was no difference in survival between those patients presenting with distant BM versus BM confined to the pelvis (p = 0.13). Patients with endometrioid histology experienced improved survival compared to serous histology (OS not yet achieved vs. 6 months; p = 0.04). We observed a trend toward improved OS in patients with single versus multiple lesions (OS not yet achieved vs. 9 months; p = 0.05).\n\nEight patients had MMR IHC or molecular tumor profiles available for review. Seven of these patients were found to have MSI (87.5%). The most common individual mutation was hypermethylation of MLH-1 which was identified in three patients (43%). Five MSI-high patients underwent germline testing, which were all negative. Two patients refused germline testing. Additionally, one patient was found to be positive for HER2/neu by IHC and confirmed by FISH (fluorescent in situ hybridization). A wide variety of treatment modalities were used in the management of BM. Three (30%) received radiation alone and three (30%) received a combination of chemotherapy and external beam radiation. Treatment was individualized for the remaining four patients including, single-agent pembrolizumab, EBRT chemotherapy followed by pembrolizumab, systemic chemotherapy alone and systemic chemotherapy with bevacizumab (Table 3).Table 3 Location and treatment of bone metastasis.\n\nPatient\tLocation of BM\tTreatment of BM\tResponse to Treatment\t\nA\tSpine: T10-L3\tEBRT\tPR, followed by progression and abdominopelvic metastasis at 9 months\t\nB\tR sacrum, T3, T11, L3\tGemcitabine + bevacizumab\tPR, currently receiving gemcitabine + bevacizumab\t\nC\tL acetabulum\tConcurrent chemoradiation: EBRT + cisplatin, followed by carboplatin + paclitaxel\tCR, currently under observation off therapy\t\nD\tR iliac & hemisacrum, L femoral neck\tEBRT, followed by carboplatin + paclitaxel, followed by pembrolizumab\tPR, currently receiving pembrolizumab\t\nE\tL iliac\tEBRT\tPR, followed by progression at 4 months\t\nF\tL iliac, T6\tEBRT\tPD, with progression in the upper abdomen at 3 months\t\nG\tR iliac, L3-4\tPLD\tSD, followed by progression in the bone and upper abdomen at 4 months\t\nH\tL iliac, T7-10, L1, L4, sternum\tEBRT, followed by PLD\tPR, followed by progression in the retroperitoneum at 5 months\t\nI\tT11\tEBRT, followed by carboplatin + paclitaxel\tPR, currently receiving carboplatin + paclitaxel\t\nJ\tL1, L3, R 7th rib\tPembrolizumab\tSD, currently receiving pembrolizumab\t\nBM: Bone metastasis; CR: complete response; EBRT: External beam radiation therapy; PLD: pegylated liposomal doxorubicin; PD: progressive disease, PR: partial response; SD: stable disease.\n\n\n\n4 Discussion\nBM is an uncommon finding in EC. Several small retrospective series have reported an incidence of only 0.8% (Uccella et al., 2013, Keheo et al., 2010, Ghosh and Rao, 2015). Interestingly, the reported incidence of subclinical BM is up to 25% in an anatomopathological studies of patients with EC undergoing autopsy. It should be noted however that in these studies, the vast majority of patients harbored metastasis at numerous sites, including the liver and lungs (Abdul-Karim et al., 1990). These findings suggest that hematogenous dissemination to bone represents a late metastatic pattern and signifies advanced, aggressive disease.\n\nThe most commonly reported locations of BM are the spine and pelvic bones (Kennecke et al., 2010). Consistent with these reports, all patients in the current study presented with metastasis at one or both of these locations. Seven patients presented with metastasis to the pelvic bones, including the sacrum and iliac bones, and six patients presented with metastasis to the spine. Additionally, four patients presented with a combination of both pelvic bone and spinal metastasis. When comparing the location of initial disease to the location of bone metastasis, all patients with pelvic bone involvement were found to have positive pelvic lymph nodes on the ipsilateral side. This suggests that despite the fact that BM is considered a hematologic phenomenon, the close proximity of other metastatic disease may imply local factors influence disease spread.\n\nAlthough there is no “tumor marker” specific to EC, CA-125 has been utilized to help predict the extent of disease at presentation and in some cases to monitor for recurrence (NCCN Guidelines, 2019). Retrospective data demonstrates correlation between elevated CA-125 and the presence of lymph node metastasis as well as advanced stage disease in patient with EC (Hoon Chung et al., 2006, Yildiz et al., 2012). Interestingly, only two patients in our cohort displayed an elevation in CA 125. One (patient J) had an elevated, but down-trending CA 125 at the time of development of BM. This is likely due to the theory that CA-125 increases as a result of intra-peritoneal processes (Rump et al., 2004). Therefore, metastasis outside the abdomen, including the bone, would not necessarily produce an abnormality in this serum analyte. Nevertheless, it is still interesting based on the fact that the majority of patients in the present report had concurrent disease at both bone and intra-abdominal locations. Normal CA-125 does not preclude the possibility of metastatic disease.\n\nThe prognosis of patients with EC found to have metastatic disease to the bone is extremely poor with dismal median OS of only 10–12 months (Uccella et al., 2013, Keheo et al., 2010). Consistent with the present study, the presence of multiple BM has been associated with worse prognosis (Uccella et al., 2013). An additional factor utilized to stratify prognosis is the degree of “platinum-sensitivity” or lack thereof (Pfisterer and Ledermann, 2006). Although this designation system originates from ovarian cancer literature, it has also been applied to EC and which, like ovarian cancer, demonstrates a direct correlation with platinum-free interval and survival (Nagao et al., 2013). In the present study, six patients were either resistant or refractory to platinum-based regimens, defined as recurrence within 6-months of platinum-based therapy or progression on platinum therapy, respectively. This demonstrates the aggressive nature of tumors metastasizing and suggests they are less likely to respond to traditional regimens.\n\nAlthough there is limited data on the management of EC metastatic to bone, a large body of literature exists regarding management of BM in breast cancer (BC). Treatment strategies include systemic therapy, bone modifying agents (BMA), radiation, surgery and analgesia. Utilization of these modalities vary based on overall disease burden, time of presentation (primary versus recurrent disease) and symptoms. The primary goal of systemic therapy is control and mitigation of disease, conversely the goal of radiation, surgery and analgesia is largely palliative (Van Poznak et al., 2017). BMA have been studied extensively in BC, specifically the bisphosphonates zoledronic acid and pamidronate, and the RANK-L inhibitor denosumab. The primary use of these medications is to prevent skeletal related adverse events (SRE), including fracture, hypercalcemia, surgery to bone and spinal cord compression, which will affect up to 65% of untreated patients and contribute to decreased quality of life (Van Poznak et al., 2017, Stopeck et al., 2010). Although there is no prospective literature on the use of BMA in gynecologic cancer, the use of these agents maybe warranted in patients at high risk for SRE. This is demonstrated by our patient who developed a femur neck fracture at the location of BM (patient D).\n\nTo our knowledge, no study has correlated molecular tumor profiles of EC with BM. In the present study, eight patients had IHC or molecular tumor profile data available. Of these patients, seven (87.5%) were found to have microsatellite instability (MSI). MSI is a result of loss of function of mismatch repair (MMR) genes, which leads to accumulation of single base-pair mismatches, as well as small insertions and deletion in tandem repeats. MSI is identified in 20–40% of endometrial carcinomas, the majority of which are due to sporadic loss of function, rather than germline mutations observed in hereditary nonpolyposis colorectal cancer (HNPCC) syndrome (Black et al., 2006, Kwon et al., 2011). Generally, these tumors are associated with endometrioid histology, however, the relationship between MSI and clinical outcomes in EC is not clearly defined. Multiple studies have reported improvement in OS in patients with MMR deficient tumor compared to their MMR proficient counterpart receiving the same adjuvant therapy. However, others have observed no difference or worse survival in MMR deficient tumors (Black et al., 2006, Kwon et al., 2011, Shikama et al., 2016, McMeekin et al., 2016). Additionally, there are conflicting reports in the literature regarding the correlation between MSI status and stage of disease at diagnosis. Several studies report no correlation, while other investigators report a more advanced disease stage at diagnosis associated with MSI high tumors (Black et al., 2006, Kwon et al., 2011, Shikama et al., 2016, McMeekin et al., 2016). The later corresponds to the present study, in which all MSI – high patients presented with stage III and IV disease. A recent large data base analysis of patients with colorectal cancer (CRC) from Australia addressed the risk of metastasis to specific distant sites, including lung and bone, in relation to the presence of MSI. However, they found no difference in patterns of metastatic disease between MSS and MSI CRC (Prasanna et al., 2018). Although these findings in CRC cannot be generalized to EC, these findings are worth noting due to the lack of literature available regarding patterns of metastasis of MSI-high EC.\n\nAt present, there is no standardized therapy for patients with EC metastatic to bone. Limited data is available and suggests that multimodality therapy is associated with improved outcomes, however these findings did not achieve statistical significance (Uccella et al., 2013). As demonstrated in the current study, a variety of modalities have been utilized based on physician preference and experience, as well as individualization based on the patient’s specific disease. Current data demonstrates that MSI – high EC exhibit good response to programmed cell death ligand 1 (PD-L1) inhibition. A recent large prospective study examined the effects of pembrolizumab on MMR deficient tumors previously treated with at least one line of standard therapy. They observed an overall response rate of 54% with an additional 23% of patients experiencing stable disease (Le, 2017). Our cohort also included one patient who tested positive for HER2/neu. Literature in BC demonstrates HER2/neu positive patients carries a higher propensity for bony spread compared to HER2/neu negative cancer (Kennecke et al., 2010). Additionally, a recent phase II evaluation of the addition of trastuzumab to carboplatin-paclitaxel demonstrates superior outcomes in HER2/neu positive serous EC compared to chemotherapy alone (Fader et al., 2018). These findings illustrate potential therapeutic pathways for patients with BM.\n\nAlthough bone metastasis in endometrial carcinoma are uncommon occurrences, they should always be considered in the differential diagnosis of patients presenting with known EC and bone pain. The identification of bone metastasis will alter treatment strategies as well has dramatically impact prognosis. Consideration should be given to the incorporation of bone modifying agents to decrease skeletal related adverse events and improve quality of life. Additionally, molecular tumor profiling should be performed to identify targeted therapy options and optimize adjuvant treatment strategies.\n\nCRediT authorship contribution statement\nJennifer McEachron: Conceptualization, Writing - original draft, Formal analysis, Investigation. Carolyn Chatterton: Formal analysis, Writing - original draft. Victoria Hastings: Investigation. Constantine Gorelick: Conceptualization, Resources. Katherine Economos: Conceptualization, Resources. Yi-Chun Lee: Conceptualization, Writing - review & editing, Resources. Marguax J. Kanis: Conceptualization, Writing - review & editing, Resources.\n\nDeclaration of Competing Interest\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\nAbdul-Karim F.W. Kida M. Wentz W.B. Carter J.R. Sorensen K. Macfee M. Bone metastasis from gynecologic carcinomas: a clinicopathologic study Gynecol. Oncol. 39 2 1990 108 114 2227582 \nBlack D. Soslow R.A. Levine D.A. Tornos C. Chen S.C. Hummer A.J. Clinicopathologic significance of defective DNA mismatch repair in endometrial carcinoma J. Clin. Oncol. 24 11 2006 1745 1752 16549821 \nBristow R.E. Zerbe M.J. Rosenshein N.B. Grumbine F.C. Montz F.J. Stage IVB endometrial carcinoma: the role of cytoreductive surgery and determinants of survival Gynecol. Oncol. 78 2000 85 91 10926785 \nBubendorf L. Schopfer A. Wagner U. Sauter G. Moch H. Willi N. Gasser T.C. Mihatsch M.J. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients Human Pathol. 31 5 2000 578 583 10836297 \nFader A.N. Roque D.M. Siegel E. Buza N. Hui P. Abdelghany O. Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous caricnomas that overexpress human epidermal growth factor receptor 2/neu J. Clin. Oncol. 36 30 2018 2044 2051 29584549 \nGhosh S. Rao P.B. Osseous metastases in gynecological epithelial malignancies: a retrospective institutional study and review of the literature J. Clin. Diagnostic Res. 9 12 2015 XC10 XC13 \nGoff B.A. Goodman A. Muntz H.G. Fuller A.F. Jr Nikrui N. Rice L.W. Surgical stage IV endometrial carcinoma: a series of 47 cases Gynecol. Oncol. 52 1994 237 240 8314145 \nHoon Chung H. Weon Kim J. Park N. Song Y. Sang S. Lee H. Use of preoperative serum CA-125 levels for prediction of lymph node metastasis and prognosis in endometrial cancer Acta Obstetricia et Gynecologic Scandinavica 85 2006 1501 1505 \nKeheo S.M. Zivanovic O. Ferguson S.E. Barakat R.R. Soslow R. Clinicopathologic features of bone metastases and outcomes in patients with primary endometrial cancer Gynecol. Oncol. 117 2010 229 233 20199802 \nKennecke Hagen Yerushalmi Rinat Woods Ryan Cheang Maggie Chon U. Voduc David Speers Caroline H. Nielsen Torsten O. Gelmon Karen Metastatic behavior of breast cancer subtypes J. Clin. Oncol. 28 20 2010 3271 3277 20498394 \nKwon J.S. Scott J.L. Gilks C.B. Daniels M.S. Sun C.C. Lu K.H. Testing women with endometrial cancer to detect Lynch syndrome J. Clin. Oncol. 29 16 2011 2247 2252 21537049 \nLe MMR deficiency predicts response of solid tumors to PD-1 blockade Science 2017 \nMariani A. Wbb M.J. Keeney G.L. Calori G. Podratz K.C. Hematogenous dissemination in corpus cancer Gynecol. Oncol. 80 2 2001 233 238 11161865 \nMcMeekin D.S. Tritchler D.L. Cohn D.E. Mutch D.G. Lankes H.A. Geller M.A. Clinicopathologic significance of mismatch repair defects in endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study J. Clin. Oncol. 34 25 2016 3026 3068 \nMiller D. Filiaci V. Gleming G. Mannel R. Cohn D. Matsumoto T. Tewari K. Randomized phase II noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study Gynecol. Oncol. 125 3 2012 771 \nNagao S. Nishio S. Michimae J. Tanabe H. Okada S. Otsuki T. Applicability of the concept of “platinum sensitivity” to recurrent endometrial cancer: The SGSG-012/GOTIC-004/Intergroup study Gynecol. Oncol. 131 3 2013 567 573 24076450 \nNational Institutes of Health, 2018. Cancer Facts: Uterine cancer. Surveillance, Epidemiology, and End Results Program.\nNCCN Guidelines, 2019. Uterine Neoplasms. Version 2.2019.\nPfisterer J. Ledermann J.A. Management ofplatinum-sensitive recurrent ovarian cancer Semin. Oncol. 33 2006 S12 S610 16716798 \nPrasanna T. Karapetis C.S. Roder D. Tie J. Padbury R. Price T. The survival outcome of patients with metastatic colorectal cancer based on site of metastases and impact of molecular markers and site of primary cancer on metastatic patter Acta Oncol. 15 11 2018 1438 1444 \nRump A. Morikawa Y. Tanaka M. Minami S. Umesaki N. Takeuchi M. Miyajima A. Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion J. Biol. Chem. 279 10 2004 91980 91988 \nShikama A. Minaguchi T. Matsumoto K. Akiyama-Abe A. Nakamura Y. Michikami H. Clinicopathologic implications of DNA mismatch repair status in endometrial carcinomas Gynecol. Oncol. 140 2 2016 226 233 26644264 \nSiegel R.L. Miller K.D. Jemal A. Cancer statistics, 2018 CA Cancer J. Clin. 68 2018 7 30 29313949 \nStopeck A.T. Lipton A. Body J.J. Steger G.G. Tonkin K. de Boer R.H. Denosumab compared with zolendronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study J. Clin. Oncol. 28 35 2010 5132 5138 21060033 \nUccella S. Morris J.M. Bakkum-Gamez J.N. Kenney G.L. Podratz K.C. Mariani A. Bone metastases in endometrial cancer: report on 19 patients and review of the medical literature Gynecol. Oncol. 130 2013 474 482 23685013 \nVan Poznak, C., Somerfield, M.R., Barlow, W.E., Sybil Beirmann, B.J., Bosserman, L.D., Clemons, M.J., et al. 2017. Role of Bone-Modifying Agents in Metastatic Breast Cancer: an American Society of Clinical Oncology – Cancer Care Ontario Focused Guideline Update. 35 (35), 3978–3986.\nYildiz A. Yetimalar H. Kasap B. Aydin C. Tatar S. Euro. J. Obstet. Gynecol. Reprod. Biol. 164 2 2012 191 195\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-5789",
"issue": "32()",
"journal": "Gynecologic oncology reports",
"keywords": "Bone metastasis; Endometrial cancer; Microsatellite instability",
"medline_ta": "Gynecol Oncol Rep",
"mesh_terms": null,
"nlm_unique_id": "101652231",
"other_id": null,
"pages": "100549",
"pmc": null,
"pmid": "32099892",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports",
"references": "20199802;21537049;29313949;10836297;22727919;14676194;10926785;20498394;26644264;17260229;28596308;16716798;23685013;24076450;2227582;26816982;29035643;21060033;30035653;29584549;16549821;8314145;11161865;27325856",
"title": "A clinicopathologic study of endometrial cancer metastatic to bone: Identification of microsatellite instability improves treatment strategies.",
"title_normalized": "a clinicopathologic study of endometrial cancer metastatic to bone identification of microsatellite instability improves treatment strategies"
} | [
{
"companynumb": "US-009507513-2003USA004163",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
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{
"abstract": "OBJECTIVE\nTo describe complications after use of mitomycin C (MMC) as a surgical adjuvant in pterygium surgery.\n\n\nMETHODS\nThis is a retrospective chart review of patients presenting to a tertiary referral center over a 7-year period with a diagnosis of scleral stromalysis after previous pterygium removal.\n\n\nRESULTS\nSixteen eyes of 15 patients were identified with scleral stromalysis after pterygium surgery with the use of adjuvant MMC. Three eyes were excluded because of insufficient chart information or previous beta-irradiation treatment. Twelve of 13 eyes underwent surgical treatment for primary pterygium, and 1 eye was treated for recurrent pterygium. Time from initial pterygium surgery to presentation ranged from 1 month to 10 years. Dosage and routes of MMC administration included 0.02% intraoperative application to either the bare sclera or Tenon capsule with a range of 30 seconds to 3 minutes or topical administration 4 times daily for 2 weeks. In some cases, the dose and route of MMC administration were unknown. Four of 13 patients (31%) required a scleral patch graft with 1 patient (8%) requiring multiple patch grafts.\n\n\nCONCLUSIONS\nUse of MMC in various forms and concentrations can cause devastating complications including scleral stromalysis. Scleral stromalysis may present anywhere from months to years after application. We suggest that MMC should be used with extreme caution when used as a surgical adjuvant for pterygium surgery. Patients must be urged to continue long-term follow-up after MMC use because of the potential for future anterior segment complications.",
"affiliations": "Division of Ophthalmology, Piedmont Hospital; Cornea Service, Eye Consultants of Atlanta, Atlanta, GA.",
"authors": "Lindquist|T Peter|TP|;Lee|W Barry|WB|",
"chemical_list": "D000477:Alkylating Agents; D016685:Mitomycin",
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000000384",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "34(4)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000477:Alkylating Agents; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016685:Mitomycin; D013508:Ophthalmologic Surgical Procedures; D011625:Pterygium; D012008:Recurrence; D012189:Retrospective Studies; D012590:Sclera; D015422:Scleral Diseases",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "398-401",
"pmc": null,
"pmid": "25719251",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Mitomycin C-associated scleral stromalysis after pterygium surgery.",
"title_normalized": "mitomycin c associated scleral stromalysis after pterygium surgery"
} | [
{
"companynumb": "US-ACCORD-029320",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MITOMYCIN"
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"drugadditional": null,
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{
"abstract": "BACKGROUND\nA combination of low-dose thalidomide and corticosteroids is a treatment option for anaemic patients with primary myelofibrosis (PMF) who are not eligible for allogeneic hematopoietic stem cell transplantation.\n\n\nMETHODS\nWe describe the outcomes of 13 patients with PMF treated with thalidomide 50 mg daily in combination with prednisone 0.5 mg/kg daily. Treatment responses were seen in 10/13 (77%) patients with a median onset of therapeutic effect at 4 weeks (range 3-7 weeks) after treatment initiation. Improvements of anaemia and thrombocytopenia and reduction in splenomegaly were observed in 70%, 38%, and 30% of patients, respectively. Four of six initially transfusion-dependent patients became transfusion independent following the therapy. The median duration of treatment response was 18 months (range 3-35 months). The treatment was well tolerated, with only one patient discontinuing therapy due to toxicity. Responders included both patients with and without JAK2 V617F, and included patients with both newly diagnosed and longstanding PMF.\n\n\nCONCLUSIONS\nOur retrospective analysis confirmed that the therapy with low-doses thalidomide with prednisone in patients with PMF achieves significant response rate in anaemia with low treatment toxicity.",
"affiliations": "4th Department of Internal Medicine - Hematology, Charles University, Faculty Hospital and Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic. belohlavkova@fnhk.cz.;4th Department of Internal Medicine - Hematology, Charles University, Faculty Hospital and Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic.;4th Department of Internal Medicine - Hematology, Charles University, Faculty Hospital and Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic.;Department of Oncology, First Faculty of Medicine and Thomayer Hospital, Prague, Czech Republic.;4th Department of Internal Medicine - Hematology, Charles University, Faculty Hospital and Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic.",
"authors": "Bělohlávková|Petra|P|;Maisnar|Vladimír|V|;Voglová|Jaroslava|J|;Buchler|Tomáš|T|;Žák|Pavel|P|",
"chemical_list": "D013792:Thalidomide; D011241:Prednisone",
"country": "Czech Republic",
"delete": false,
"doi": "10.14712/18059694.2016.89",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1211-4286",
"issue": "59(2)",
"journal": "Acta medica (Hradec Kralove)",
"keywords": "Immunomodulatory agents; Primary myelofibrosis; Thalidomide; Treatment",
"medline_ta": "Acta Medica (Hradec Kralove)",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000741:Anemia, Aplastic; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D011241:Prednisone; D055728:Primary Myelofibrosis; D013792:Thalidomide",
"nlm_unique_id": "9705947",
"other_id": null,
"pages": "50-3",
"pmc": null,
"pmid": "27526305",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Improvement of Anaemia in Patients with Primary Myelofibrosis by Low-Dose Thalidomide and Prednisone.",
"title_normalized": "improvement of anaemia in patients with primary myelofibrosis by low dose thalidomide and prednisone"
} | [
{
"companynumb": "CZ-MYLANLABS-2017M1017487",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THALIDOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nFew data exist regarding use of nucleos(t)ide analogs started in early pregnancy for mothers with active chronic hepatitis B (CHB). We assessed the safety and efficacy of lamivudine/telbivudine initiated in the first trimester versus no treatment in mothers with active CHB.\n\n\nMETHODS\nWe retrospectively enrolled 94 mothers newly diagnosed with active CHB in the first trimester of pregnancy. Patients with or without antiviral therapy were followed until postpartum week 28. All newborns received immunoprophylaxis. The primary endpoint was the safety of mothers and infants. The secondary endpoints were hepatitis B virus (HBV) DNA suppression and mother-to-child transmission (MTCT) rate.\n\n\nRESULTS\nFifty-nine of the 94 mothers initiated lamivudine/telbivudine (27/32) in the first trimester of pregnancy; 35 received no treatment. At delivery, the viral load reduction was similar between lamivudine and telbivudine. Early initiation of lamivudine/telbivudine significantly increased the proportion of mothers achieving HBV DNA <106 copies/ml compared with those with no treatment (100 versus 42.42 %, p < 0.001). At postpartum week 28, the MTCT rate was significant lower in the treated group than in the control group (0/61 or 0 versus 4/34 or 11.76 %, p = 0.028). Lamivudine and telbivudine were well tolerated in the mothers except mild creatine kinase (CK) elevation. There existed no differences in gestational age, infant length and weight, Apgar score, adverse events, or birth defect rates between infants from treated and untreated mothers.\n\n\nCONCLUSIONS\nTreatment with lamivudine or telbivudine for active CHB in early pregnancy appears to be safe and effective for controlling maternal disease as well as interrupting MTCT.",
"affiliations": "Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-an Road, Xicheng District, Beijing, 100050, China.;Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing-shun East Street, Chaoyang District, Beijing, 100015, China.;Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.;Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-an Road, Xicheng District, Beijing, 100050, China.;Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing-shun East Street, Chaoyang District, Beijing, 100015, China.;Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing-shun East Street, Chaoyang District, Beijing, 100015, China. yiwei1215@163.com.;Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-an Road, Xicheng District, Beijing, 100050, China. jia_JD@ccmu.edu.cn.",
"authors": "He|Tianyu|T|;Bai|Yuqing|Y|;Cai|Haodong|H|;Ou|Xiaojuan|X|;Liu|Min|M|;Yi|Wei|W|;Jia|Jidong|J|http://orcid.org/0000-0002-4673-8890",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D017325:Hepatitis B Vaccines; D006513:Hepatitis B e Antigens; D007136:Immunoglobulins; D000077712:Telbivudine; D019259:Lamivudine; D013936:Thymidine; C045213:hepatitis B hyperimmune globulin",
"country": "United States",
"delete": false,
"doi": "10.1007/s12072-017-9839-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1936-0533",
"issue": "12(2)",
"journal": "Hepatology international",
"keywords": "Chronic hepatitis B; Early; Lamivudine; Mother-to-child transmission; Telbivudine",
"medline_ta": "Hepatol Int",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D016022:Case-Control Studies; D004279:DNA, Viral; D005260:Female; D017325:Hepatitis B Vaccines; D006513:Hepatitis B e Antigens; D019694:Hepatitis B, Chronic; D006801:Humans; D007116:Immunization, Passive; D007136:Immunoglobulins; D007223:Infant; D018445:Infectious Disease Transmission, Vertical; D019259:Lamivudine; D061214:Patient Safety; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First; D012189:Retrospective Studies; D000077712:Telbivudine; D013936:Thymidine; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "101304009",
"other_id": null,
"pages": "118-125",
"pmc": null,
"pmid": "29344772",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": "28551372;19729084;26565396;26566064;27317879;27749537;23236240;26725906;28407735;25361021;25251571;22239517;24168259;22343511;19585616;19175878;27305192;21703206;28025872;21867707",
"title": "Safety and efficacy of lamivudine or telbivudine started in early pregnancy for mothers with active chronic hepatitis B.",
"title_normalized": "safety and efficacy of lamivudine or telbivudine started in early pregnancy for mothers with active chronic hepatitis b"
} | [
{
"companynumb": "PHHY2018CN013284",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TELBIVUDINE"
},
"drugadditional": null,
"dru... |
{
"abstract": "The existing data with regard to immune-related neutropenia (irN), a rare (incidence-1%) immune-related adverse event of immune checkpoint inhibitors, are scarce. Eight patients with irN were identified through internal databases of 3 participating Israeli cancer centers. In addition, 11 original articles focusing on the clinical course of 24 patients with irN were selected during the PubMed search. Descriptive analysis of clinical and pathologic factors related to irN was performed (n=32); the effect of these on the irN outcomes was assessed. An algorithm for irN evaluation and treatment was proposed. The median time-to-onset of irN (n=32) was 60 days (range, 10-465 d). Grade 3-5 irN, febrile neutropenia, and irN-related death occurred in 81%, 50%, and 9% of patients, respectively. In all, 56%, 22%, 62%, and 25% of patients received PO corticosteroids, IV corticosteroids, granulocyte colony-stimulating factor (GCSF), and intravenous immunoglobulins (IVIG), respectively, with an improvement/resolution rate of 84%. Odds ratios for irN improvement/resolution were as follows: 1.40 [95% confidence interval (CI), 0.03-68.72], 0.43 (95% CI, 0.04-4.22), 2.60 (95% CI, 0.07-97.24), 0.36 (95% CI, 0.03-4.38), 4.02 (95% CI, 0.16-99.48), 2.01 (95% CI, 0.32-12.70), 1.08 (95% CI, 0.02-49.89), 0.42 (95% CI, 0.06-2.91), and 2.73 (95% CI, 0.42-17.51) for granulocyte hyperplasia, granulocyte/all lineage hypoplasia, granulocyte maturation blockade, lymphocyte infiltration on bone marrow biopsy, IV corticosteroids, PO corticosteroids, cyclosporine, IVIG, and GCSF, respectively (P>0.05 for all factors). IrN recurrence rate following immune checkpoint inhibitors rechallenge was 80%. IrN is a rare, life-threatening, early-onset immune-related adverse event. Differentiating between the central, peripheral, and modified peripheral types allows a better prognosis definition. Corticosteroids and GCSF represent the main treatment approaches; IVIG and cyclosporine should be used as salvage treatment.",
"affiliations": "Thoracic Cancer Service, Davidoff Cancer Center.;Thoracic Cancer Service, Davidoff Cancer Center.;Thoracic Cancer Service, Rambam Health Care Campus, Haifa.;Thoracic Cancer Service, Tel Aviv Sourasky Medical Center, Tel Aviv.;The Legacy Heritage Oncology Center, Soroka Medical Center.;Thoracic Cancer Service, Rambam Health Care Campus, Haifa.;Statistical Consulting Unit, Rabin Medical Center, Petah Tikva.;Thoracic Cancer Service, Davidoff Cancer Center.",
"authors": "Finkel|Inbar|I|;Sternschuss|Michal|M|;Wollner|Mira|M|;Shamai|Sivan|S|;Peled|Nir|N|;Turgeman|Ilit|I|;Shochat|Tzippy|T|;Dudnik|Elizabeth|E|;|||",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors; D016756:Immunoglobulins, Intravenous; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor",
"country": "United States",
"delete": false,
"doi": "10.1097/CJI.0000000000000293",
"fulltext": null,
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"issn_linking": "1524-9557",
"issue": "43(2)",
"journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)",
"keywords": null,
"medline_ta": "J Immunother",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D016756:Immunoglobulins, Intravenous; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009503:Neutropenia",
"nlm_unique_id": "9706083",
"other_id": null,
"pages": "67-74",
"pmc": null,
"pmid": "31498181",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis",
"references": null,
"title": "Immune-related Neutropenia Following Treatment With Immune Checkpoint Inhibitors.",
"title_normalized": "immune related neutropenia following treatment with immune checkpoint inhibitors"
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"abstract": "Multiple myeloma (MM) typically affects older patients with a median age at diagnosis of 67 to 70 years and only 3% of cases are diagnosed before the age of 40. Moreover, MM is more common in men. Therefore, pregnancy rarely occurs in patients with MM and only 37 cases of MM in pregnancy have been reported in the literature. Herein we report an additional 5 cases. The diagnosis of MM might be problematic in this context because some of the symptoms and signs, such as back pain and anemia, can be attributed to pregnancy. Furthermore, if the patient wishes to continue her pregnancy, therapeutic options are currently limited. The list of agents that can be safely administered in pregnant women includes glucocorticoids. Moreover, any continuation of pregnancy has obvious long-term psychosocial repercussions for the patient and her family because of the currently incurable nature of MM. The reported cases of MM in pregnancy represent a spectrum of clinical manifestations. The selection of efficacious and safe treatments is challenging, especially if continuation of pregnancy is desired. Although some authors postulate that pregnancy might lead to progression of MM, data are limited and no consensus on this point has been reached.",
"affiliations": "Department and Clinic of Haematology, Jagiellonian University Medical College, Krakow, Poland. Electronic address: mmjurczy@cyf-kr.edu.pl.;Department of Haematology, Blood Neoplasms and Bone Marrow Transplantation, Medical University, Wroclaw, Poland.;John Theurer Cancer Center at Hackensack UMC, Hackensack, NJ.;John Theurer Cancer Center at Hackensack UMC, Hackensack, NJ and Georgetown University, Department of Medicine, Washington, DC.;John Theurer Cancer Center at Hackensack UMC, Hackensack, NJ.;Dana Farber Cancer Institute, Department of Medicine, Boston, MA.;Dana Farber Cancer Institute, Department of Medicine, Boston, MA.;Carbone Cancer Center, Department of Medicine, University of Wisconsin, Madison, WI.;Department and Clinic of Obstetrics and Perinatology, Jagiellonian University, Medical College, Krakow, Poland.;Department and Clinic of Haematology, Jagiellonian University Medical College, Krakow, Poland.",
"authors": "Jurczyszyn|Artur|A|;Olszewska-Szopa|Magdalena|M|;Vesole|Adam S|AS|;Vesole|David H|DH|;Siegel|David S|DS|;Richardson|Paul G|PG|;Paba-Prada|Claudia|C|;Callander|Natalie S|NS|;Huras|Hubert|H|;Skotnicki|Aleksander B|AB|",
"chemical_list": null,
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"issn_linking": "2152-2669",
"issue": "16(3)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Diagnosis; Management; Multiple myeloma; Pregnancy; Therapy",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D003131:Combined Modality Therapy; D003952:Diagnostic Imaging; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D009101:Multiple Myeloma; D009367:Neoplasm Staging; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D016896:Treatment Outcome",
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"references": null,
"title": "Multiple Myeloma in Pregnancy--A Review of the Literature and a Case Series.",
"title_normalized": "multiple myeloma in pregnancy a review of the literature and a case series"
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"abstract": "The Coronavirus disease-2019 (COVID-19) has been declared as a pandemic in March 2020 by the World Health Organization (WHO). Since then, this pandemic has dramatically affected the entire world, even radically influencing the way patients are framed at triage. Symptoms and tests in most cases lead to a correct diagnosis; however, error may be around the corner.\nA 60 years old patient was referred with weight loss, fatigue and mild fever for 3 weeks as he was working in a COVID-19 ward. After a positive swab and chest CT scan, he was admitted in the hospital and treated as mild COVID-19 patient. A CT scan performed after the patient was discharged revealed a renal lesion misidentified as a tumor then clarified to be an abscess which retrospectively appears to be the main cause of his symptoms.\nClinicians should consider other life-threatening disease in the differential diagnosis of patients presenting with similar symptoms to minimize mistakes and avoid further unnecessary investigations.",
"affiliations": "Department of Urology, University of Modena and Reggio Emilia, Modena, Italy.;Department of Urology, University of Modena and Reggio Emilia, Modena, Italy.;Department of Urology, OLV, Aalst, Belgium.;Department of Urology, OLV, Aalst, Belgium.;Department of Urology, OLV, Aalst, Belgium.;Department of Urology, University of Modena and Reggio Emilia, Modena, Italy.;Department of Urology, University of Modena and Reggio Emilia, Modena, Italy.;Department of Urology, University of Modena and Reggio Emilia, Modena, Italy.;Department of Urology, University of Modena and Reggio Emilia, Modena, Italy.;Department of Urology, OLV, Aalst, Belgium.;Department of Urology, University of Modena and Reggio Emilia, Modena, Italy.",
"authors": "Amato|Marco|M|;Eissa|Ahmed|A|https://orcid.org/0000-0001-6817-6887;Rosiello|Giuseppe|G|;Farinha|Rui|R|;Piazza|Pietro|P|;Sighinolfi|Maria Chiara|MC|;Rocco|Bernardo|B|https://orcid.org/0000-0001-7211-0485;Bianchi|Giampaolo|G|;Micali|Salvatore|S|;Mottrie|Alexandre|A|;Puliatti|Stefano|S|https://orcid.org/0000-0002-3098-2899",
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"fulltext": "\n==== Front\nUrologia\nUrologia\nURJ\nspurj\nUrologia\n0391-5603\n1724-6075\nSAGE Publications Sage UK: London, England\n\n33550944\n10.1177/0391560321993592\n10.1177_0391560321993592\nArticles\nDiagnostic bias during the COVID-19 era: COVID-19 or renal abscess?\nAmato Marco 123\nhttps://orcid.org/0000-0001-6817-6887\nEissa Ahmed 14\nRosiello Giuseppe 2356\nFarinha Rui 23\nPiazza Pietro 237\nSighinolfi Maria Chiara 1\nhttps://orcid.org/0000-0001-7211-0485\nRocco Bernardo 1\nBianchi Giampaolo 1\nMicali Salvatore 1\nMottrie Alexandre 23\nhttps://orcid.org/0000-0002-3098-2899\nPuliatti Stefano 123\n1 Department of Urology, University of Modena and Reggio Emilia, Modena, Italy\n2 Department of Urology, OLV, Aalst, Belgium\n3 ORSI Academy, Melle, Belgium\n4 Urology Department, Faculty of Medicine, Tanta University, Tanta, Egypt\n5 Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy\n6 Vita-Salute San Raffaele University, Milan, Italy\n7 Department of Urology, University of Bologna, Bologna, Italy\nStefano Puliatti, Department of Urology, University of Modena and Reggio Emilia, viaa del Pozzo, 71, Modena 41124, Italy. Email: stefanopuliatti@gmail.com\n7 2 2021\n8 2021\n88 3 218222\n28 8 2020\n13 1 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nIntroduction:\n\nThe Coronavirus disease-2019 (COVID-19) has been declared as a pandemic in March 2020 by the World Health Organization (WHO). Since then, this pandemic has dramatically affected the entire world, even radically influencing the way patients are framed at triage. Symptoms and tests in most cases lead to a correct diagnosis; however, error may be around the corner.\n\nCase report:\n\nA 60 years old patient was referred with weight loss, fatigue and mild fever for 3 weeks as he was working in a COVID-19 ward. After a positive swab and chest CT scan, he was admitted in the hospital and treated as mild COVID-19 patient. A CT scan performed after the patient was discharged revealed a renal lesion misidentified as a tumor then clarified to be an abscess which retrospectively appears to be the main cause of his symptoms.\n\nConclusion:\n\nClinicians should consider other life-threatening disease in the differential diagnosis of patients presenting with similar symptoms to minimize mistakes and avoid further unnecessary investigations.\n\nCOVID-19\nrenal abscess\nkidney tumor\nSars-CoV-2\ndiagnosis\ntypesetterts1\n==== Body\nIntroduction\n\nCoronavirus disease-2019 (COVID-19) pandemic has spread rapidly all over the world, putting COVID-19 in the spotlight, being the “pathology of the hour.” With approximately 20 million positive cases and 730 thousand deaths, all national healthcare systems were put to the test.1,2\n\nThe clinical spectrum can vary from mild symptoms (cough and loss of taste and smell) to severe respiratory failure. Even with mild symptoms, our level of suspicion should be high in risky groups.3–5 Noteworthy, symptoms alone may be deceiving, and other life-threatening pathologies should not be underestimated, even in times of a pandemic where generalized fear can be deceptive. We present a case report of a 60-year old patient, admitted to the hospital with mild respiratory symptoms, fever and COVID-19 positive swab treated as SARS-CoV-2, who was found to have another potentially life-threatening disease.\n\nCase report\n\nA 60-year-old diabetic man, with a history of regular medical follow-up, was admitted to the hospital by the beginning of March 2020. Mild fever, malaise, and weight loss occurred about 3 weeks before hospitalization without any other symptoms. As the patient was an anesthetist working in an Italian COVID-19 ward, and complying with a strict testing protocol, he had two negative COVID-19 swabs in the last weeks. However, due to the persistence of general malaise and one episode of fever, he had a third swab that demonstrated positive results for COVID-19. A chest CT scan showed left basal interstitial pneumonia (Figure 1), so the patient was hospitalized with COVID-19 diagnosis. At admission his vital signs were stable. On physical examination there was abdominal distension and rebounding pain on the left upper quadrant of the abdomen. Laboratory tests are summarized in Table 1. Being labeled as “COVID-19 positive” patient, he received intravenous ceftriaxone and clarithromycin, hydroxychloroquine, enoxaparin, vitamin D and tocilizumab for 2 weeks. During the hospital stay the patient remained stable showing no exacerbation of respiratory symptoms (minimum O2ps 94%) but only mild fever for three consecutive days. No further medications were administered nor support with oxygen was needed. After 15 days and two consecutive negative swabs the patient was discharged. The last blood tests are showed in the Table 1. A CT scan was performed 2 days after discharge (Figure 2) showed persistent interstitial pneumonia and also an incidental unclear shape of the left kidney, that motivated a third thoraco-abdomin-pelvic CT scan. The total body CT showed a 5.4 × 4.5 cm mass with thick walls and central colliquation, involving the renal parenchyma and the renal fat but without involving the renal sinus, suspicious for advanced malignant tumor. A previous CT done 1 year earlier for other purpose (diverticulitis) did not show any pathology in the left kidney. An MRI scan was then performed to better clarify the nature of the lesion, but no certain diagnosis was achieved (Figure 3). After urological consultation done in another hospital, the initial decision was to perform radical nephrectomy for suspicious of an advanced malignant renal disease. However, after a second opinion of an expert, considering the reported symptoms previously attributed exclusively to the virus, renal abscess was suspected and a renal biopsy was recommended. This lesion was then drained and specimens were sent to cytologic examination showing it was a renal abscess (presence of inflammatory cells and no bacteria) which did not require surgical removal. The patient started oral antibiotic treatment and performed a follow-up ultrasound at 3 months that revealed reduction in the diameter of the renal abscess.\n\nFigure 1. Thorax CT scan: left apical interstitial pneumonia.\n\nTable 1. Blood tests at 1st day and at 15th day.\n\nBlood tests\tReference values\tFirst day\t15th day\t\nHemoglobin (g/dL)\t13.5–17.5\t16\t15.4\t\nPlatelet\t150–400 103/uL\t235 103/uL\t347 103/uL\t\nWhite blood cells\t4.00–10.0 103/uL\t14 103/uL\t9 103/uL\t\nNeutrophils (%)\t41–73\t70\t75\t\nLymphocytes (%)\t19.4–44.9\t21\t12\t\nCreatinine (mg/dL)\t0.72–1.25\t1.29\t0.97\t\nHs-C-reactive protein (mg/dL)\t<0.5\t2.17\t0.06\t\nGlucose (mg/dL)\t70–105\t108\t150\t\nProcalcitonin (ng/mL)\t0.00–0.08\t0.05\t–\t\nInterleuchyn-6 (pg/mL)\t<3.4\t16.1\t12.6\t\nVES (mm)\t0–20\t37\t12\t\nSars-CoV-2 IgM (AU/mL)\t<10\t42.03\t21.92\t\nSars-CoV-2 IgG (AU/mL)\t<10\t71\t67\t\nUrine-culture\tNegative\tNegative\t–\t\n\nFigure 2. Abdominal CT scan: (a) no contrast, (b) arteriosus phase, (c) venous phase, and (d) excretory phase.\n\nFigure 3. Abdominal MRI: (a) T1-weighted axial image and (b) coronal image.\n\nDiscussion\n\nCOVID-19 pandemic is an unprecedented medical emergency, where, the healthcare systems all over the world took extreme measures, stopping all non-urgent elective surgeries, increasing the financial support and the number of personal protective devices, and directing all the available medical resources to face this pandemic.1 Considering the highly contagious nature of SARS-COV-2, healthcare personnel were classified among the groups at high risk of getting infected as they are in close contact with confirmed COVID-19 patients.6 Furthermore, the most severe cases were surprisingly manifested in younger medical staff with fever and cough as main symptoms. This could be due to the longer working hours of younger personnel, but data to support this is not yet available.7 Importantly, the massive increase in the number of patients beyond the capacity of the healthcare systems and the increased risk of infection amongst the medical workforce result in workers burnout that can lead to error.8 Moreover, pitfall of judgment because COVID-19 is a more attractive diagnosis could direct the physician in the wrong direction.9\n\nRenal abscess is a relatively uncommon debilitating and potentially fatal disease (1–10 in 10,000 hospital admissions) with mortality rates historically ranging from 12% to 50% and diabetes appears to be the leading risk factor. Fever and flank pain are usually the main symptoms, however nonspecific symptoms have been observed, such as weight loss, fatigue and rarely lower respiratory tract symptoms.10 Urinary tract infections are usually the cause of a renal abscess, however in our case both urine culture and aspirate were negative. In the literature according to our knowledge there are no cases of aseptic renal abscesses of unknown etiology. A case report was recently published on a renal abscess in a patient suffering from Chron disease, often associated with aseptic abscesses.11 In our case there is no pathology that can explain the onset of sterile abscesses. However, diabetes is the most important predisposing factor for renal abscesses which are generally infectious. We think that the bacterial load of the pathogen responsible for the renal abscess in our case has been eliminated by the use of broad-spectrum antibiotics according to the pharmacological COVID-19 protocol used. In the current clinical case, the symptoms were ambiguous, but positivity of the swab and the chest CT scan resulted in the underestimations of other symptoms that are more likely related to the abscess. However, it was reasonable to focus on COVID-19 because of history, other main symptoms and work category risk that have been misleading. Moreover, in the first instance according to CT and MRI images and negative urine culture, malignancy of the lesion suitable for nephrectomy was the main hypothesis and not abscess, but only kidney biopsy unveiled the real nature of the lesion sparing an invasive surgery.12 On the other hand, we cannot exclude the overlapping of two pathologies at the same time.13,14 Acute renal injuries from COVID have been described in the literature,1 but no cases of virus-related abscess. However, the impact on immune system due to COVID can be a predisposing factor for infectious diseases.15 In the same setting, the absence of symptoms and fully recovery of blood tests even with CT signs of pneumonia suggests more for abscess-related initial illness rather than COVID. This case must be contextualized in the historical moment of maximum criticality for the healthcare systems.16 The fear of contagion, the harmful consequences of the COVID-19 and the small knowledge at that time, added to the subsequent fear of a potential advanced tumor were smoke and mirrors for clinicians who have over diagnosed and overtreated the patient.\n\nConclusion\n\nCOVID 19 is a tremendous problem that is affecting the economic system and the health system around the world, however overdiagnosis can lead to error. Other pathologies can have symptoms similar to moderate forms of COVID and accurate examination should be carried out before running to conclusion. This is an example of how a kidney disease can mislead the clinician for pitfall of judgment.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nORCID iDs: Ahmed Eissa https://orcid.org/0000-0001-6817-6887\n\nBernardo Rocco https://orcid.org/0000-0001-7211-0485\n\nStefano Puliatti https://orcid.org/0000-0002-3098-2899\n==== Refs\nReferences\n\n1 Puliatti S Eissa A Eissa R , et al . COVID-19 and urology: a comprehensive review of the literature. BJU Int 2020; 125 (6 ): E7–E14.32249538\n2 World Health Organization. Coronavirus disease (COVID-19) situation report – 204, https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200811-covid-19-sitrep-204.pdf?sfvrsn=1f4383dd_2 (accessed 12 August 2020).\n3 Mottrie A. ERUS (EAU Robotic Urology Section) guidelines during COVID-19 emergency. Eur Urol 2020; 25 : 1–6.\n4 Fahmy DH El-Amawy HS El-Samongy MA , et al . COVID-19 and dermatology: a comprehensive guide for dermatologists. J Eur Acad Dermatol Venereol 2020; 34 (7 ): 1388–1394.32428303\n5 Ribal MJ Cornford P Briganti A , et al . European Association of Urology Guidelines Office Rapid Reaction Group: an organisation-wide collaborative effort to adapt the European Association of Urology guidelines recommendations to the coronavirus disease 2019 era. Eur Urol 2020; 78 (1 ): 21–28.32376137\n6 Li Q Guan X Wu P , et al . Early transmission dynamics in Wuhan, China, of novel coronavirus–infected pneumonia. N Engl J Med 2020; 382 (13 ): 1199–1207.31995857\n7 Chu J Yang N Wei Y , et al . Clinical characteristics of 54 medical staff with COVID-19: a retrospective study in a single center in Wuhan, China. J Med Virol 2020; 92 (7 ): 807–813.32222986\n8 Hu D Kong Y Li W , et al . Frontline nurses’ burnout, anxiety, depression, and fear statuses and their associated factors during the COVID-19 outbreak in Wuhan, China: a large-scale cross-sectional study. EClinicalMedicine 2020; 24 : 100424.32766539\n9 Redelmeier DA Shafir E. Pitfalls of judgment during the COVID-19 pandemic. Lancet Public Health 2020; 5 : e306–e308.32334647\n10 Chang SH Hsieh CH Weng YM , et al . Performance assessment of the mortality in emergency department sepsis score, modified early warning score, rapid emergency medicine score, and rapid acute physiology score in predicting survival outcomes of adult renal abscess patients in the emergency department. Biomed Res Int 2018; 2018 : 6983568.30327779\n11 Soffer S Dahan S Maklakovski M , et al . A case of aseptic renal abscesses associated with IBD. Inflamm Bowel Dis. Epub ahead of print November 2020. DOI: 10.1093/ibd/izaa284.\n12 Moschovas MC Mazzone E Puliatti S , et al . Selecting the most appropriate oncological treatment for patients with renal masses during the COVID-19 pandemic: recommendations from a referral center. Eur Urol Focus 2020; 6 (5 ): 1130–1131.32475783\n13 Sighinolfi MC Rocco B Mussini C. COVID-19: importance of the awareness of the clinical syndrome by urologists. Eur Urol 2020; 78 (1 ): e40–e41.32345522\n14 Lansbury L Lim B Baskaran V , et al . Co-infections in people with COVID-19: a systematic review and meta-analysis. J Infect 2020; 81 (2 ): 266–275.32473235\n15 Liu J Li S Liu J , et al . Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine 2020; 55 : 102763.32361250\n16 Rocco B Sighinolfi MC Sandri M , et al . The dramatic COVID-19 outbreak in Italy is responsible of a huge drop in urological surgical activity: a multicenter observational study. BJU Int 2020; 127 (1 ): 156–163.\n\n",
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"issue": "88(3)",
"journal": "Urologia",
"keywords": "COVID-19; Sars-CoV-2; diagnosis; kidney tumor; renal abscess",
"medline_ta": "Urologia",
"mesh_terms": "D018784:Abdominal Abscess; D015746:Abdominal Pain; D000072077:Anesthetists; D000086382:COVID-19; D048909:Diabetes Complications; D003951:Diagnostic Errors; D004322:Drainage; D005221:Fatigue; D005334:Fever; D006801:Humans; D007680:Kidney Neoplasms; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure; D058873:Pandemics; D000086402:SARS-CoV-2; D014057:Tomography, X-Ray Computed; D015431:Weight Loss",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Diagnostic bias during the COVID-19 era: COVID-19 or renal abscess?",
"title_normalized": "diagnostic bias during the covid 19 era covid 19 or renal abscess"
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"abstract": "Invasive fungal rhinosinusitis (IFRS) is a serious illness requiring early diagnosis, surgical debridement, and administration of antifungals. We report a case of an acute IFRS caused by Curvularia in a patient with diabetes mellitus. An 18-year-old female presented to the emergency department with an acute onset of fever, headache, facial discomfort, and a blood glucose reading of 500 mg/dL. The patient was admitted for the management of hyperosmolar hyperglycemia. Her past medical history includes uncontrolled type 1 diabetes mellitus and a recent toothache. A computed tomography scan of the facial maxillary region revealed sinus disease with bony erosion. Empiric therapy with liposomal amphotericin B 400 mg i.v. every 24 hours, piperacillin/tazobactam 4.5 g i.v. every 6 hours and vancomycin 1 g i.v. every 12 hours was started. A functional endoscopic sinus surgery revealed invasive rhinosinusitis and cultures were positive for fungal elements. The patient was discharged on liposomal amphotericin B 400 mg i.v. daily and cefuroxime 500 mg orally twice daily. However, she was readmitted for the management of acute kidney injury and was discharged on itraconazole capsules 200 mg orally twice daily. Sinus cultures grew Curvularia and itraconazole was prescribed for 6 weeks, but the patient discontinued treatment after 3 weeks and had no signs or symptoms of rhinosinusitis when she was last seen in the clinic. The possibility of IFRS should be explored in patients with diabetes and signs and symptoms of rhinosinusitis.",
"affiliations": "Broward Health Medical Center, Fort Lauderdale, FL, USA.;Gregory School of Pharmacy, 8527Palm Beach Atlantic University, West Palm Beach, FL, USA.;Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA.",
"authors": "Marinucci|Victoria|V|;Chahine|Elias B|EB|https://orcid.org/0000-0003-1775-9497;Bush|Larry M|LM|",
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"journal": "Journal of pharmacy practice",
"keywords": "Curvularia; amphotericin B; invasive fungal rhinosinusitis; itraconazole",
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"title": "Invasive Fungal Rhinosinusitis Caused by Curvularia in a Patient With Type 1 Diabetes Mellitus: A Case Report.",
"title_normalized": "invasive fungal rhinosinusitis caused by curvularia in a patient with type 1 diabetes mellitus a case report"
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"abstract": "We attempted to explore novel treatment options for progressive diffuse large B-cell lymphoma (DLBCL) with TP53 mutation that has a poor response to rituximab-based immunochemotherapy. Herein, we report the case of a patient with DLBCL having TP53 mutation who showed progression following four cycles of rituximab-based immunochemotherapy but achieved sustained partial remission following chidamide-based chemotherapy. In vitro experiments performed using the DLBCL cell lines OCI-ly1 (LY1; mutant TP53), OCI-ly10 (LY10; wild-type TP53) and OCI-ly19 (LY19, wild-type TP53) demonstrated that chidamide is more potent against cells with mutant TP53 mutant than those with wild-type TP53. Moreover, chidamide can reduce the mRNA and protein expression levels of mutant TP53 and upregulate the surface expression of the CD20 antigen in lymphoma cells.",
"affiliations": "Department of Hematology & Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.;Department of Hematology & Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.;Department of Hematology & Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.;Department of Hematology & Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.;Department of Hematology & Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.",
"authors": "Li|Qing|Q|;Huang|Jingcao|J|;Ou|Yang|Y|;Li|Yan|Y|;Wu|Yu|Y|",
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"country": "England",
"delete": false,
"doi": "10.2217/imt-2018-0083",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1750-743X",
"issue": "11(4)",
"journal": "Immunotherapy",
"keywords": " mutation; CD20; chidamide; diffuse large B-cell lymphoma; immunochemotherapy; immunomodulator; thalidomide",
"medline_ta": "Immunotherapy",
"mesh_terms": "D000368:Aged; D000631:Aminopyridines; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D001549:Benzamides; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007155:Immunologic Factors; D016393:Lymphoma, B-Cell; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D009154:Mutation; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D015854:Up-Regulation",
"nlm_unique_id": "101485158",
"other_id": null,
"pages": "265-272",
"pmc": null,
"pmid": "30606076",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Progressive diffuse large B-cell lymphoma with TP53 gene mutation treated with chidamide-based chemotherapy.",
"title_normalized": "progressive diffuse large b cell lymphoma with tp53 gene mutation treated with chidamide based chemotherapy"
} | [
{
"companynumb": "CN-PFIZER INC-2019077647",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
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"abstract": "Neoadjuvant chemotherapy (NAC) has been conducted for patients with non-resectable colorectal cancer; however, few reports of a systematic approach to NAC exist. At our hospital, bevacizumab with capecitabine and oxaliplatin (B-mab XELOX) has been used as chemotherapy for Stage IV colorectal cancer since 2014. We aimed to evaluate the efficacy and safety of NAC with a molecular-targeting agent for Stage IV colorectal cancer.\nA retrospective, single-institute analysis was performed including 27 patients with advanced recurrent cancer following primary tumor resection and 43 patients with non-resectable tumors and remote metastasis. At the time of resection, 17 were receiving chemotherapy. All 70 patients received at least 3 cycles of B-mab XELOX (total: 920 cycles). We determined the 1-year progression-free survival (1Y-PFS), 1-year overall survival (1Y-OS), 3Y-PFS, 3Y-OS, and number of treatment cycles. The objective response rate, clinical benefit rate, and adverse events were assessed. The number of chemotherapy cycles, survival time, and R0 surgery rate were determined for patients who underwent RO conversion surgery.\nThe 1Y-PFS was 28.5% [median survival time (MST): 7.4 months], 1Y-OS was 76.6% (MST not reached), 3Y-PFS was 5.5% (MST: 7.4 months), and 3Y-OS was 26.4% (MST: 25.2 months). The mean and median number of cycles of B-mab XELOX was 13.1 and 10.5, respectively. The objective response rate was 28.6%, and the clinical benefit rate was 58.6%. Grade 1 or Grade 2 adverse events occurred in 60 patients (85.7%); however, they all resolved without intervention. A single Grade 4 event (perforation of the primary tumor) occurred in 1 patient (1.4%). RO conversion surgery was performed in 7 patients (10.0%; primary + liver in 2 patients, primary + lung in 1 patient, liver in 3 patients, and primary in 1 patient). These patients received 3 to 10 cycles preoperatively (mean: 7.3; median: 6.5). R0 surgery was achieved in 5 of the 7 patients (71.4%). Postoperative survival ranged from 1 to 26 months (MST: 8 months).\nThis modified regimen was safe and effective in Japanese patients, and a high quality of life/quality-adjusted life-year was achieved. To further evaluate PFS and OS, more patients are being investigated.",
"affiliations": "Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan.;Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan.;Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan.;Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan.;Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan.;Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan.;Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan.;Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan.;Department of Surgery, Tokai University Tokyo Hospital, Shibuya, Tokyo, Japan.;Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan.;Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan.",
"authors": "Yokoyama|Daiki|D|;Mukai|Masaya|M|;Uda|Shuji|S|;Kishima|Kyouko|K|;Koike|Takuya|T|;Hasegawa|Sayuri|S|;Izumi|Hideki|H|;Yamamoto|Souichirou|S|;Tajima|Takayuki|T|;Nomura|Eiji|E|;Makuuchi|Hiroyasu|H|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/jgo-20-350",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2078-6891",
"issue": "12(2)",
"journal": "Journal of gastrointestinal oncology",
"keywords": "Colorectal cancer; XELOX; bevacizumab; chemotherapy; recurrent/non-resectable cancer; stage IV",
"medline_ta": "J Gastrointest Oncol",
"mesh_terms": null,
"nlm_unique_id": "101557751",
"other_id": null,
"pages": "527-534",
"pmc": null,
"pmid": "34012646",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": "19097774;10944126;20133499;8857855;9332468;24717570;28449055;28275039;26109816;18360567;25468456;28787661;20519275;21829769;23216053;27239240;29113730;25862517;2143063;29293874;28817103;20680105;2957943;20708966;2530317;28407110;21498982;11346931;18421054",
"title": "Efficacy of modified bevacizumab-XELOX therapy in Japanese patients with stage IV recurrent or non-resectable colorectal cancer.",
"title_normalized": "efficacy of modified bevacizumab xelox therapy in japanese patients with stage iv recurrent or non resectable colorectal cancer"
} | [
{
"companynumb": "JP-ROCHE-2833221",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "In patients who had advanced endometriosis, we use different protocols including GnRH agonist, GnRH antagonist and progestin-primed ovarian stimulation (PPOS) protocols to assess live-birth congenital malformations delivered after in vitro fertilization (IVF) and vitrified embryo transfer cycles.\nA retrospective cohort study is conducted by us. It includes 1495 live-born infants in maternal endometriosis. From January 2010 to January 2017, we brought into infants who underwent either gonadotropin-releasing hormone agonist long protocol, gonadotropin-releasing hormone antagonist protocol or PPOS. We chose neonatal outcomes and congenital malformations as our major measures.\nNeonatal outcomes, as well as congenital malformations, were considered as the main measures, and gestational age, birth weight, birth length, multiple births and early neonatal death are included. All groups were comparable. The GnRH antagonist group (1.41%) and the GnRH antagonist protocol group (1.8%) had the same incidence of live-birth defects as the PPOS groups (1.33%) were similar. There were no apparent differences when it came to congenital malformations among the three groups. Multivariate logistic regression showed that infertility-time factors as well as multiple births combined to add the risk of congenital malformations; the adjusted odds were 1.143 (95% confidence interval [CI]: 0.988-1.323) and 3.253 (95% CI: 1.359-7.788). Besides, no association was found among various ovarian stimulations as well as congenital birth defect programs, maternal age, body mass index, parity or infant sex.\nThis study suggests that, in contrast to conventional ovarian stimulation, PPOS neither has any effect on neonatal outcomes in IVF adverse effects nor does it elevate the rate of congenital malformations in late endometriosis. However, randomized controlled trials of the long-term outcomes of children born after PPOS protocols for maternal endometriosis are needed and the follow-up studies were conducted to confirm this result.",
"affiliations": "Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.;Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.;Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.",
"authors": "Liang|Zhou|Z|;Wang|Yun|Y|;Kuang|Yanping|Y|",
"chemical_list": "D006727:Hormone Antagonists; D011372:Progestins",
"country": "New Zealand",
"delete": false,
"doi": "10.2147/DDDT.S263138",
"fulltext": "\n==== Front\nDrug Des Devel Ther\nDrug Des Devel Ther\ndddt\ndddt\nDrug Design, Development and Therapy\n1177-8881 Dove \n\n263138\n10.2147/DDDT.S263138\nOriginal Research\nLive-Birth Outcomes and Congenital Malformations After Progestin-Primed Ovarian Stimulation in Maternal Endometriosis\nLiang et alLiang et alLiang Zhou 1 Wang Yun 1 Kuang Yanping 1 1 Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China\nCorrespondence: Yun Wang; Yanping KuangDepartment of Assisted Reproduction, Shanghai Ninth People’s Hospital, No. 639, Zhizaoju Road, Huangpu District, Shanghai200011, People’s Republic of ChinaTel +86-21-23271699 Email sammy20080228@icloud.com; kuangyp1506@sh9hospital.org\n10 12 2020 \n2020 \n14 5459 5467\n15 7 2020 23 10 2020 © 2020 Liang et al.2020Liang 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).Purpose\nIn patients who had advanced endometriosis, we use different protocols including GnRH agonist, GnRH antagonist and progestin-primed ovarian stimulation (PPOS) protocols to assess live-birth congenital malformations delivered after in vitro fertilization (IVF) and vitrified embryo transfer cycles.\n\nMethods\nA retrospective cohort study is conducted by us. It includes 1495 live-born infants in maternal endometriosis. From January 2010 to January 2017, we brought into infants who underwent either gonadotropin-releasing hormone agonist long protocol, gonadotropin-releasing hormone antagonist protocol or PPOS. We chose neonatal outcomes and congenital malformations as our major measures.\n\nResults\nNeonatal outcomes, as well as congenital malformations, were considered as the main measures, and gestational age, birth weight, birth length, multiple births and early neonatal death are included. All groups were comparable. The GnRH antagonist group (1.41%) and the GnRH antagonist protocol group (1.8%) had the same incidence of live-birth defects as the PPOS groups (1.33%) were similar. There were no apparent differences when it came to congenital malformations among the three groups. Multivariate logistic regression showed that infertility-time factors as well as multiple births combined to add the risk of congenital malformations; the adjusted odds were 1.143 (95% confidence interval [CI]: 0.988–1.323) and 3.253 (95% CI: 1.359–7.788). Besides, no association was found among various ovarian stimulations as well as congenital birth defect programs, maternal age, body mass index, parity or infant sex.\n\nConclusion\nThis study suggests that, in contrast to conventional ovarian stimulation, PPOS neither has any effect on neonatal outcomes in IVF adverse effects nor does it elevate the rate of congenital malformations in late endometriosis. However, randomized controlled trials of the long-term outcomes of children born after PPOS protocols for maternal endometriosis are needed and the follow-up studies were conducted to confirm this result.\n\nKeywords\nmedroxyprogesterone acetatecongenital malformationin vitro fertilizationlive birthendometriosisNational Natural Science Foundation of China10.13039/501100001809Shanghai Ninth People’s Hospital Foundation of ChinaGrants from the National Natural Science Foundation of China (NSFC) (31770989 to Y.W.;) and the Shanghai Ninth People’s Hospital Foundation of China (JYLJ030 to Y.W.).\n==== Body\nIntroduction\nEndometriosis, a female disorder, is characterized by endometrial glands or stroma which are outside the uterine cavity. The lesion is usually localized in the peritoneum or ovaries. Among all conditions, endometriosis stands out as one of the most demanding ones for doctors who work on conceiving infertile women. At present, many theories exist to attempt to explain its cause. Some draw on Retrograde menstruation/Sampson’s theory, coelomic metaplasia, lymphatic spread, spread via pelvic veins, surgical transplantation, induction theory, stem cell theory and activation of Müllerian cell in resting state.\n\nAccording to previous relevant studies, infertility in patients who suffer from endometriosis is primarily due to reduced ovarian reserve and ovarian response, higher FSH levels, lower levels of anti-Müllerian hormones, and abnormal protein expression. Besides, patients who suffer from endometriosis have increased production of cytokines and inflammatory factors, inducing endocrine and paracrine and autocrine pathways are altered, which may contribute to the reduced implantation rate. There are some observed changes in maternal endometriosis, they could lead to low oocyte quality and reduced implantation capacity.1,2\n\nDuring pregnancy and childbirth, women who suffer from endometriosis in advanced condition have a higher tendency to a number of adverse outcomes. What is worse, they are at a higher risk of other conditions such as premature birth, congenital malformations and neonatal death.3 For women suffering from endometriosis, while the disease has its incidence peaked during the reproductive years and endometriosis can complicate conception as well as pregnancy, and the health of their children has caught more attention recently. Newly released research has found that women with endometriosis have an inclined tendency to have pregnancy complications, which include miscarriage as well as ectopic pregnancy.4 Furthermore, according to the literature, women, who suffer from endometriosis would face with a higher tendency of preterm birth,5–8 even though conflicting results exist.9,10\n\nIVF is considered as a common method in dealing with maternal endometriosis-related infertility. The use of IVF-ET has the possibility to bypass the suspected dysfunction of endometriosis affecting the natural cycle described above. It has been suggested that IVF is less effective in endometriosis cases than in other indications;18 nevertheless, a number of articles and national registries prove that IVF can provide the same effect for endometriosis.11\n\nDuring the last decade, ART technique has made great strides. One most significant aspect is to control the LH spike in non-downregulated COH cycles.12–15 In 2009 and 2015, we had relevant reports on the efficiency and feasibility of luteal phase stimulation as well as PPOS protocol. Moreover, their safety of the offsprings was also reported.16–19\n\nIn 2017, we reported on oocyte quality and implantation rate by using PPOS for maternal endometriosis. The rate is comparable to that of the GnRH-agonist regimen. Since this regimen has benefited more than a thousand children with maternal endometriosis, it is important to report these, given its safety data for infants with endometriosis.\n\nThis study is designed with the aim of a comparison between live-birth outcomes and defects born after in vitro fertilization (IVF) as well as vitrified embryo transfer cycles with the use of PPOS treatment with conventional protocols in women with advanced endometriosis. As it is mostly used worldwide, the GnRH agonist and antagonist protocols were chosen and applied in the control groups with the purpose to assess the safety of those born to PPOS.\n\nMaterials and Methods\nStudy Population and Design\nThis study was conducted in accordance with the Declaration of Helsinki. At the Department of Assisted Reproduction of the Ninth People’s Hospital of Shanghai Jiao Tong University School of Medicine, we conducted a retrospective cohort study that was approved by the ethics committee of the hospital. Infertile patients with endometriosis recruited at our center went through IVF or intracytoplasmic sperm injection (ICSI) treatment, with the use of PPOS protocol, GnRHa agonist protocols or antagonist protocols for frozen and later on thawed embryo transfer (FET). Written informed consent is given by the participants after we described the whole study in great detail.\n\nThey all suffered from endometriosis, which was diagnosed by laparoscopic or abdominal surgery. According to the American Fertility Society’s revised classification (1997), endometriosis was scored.\n\nThese patients had gone through the procedures from January 1, 2010 to January 1, 2017, and they were expected to give births between November 1, 2010 and November 1, 2017. As these factors may be associated with birth defects, this analysis excludes reported cases of gestational diabetes, hypertension, thyroid disease, and babies born to mothers with maternal diseases or exposed to adverse environmental conditions during the period of pregnancy.\n\nBirth defects were defined and coded according to the International Classification of Diseases, 10th Revision (ICD-10). Minor birth defects were excluded, except those that required treatment or were disfiguring. The cases with several birth defects were counted as one case in each subgroup, but they could be assigned to more than one subgroup.\n\nOvarian Stimulation Protocols\nIn the PPOS group, each day patients were injected with human menopausal gonadotropin (hMG; Anhui Fengyuan Pharmaceutical Co. Ltd) of 150–225 IU and MPA 10 mg daily till the trigger day. Follicular monitoring got performed every 2 to 4 days starting from MC9-11; also, serum at the final stage of oocyte maturation was measured FSH, LH, E2 and progesterone concentrations.\n\nIn the GnRH agonist treatment group, the dosage of gonadotropins was determined based on patient characteristics such as age, serum hormone levels, and number of antral follicles in the anterior chamber. Patients undergo a continuous transvaginal ultrasound and hormone monitoring during periods of hyperstimulation.\n\nIn the GnRH antagonist treatment group, the starting dose of gonadotropin was 150–225 IU of hMG. Day 2 or 3 saw the start of stimulation of the menstrual cycle and there was a commenced GnRH antagonist on Day 5 of stimulation (certrotide 0.25 mg, Baxter). On day 8 or 9 of stimulation, a pelvic ultrasound and serum hormone assessment were performed.\n\nOvarian response was assessed through ultrasound and serum E2 levels. When 1–3 follicles reached 18 mm in diameter, for PPOS groups and GnRH antagonist groups, alone or with 1000–5000 IU of hCG (Zhuhai Lizhu Pharmaceutical Group Company) co-triggered the final stage of oocyte maturation. For the GnRH agonist protocol group, we set 5000 IU of hCG (Zhuhai Lizhu Pharmaceutical Group Inc).\n\nOocyte retrieval was undertaken within 32–36 hours following maturation induction or ovarian stimulation (depending on the protocol per group). Conventional IVF was carried out in females who had indications for tubal or idiopathic infertility, and ICSI was carried out for male factor indications. Culture, as well as scoring of embryos, was in accordance with the previous description. Embryo freezing and thawing procedures, methods of synchronization of embryos and endometrium during natural, ovulation-stimulated, or artificial cycles; and the timing of FET is described elsewhere. Once pregnant, progesterone (P) supplementation would be continued till 10-week gestation.\n\nFollow-Up and Definitions\nAccording to the definition used by the World Health Organization, the term live birth is a delivery with any evidence of life, despite the gestational length. The assessment details of birth defects have been shown in a formerly published paper. In brief, newborns born in our hospital undergo routine medical examinations at birth, and those born in other hospitals are attended by a written health report, which is provided by the pediatrician. Birth defects are defined and coded under the 10th revision of the International Classification of Diseases (ICD-10).\n\nAccording to the definition, gestational age refers to the age of the embryo or fetus and is calculated as the number of full weeks since fertilization plus 14 days (for FETs, estimated Fertilization date was calculated by subtracting the embryo age from the FET cycle transfer date on the cryopreservation date). Preterm birth (PTB) and very premature birth (VPTB) were considered as deliveries prior to 37 and 32 weeks of gestation, respectively. Low birth weight (LBW) and very low birth weight (VLBW) were considered as <2500 g and <1500 g, respectively. Stillbirth was identified as Intrauterine or intrapartum death of an infant ≥20 weeks gestation or birth weight ≥500 g, with early neonatal death being defined as live-born babies’ death within 7 days of birth.\n\nStatistical Analysis\nStatistics was analyzed using SPSS 17.0 software (SPSS Inc.). Data are expressed as mean ± SD if the data are normally distributed, or as median (range) are expressed; qualitative data are expressed as percentage indicated. Mean differences in continuous parameter data were defined by one-way ANOVA or Kruskal–Wallis test, and differences of the means amid the three groups of Ratios were compared using χ2 test or Fisher’s exact test, as appropriate. Binary logistic regression was performed to quantify the effect of risk factors on congenital malformations between groups. The effect generated by risk factors on congenital malformations by adjusted odds ratio (OR) and 95confence interval (CI) indicated. Multivariate logistic regression analysis was used to assess the association of congenital malformations with maternal age, duration of infertility, parity, ovarian stimulation method, multiple birth, and infant gender.\n\nResults\nPregnancies and Deliveries Outcomes\nA total of 1398 continued gestational cycles resulted in 1495 births. Out of these, 1108 continued pregnancies (gestational weeks ≥20 weeks) resulted in 1203 infants treated with PPOS. Of the 221 infants, 215 from ongoing pregnancies were born after receiving the GnRH agonist regimen treatment. Seventy-one infants resulting from 75 ongoing pregnancies were born after receiving GnRH antagonist stimulation. These results imply that each of the three ovarian stimulation regimens had a significant proportion of pregnancies resulting in live births of infants (The flowcharts in Figure 1 and Table 1 provide a detailed overview of the distribution of the groups.).Table 1 Characteristics and Neonatal Outcome by Regimen Group\n\n\tPPOS (n=974)\tGnRH Agonist (n=180)\tGnRH Antagonist (n=58)\tF/χ2\tP value\t\nMaternal age (years)\t34.48±3.87\t34.7±3.59\t34.45±2.76\t0.942\t0.487\t\nInfertility duration\t3.185±2.35\t3.383±2.15\t3.536±2.44\t0.973\t0.379\t\nBody mass index\t20.77±3.30\t20.66±3.42\t20.29±4.51\t0.585\t0.558\t\nPregnancies\t\t\t\t\t\t\n 0\t656(67.3)\t117(65.0)\t37(63.8)\t0.124\t0.938\t\n 1\t195(20.0)\t40(22.2)\t15(25.9)\t0.945\t0.625\t\n 》2\t123(12.7)\t23(12.8)\t6(10.3)\t0.216\t0.898\t\nTotal Ets\t1803\t357\t107\t–\t–\t\nEmbryos from IVF cycles\t1257(69.7)\t242(67.8)\t72(67.3)\t0.735\t0.693\t\nEmbryos from ICSI cycles\t546(30.3)\t115(32.2)\t35(32.7)\t0.735\t0.693\t\nCleavage-stage embryos\t1602(88.9)\t315 (88.2)\t96 (89.7)\t0.210\t0.900\t\nBlastocyst embryos\t201(11.1)\t42(11.8)\t11(10.3)\t0.210\t0.900\t\nLive-born infants\t1203\t221\t71\t–\t–\t\nGestational age\t37.92±2.07\t37.63±2.22\t37.95±1.74\t0.945\t0.389\t\n<32\t12(1.2)\t3(1.7)\t0(0)\t0.981\t0.612\t\n32《age<37\t638(65.5)\t99(55.0)\t32(55.1)\t2.101\t0.350\t\n》37\t324(33.3)\t78(43.3)\t26(44.9)\t4.182\t0.124\t\nBirth weight (g)\t3145±609.2\t3163±577.2\t3180±499.5\t0.124\t0.884\t\nBirth length\t49.5±2.38\t49.24±2.22\t49.59±1.85\t0.443\t0.642\t\nMultiple delivery cycles\t230(23.6)\t42(23.3)\t14(24.1)\t–\t–\t\nMultiple delivery rate\t23.6\t23.3\t24.1\t0.010\t0.995\t\nEarly neonatal death\t4(0.4)\t1(0.5)\t1(1.7)\t1.893\t0.388\t\n\nFigure 1 Flowchart of the study.\n\n\n\nMajor parameters which include maternal age, infertility duration, BMI, gestational age, birth weight, birth length, embryo transfer date as well as multiple delivery rates were all considered comparable between the groups.\n\nTotally, 21 (1.40%) of all live births were consistent with congenital defects, as defined by the International Classification of Diseases. HMG and 16 of 1203 cases (1.33%) in the MPA group were defective, 4 of 221 cases in the GnRH agonist protocol group (1.80%) and 1 of 71 cases (1.41%) in the GnRH antagonist group had defects, with no significant difference. The comparison between birth defect groups according to neonatal sex, singleton and multiple births is shown in Table 2.Table 2 Incidence of Birth Defects in Live-Born Infants\n\nCharacteristics\tPPOS (n=1203)\tGnRH Agonist(n=221)\tGnRH-Antagonist (n=71)\tχ2\tP value\t\nNumber of birth defects\t16 (1.33)\t4 (1.81)\t1 (1.41)\t0.301\t0.860\t\nNumber of deliveries\t\t\t\t1.604\t0.448\t\n Singletons\t6 (0.50)\t2 (1.81)\t1 (1.41)\t\t\t\n Multiples\t10 (0.83)\t2 (1.81)\t0 (0)\t\t\t\nBirth defects, by gender\t\t\t\t1.205\t0.547\t\n Male\t9 (0.75)\t2 (1.81)\t0 (0)\t\t\t\n Female\t7 (0.58)\t2 (1.81)\t1 (1.41)\t\t\t\nNotes: Data are n (%) and were compared using Fisher’s exact test. N=1495.\n\n\n\n\nTable 3 shows in detail the breakdown of the detected malformations under different organ systems. The results showed that relatively higher percentages of cardiac defects (0.47%) and musculoskeletal system problems (0.20%) were observed.Table 3 Types of Malformations Among1495 Live-Born Infants\n\nTotal\tPPOS (n=1203)\tGnRH Agonist (n=221)\tGnRH Antagonist (n=71)\t\n16(1.33)\t4(1.80)\t1(1.41)\t\nNervous system (Q00–Q07)\t0\t0\t0\t\n Eye, ear, face and neck (Q10–Q18)\t0\t0\t0\t\nCirculatory system (Q20–Q28)\t7(0.58)\t0\t0\t\nRespiratory system (Q30–Q34)\t0\t1(0.45)\t1(1.41)\t\n Cleft lip and cleft palate (Q35–Q37)\t2(0.17)\t0\t0\t\n Digestive system (Q38–Q45)\t0\t0\t0\t\nGenital organs (Q50–Q56)\t1(0.08)\t0\t0\t\n Urinary system (Q60–Q64)\t2(0.17)\t0\t0\t\nMusculoskeletal system (Q65–Q79)\t2(0.17)\t1(0.45)\t0\t\nOther malformations (Q80–Q89)\t1(0.08)\t2(0.90)\t0\t\nChromosomal anomalies (Q90–Q99)\t1(0.08)\t0\t0\t\n\n\n\nTable 4 shows the results of logistic regression of factors potentially influencing congenital malformations. The binary logistic regression was used for the analysis of treatment as well as patient characteristics for risk factors related to adverse outcomes for risk factors, including maternal age, BMI, infertility duration, parity, multiple births, gender of infants, and ovarian stimulation protocol. Multiple births (X1), BMI (X2), and infertility duration (X3) were contained within the logistic regression equation as: logit P= −2.382+0.872X1 −0.113 X2 −0.163 X3. The probability of adverse outcomes was significantly increased in both models for infertility duration and multiple births.Table 4 Logistic Regression for Factors Influenced Congenital Malformations\n\nVariables\tCoefficient (B)\tOR (95% CI)\tWald(χ2)\tP value\t\nUnadjusted model\t\t\t\t\t\n Maternal age\t−0.090\t0.913(0.803 −1.040)\t1.878\t0.171\t\n BMI\t−0.106\t0.900(0.742 −1.091)\t1.152\t0.283\t\n Infertility duration\t0.199\t1.220(1.029 −1.446)\t5.264\t0.022\t\n Parity\t0.378\t1.459(0.187 −11.388)\t0.130\t0.718\t\n Multiple births\t1.017\t2.765(1.128 −6.778)\t4.943\t0.026\t\n Gender of infants\t0.692\t1.997(0.706 −5.649)\t1.701\t0.192\t\n GnRH agonist protocol\t−0.863\t0.422(0.054 −3.316)\t0.673\t0.412\t\n Antagonist protocol\t−17.032\t0.000\t0.000\t0.997\t\nAdjusted model\t\t\t\t\t\n BMI\t−0.119\t0.888(0.728–1.082)\t1.388\t0.239\t\n Infertility duration\t0.134\t1.143(0.988–1.323)\t3.232\t0.072\t\n Multiple births\t1.180\t3.253(1.359–7.788)\t7.015\t0.008\t\n\n\n\nDiscussion\nMore than 150 million women worldwide are affected by endometriosis. According to estimation, 7–12% of reproductive-aged women are affected. The prevalence is even higher among infertile women. It affects as many as a quarter of patients treated with ART and 20–40% of them develop ovarian endometriosis.20,21\n\nAlthough there is no causal relationship, possible pathways of infertility due to endometriosis involve endocrine as well as ovulatory abnormalities,22 effects on oocytes and sperm,23 inflammation/altered peritoneal environment, distorted pelvic anatomy,24 abnormal uterine transport, altered hormonal and cell-mediated function,25 impaired implantation and other unknown mechanisms.26–28\n\nIVF is considered effective in treating endometriosis in infertile women even though its rate of success may be affected by the disease on its own.\n\nIn women who suffer from endometriosis, MRI scans and biopsies reveal abnormalities in the function and structure of the lining of the uterus, called junctional zone, which means endometriosis is associated with adenomyosis, a junctional zone disease. It could lead to transformation defects in the spiral arteries, which can influence placentation thereby.29 It has already become a theory that this has the possibility to result in a greater risk of preeclampsia, intrauterine growth restriction, preterm labor and placental abruption.30\n\nWe introduced PPOS protocols not merely because, compared to GnRH agonist and antagonist protocols, PPOS options are not unfavorable regarding pregnancy and implantation rates. What is more important, it could also offer a more economical and patient-friendly therapeutic option.\n\nGenerally, the congenital malformation rate, which is 1.4% shown in this study, is similar to 1.11–1.58% in a Chinese study, which is a population-based one. The rate of birth defects occurring within 7 days of delivery is consistent with that of IVF.31 Our cohort study proves that among all organ systems, the cardiovascular system has the highest frequency to be affected by congenital malformations, which is also consistent with previous studies.\n\nSome studies have discussed the maternal factors’ influence on congenital malformation. Only two studies previously focused on the boys having anomalies with their genitals among boys delivered by women having endometriosis (without IVF). Possible linkage with specific factors from the maternal angle and the genital anomaly cryptorchidism (undescended testis) was investigated by a case–control study by Mavrogenis in 2014.32 The investigators in that study determined that the risk of cryptorchidism among sons born to mothers with endometriosis was double. Nevertheless, a register-based Danish study in 2017 revealed the lack of any substantial evidence for the greater incidence of endometriosis-afflicted women giving birth to boys with genital anomalies.33\n\nCongenital malformations are observed more commonly in twin pregnancies than in singleton pregnancies.34,35 Some studies show that twins are about four times more likely to have congenital malformations than singletons.36 These congenital abnormalities could come from twinning itself, from vascular connections between the twins or compression deformation from uterine crowding. Developmental disorders can occur during twinning, too, which may lead to susceptibility to environmental factors.37\n\nAs the use of fertility drugs increases and assisted reproduction technology gets improved, the twinning rate has also grown, which could also give rise to an increasingly higher frequency of congenital defects. Previous studies show a significantly grown risk of multiple birth defects, including inadequate nutritional supply, common genetic background and crowded uterine conditions.38,39\n\nSome limitations do exist in this study. There are several possible reasons as to why the birth defect rate in this study is lower, they are: (1) The congenital malformation rate was determined with the use of both living newborns and terminated pregnancies, which means that the data are not comprehensive enough to provide a representation of the entire spectrum of birth defects, for example, those linked to miscarriages and stillbirths. As a result, it is possible that the real rate of congenital malformations is higher than our data implies. (2) We purposefully restricted participants to women who had experienced no reported cases of maternal disease or negative environmental exposures in the course of pregnancy, enabling us to more precisely evaluate the isolated effects of different types of ovarian stimulation regimens regarding subsequent neonatal outcomes. (3) We collected neonatal outcome data through questionnaires of patients instead of direct review of medical records. (4) In this study, though the sample size is comparatively large, it may have limited statistical power in detecting disparities among such rare outcome measures like congenital malformations. Nevertheless, the findings of our data are reassuring, as many other confounding variables remain unchanged. (5) In this study, the infants were all born from FET cycles, which were considered to have a less degree of risk-concerned birth defects, in comparison with fresh ET cycles.]\n\nThis study shows that, compared to the other two ovarian stimulation maternal endometriosis protocols, infants born after PPOS protocols embrace no notable distinctions in neonatal outcomes or congenital malformations. This means that the regimen could be safe while effective alternative to the conventional one for the birth of women with endometriosis. Nonetheless, a proper randomized study is needed to evaluate, as well as to further validate if this new ovarian stimulation protocol is safe and effective in women with endometriosis.\n\nAcknowledgments\nWe sincerely acknowledge all staff members of the department of assisted reproduction in Shanghai Ninth People’s Hospital for their ardent and warm support and cooperation.\n\nAuthor Contributions\nY.W. supervised the entire study, including the procedures, conception, design and completion. Z.L. was responsible for the collection of data. Z.L. contributed the data analysis and drafted the article. Y.P.K participated in the interpretation of the study data and revisions to the article. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.\n\nDisclosure\nNone of the authors have any conflicts of interest to declare.\n==== Refs\nReferences\n1. Pellicer \nA , Oliveira \nN , Ruiz \nA , Remohi \nJ , Simon \nC . Exploring the mechanism(s) of endometriosis-related infertility: an analysis of embryo development and implantation in assisted reproduction\n. Hum Reprod . 1995 ;10 (Suppl 2 ):91 –97\n. doi:10.1093/humrep/10.suppl_2.91 \n2. Simon \nC , Gutierrez \nA , Vidal \nA , et al. Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation\n. 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Zheng \nZ , Chen \nL , Yang \nT , Yu \nH , Wang \nH , Qin \nJ . Multiple pregnancies achieved with IVF/ICSI and risk of specific congenital malformations: a meta-analysis of cohort studies\n. Reprod Biomed Online . 2018 ;36 (4 ):472 –482\n. doi:10.1016/j.rbmo.2018.01.009 29609768 \n16. Chen \nH , Wang \nY , Lyu \nQ , et al. Comparison of live-birth defects after luteal-phase ovarian stimulation vs. conventional ovarian stimulation for in vitro fertilization and vitrified embryo transfer cycles\n. Fertil Steril . 2015 ;103 (5 ):1194 –1201 e2\n. doi:10.1016/j.fertnstert.2015.02.020 25813280 \n17. Kuang \nY , Chen \nQ , Fu \nY , et al. Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization\n. Fertil Steril . 2015 ;104 (1 ):62 –70 e3\n. doi:10.1016/j.fertnstert.2015.03.022 25956370 \n18. Qin \nN , Chen \nQ , Hong \nQ , et al. Flexibility in starting ovarian stimulation at different phases of the menstrual cycle for treatment of infertile women with the use of in vitro fertilization or intracytoplasmic sperm injection\n. Fertil Steril . 2016 ;106 (2 ):334 –341 e1\n. doi:10.1016/j.fertnstert.2016.04.006 27114329 \n19. Zhang \nJ , Mao \nX , Wang \nY , et al. Neonatal outcomes and congenital malformations in children born after human menopausal gonadotropin and medroxyprogesterone acetate treatment cycles\n. Arch Gynecol Obstet . 2017 ;296 (6 ):1207 –1217\n. doi:10.1007/s00404-017-4537-z 28948397 \n20. Benaglia \nL , Candotti \nG , Papaleo \nE , et al. Pregnancy outcome in women with endometriosis achieving pregnancy with IVF\n. Hum Reprod . 2016 ;31 (12 ):2730 –2736\n. doi:10.1093/humrep/dew210 27664955 \n21. Keay \nSD , Cahill \nDJ . Different aetiological mechanisms for unexplained and endometriosis-associated infertility cannot be inferred from unstimulated IVF cycles using HCG to induce ovulation\n. Hum Reprod . 2002 ;17 (7 ):1926–7; author reply 1927. doi:10.1093/humrep/17.7.1926 \n22. Doody \nMC , Gibbons \nWE , Buttram \nVC . Linear regression analysis of ultrasound follicular growth series: evidence for an abnormality of follicular growth in endometriosis patients\n. Fertil Steril . 1988 ;49 (1 ):47 –51\n. doi:10.1016/S0015-0282(16)59646-0 3275551 \n23. Garrido \nN , Navarro \nJ , Garcia-Velasco \nJ , Remoh \nJ , Pellice \nA , Simon \nC . The endometrium versus embryonic quality in endometriosis-related infertility\n. Hum Reprod Update . 2002 ;8 (1 ):95 –103\n. doi:10.1093/humupd/8.1.95 11866246 \n24. Vicente-Munoz \nS , Morcillo \nI , Puchades-Carrasco \nL , Paya \nV , Pellicer \nA , Pineda-Lucena \nA . Nuclear magnetic resonance metabolomic profiling of urine provides a noninvasive alternative to the identification of biomarkers associated with endometriosis\n. Fertil Steril . 2015 ;104 (5 ):1202 –1209\n. doi:10.1016/j.fertnstert.2015.07.1149 26297644 \n25. Zhang \nT , De Carolis \nC , Man \nGCW , Wang \nCC . The link between immunity, autoimmunity and endometriosis: a literature update\n. Autoimmun Rev . 2018 ;17 :945 –955\n. doi:10.1016/j.autrev.2018.03.017 30107265 \n26. Hickman \nTN . Impact of endometriosis on implantation. Data from the Wilford Hall Medical Center IVF-ET program\n. J Reprod Med . 2002 ;47 (10 ):801 –808\n.12418061 \n27. Rodriguez-Purata \nJ , Coroleu \nB , Tur \nR , Carrasco \nB , Rodriguez \nI , Barri \nPN . Endometriosis and IVF: are agonists really better? Analysis of 1180 cycles with the propensity score matching\n. Gynecol Endocrinol . 2013 ;29 (9 ):859 –862\n. doi:10.3109/09513590.2013.808327 23875964 \n28. Barri \nPN , Coroleu \nB , Tur \nR , Barri-Soldevila \nPN , Rodriguez \nI . Endometriosis-associated infertility: surgery and IVF, a comprehensive therapeutic approach\n. Reprod Biomed Online . 2010 ;21 (2 ):179 –185\n. doi:10.1016/j.rbmo.2010.04.026 20541976 \n29. Burney \nRO , Giudice \nLC . Pathogenesis and pathophysiology of endometriosis\n. Fertil Steril . 2012 ;98 (3 ):511 –519\n. doi:10.1016/j.fertnstert.2012.06.029 22819144 \n30. Brosens \nI , Pijnenborg \nR , Benagiano \nG . Defective myometrial spiral artery remodelling as a cause of major obstetrical syndromes in endometriosis and adenomyosis\n. Placenta . 2013 ;34 (2 ):100 –105\n. doi:10.1016/j.placenta.2012.11.017 23232321 \n31. Yan \nJ , Huang \nG , Sun \nY , et al. Birth defects after assisted reproductive technologies in China: analysis of 15,405 offspring in seven centers (2004 to 2008)\n. Fertil Steril . 2011 ;95 (1 ):458 –460\n. doi:10.1016/j.fertnstert.2010.08.024 20850722 \n32. Mavrogenis \nS , Urban \nR , Czeizel \nAE , Acs \nN . Possible association of maternal factors with the higher risk of isolated true undescended testis: a population-based case-control study\n. Congenit Anom (Kyoto) . 2014 ;54 (3 ):178 –183\n. doi:10.1111/cga.12061 24754829 \n33. Arendt \nLH , Lindhard \nMS , Henriksen \nTB , Forman \nA , Olsen \nJ , Ramlau-Hansen \nCH . Maternal endometriosis and genital malformations in boys: a Danish register-based study\n. Fertil Steril . 2017 ;108 (4 ):687 –693\n. doi:10.1016/j.fertnstert.2017.07.009 28863937 \n34. Bahtiyar \nMO , Dulay \nAT , Weeks \nBP , Friedman \nAH , Copel \nJA . Prevalence of congenital heart defects in monochorionic/diamniotic twin gestations: a systematic literature review\n. J Ultrasound Med . 2007 ;26 (11 ):1491 –1498\n. doi:10.7863/jum.2007.26.11.1491 17957043 \n35. Sperling \nL , Kiil \nC , Larsen \nLU , et al. Detection of chromosomal abnormalities, congenital abnormalities and transfusion syndrome in twins\n. Ultrasound Obstet Gynecol . 2007 ;29 (5 ):517 –526\n. doi:10.1002/uog.3918 17429797 \n36. Glinianaia \nSV , Rankin \nJ , Wright \nC . Congenital anomalies in twins: a register-based study\n. Hum Reprod . 2008 ;23 (6 ):1306 –1311\n. doi:10.1093/humrep/den104 18387962 \n37. Yang \nMJ , Tzeng \nCH , Tseng \nJY , Huang \nCY . Determination of twin zygosity using a commercially available STR analysis of 15 unlinked loci and the gender-determining marker amelogenin–a preliminary report\n. Hum Reprod . 2006 ;21 (8 ):2175 –2179\n. doi:10.1093/humrep/del133 16772284 \n38. Sunday-Adeoye \nI , Okonta \nPI , Egwuatu \nVE . Congenital malformations in singleton and twin births in rural Nigeria\n. Niger Postgrad Med J . 2007 ;14 (4 ):277 –280\n.18163133 \n39. Mitchell \nSE , Reidy \nK , Da Silva Costa \nF , Palma-Dias \nR , Cade \nTJ , Umstad \nMP . Congenital malformations associated with a single umbilical artery in twin pregnancies\n. Twin Res Hum Genet . 2015 ;18 (5 ):595 –600\n. doi:10.1017/thg.2015.59 26289035\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-8881",
"issue": "14()",
"journal": "Drug design, development and therapy",
"keywords": "congenital malformation; endometriosis; in vitro fertilization; live birth; medroxyprogesterone acetate",
"medline_ta": "Drug Des Devel Ther",
"mesh_terms": "D015331:Cohort Studies; D000013:Congenital Abnormalities; D004715:Endometriosis; D005260:Female; D006727:Hormone Antagonists; D006801:Humans; D007223:Infant; D050498:Live Birth; D008297:Male; D010062:Ovulation Induction; D011247:Pregnancy; D011372:Progestins; D012189:Retrospective Studies",
"nlm_unique_id": "101475745",
"other_id": null,
"pages": "5459-5467",
"pmc": null,
"pmid": "33328724",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "8046030;26297644;27664955;3275551;27428865;25813280;16428333;28863937;23875964;12093863;22819144;12418061;28948397;17429797;17957043;24268981;27068240;23232321;29266553;16772284;22447627;20541976;18387962;25956370;24754829;16006468;29063747;24679602;24134807;8745306;30107265;11866246;20378616;20850722;28181672;18163133;26289035;27114329;29609768",
"title": "Live-Birth Outcomes and Congenital Malformations After Progestin-Primed Ovarian Stimulation in Maternal Endometriosis.",
"title_normalized": "live birth outcomes and congenital malformations after progestin primed ovarian stimulation in maternal endometriosis"
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"abstract": "Ibrutinib is a selective Bruton's tyrosine kinase inhibitor (BTKi) approved for the treatment of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Invasive fungal infections (IFIs) have recently been reported in patients on BTKis despite the absence of significant immunocompromise raising great interest among oncologists regarding the mechanism by which BTKi's permit fungal infections. Here, we describe a fatal case of cerebral aspergillosis in a patient with relapsed CLL while on treatment with ibrutinib. There are few hypotheses on the mechanism by which ibrutinib permits fungal infections. As it becomes more widely used in B-cell cancers, clinicians should be aware of the potential for decreased anti-fungal immunity with this drug.",
"affiliations": "Internal Medicine/Hematology and Oncology, Danbury Hospital, Yale School of Medicine, Danbury, USA.;Internal Medicine, Danbury Hospital, Yale School of Medicine, Danbury, USA.;Internal Medicine, Danbury Hospital, Yale School of Medicine, Danbury, USA.",
"authors": "Rajapakse|Pramuditha|P|;Gupta|Manish|M|;Hall|Rewaida|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.16009",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.16009\nInfectious Disease\nOncology\nHematology\nInvasive Fungal Infection Complicating Treatment With Ibrutinib\nMuacevic Alexander\nAdler John R\nRajapakse Pramuditha 1\nGupta Manish 2\nHall Rewaida 2\n1 Internal Medicine/Hematology and Oncology, Danbury Hospital, Yale School of Medicine, Danbury, USA\n2 Internal Medicine, Danbury Hospital, Yale School of Medicine, Danbury, USA\nPramuditha Rajapakse pramudirj28@gmail.com\n29 6 2021\n6 2021\n13 6 e1600928 6 2021\nCopyright © 2021, Rajapakse et al.\n2021\nRajapakse 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/59215-invasive-fungal-infection-complicating-treatment-with-ibrutinib\nIbrutinib is a selective Bruton’s tyrosine kinase inhibitor (BTKi) approved for the treatment of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Invasive fungal infections (IFIs) have recently been reported in patients on BTKis despite the absence of significant immunocompromise raising great interest among oncologists regarding the mechanism by which BTKi's permit fungal infections. Here, we describe a fatal case of cerebral aspergillosis in a patient with relapsed CLL while on treatment with ibrutinib. There are few hypotheses on the mechanism by which ibrutinib permits fungal infections. As it becomes more widely used in B-cell cancers, clinicians should be aware of the potential for decreased anti-fungal immunity with this drug.\n\nibrutinib\ninvasive fungal infections\ntyrosine kinase inhibitors\nchronic lymphocytic leukemia\ncerebral aspergillosis\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nIbrutinib is a selective Bruton’s tyrosine kinase inhibitor (BTKi) that was initially approved in 2013 by the US Food and Drug Administration (FDA) for treatment of mantle cell lymphoma and subsequently for the treatment of CLL, Waldenstrom macroglobulinemia, marginal zone lymphoma, and chronic graft‐versus‐host disease [1,2]. Although considered to be less immunosuppressive than conventional immunochemotherapy, invasive fungal infections (IFIs) have recently been reported in patients on BTKi's [3,4]. Invasive fungal infections are life‐threatening infections that can affect multiple organ systems. Underlying conditions that compromise the immune responses to inhaled fungal species serve as risk factors for IFIs. Classic risk factors include severe and prolonged neutropenia, high doses of glucocorticoids, and other drugs or conditions that lead to chronically impaired cellular responses (eg, immunosuppressive regimens administered to treat autoimmune diseases and to prevent organ rejection, AIDS) [5]. An increasing number of reports of IFIs and other opportunistic infections during ibrutinib treatment have been reported over the last few years raising a concern if there is an association between ibrutinib and antifungal immunity [1,3].\n\nCase presentation\n\nWe report a case of a 53-year-old male with a past medical history of CLL who presented to the hospital with persistent fever, cough, and generalized weakness for two weeks. He was diagnosed with CLL in 2014 and was initially treated with bendamustine and rituximab. Then in 2015, he was found to have a relapse, which was treated with Imbruvica. He had been on ibrutinib for five years for relapsed CLL. He was an avid gardener and was very functional with daily activities before the onset of symptoms. On arrival at the emergency department, he was febrile with a temperature of 37.9°C. He was tachycardic with a heart rate of 106. Physical exam was negative for focal neurologic findings. Initial laboratory evaluation showed leukocytosis with a white blood cell (WBC) count of 132.8 x 109/L (range 3.5-10 x 109/L), absolute lymphocyte count of 99.47 x 109/L (range 1-4 x 109/L ), absolute neutrophil count of 6.87 x 109/L (range 2-7.5 x 109/L), thrombocytopenia with a platelet count of 84.5 x 109/L (range 150-400 x 109/L). Complete blood count (CBC) one month prior to the presentation was normal. Serum chemistry showed elevated creatinine at 1.41 mg/dL (range 0.67-1.23 mg/dL) and normal liver function tests. Due to the concern of sepsis given the ongoing treatment with ibrutinib, the patient underwent an infectious workup. Blood cultures yielded no growth, chest x-ray, urinalysis, and computed tomography (CT) of the chest abdomen, and pelvis was unremarkable.\n\nTwo days later, the patient developed acute onset confusion and global aphasia. This prompted further studies including a CT scan of the head without intravenous (IV) contrast. CT scan findings were suggestive of a brain abscess, which included midline shift, and occlusion of the right lateral ventricle with mild dilatation of the right lateral ventricle (Figure 1).\n\nFigure 1 Computed tomography (CT) scan of the head without intravenous contrast with findings concerning the development of a brain abscess particularly on the right where there was mass effect, midline shift, and occlusion of the right lateral ventricle with mild dilatation of the right lateral ventricle.\n\nMagnetic resonance imaging (MRI) with contrast showed mass-like peripherally enhancing lesions in the left frontal lobe and a non-enhancing mass-like lesion in the left cerebellum, and there was an extensive infiltrative process in the right frontal lobe that involved the corpus callosum, septum pellucidum, likely invading the ependymal surface of the right lateral ventricle (Figures 2 and 3).\n\nFigure 2 MRI brain with contrast showing mass-like peripherally enhancing lesions in the left frontal lobe.\n\nFigure 3 MRI brain with contrast showing a non-enhancing mass-like lesion in the left cerebellum.\n\nThe patient was transferred to the intensive care unit for close monitoring. Infectious disease, Hematology/Oncology, and Neurosurgery teams were consulted. The patient was managed initially with broad-spectrum antibiotics including vancomycin, ceftriaxone, and metronidazole. The patient was also started on IV dexamethasone. Levetiracetam was initiated for seizure prophylaxis. Three days after admission, he underwent a left frontal stereotactic craniotomy and resection of the brain. Examination of frozen pathology sections showed fungal hyphae within this necrotic brain tissue highlighted by Grocott-Gomori’s methenamine silver (GMS) stain and was characterized by acute-angle branching and transverse septations. This morphology is consistent with Aspergillus species and therefore a diagnosis of necrotizing aspergillosis was made after histopathological evaluation. The clinical course was further complicated by the development of left hemiparesis and worsening encephalopathy. Subsequently, he was intubated for airway protection. The patient also underwent emergent burr hole and ventriculostomy placement due to imaging findings showing periventricular edema with mass-effect and sub-falcine herniation. He was started on voriconazole and amphotericin B. The patient was successfully extubated a day later. However, encephalopathy continued to worsen. His prognosis remained guarded, and the family made the decision to transition him to comfort measures. The patient expired two weeks later.\n\nDiscussion\n\nThis report supports the possible association between treatment with ibrutinib for CLL or non-Hodgkin lymphoma (NHL) and the development of IFIs. Ibrutinib‐associated IFIs have been described in several case reports and a series of patients [1,3]. BTK inhibition can make the patients susceptible to invasive aspergillosis as evidenced by pre-clinical studies [6]. BTK is an important mediator of NF-κB (nuclear factor k beta), which is a major transcription factor that regulates genes responsible for both the innate and adaptive immune response. It plays a critical role in immune surveillance of fungal spores and acts as the primary defense against fungal infections, especially in the lung and central nervous system (CNS). BTKi's cause functional defects in fungal immune surveillance, by inhibition of myeloid cells [7]. BTK signaling also regulates effector functions of myeloid cells, including chemotaxis adhesion, transmigration, reactive oxygen species production, and cytokine response [8]. However, myeloid dysfunction alone does not appear to be sufficient to account for ibrutinib‐associated IFI as only a small percentage of patients treated with BTKi's have developed this. Multiple predisposing factors have been linked to the development of IFI including neutropenia, the use of steroids, diabetes mellitus, and liver disease [9]. CNS aspergillosis generally occurs as a result of direct invasion from adjacent structures or through hematogenous spread. Ibrutinib has good penetration of the blood‐brain barrier, and after entering the CNS, ibrutinib could potentially inhibit CNS macrophages thus eliminating fungal immune surveillance [10].\n\nThe largest study that evaluated this association between ibrutinib and IFI is from Israel and included 35 patients. A male predominance, an underlying diagnosis of CLL was seen in most patients, with a notably high percentage of CLL patients with high‐risk features such as 17p deletions or TP53 mutations. But only a few had neutropenia. Aspergillus species was the most common pathogen, with frequent CNS dissemination. Symptoms started shortly after initiating treatment with ibrutinib, in some as early as one day [11]. The number of reports of IFI with ibrutinib appears to be increasing. Early occurrence after starting ibrutinib has been suggested to be related to colonization by fungi prior to starting ibrutinib and may be supported by the short Tmax of ibrutinib (1‐2 hours) [6,8]. A recent publication reported 16 (4.2%) IFIs out of 378 CLL and NHL patients treated with ibrutinib over five years, the majority of whom lacked classic clinical risk factors for IFI. The patients had an unusually high rate of IFI involving the CNS (49%), and multiorgan involvement (60%) predominantly by molds. They had a very high mortality rate of 69% [12].\n\nA literature review of previous case reports reveals that most patients were not neutropenic in the month prior to initiation of treatment with ibrutinib, similar to our patient [12,13]. Notably, the symptoms of IFIs often appeared very early after treatment was initiated in most cases in contrast to our patient who developed IFIs years later. Aspergillus species was the most common pathogen [14]. Despite prompt initiation of appropriate antifungal therapy, mortality was extremely high in previous cases similar to our patient [11]. This emphasizes the importance of early recognition. Staging CT scans are an opportunity to diagnose subclinical fungal infections. Larger studies are needed to attain a better understanding of ibrutinib‐associated IFI and to identify patients at risk, who may benefit from intensified monitoring or chemoprophylaxis. In the interim, there is no recommendation for prophylaxis [15]. When IFI is suspected, it is recommended to consider stopping ibrutinib until the diagnosis is ruled out or the infection has been brought under control.\n\nConclusions\n\nClinicians should be aware of the potential for decreased anti-fungal immunity and the risk for aspergillus infections with ibrutinib, even in the absence of clinically overt immune suppression. The overall incidence of these infections is low enough that routine prophylaxis for all patients with CLL who are taking ibrutinib would be unnecessary. However, prophylaxis is reasonable in select patients with additional risk factors. We would like to make the clinicians aware of this association because early recognition and prompt treatment are critical to prevent life-threatening complications.\n\nHuman Ethics\n\nI would like to thank the Hematologist/Oncologist Dr. Vincent Rella, Infectious Disease Physicians Dr. John Stratidis, Dr. Gary Schleiter, Pulmonary and Critical Care physicians, Dr. Thomas Botta, Dr. John Chronakos, Dr. Jose Mendez, the Internal Medicine residents, and the nursing staff who took care of the patient in the Intensive Care Unit at Danbury Hospital.\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 Bruton's tyrosine kinase inhibitors and their clinical potential in the treatment of B-cell malignancies: focus on ibrutinib Ther Adv Hematol Aalipour A Advani RH 121 133 5 2014 25360238\n2 FDA approval: ibrutinib for patients with previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia Clin Cancer Res de Claro RA Karen M Verdun N 3586 3590 21 2015 26275952\n3 The infectious thyroid nodule: a case report of mucormycosis associated with ibrutinib therapy J Otolaryngol Head Neck Surg Mascarella MA Schweitzer L Alreefi M 49 48 2019 31619294\n4 Ibrutinib: a risk factor for invasive fungal infections? Blood Ruchlemer R Ben Ami R Bar-Meir M 4323 130 2017\n5 Epidemiology, Outcomes, and Risk Factors of Invasive Fungal Infections in Adult Patients with Acute Myelogenous Leukemia after Induction Chemotherapy. Diagnostic Microbiology and Infectious Disease Neofytos D Kit L Amy H 144 149 75 2013 https://doi.org/10.1016/j.diagmicrobio.2012.10.001 23142166\n6 Inhibition of B cell receptor signaling by ibrutinib in primary CNS lmphoma Cancer Cell 52021 Lionakis MS Dunleavy K Roschewski M 833 843 31 2017 28552327\n7 Call for action: invasive fungal infections associated with ibrutinib and other small molecule kinase inhibitors targeting immune signaling pathways Clin Infect Dis Chamilos G Lionakis MS Kontoyiannis DP 140 148 66 2018 29029010\n8 Ibrutinib in PCNSL: the curious cases of clinical responses and aspergillosis Cancer Cell Grommes C Younes A 731 733 31 2017 28552326\n9 Risk stratification for invasive fungal infections in patients with hematological malignancies: SEIFEM recommendations Blood Rev Pagano L Busca A Candoni A 17 29 31 2017 27682882\n10 Fungal infections of the immunocompromised host: clinical and laboratory aspects Clin Microbiol Rev 52021 Musial CE Cockerill FR 3rd Roberts GD 349 364 1 1988 3069198\n11 Ibrutinib-associated invasive fungal diseases in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: an observational study Mycoses Ruchlemer R Ben-Ami R Bar-Meir M 1140 1147 62 2019 31520441\n12 Serious infections in patients receiving Ibrutinib for treatment of lymphoid cancer Clin Infect Dis Varughese T Taur Y Cohen N 687 692 67 2018 29509845\n13 Fungal infections in patients treated with ibrutinib: two unusual cases of invasive aspergillosis and cryptococcal meningoencephalitis Leuk Lymphoma Baron M Zini JM Belval TC 2981 2982 58 2017 28554246\n14 Incidence and characterization of fungal infections in chronic lymphocytic leukemia patients receiving ibrutinib Leukemia & Lymphoma Frei M Aitken SL Jain N 2488 2491 61 2020 32530347\n15 Ibrutinib and fungus: an invasive concern Blood Rogers K 1882 1884 131 2018 29699994\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(6)",
"journal": "Cureus",
"keywords": "cerebral aspergillosis; chronic lymphocytic leukemia; ibrutinib; invasive fungal infections; tyrosine kinase inhibitors",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e16009",
"pmc": null,
"pmid": "34336499",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": "23142166;28552327;27682882;32530347;28552326;28554246;31619294;29509845;29699994;25360238;26275952;3069198;31520441;29029010",
"title": "Invasive Fungal Infection Complicating Treatment With Ibrutinib.",
"title_normalized": "invasive fungal infection complicating treatment with ibrutinib"
} | [
{
"companynumb": "US-ABBVIE-21K-163-4044472-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
},
"drugadditional": null,
... |
{
"abstract": "Ibrutinib is a Bruton tyrosine kinase inhibitor that is used for the treatment of lymphoid cancers, including chronic lymphocytic leukemia, Waldenström macroglobulinemia, and mantle cell lymphoma. Several case series have described opportunistic infections among ibrutinib recipients, but the full extent of these infections is unknown. We sought to determine the spectrum of serious infections associated with ibrutinib treatment.\n\n\n\nWe reviewed the electronic medical records of patients with lymphoid cancer at Memorial Sloan Kettering Cancer Center who received ibrutinib during a 5-year period from 1 January 2012 to 31 December 2016. Serious infections were identified by review of the relevant microbiology, clinical laboratory, and radiology data. Risk factors for infection were determined by means of univariate and multivariate analyses.\n\n\n\nWe analyzed findings in 378 patients with lymphoid cancer who received ibrutinib. The most common underlying cancers were chronic lymphocytic leukemia and mantle cell lymphoma. 84% of patients received ibrutinib as monotherapy. Serious infection developed in 43 patients (11.4%), primarily during the first year of ibrutinib treatment. Invasive bacterial infections developed in 23 (53.5%) of these patients, and invasive fungal infections (IFIs) in 16 (37.2%) .The majority of patients with IFIs during ibrutinib therapy (62.5%) lacked classic clinical risk factors for fungal infection (ie, neutropenia, lymphopenia, and receipt of corticosteroids). Infection resulted in death in 6 of the 43 patients (14%).\n\n\n\nPatients with lymphoid cancer receiving ibrutinib treatment are at risk for serious infections, including IFIs.",
"affiliations": "Infectious Diseases Service, Memorial Sloan Kettering Cancer Center.;Infectious Diseases Service, Memorial Sloan Kettering Cancer Center.;Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Weill Cornell Medical College.;Infectious Diseases Service, Memorial Sloan Kettering Cancer Center.;Infectious Diseases Service, Memorial Sloan Kettering Cancer Center.;Infectious Diseases Service, Memorial Sloan Kettering Cancer Center.",
"authors": "Varughese|Tilly|T|;Taur|Ying|Y|;Cohen|Nina|N|;Palomba|M Lia|ML|;Seo|Susan K|SK|;Hohl|Tobias M|TM|;Redelman-Sidi|Gil|G|",
"chemical_list": "D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciy175",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "67(5)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": null,
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001424:Bacterial Infections; D057286:Electronic Health Records; D005260:Female; D006801:Humans; D000072742:Invasive Fungal Infections; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D020522:Lymphoma, Mantle-Cell; D008231:Lymphopenia; D008297:Male; D008875:Middle Aged; D009518:New York; D009894:Opportunistic Infections; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "687-692",
"pmc": null,
"pmid": "29509845",
"pubdate": "2018-08-16",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "25150798;18462102;28554246;23782157;28377877;8380905;28552327;8425221;23782158;27503501;23825946;28184982;25700432;23045577;24332241;29437588;29029010;28480254;18566394;22312285;8332900;27703818;25042202;28536906;19290921;27096597;28924018;8982147;27641225;28815693;25669675;25853747;28167659;28641100",
"title": "Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Cancer.",
"title_normalized": "serious infections in patients receiving ibrutinib for treatment of lymphoid cancer"
} | [
{
"companynumb": "US-TEVA-2018-US-986520",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BENDAMUSTINE"
},
"drugadditional": null,
... |
{
"abstract": "Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex 1 virus (HSV-1) approved for cancer therapy. We investigate its effect on the clinical, histological, single-cell transcriptomic, and immune repertoire level using repeated fine-needle aspirates (FNAs) of injected and noninjected lesions in primary cutaneous B cell lymphoma (pCBCL). Thirteen patients received intralesional T-VEC, 11 of which demonstrate tumor response in the injected lesions. Using single-cell sequencing of the FNAs, we identify the malignant population and separate three pCBCL subtypes. Twenty-four hours after the injection, we detect HSV-1T-VEC transcripts in malignant and nonmalignant cells of the injected lesion but not of the noninjected lesion. Oncolytic virotherapy results in a rapid eradication of malignant cells. It also leads to interferon pathway activation and early influx of natural killer cells, monocytes, and dendritic cells. These events are followed by enrichment in cytotoxic T cells and a decrease of regulatory T cells in injected and noninjected lesions.",
"affiliations": "Dermatology Department, University Hospital Zurich and Medical Faculty, University of Zurich, 8091 Zurich, Switzerland.;Dermatology Department, University Hospital Zurich and Medical Faculty, University of Zurich, 8091 Zurich, Switzerland.;Department of Quantitative Biomedicine, University of Zurich, 8057 Zurich, Switzerland; Biomedical Informatics, University Hospital of Zurich, 8057 Zurich, Switzerland.;Dermatology Department, University Hospital Zurich and Medical Faculty, University of Zurich, 8091 Zurich, Switzerland; Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.;Dermatology Department, University Hospital Zurich and Medical Faculty, University of Zurich, 8091 Zurich, Switzerland.;Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.;Dermatology Department, University Hospital Zurich and Medical Faculty, University of Zurich, 8091 Zurich, Switzerland; Department of Dermatology, Lausanne University Hospital (CHUV) and Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland.;Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.;Department of Quantitative Biomedicine, University of Zurich, 8057 Zurich, Switzerland; Biomedical Informatics, University Hospital of Zurich, 8057 Zurich, Switzerland.;Dermatology Department, University Hospital Zurich and Medical Faculty, University of Zurich, 8091 Zurich, Switzerland.;Dermatology Department, University Hospital Zurich and Medical Faculty, University of Zurich, 8091 Zurich, Switzerland. Electronic address: reinhard.dummer@usz.ch.",
"authors": "Ramelyte|Egle|E|;Tastanova|Aizhan|A|;Balázs|Zsolt|Z|;Ignatova|Desislava|D|;Turko|Patrick|P|;Menzel|Ulrike|U|;Guenova|Emmanuella|E|;Beisel|Christian|C|;Krauthammer|Michael|M|;Levesque|Mitchell Paul|MP|;Dummer|Reinhard|R|",
"chemical_list": "D001688:Biological Products; C000629782:talimogene laherparepvec",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ccell.2020.12.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1535-6108",
"issue": "39(3)",
"journal": "Cancer cell",
"keywords": "T-VEC-induced innate and adaptive immunity; nonspecific cell infection; oncolytic virotherapy; primary cutaneous B cell lymphoma; single-cell RNA sequencing; single-cell immune repertoire profiling",
"medline_ta": "Cancer Cell",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001688:Biological Products; D003713:Dendritic Cells; D005260:Female; D018259:Herpesvirus 1, Human; D006801:Humans; D007694:Killer Cells, Natural; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D009000:Monocytes; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses; D059010:Single-Cell Analysis; D013602:T-Lymphocytes, Cytotoxic; D050378:T-Lymphocytes, Regulatory",
"nlm_unique_id": "101130617",
"other_id": null,
"pages": "394-406.e4",
"pmc": null,
"pmid": "33482123",
"pubdate": "2021-03-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Oncolytic virotherapy-mediated anti-tumor response: a single-cell perspective.",
"title_normalized": "oncolytic virotherapy mediated anti tumor response a single cell perspective"
} | [
{
"companynumb": "CH-AMGEN-CHESP2021092931",
"fulfillexpeditecriteria": "2",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TALIMOGENE LAHERPAREPVEC"
},
"drugadditional":... |
{
"abstract": "Purpose Pneumonitis is an uncommon but potentially fatal toxicity of anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. Methods Patients who received anti-PD-1/PD-L1 monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015). Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Clinical, radiologic, and pathologic features of pneumonitis were collected. Associations among pneumonitis incidence, therapy received, and underlying malignancy were examined with Fisher's exact test as were associations between pneumonitis features and outcomes. Results Of 915 patients who received anti-PD-1/PD-L1 mAbs, pneumonitis developed in 43 (5%; 95% CI, 3% to 6%; Memorial Sloan Kettering Cancer Center, 27 of 578 [5%]; Melanoma Institute of Australia, 16 of 337 [5%]). Time to onset of pneumonitis ranged from 9 days to 19.2 months. The incidence of pneumonitis was higher with combination immunotherapy versus monotherapy (19 of 199 [10%] v 24 of 716 [3%]; P < .01). Incidence was similar in patients with melanoma and non-small-cell lung cancer (overall, 26 of 532 [5%] v nine of 209 [4%]; monotherapy, 15 of 417 v five of 152 [ P = 1.0]; combination, 11 of 115 v four of 57 [ P = .78]). Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. Conclusion Pneumonitis associated with anti-PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti-PD-1/PD-L1 mAbs are combined with anti-cytotoxic T-cell lymphocyte-4 mAb. Most events are low grade and improve/resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death.",
"affiliations": "Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.;Jarushka Naidoo, Kaitlin M. Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Neil H. Segal, Margaret K. Callahan, Alexander M. Lesokhin, Jonathan Rosenberg, Martin H. Voss, Charles M. Rudin, Jedd D. Wolchok, Michael A. Postow, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Jarushka Naidoo, Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; Xuan Wang, Peking University Cancer Hospital and Institute, Beijing; Xue Hou, Sun Yat-sen University Cancer Center, Guangdong Province, People's Republic of China; Xuan Wang, Matteo S. Carlino, Benjamin Y. Kong, and Georgina V. Long, The University of Sydney; Alexander M. Menzies and Alexander D. Guminski, Royal North Shore and Mater Hospital; and Matteo S. Carlino and Benjamin Y. Kong, Westmead and Blacktown Hospitals, Sydney, Australia.",
"authors": "Naidoo|Jarushka|J|;Wang|Xuan|X|;Woo|Kaitlin M|KM|;Iyriboz|Tunc|T|;Halpenny|Darragh|D|;Cunningham|Jane|J|;Chaft|Jamie E|JE|;Segal|Neil H|NH|;Callahan|Margaret K|MK|;Lesokhin|Alexander M|AM|;Rosenberg|Jonathan|J|;Voss|Martin H|MH|;Rudin|Charles M|CM|;Rizvi|Hira|H|;Hou|Xue|X|;Rodriguez|Katherine|K|;Albano|Melanie|M|;Gordon|Ruth-Ann|RA|;Leduc|Charles|C|;Rekhtman|Natasha|N|;Harris|Bianca|B|;Menzies|Alexander M|AM|;Guminski|Alexander D|AD|;Carlino|Matteo S|MS|;Kong|Benjamin Y|BY|;Wolchok|Jedd D|JD|;Postow|Michael A|MA|;Long|Georgina V|GV|;Hellmann|Matthew D|MD|",
"chemical_list": "D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D026901:Membrane Transport Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C583905:SLC44A4 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2016.68.2005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "35(7)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D060890:B7-H1 Antigen; D006801:Humans; D007167:Immunotherapy; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009369:Neoplasms; D011014:Pneumonia; D061026:Programmed Cell Death 1 Receptor; D016896:Treatment Outcome",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "709-717",
"pmc": null,
"pmid": "27646942",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": "26412456;25428504;16735708;26952546;26176400;25908033;25034862;25512168;22658127;1692087;16335013;1384147;25482239;24844883;26407727;26406148;26858122;26865455;26712084;25591580;25795410;25993145;17873198;26371282;2178673;16574271;26028407;25891174;25477616;25918278;26027431;26028255;20194812",
"title": "Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy.",
"title_normalized": "pneumonitis in patients treated with anti programmed death 1 programmed death ligand 1 therapy"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201704529",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": ... |
{
"abstract": "A 17-month-old male presented to a community hospital emergency department in respiratory distress suggestive of reactive airway exacerbation or pneumonia. He rapidly deteriorated into fulminant respiratory failure with multilobar atelectasis. He was managed with continuous albuterol, intravenous antibiotics, corticosteroids, intubation, and vasopressors. He was then transported to a tertiary Children's Hospital. The patient was extubated 20 hours after presentation and again developed respiratory failure while in the pediatric intensive care unit. During preparation for extracorporeal membrane oxygenation, he quickly stabilized following reintubation and bronchodilator therapy. He was extubated approximately 24 hours later, and subsequently discharged after a 9-day hospitalization. Outpatient investigation after discharge revealed dysphagia, milk allergy, and eosinophilic esophagitis. In this case, it is highly probable that aspiration secondary to dysphagia and eosinophilic esophagitis led to respiratory failure. This case demonstrates the possible rapid decompensation from aspiration due to insidious inflammation of the esophagus and dysphagia in an otherwise anatomically normal toddler.",
"affiliations": "F. Edward Hébert School of Medicine, Uniformed Services University of Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814.;F. Edward Hébert School of Medicine, Uniformed Services University of Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814.;Department of Military and Emergency Medicine, F. Edward Hébert School of Medicine, Uniformed Services University of Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814.",
"authors": "Davis|Gerrit W|GW|;Lockett|Casey J|CJ|;Charny|Grigory|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/milmed/usz459",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0026-4075",
"issue": "185(7-8)",
"journal": "Military medicine",
"keywords": null,
"medline_ta": "Mil Med",
"mesh_terms": "D015199:Extracorporeal Membrane Oxygenation; D006801:Humans; D007223:Infant; D007442:Intubation, Intratracheal; D008297:Male; D001261:Pulmonary Atelectasis; D012131:Respiratory Insufficiency; D062606:Tertiary Care Centers",
"nlm_unique_id": "2984771R",
"other_id": null,
"pages": "e1329-e1333",
"pmc": null,
"pmid": "31915822",
"pubdate": "2020-08-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mysterious Cause of Respiratory Failure and Multilobar Atelectasis in a 17-Month-Old Male.",
"title_normalized": "mysterious cause of respiratory failure and multilobar atelectasis in a 17 month old male"
} | [
{
"companynumb": "US-TARO-2021TAR00438",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "We describe three children with Angelman syndrome and medically refractory epilepsy.\n\n\n\nCase series of three pediatric patients with Angelman syndrome and medically refractory epilepsy. All three patients failed medical treatment and were recommended for vagal nerve stimulator (VNS) implantation.\n\n\n\nFollowing VNS implantation, all three patients experienced reduction in seizure frequency greater than that afforded by medication alone.\n\n\n\nWe present vagal nerve stimulator implantation as a viable treatment option for medically refractory epilepsy associated with Angelman syndrome.",
"affiliations": "University Hospitals Case Medical Center, Rainbow Babies and Children's Hospital, Cleveland, OH, USA.;Department of Neurological Surgery, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.;Department of General Surgery, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.;Department of Neurology, Rutgers New Jersey Medical School Newark, Newark, NJ, USA.;Department of Neurological Surgery, Rutgers New Jersey Medical School, 90 Bergen Street, Suite 8100, Newark, NJ, 07101-1709, USA. goldstir@njms.rutgers.edu.",
"authors": "Tomei|Krystal L|KL|;Mau|Christine Y|CY|;Ghali|Michael|M|;Pak|Jayoung|J|;Goldstein|Ira M|IM|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00381-018-3723-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0256-7040",
"issue": "34(3)",
"journal": "Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery",
"keywords": "Angelman syndrome; Medically refractory epilepsy; Vagal nerve stimulation",
"medline_ta": "Childs Nerv Syst",
"mesh_terms": "D017204:Angelman Syndrome; D002648:Child; D002675:Child, Preschool; D000069279:Drug Resistant Epilepsy; D005260:Female; D006801:Humans; D008297:Male; D055536:Vagus Nerve Stimulation",
"nlm_unique_id": "8503227",
"other_id": null,
"pages": "395-400",
"pmc": null,
"pmid": "29350262",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "18477280;19469845;15963670;21801274;20434691;12414094;17904873;9369151;16816981;16132273;10413015;21204213;22341959;17326790;10536901;15741136;9546330;19666884;1504837;19968524;16401744;16962076;11673606;15668045;16227993;8599374;17848870;17339270;20803659;20398390;11732771;16492624;1714232;12460253;15668046;20981772;22441038;9523823;11126906;9108119;10720296;19453717;21838505;14979784",
"title": "Vagal nerve stimulation for medically refractory epilepsy in Angelman syndrome: a series of three cases.",
"title_normalized": "vagal nerve stimulation for medically refractory epilepsy in angelman syndrome a series of three cases"
} | [
{
"companynumb": "US-UCBSA-2018026208",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OXCARBAZEPINE"
},
"drugadditional": null,
... |
{
"abstract": "Thrombotic microangiopathy (TMA) after renal transplantation can be a diagnostic challenge. TMA can occur with calcineurin inhibitors, allograft rejection, infection, mutations in complement regulatory proteins and autoimmunity. A 52-year-old male renal transplant recipient presented with extensive deep vein thrombosis. He developed transfusion-dependent microangiopathic haemolytic anaemia with thrombocytopenia. He did not respond calcineurin inhibitor cessation, eculizumab or plasma exchange. ADAMTS13 and complement levels were normal. Infection and autoimmune screens were negative. A diagnosis of metastatic adenocarcinoma was made on bone marrow biopsy. This represents a rare case of malignancy-associated TMA in a renal transplant recipient. Early diagnosis can facilitate the prompt initiation of chemotherapy which is the only treatment option.",
"affiliations": "School of Epidemiology and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.;Haematology Department, Calvary Mater Hospital, Newcastle, New South Wales, Australia.;School of Epidemiology and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.;Medical Department, Liverpool Hospital, Sydney, New South Wales, Australia.",
"authors": "Vilayur|Eswari|E|;de Malmanche|Jillian|J|;Trevillian|Paul|P|;Ferreira|David|D|http://orcid.org/0000-0003-3142-4503",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-226707",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "11(1)",
"journal": "BMJ case reports",
"keywords": "acute renal failure; haematology (incl blood transfusion); renal transplantation; respiratory cancer",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D006801:Humans; D016030:Kidney Transplantation; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011183:Postoperative Complications; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30567242",
"pubdate": "2018-12-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11747383;24811438;27433282;24076560;2650537;22990018;20642678;21622241;20659088;16961769;14582050;25414441;23373055;22732949;22185974;26185750;21831149;23868759;23026601;8486781",
"title": "Metastatic lung adenocarcinoma- associated thrombotic microangiopathy in a renal transplant recipient.",
"title_normalized": "metastatic lung adenocarcinoma associated thrombotic microangiopathy in a renal transplant recipient"
} | [
{
"companynumb": "AU-ASTELLAS-2019US000176",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nIt is known that chemotherapeutic agents cause myocardial cell damage leading to left ventricular dysfunction and heart failure. Fragmented QRS is an indication of fibrosis developing as a result of myocardial cell damage. The aim of this study is to assess whether there is a relationship between the chemotherapeutic treatment and the development of the fragmented QRS complex in electrocardiography (ECG).\n\n\nMETHODS\nAmong 130 patients who were diagnosed with non-Hodgkin lymphoma and received an R-CHOP treatment regimen, the potential emergence of fragmented QRS on ECG as well as the changes in the left ventricular ejection fraction (LVEF) (on transthoracic echocardiography) in response to various chemotherapeutic regimens were sought.\n\n\nRESULTS\nNew development of a fragmented QRS pattern was observed in 53 of the 130 patients (40.8%). These patients were found to have lower LVEF values along with higher numbers of chemotherapy courses and cumulative doses. In the logistic regression analysis, age (OR = 1.042; 95% CI 1.009-1.076; p = 0.012) and number of courses (OR = 1.848; 95% CI 1.409-2.423; p < 0.001) were found to be the most important predictors of fragmented QRS development. In subjects with a fragmented QRS pattern, there was a significant difference between the initial and repeat LVEF values (p < 0.001). Importantly the emergence of a fragmentation pattern occurred much earlier compared to the drop in LVEF values (10.62 ± 4.04 vs. 15.24 ± 7.49 months).\n\n\nCONCLUSIONS\nDevelopment of a fragmented QRS pattern in response to cancer therapy emerges as a new parameter potentially predictive of chemotherapy-induced cardiotoxicity.",
"affiliations": "Department of Cardiology, School of Medicine, Trakya University, Edirne, Turkey, drmgurdogan@gmail.com.;Department of Cardiology, School of Medicine, Trakya University, Edirne, Turkey.",
"authors": "Gurdogan|Muhammet|M|;Ozkan|Ugur|U|",
"chemical_list": "C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Netherlands",
"delete": false,
"doi": "10.1159/000500439",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2296-5270",
"issue": "42(7-8)",
"journal": "Oncology research and treatment",
"keywords": "Cancer chemotherapy; Cardio-oncology; Cardiotoxicity; Fragmented QRS; Non-Hodgkin lymphoma",
"medline_ta": "Oncol Res Treat",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D066126:Cardiotoxicity; D003520:Cyclophosphamide; D004317:Doxorubicin; D004562:Electrocardiography; D005260:Female; D006801:Humans; D016015:Logistic Models; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D012189:Retrospective Studies; D000069283:Rituximab; D016277:Ventricular Function, Left; D014750:Vincristine",
"nlm_unique_id": "101627692",
"other_id": null,
"pages": "375-381",
"pmc": null,
"pmid": "31132772",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Novel Predictor of Chemotherapeutic Cardiotoxicity in Patients with Non-Hodgkin Lymphoma.",
"title_normalized": "a novel predictor of chemotherapeutic cardiotoxicity in patients with non hodgkin lymphoma"
} | [
{
"companynumb": "TR-JNJFOC-20190836642",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"... |
{
"abstract": "Retinopathy of prematurity is the leading cause of preterm infants' blindness. The preferred method for the management of aggressive posterior ROP is the anti-vascular endothelial growth factor (anti-VEGF). However, systemic and ocular adverse effects of anti-VEGF drugs remain a concern.\nA case report of a preterm infant with a history of hypertension underwent intravitreal injection of aflibercept at the 50-week postmenstrual age because of aggressive posterior retinopathy of prematurity (ROP) in both eyes. Seven days after the intravitreal administration of aflibercept, he has a hypertension crisis and an ischemic stroke. Serial fundoscopies implied complete arrest of vascularization till seven months after receiving treatment.\nWe report a case of an infant, with a history of hypertension, had an ischemic stroke just one week after the intravitreal injection of aflibercept for aggressive posterior ROP. We can conclude that in cases of preterm infants with systemic comorbidities, like uncontrolled hypertension, that predispose patients to thromboembolic events, we should be cautious about the potential increase in the risk of thromboembolic events after administration of anti-vascular endothelial growth factor agents (anti-VEGF), especially those with a longer half-life, like aflibercept.",
"affiliations": "Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Ali Asghar Children's Hospital, Iran University of Medical Sciences, Tehran, Iran.;Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Bazvand|Fatemeh|F|;Khalili Pour|Elias|E|0000-0001-8123-4375;Gharehbaghi|Golnaz|G|;Faghihi|Hooshang|H|;Khodabandeh|Alireza|A|;Mehrabi Bahar|Mohammadreza|M|0000-0001-8829-053X;Riazi-Esfahani|Hamid|H|0000-0003-2277-398X",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IMCRJ.S258881",
"fulltext": "\n==== Front\nInt Med Case Rep J\nInt Med Case Rep J\nIMCRJ\nimcrj\nInternational Medical Case Reports Journal\n1179-142X Dove \n\n258881\n10.2147/IMCRJ.S258881\nCase Report\nHypertension and Ischemic Stroke After Aflibercept for Retinopathy of Prematurity\nBazvand et alBazvand et alBazvand Fatemeh 1 http://orcid.org/0000-0001-8123-4375Khalili pour Elias 1 Gharehbaghi Golnaz 2 Faghihi Hooshang 1 Khodabandeh Alireza 1 http://orcid.org/0000-0001-8829-053XMehrabi Bahar Mohammadreza 1 http://orcid.org/0000-0003-2277-398XRiazi-Esfahani Hamid 1 1 Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran\n2 Ali Asghar Children’s Hospital, Iran University of Medical Sciences, Tehran, Iran\nCorrespondence: Mohammadreza Mehrabi Bahar Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Farabi Eye Hospital, Qazvin Square, South Kargar Street, Tehran1336616351, IranTel +982155421002 Email mreza.mehrabibahar@gmail.com\n03 7 2020 \n2020 \n13 243 247\n24 4 2020 23 6 2020 © 2020 Bazvand et al.2020Bazvand 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).Background\nRetinopathy of prematurity is the leading cause of preterm infants’ blindness. The preferred method for the management of aggressive posterior ROP is the anti-vascular endothelial growth factor (anti-VEGF). However, systemic and ocular adverse effects of anti-VEGF drugs remain a concern.\n\nCase Presentation\nA case report of a preterm infant with a history of hypertension underwent intravitreal injection of aflibercept at the 50-week postmenstrual age because of aggressive posterior retinopathy of prematurity (ROP) in both eyes. Seven days after the intravitreal administration of aflibercept, he has a hypertension crisis and an ischemic stroke. Serial fundoscopies implied complete arrest of vascularization till seven months after receiving treatment.\n\nConclusion\nWe report a case of an infant, with a history of hypertension, had an ischemic stroke just one week after the intravitreal injection of aflibercept for aggressive posterior ROP. We can conclude that in cases of preterm infants with systemic comorbidities, like uncontrolled hypertension, that predispose patients to thromboembolic events, we should be cautious about the potential increase in the risk of thromboembolic events after administration of anti-vascular endothelial growth factor agents (anti-VEGF), especially those with a longer half-life, like aflibercept.\n\nKeywords\nretinopathy of prematurityafliberceptintravitreal injectionstrokecerebrovascular accidentsecured for this studyNo funding was secured for this study.\n==== Body\nIntroduction\nRetinopathy of prematurity is a proliferative vasculopathy of immature retinal vessels in premature infants and the leading cause of preterm infants’ blindness. Although the preferred method for management of high risk-ROP was laser photoablation for many years, the BEAT-ROP study shows the efficacy and favorable results in managing of prethereshhold type 1 ROP with anti-vasoendothelial growth factor (anti-VEGF) especially in zone 1.1 Studies show a reduction in serum VEGF level after administration of Anti-VEGF intravitreally, and systemic adverse effects of these conditions remain a concern.2\n\nAflibercept is a potent recombinant fusion protein that blocks all isoforms of VEGF-A, VEGF-B, and placental growth factors. It has a higher binding capacity to VEGF and longer duration of action in the eye compared to previous anti-VEGF agents.3 The systemic administration of aflibercept in cancer patients is associated with a significantly increased risk of hypertension.4 But in a systematic review of ocular side effects of intravitreal aflibercept in adults shows that hypertension was similar to those of controls and similar across disease states in evaluated IAI trials. The Committee for Medicinal Products for Human Use pointed attention to the increase in cerebrovascular events with the use of aflibercept. However, systematic studies show no increase in cerebrovascular side effects in intravitreal use of aflibercept in adults’ retinal vasculopathy.5 However, there is no study to evaluate hypertension and cerebrovascular side effects of anti-VEGF used in ROP patients.\n\nWe report a case of cerebral stroke and hypertension crisis one week after administering intravitreal aflibercept and complete retinal vascular arrest until seven months after receiving treatment for aggressive posterior ROP.\n\nCase Report\nThe case concerned a preterm infant with a gestational age of 34 weeks (36 weeks postmenstrual age (PMA)) and birth weight of 1970 mg. He was admitted to the neonatal intensive care unit (NICU) because of respiratory distress syndrome and treated with a single dose of intratracheal surfactant. He had neonatal jaundice that responded well to phototherapy alone. He developed hypertension and was treated with propranolol. His first visit for ROP was in his 41 weeks PMA and showed ROP in zone 1–2. The ophthalmologist recommended revisiting in 1 week to decide any necessary treatment. However, he was non-adherent to eye exams due to systemic comorbidities and needed hospitalization for necessary workup. He was admitted in 42 weeks PMA due to uncontrolled hypertension, and his cardiac workup revealed no abnormality, and they referred him to a pediatric nephrologist. In 43 weeks PMA, he was admitted for subsequent nephrology workup, they found renal artery stenosis confirmed with computed tomography angiography (CT-Angiography) and Color Doppler sonography. He was treated with amlodipine after consultation with a pediatric nephrologist. He had one episode of tonic-clonic seizure in his 48 weeks PMA, and in obtained electroencephalography, no abnormalities were detected. He was treated with phenytoin and phenobarbital.\n\nAfter serial systemic workups, he was discharged from the pediatric hospital with controlled blood pressure with enalapril and amlodipine medication. One day after discharge, he visited in our hospital at his 50 weeks PMA. He underwent bilateral intravitreal aflibercept (1mg/0.025mL) (Eylea®, Regeneron) injection under topical anesthesia due to aggressive posterior ROP (zone 1 stage 3 flat neovascularization with plus) as shown in Figure 1A and B. In our center, routine anti-VGEF is bevacizumab. However, at that time, due to the unavailability of bevacizumab, aflibercept was prescribed. He was treated with a topical antibiotic (chloramphenicol 0.5% four times a day) to prevent infection. One week after the administration of aflibercept, he presented in the emergency ward for a hypertension crisis (BP 110/87) and a decrease in left upper and lower extremities’ motion and agitation. Based on neurologic examination, computed tomography scan (CT scan), and magnetic resonance imaging (MRI), they confirmed the acute ischemic cerebrovascular stroke at the occipital lobe, parietal lobe, and also splenium of the corpus callosum at territories of posterior cerebral and middle cerebral artery (Figure 1G and H). His systemic workup includes hypercoagulable state like antiphospholipid and anticardiolipin antibody was done, and all of them were normal. He was discharged with aspirin, phenytoin, phenobarbital, amlodipine, and enalapril.Figure 1 (A and B) Fundus photographs of right and left eye of the patient at the 50 weeks postmenstrual age (PMA) show aggressive posterior ROP (flat neovascularization) in zone 1, on the same day intravitreal aflibercept injected. (C and D) fundus photos at the 65 weeks PMA show regression of neovascularization but stop in vascularization at zone 1 in both eyes. (E and F) fundus photographs at the 75 weeks PMA show still complete stop in vascularization at zone 1 in both eyes. (G) diffusion-weighted axial MRI images evidence diffusion restriction at right occipital and parietal lobes and also splenium of the corpus callosum, compatible with acute ischemic non-hemorrhagic infarct. (H) axial CT scan shows the same findings.\n\n\n\nBecause of uncontrolled hypertension, and suspicious to the vascular anomaly, he underwent comprehensive examinations and imagings including thoracic and abdominal CT-Angiography, cervical color Doppler sonography, and transesophageal echocardiography. He revealed no apparent vascular involvement except for the right renal artery stenosis. Serial cardiac and nephrology workups and visits, till 75 weeks PMA, documented no further abnormality and controlled Blood Pressure with amlodipine and enalapril.\n\nIn eye exams, after intravitreal aflibercept injection in serial fundoscopies, we found a complete stop in vascularization progression until 75 weeks PMA (Figure 1C and D. fundus photographs of the right and left eye at the 65 weeks PMA and Figure1E and F at the 75 weeks PMA). In this time, due to non-adherent to eye exams, we have done laser photoablation in the retinal avascular zone.\n\nDiscussion\nIn cases of treatment-requiring ROP, the standard of care is laser photoablation of the avascular retina. BEAT-ROP study revealed favorable positive results and low ocular morbidity compared to conventional laser in the treatment of ROP in posterior zones.1 More recently, with the increased availability and easy administration of Anti-VEGF drugs in ROP, interests in the administration of all kinds of Anti-VEGF has been increased. But still, concerns and questions remain regarding timing, dosage, and ocular and systemic adverse events of using anti-VEGF agents for ROP.6 An interestingly reviewed data from the Canadian Neonatal Network showed higher odds of severe neurodevelopmental disabilities in preterm infants born before 29 weeks’ gestation and treated with bevacizumab, after adjusting for all key confounders like gestation, gender, maternal education, Score for Neonatal Acute PhysiologyII (SNAP-II) score, bronchopulmonary dysplasia, sepsis, and severe brain injury.7\n\nAflibercept has several advantages in comparison to other Anti-VEGF drugs. It has a high binding affinity to VEGF receptors, and it binds to VEGF-A, VEGF-B, and PLGF receptors. The high efficacy and the long duration of action of Aflibercept, possibly will help in inducing regression of ROP in very severe cases and benefit from preserving the regression. Salman et al were the first to report that a single injection of aflibercept was an effective therapy for high-risk prethreshold type 1 ROP, with favorable structural, visual, and refractive outcomes.3 Furthermore, several studies show the efficacy of these agents in the management of ROP.6\n\nAflibercept (Eylea®, Regeneron) has the FDA-approval for intravitreal injections in adults, but its use in ROP remains off-label.3 There is some concern about thromboembolic events in patients using intravitreal aflibercept.5 Anti-VEGF agents act on endothelium directly and considering the imperative role of the endothelium to sustain hemostatic balance, anti-VEGF agents may have the potential to increase the risk of thromboembolic events. However, several clinical trials show no difference in hypertension and thromboembolic events between intravitreal ranibizumab and placebo, nor between ranibizumab and aflibercept. On the other hand, patients receiving anti-VEGF have several risk factors for thromboembolic events.5\n\nThere are several case reports on Ischemic stroke after administration of aflibercept in adults, and all of them mentioned that potential risk factors like hypertension might play a role in thromboembolic adverse events but, to the best of our knowledge, there is no case report about ischemic stroke after anti-VEGF use in ROP patients even with systemic comorbidities like uncontrolled hypertension.5\n\nRecently an interesting case report of a premature infant treated for stage 3 ROP with intravitreal bevacizumab developed new-onset systemic hypertension and neuroimaging changes. Neuroimaging showed new areas of vasogenic edema, which improved over time.8\n\nWe report a preterm infant with an ischemic stroke just one week after the intravitreal injection of aflibercept for ROP. Still, we cannot directly address that because of the anti-VEGF agent’s pharmacodynamics effect. Our patient was suffered from poorly controlled hypertension. Importantly, our patient also showed a delayed retinal vascularization. Although his birth age was 36 weeks PMA, in the funduscopic exam in 41 weeks PMA, he had ROP in zone 1–2. Additionally, in 50 weeks PMA, he had aggressive posterior ROP, which is atypical for that age. With all together and systemic comorbidities like renal artery stenosis, he probably had a disorder that delayed retinal vascularization. Moreover, in serial fundus exams following administration of intravitreal aflibercept, complete arrest of retinal vascular growth was noted; it might be due to the long duration of aflibercept’s action, even though he probably had the disorder to slow down retinal vascularization. We do not know these both complications were due to the side effects of aflibercept or due to the systemic condition of our patient.\n\nIn conclusion, we mentioned, in similar cases of preterm infants with systemic comorbidities, especially uncontrolled hypertension, we should be vigilant about the potential increase in the risk of thromboembolic events after the administration of anti-VEGF agents, particularly agents with a longer half-life, like aflibercept. Although we should be cautious about infants with delayed retinal vascularization like our patients, and should not use such long-acting agents.\n\nAbbreviations\nROP, retinopathy of prematurity; VEGF, vascular endothelial growth factor; CT-Angiography, computed tomography angiography; PMA, postmenstrual age.\n\nData Sharing Statement\nNot applicable.\n\nEthics Approval and Consent to Participate\nThe Health Research Authority decision tool (http://www.hra-decisiontools.org.uk/research) confirmed this project was not research and so ethical approval was not sought.\n\nConsent for Publication\nWritten informed consent was obtained from his parents for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\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 declare that they have no competing interests.\n==== Refs\nReferences\n1. Mintz-Hittner \nHA , Kennedy \nKA , Chuang \nAZ . Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity\n. N Engl J Med . 2011 ;364 (7 ):603 –615\n. doi:10.1056/NEJMoa1007374 21323540 \n2. Pertl \nL , Steinwender \nG , Mayer \nC , et al. A systematic review and meta-analysis on the safety of Vascular Endothelial Growth Factor (VEGF) inhibitors for the treatment of retinopathy of prematurity\n. PLoS One . 2015 ;10 (6 ):e0129383 . doi:10.1371/journal.pone.0129383 26083024 \n3. Salman \nAG , Said \nAM . Structural, visual and refractive outcomes of intravitreal aflibercept injection in high-risk prethreshold type 1 retinopathy of prematurity\n. Ophthalmic Res . 2015 ;53 (1 ):15 –20\n. doi:10.1159/000364809 25471087 \n4. Qi \nW-X , Shen \nZ , Tang L-N \nYY . Risk of hypertension in cancer patients treated with aflibercept: a systematic review and meta-analysis\n. Clin Drug Investig . 2014 ;34 (4 ):231 –240\n. doi:10.1007/s40261-014-0174-5 \n5. Beaumont \nPE , Petocz \nP , Kang \nHK . Is there risk of stroke with aflibercept?\n\nOphthalmology . 2014 ;121 (1 ):e4 . doi:10.1016/j.ophtha.2013.09.020 24268853 \n6. Klufas \nMA , Chan \nRV . Intravitreal anti-VEGF therapy as a treatment for retinopathy of prematurity: what we know after 7 years\n. J Pediatr Ophthalmol Strabismus . 2015 ;52 (2 ):77 –84\n. doi:10.3928/01913913-20150216-01 25798707 \n7. Morin \nJ , Luu \nTM , Superstein \nR , et al. Neurodevelopmental outcomes following bevacizumab injections for retinopathy of prematurity\n. Pediatrics . 2016 ;137 :4 . doi:10.1542/peds.2015-3218 \n8. Twitty \nG , Weiss \nM , Albayram \nMS , O’Mara \nK , Mowitz \nME . Hypertension and neuroimaging changes after bevacizumab for retinopathy of prematurity\n. Pediatrics . 2020 ;145 (1 ):e20191814 . doi:10.1542/peds.2019-1814 31806670\n\n",
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"journal": "International medical case reports journal",
"keywords": "aflibercept; cerebrovascular accident; intravitreal injection; retinopathy of prematurity; stroke",
"medline_ta": "Int Med Case Rep J",
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"title": "Hypertension and Ischemic Stroke After Aflibercept for Retinopathy of Prematurity.",
"title_normalized": "hypertension and ischemic stroke after aflibercept for retinopathy of prematurity"
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"abstract": "A 45-year-old woman who received a renal transplant 7 years prior presented with a 3-week history of low-grade fever, night sweats, and a dry cough with scant sputum production. Additionally, she reported generalized weakness and increased fatigability. She denied hemoptysis or weight loss, and there had been no change in medication or foreign travel. She had no history of latent tuberculosis or sick contacts. She had recently relocated to Baton Rouge, Louisiana. She was sexually active with her boyfriend who worked as a prison guard. She also reported that she was briefly incarcerated 7 years ago shortly after her renal transplantation. Her immunosuppression consisted of tacrolimus, mycophenolate, and prednisone.",
"affiliations": "Department of Pulmonary and Critical Care, Tulane University School of Medicine, New Orleans, LA. Electronic address: tkyaw@tulane.edu.;Department of Pathology, Tulane University School of Medicine, New Orleans, LA.;Department of Pulmonary and Critical Care, Tulane University School of Medicine, New Orleans, LA.",
"authors": "Kyaw|Than Htaik|TH|;Sullivan|Lacey|L|;Klingsberg|Ross C|RC|",
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"title": "A 45-Year-Old Woman With 3 Weeks of Cough and Night Sweats.",
"title_normalized": "a 45 year old woman with 3 weeks of cough and night sweats"
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"abstract": "A 72-year-old man was admitted to our hospital department in September 2014 because of a positive fecal occult blood test.Colonoscopy showed a type 2 tumor in half of the AV 15 cm rectosigmoid colon.Histology of the biopsy indicated a moderately differentiated adenocarcinoma, and the RAS gene test found wild type.On CT examination, there were multiple liver lung metastases and a 30mm diameter tumor with pancreatic duct extension to the pancreatic body.A PET-CT examination had a high SUVmax at the same site.Because of the location of the tumor EUS-FNA was not used.However, the possibility of pancreatic body cancer could not be denied after the CT examination.Treatment by radical resection was impossible because of the spread of the cancer so we selected chemotherapy.Undeniable pancreatic metastasis of rectal cancer, pancreatic cancer was used as a prognostic factor as double cancer of rectal cancer and pancreatic cancer, from that UGT1A1 test side effects appearance was a low-risk decision, was selected FOLFIRINOX in the treatment regimen.After 25 cycles, the pancreatic body tumor and liver metastases and also the primary tumor were reduced, the multiple lung metastases disappeared, and disease control was good.Side effects were diarrhea on the day of administration of irinotecan, but this was controllable by administering oral loperamide when starting the infusion.Grade 3 or more peripheral neuropathy has not developed, and this regimen is continuing.Pancreatic cancer is a solid cancer with a poor prognosis; if you do not reach the tissue diagnosis of metastatic pancreatic cancer, was a case in which no choice but to select a regimen to carcinoma of the prognostic.",
"affiliations": "Dept. of Surgery, Ogikubo Hospital.",
"authors": "Yabe|Nobushige|N|;Murai|Shinji|S|;Ozawa|Hiroki|H|;Yokose|Takahiro|T|;Oto|Ippei|I|;Yoshikawa|Takahisa|T|;Kitasato|Kenjiro|K|;Shimizu|Hirotomo|H|;Kojima|Kenji|K|;Hasegawa|Hirotoshi|H|;Kitagawa|Yuko|Y|",
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"issue": "43(12)",
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"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D006801:Humans; D008297:Male; D010190:Pancreatic Neoplasms; D012004:Rectal Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "7810034",
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"title": "A Case of Unresectable Advanced Rectal Cancer with a Pancreatic Tumor That Was Successfully Treated with FOLFIRINOX.",
"title_normalized": "a case of unresectable advanced rectal cancer with a pancreatic tumor that was successfully treated with folfirinox"
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"abstract": "Atypical antipsychotics commonly cause isolated asymptomatic increase in the aminotransferase levels. Among these atypical antipsychotics, mostly transient, asymptomatic increase in hepatic enzymes has been reported with olanzapine, however olanzapine rarely may induce a clinical and/or biological hepatic toxicity. The pathogenesis of olanzapine-associated hepatotoxicity is not well known and is mostly a transient phenomenon. However, substantial and lasting changes may occur and result in symptomatic hepatitis. In the following case report, we report on a 44-year-old female patient diagnosed as Bipolar Disorder Type I, whose liver enzyme levels increased ten fold of normal ranges during the third year of the olanzapine treatment and returned to the normal levels within three weeks after olanzapine discontinuation. Although significant liver enzyme elevations are uncommon during olanzapine treatment, based on reports of serious hepatotoxicity, controlled and longitudinal research are needed to learn side effects of this drug on liver. Clinicians should be aware of possible hepatotoxic effects of atypical antipsychotics and should monitor the liver enzyme levels whenever they feel necessary.",
"affiliations": "Department of Psychiatry, International Hospital, Istanbul, Turkey.",
"authors": "Ozcanli|Tuba|T|;Erdogan|Ayten|A|;Ozdemir|Samuray|S|;Onen|Bariş|B|;Ozmen|Mine|M|;Doksat|Kerem|K|;Sonsuz|Abdullah|A|",
"chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000077152:Olanzapine",
"country": "England",
"delete": false,
"doi": "10.1016/j.pnpbp.2006.03.014",
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"issn_linking": "0278-5846",
"issue": "30(6)",
"journal": "Progress in neuro-psychopharmacology & biological psychiatry",
"keywords": null,
"medline_ta": "Prog Neuropsychopharmacol Biol Psychiatry",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D001714:Bipolar Disorder; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D008099:Liver; D000077152:Olanzapine; D011569:Psychiatric Status Rating Scales",
"nlm_unique_id": "8211617",
"other_id": null,
"pages": "1163-6",
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"pmid": "16632162",
"pubdate": "2006-08-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe liver enzyme elevations after three years of olanzapine treatment: a case report and review of olanzapine associated hepatotoxicity.",
"title_normalized": "severe liver enzyme elevations after three years of olanzapine treatment a case report and review of olanzapine associated hepatotoxicity"
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{
"companynumb": "TR-MACLEODS PHARMACEUTICALS US LTD-MAC2022035641",
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"activesubstancename": "OLANZAPINE"
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{
"abstract": "We sought to determine the feasibility of co-administering everolimus with a four-drug reinduction in children and adolescents with acute lymphoblastic leukemia (ALL) experiencing a first marrow relapse.\n\n\n\nThis phase I study tested everolimus with vincristine, prednisone, pegaspargase and doxorubicin in patients with marrow relapse occurring >18 months after first complete remission (CR). The primary aim was to identify the maximum tolerated dose of everolimus. Three dose levels (DLs) were tested during dose escalation (2, 3, and 5 mg/m2 /day). Additional patients were enrolled at the 3- and 5 mg/m2 /day DLs to further evaluate toxicity (dose expansion).\n\n\n\nThirteen patients enrolled during dose escalation and nine during dose expansion. During dose escalation, one dose-limiting toxicity occurred (grade 4 hyperbilirubinemia) in six evaluable patients at DL3 (5 mg/m2 /day). The most common grade ≥3 adverse events were febrile neutropenia, infections, transaminitis, hyperbilirubinemia, and hypophosphatemia. Two of the 12 patients treated at DL3 developed Rothia mucilaginosa meningitis. Nineteen patients (86%) achieved a second CR (CR2). Of those, 13 (68%) had a low end-reinduction minimal residual disease (MRD) level (≤10-3 by polymerase chain reaction-based assay). The CR2 rate for patients with B-cell ALL treated at DL3 (n = 12) was 92%; 82% of these patients had low MRD.\n\n\n\nEverolimus combined with four-drug reinduction chemotherapy was generally well tolerated and associated with favorable rates of CR2 and low end-reinduction MRD. The recommended phase 2 dose of everolimus given in combination with a four-drug reinduction is 5 mg/m2 /day. This promising combination should be further evaluated in a larger patient cohort.",
"affiliations": "Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.;Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.;Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.;Department of Pediatrics, Children's Healthcare of Atlanta/Emory University School of Medicine, Atlanta, Georgia.;Division of Pediatric Hematology, Oncology, and Stem Cell Transplant, Columbia University, New York City, New York.;Division of Hematology, Oncology, and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital/Northwestern University Feinberg School of Medicine, Chicago, Illinois.;Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado.;Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, Washington.;Department of Pediatrics, Benioff Children's Hospital, University of California at San Francisco, San Francisco, California.;Department of Medicine and Surgery, University of Parma, Parma, Italy.;Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.;Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.;Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.;Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.;Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.",
"authors": "Place|Andrew E|AE|0000-0002-9604-4213;Pikman|Yana|Y|;Stevenson|Kristen E|KE|;Harris|Marian H|MH|;Pauly|Melinda|M|;Sulis|Maria-Luisa|ML|0000-0003-2110-0193;Hijiya|Nobuko|N|0000-0002-0199-054X;Gore|Lia|L|;Cooper|Todd M|TM|;Loh|Mignon L|ML|;Roti|Giovanni|G|;Neuberg|Donna S|DS|0000-0003-2566-3145;Hunt|Sarah K|SK|;Orloff-Parry|Sarah|S|;Stegmaier|Kimberly|K|;Sallan|Stephen E|SE|;Silverman|Lewis B|LB|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D011092:Polyethylene Glycols; D014750:Vincristine; C042705:pegaspargase; D004317:Doxorubicin; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D001215:Asparaginase; D011241:Prednisone",
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"issue": "65(7)",
"journal": "Pediatric blood & cancer",
"keywords": "developmental therapeutics; mTOR inhibitor; relapsed acute lymphoblastic leukemia",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D000068338:Everolimus; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local; D011092:Polyethylene Glycols; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011241:Prednisone; D047428:Protein Kinase Inhibitors; D012074:Remission Induction; D058570:TOR Serine-Threonine Kinases; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "101186624",
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"pmid": "29603593",
"pubdate": "2018-07",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase I trial of the mTOR inhibitor everolimus in combination with multi-agent chemotherapy in relapsed childhood acute lymphoblastic leukemia.",
"title_normalized": "phase i trial of the mtor inhibitor everolimus in combination with multi agent chemotherapy in relapsed childhood acute lymphoblastic leukemia"
} | [
{
"companynumb": "PHHY2018US058738",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "OBJECTIVE\nWe attempted treatment of chronic psychogenic pseudosyncope with serial conscious sedation interviews.\n\n\nMETHODS\nThree conscious sedation interviews were performed.\n\n\nRESULTS\nThe patient's symptoms lessened significantly, and improvement lasted for 3 months; however, gradually, her symptoms returned to prior level of severity.\n\n\nCONCLUSIONS\nConscious sedation interviews may improve symptoms of the psychogenic pseudosyncope, but the improvement may be temporary.",
"affiliations": "Veterans Affairs Medical Center, Seattle, WA 98108, USA; University of Washington Medical Center, Seattle, WA, USA. Electronic address: anna.borisovskaya@va.gov.",
"authors": "Borisovskaya|Anna|A|;Horibe|Mayumi|M|;Bright|Alexandra|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-8343",
"issue": "35(6)",
"journal": "General hospital psychiatry",
"keywords": "Conscious sedation; Conversion disorder; Pseudosyncope",
"medline_ta": "Gen Hosp Psychiatry",
"mesh_terms": "D016292:Conscious Sedation; D003291:Conversion Disorder; D005260:Female; D006801:Humans; D007406:Interview, Psychological; D008875:Middle Aged; D013575:Syncope; D016896:Treatment Outcome",
"nlm_unique_id": "7905527",
"other_id": null,
"pages": "679.e9-10",
"pmc": null,
"pmid": "23601923",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Conscious sedation interview for psychogenic pseudosyncope.",
"title_normalized": "conscious sedation interview for psychogenic pseudosyncope"
} | [
{
"companynumb": "US-APOTEX-2015AP007281",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIDAZOLAM HYDROCHLORIDE"
},
"drugadditional": nu... |
{
"abstract": "Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired clonal haematological disease characterized by complement-mediated haemolysis, bone marrow failure and venous thrombosis. Anticomplement therapy eculizumab improves survival and reduces complications. Severe acute respiratory distress syndrome corona virus 2 (SARS-CoV-2) disease 2019 (COVID-19) is associated with high incidence of both venous and arterial thrombosis in hospitalized patients with pneumonia. Deep venous thrombosis (DVT) as the presenting symptom of COVID-19 is a rare event. We describe a well-controlled PNH patient on eculizumab for more than 5 years who presented with DVT, while on warfarin, as the first sign of COVID-19. To our knowledge, this is the first described case of DVT in a PNH patient with COVID-19.",
"affiliations": "Clinic of Haematology, University Clinical Centre of Serbia, Belgrade, Serbia.;Clinic of Haematology, University Clinical Centre of Serbia, Belgrade, Serbia.;Clinic of Haematology, University Clinical Centre of Serbia, Belgrade, Serbia.;Clinic of Haematology, University Clinical Centre of Serbia, Belgrade, Serbia.;Clinic of Haematology, University Clinical Centre of Serbia, Belgrade, Serbia.;Clinic of Haematology, University Clinical Centre of Serbia, Belgrade, Serbia.;Clinic of Haematology, University Clinical Centre of Serbia, Belgrade, Serbia.",
"authors": "Pravdic|Zlatko|Z|;Mitrovic|Mirjana|M|;Bogdanovic|Andrija|A|;Virijevic|Marijana|M|;Sabljic|Nikica|N|;Pantic|Nikola|N|;Vukovic|Nada Suvajdzic|NS|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000925:Anticoagulants; D051056:Complement Inactivating Agents; D014859:Warfarin; C481642:eculizumab",
"country": "Germany",
"delete": false,
"doi": "10.1055/a-1554-6432",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0720-9355",
"issue": "41(5)",
"journal": "Hamostaseologie",
"keywords": null,
"medline_ta": "Hamostaseologie",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000925:Anticoagulants; D000086382:COVID-19; D051056:Complement Inactivating Agents; D006457:Hemoglobinuria, Paroxysmal; D006801:Humans; D008297:Male; D000086402:SARS-CoV-2; D020246:Venous Thrombosis; D014859:Warfarin",
"nlm_unique_id": "8204531",
"other_id": null,
"pages": "397-399",
"pmc": null,
"pmid": "34544179",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "COVID-19 Presented with Deep Vein Thrombosis in a Patient with Paroxysmal Nocturnal Haemoglobinuria.",
"title_normalized": "covid 19 presented with deep vein thrombosis in a patient with paroxysmal nocturnal haemoglobinuria"
} | [
{
"companynumb": "RS-ALXN-A202110810",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ECULIZUMAB"
},
"drugadditional": null,
"dr... |
{
"abstract": "Bisphosphonates are the most commonly prescribed drugs to treat osteoporosis because they have been proposed to prevent bone loss. Nevertheless, in up to 0.1% of patients, long-term use may cause atypical stress or insufficiency femoral fractures. Bilateral femoral shaft fractures have been reported after long-term use of bisphosphonates; however, there is limited evidence of the effect of short-term use. The current study reports a case of bilateral femoral fractures after a low-energy fall in a 56-year-old woman and provides a review of the literature on bilateral femoral shaft fractures after long-term use of bisphosphonates. Patients should be educated about the potential for stress fractures with the use of this treatment. In patients with thigh pain, a thorough history and physical examination, including the contralateral thigh, may be beneficial to detect bilateral traumatic or atypical stress fracture patterns. More studies with larger sample sizes are necessary to better identify patients who may be at risk for fracture, including histomorphometric evidence of low bone turnover in patients with unfortunate bilateral cases.",
"affiliations": null,
"authors": "Rifai|Aiman|A|;Pourtaheri|Sina|S|;Carbone|Andrew|A|;Callaghan|John J|JJ|;Stadler|Chris M|CM|;Record|Nicole|N|;Issa|Kimona|K|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "United States",
"delete": false,
"doi": "10.3928/01477447-20150204-90",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-7447",
"issue": "38(2)",
"journal": "Orthopedics",
"keywords": null,
"medline_ta": "Orthopedics",
"mesh_terms": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D015775:Fractures, Stress; D006801:Humans; D008875:Middle Aged; D010024:Osteoporosis",
"nlm_unique_id": "7806107",
"other_id": null,
"pages": "e139-42",
"pmc": null,
"pmid": "25665120",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral femur fractures associated with short-term bisphosphonate use.",
"title_normalized": "bilateral femur fractures associated with short term bisphosphonate use"
} | [
{
"companynumb": "US-ROCHE-1583312",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBANDRONIC ACID"
},
"drugadditional": "3",
"... |
{
"abstract": "Serious immune checkpoint inhibitor (ICI)-related neurotoxicity is rare. There is limited data on the specifics of care and outcomes of patients with severe neurological immune related adverse events (NirAEs) admitted to the Intensive Care Unit (ICU).\n\n\n\nRetrospective study of patients with severe NirAEs admitted to the ICU at 3 academic centers between January 2016 and December 2018. Clinical data collected included ICI exposure, type of NirAE (central [CNS] or peripheral nervous system [PNS) disorders), and patient outcomes including neurological recovery and mortality.\n\n\n\nSeventeen patients developed severe NirAEs. Eight patients presented with PNS disorders; 6 with myasthenia gravis (MG), 1 had a combination of MG and polyneuropathy and 1 had Guillain-Barre syndrome. Nine patients had CNS disorders (6 seizures and 5 had concomitant encephalopathy. During ICU admission, 65% of patients required mechanical ventilation, 35% vasopressors, and 18% renal replacement therapy. The median ICU and hospital length of stay were 7 (2-36) and 18 (4-80) days, respectively. Hospital mortality was 29%. At hospital discharge, 18% of patients made a full neurologic recovery, 41% partial recovery, and 12% did not recover.\n\n\n\nSevere NirAEs while uncommon, can be serious or even life-threatening if not diagnosed and treated early.",
"affiliations": "Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America. Electronic address: rajendp1@mskcc.org.;Department of Pharmacy, Cleveland Clinic, Cleveland, OH, United States of America.;Department of Critical Care Medicine, Cleveland Clinic, Cleveland, OH, United States of America.;Department of Critical Care Medicine, MD Anderson Cancer Center, Houston, TX, United States of America.;Department of Critical Care Medicine, MD Anderson Cancer Center, Houston, TX, United States of America.;Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.;Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.;Department of Critical Care Medicine, MD Anderson Cancer Center, Houston, TX, United States of America.",
"authors": "Rajendram|Prabalini|P|;Torbic|Heather|H|;Duggal|Abhijit|A|;Campbell|Jeannee|J|;Hovden|Michael|M|;Dhawan|Vikram|V|;Pastores|Stephen M|SM|;Gutierrez|Cristina|C|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jcrc.2021.05.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-9441",
"issue": "65()",
"journal": "Journal of critical care",
"keywords": "CTLA-4; Immune checkpoint inhibitors; Immune related adverse events; Intensive care unit; Neurotoxicity; PD-1/PD-L1",
"medline_ta": "J Crit Care",
"mesh_terms": "D016638:Critical Illness; D020275:Guillain-Barre Syndrome; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007362:Intensive Care Units; D009157:Myasthenia Gravis; D012189:Retrospective Studies",
"nlm_unique_id": "8610642",
"other_id": null,
"pages": "126-132",
"pmc": null,
"pmid": "34139658",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Critically ill patients with severe immune checkpoint inhibitor related neurotoxicity: A multi-center case series.",
"title_normalized": "critically ill patients with severe immune checkpoint inhibitor related neurotoxicity a multi center case series"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-065420",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "A man with cytopenias, dysplasia, excess blasts, P53 and RUNX1 mutations, and ring chromosome 7 recovered after stopping lenalidomide.",
"affiliations": "Department of Pathology, Rush University Medical Center, Chicago, IL.;Department of Pathology, Rush University Medical Center, Chicago, IL.;BioReference Laboratories, Elmwood Park, NJ; and.;Department of Internal Medicine, Rush University Medical Center, Chicago, IL.",
"authors": "Miller|Ira J|IJ|;Hsu|Wei-Tong|WT|;Weisberger|James|J|;Venugopal|Parameswaran|P|0000-0002-7518-9579",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1182/bloodadvances.2017006114",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2473-9529",
"issue": "1(16)",
"journal": "Blood advances",
"keywords": null,
"medline_ta": "Blood Adv",
"mesh_terms": null,
"nlm_unique_id": "101698425",
"other_id": null,
"pages": "1238-1242",
"pmc": null,
"pmid": "29296763",
"pubdate": "2017-07-11",
"publication_types": "D016428:Journal Article",
"references": "26582244;24292625;11801466;21527522;14627986;27930389;25487151;28028022;16840727;24292623;17686058;9509975;24914135",
"title": "A case of lenalidomide-dependent myelodysplastic syndrome.",
"title_normalized": "a case of lenalidomide dependent myelodysplastic syndrome"
} | [
{
"companynumb": "US-CELGENEUS-USA-2016127937",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "The off-label use of Cytotec (misoprostol) to induce labor has increased over the past few decades. The increase in medical interventions in childbirth, many of which are not based on scientific evidence, and the rise in maternal and infant morbidity and in maternal and infant mortality cannot continue to go unrecognized. This column serves as a teaching tool for childbirth educators and provides an example of two unnecessary, potentially avoidable deaths that occurred during a birth with questionable medical interventions.",
"affiliations": "MADELINE ODEN is currently the Executive Chairperson of The Tatia Oden French Memorial Foundation, the Chairperson of the Maternal, Child Health subcommittee of the Alameda County Public Health (ACPH) Commission in California, and a commissioner on the ACPH Commission. She has been a certified practicing doula for 3 years.",
"authors": "Oden|Madeline|M|;Certificate|Doula|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1624/105812409X426332",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-1243",
"issue": "18(2)",
"journal": "The Journal of perinatal education",
"keywords": "Cytotec; avoiding adverse events; evidence-based practices; labor and birth; misoprostol; standard of care",
"medline_ta": "J Perinat Educ",
"mesh_terms": null,
"nlm_unique_id": "9301158",
"other_id": null,
"pages": "48-51",
"pmc": null,
"pmid": "20190849",
"pubdate": "2009",
"publication_types": "D016428:Journal Article",
"references": "14596100;19252683",
"title": "The freedom to birth-the use of cytotec to induce labor: a non-evidence-based intervention.",
"title_normalized": "the freedom to birth the use of cytotec to induce labor a non evidence based intervention"
} | [
{
"companynumb": "US-PFIZER INC-2012221621",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MISOPROSTOL"
},
"drugadditional": "3",
... |
{
"abstract": "Endovascular recanalization of occluded venous femoropopliteal bypass grafts is widely used because of easy access. This case report describes pseudoaneurysm developing 4 weeks after endovascular recanalization of an occluded in situ venous femoropopliteal graft. The patient was treated for a popliteal aneurysm with a venous femoropopliteal bypass graft, which subsequently occluded. Four weeks after DEB PTA, the occluded graft developed 3 pseudoaneurysms. Impaired vessel wall healing after intraluminal paclitaxel administration could have contributed to this. This case adds a perspective to the choice of treatment of occluded venous femoropopliteal bypass grafts.",
"affiliations": "Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden; Department of Surgery, Helsingborg Hospital, Helsingborg, Sweden. Electronic address: Henrik.bergenfeldt@med.lu.se.;Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden; Department of Surgery, Section of Interventional Radiology/Vascular Surgery, Helsingborg Hospital, Helsingborg, Sweden.;Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden; Department of Surgery, Section of Interventional Radiology/Vascular Surgery, Helsingborg Hospital, Helsingborg, Sweden.",
"authors": "Bergenfeldt|Henrik|H|;Lindgren|Hans|H|;Kühme|Tobias|T|",
"chemical_list": "D020099:Coated Materials, Biocompatible",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.avsg.2020.10.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-5096",
"issue": "72()",
"journal": "Annals of vascular surgery",
"keywords": null,
"medline_ta": "Ann Vasc Surg",
"mesh_terms": "D000369:Aged, 80 and over; D000783:Aneurysm; D017541:Aneurysm, False; D000800:Angioplasty, Balloon; D019917:Blood Vessel Prosthesis Implantation; D020099:Coated Materials, Biocompatible; D006083:Graft Occlusion, Vascular; D006801:Humans; D008297:Male; D011150:Popliteal Artery; D016896:Treatment Outcome; D062666:Vascular Access Devices; D014680:Veins",
"nlm_unique_id": "8703941",
"other_id": null,
"pages": "665.e5-665.e8",
"pmc": null,
"pmid": "33227471",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pseudoaneurysm Development after Drug-Eluting Balloon (DEB) Angioplasty of a Venous Femoropopliteal Bypass Graft.",
"title_normalized": "pseudoaneurysm development after drug eluting balloon deb angioplasty of a venous femoropopliteal bypass graft"
} | [
{
"companynumb": "SE-PFIZER INC-2021013089",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nMethotrexate (MTX) is a potent teratogen when used in high doses for cancer or termination of tubal pregnancy. In contrast, it has been perceived as safe when used once weekly at low dose for rheumatological conditions.\n\n\nMETHODS\nA prospective observational controlled study of women exposed to low dose MTX. The control group were women exposed to MTX only before conception.\n\n\nRESULTS\nAmong the 8 MTX-exposed pregnancies, there was a case of typical MTX embryopathy, the first to be described to date at this lower once weekly dose Schedule.\n\n\nCONCLUSIONS\nThis case has important implications for rheumatologists treating women of reproductive age, as the assumption of fetal safety of MTX, implied from small cohorts, is premature.",
"affiliations": null,
"authors": "Martín|María Cecilia|MC|;Barbero|Pablo|P|;Groisman|Boris|B|;Aguirre|Miguel Ángel|MÁ|;Koren|Gideon|G|",
"chemical_list": "D018501:Antirheumatic Agents; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.reprotox.2013.10.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-6238",
"issue": "43()",
"journal": "Reproductive toxicology (Elmsford, N.Y.)",
"keywords": null,
"medline_ta": "Reprod Toxicol",
"mesh_terms": "D000015:Abnormalities, Multiple; D000293:Adolescent; D000328:Adult; D018501:Antirheumatic Agents; D019465:Craniofacial Abnormalities; D005260:Female; D005315:Fetal Diseases; D006801:Humans; D008431:Maternal-Fetal Exchange; D008727:Methotrexate; D011247:Pregnancy; D012216:Rheumatic Diseases; D055815:Young Adult",
"nlm_unique_id": "8803591",
"other_id": null,
"pages": "26-9",
"pmc": null,
"pmid": "24513926",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Methotrexate embryopathy after exposure to low weekly doses in early pregnancy.",
"title_normalized": "methotrexate embryopathy after exposure to low weekly doses in early pregnancy"
} | [
{
"companynumb": "AR-WATSON-2014-24155",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "BACKGROUND\nThe anterior chamber has been shown by pharmacokinetic studies to represent a sanctuary never achieving a tumoricidal dose with the present administration routes, such as systemic, intra-arterial, or intravitreal injections.\n\n\nMETHODS\nA novel intracameral chemotherapy technique is described to control aqueous seeding in a pilot unilateral group E retinoblastoma case with primary aqueous seeding. Anterior segment toxicity was carefully monitored.\n\n\nRESULTS\nControl of the retinal tumor and vitreous seeding was achieved by intra-arterial and intravitreal chemotherapies. Sterilization of the aqueous was achieved after a first cycle of 7 melphalan injections in the anterior chamber, but relapse was noted 3.5 months later. This relapse was finally controlled with a second cycle of 6 intracameral injections targeting the posterior chamber. Corneal endothelial cell density remained stable over the injection period. Heterochromia and a progressive cataract developed, which required cataract surgery. At 5 years' follow-up, the patient is tumor free with normal vision (20/20 in both eyes), full binocularity, and no metastasis.\n\n\nCONCLUSIONS\nThe present bicameral injection technique appears to be safe and effective with limited toxicity. Melphalan-induced side effects were noted on the iris and lens but with no impact on the final visual function.",
"affiliations": "Jules-Gonin Eye Hospital, University of Lausanne, Switzerland.;Jules-Gonin Eye Hospital, University of Lausanne, Switzerland.;Jules-Gonin Eye Hospital, University of Lausanne, Switzerland.;Institute of Pathology, University of Lausanne, Switzerland.;Unit of Pediatric Hematology-Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.",
"authors": "Munier|Francis L|FL|;Gaillard|Marie-Claire|MC|;Decembrini|Sarah|S|;Bongiovanni|Massimo|M|;Beck-Popovic|Maja|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000453617",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2296-4657",
"issue": "3(2)",
"journal": "Ocular oncology and pathology",
"keywords": "Anterior chamber fluid; Aqueous seeding; Chemotherapy; Intracameral chemotherapy; Intravitreal injection; Melphalan; Pathology of the anterior segment; Retinoblastoma",
"medline_ta": "Ocul Oncol Pathol",
"mesh_terms": null,
"nlm_unique_id": "101656139",
"other_id": null,
"pages": "149-155",
"pmc": null,
"pmid": "28868287",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": "26785130;18342944;25321846;11146725;22694968;21273941;3587918;23399379;18962920;24732059;24227977;22368262;3115934;26522706",
"title": "Intracameral Chemotherapy (Melphalan) for Aqueous Seeding in Retinoblastoma: Bicameral Injection Technique and Related Toxicity in a Pilot Case Study.",
"title_normalized": "intracameral chemotherapy melphalan for aqueous seeding in retinoblastoma bicameral injection technique and related toxicity in a pilot case study"
} | [
{
"companynumb": "CH-MYLANLABS-2017M1059882",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPrimitive neuroendocrine prostate neoplasms are rarely reported. This entity comprises carcinoïd tumors and poorly differentiated neuroendocrine tumors, mainly those of the small-cell type. Large-cell-type primitive tumors are exceptional, and only nine cases are reported in the literature. Similar to neuroendocrine tumors of the prostate, large-cell-type primitive tumors may be observed in the context of conventional adenocarcinoma during androgen deprivation therapy or as prostatic metastasis of a distant neuroendocrine tumor, mainly pulmonary neoplasms.\n\n\nMETHODS\nWe report a Caucasian case of a mixed prostatic carcinoma, with the largest component being the large-cell neuroendocine carcinoma, in a patient who underwent a total prostatectomy for a localized cancer. Diagnostic, histological, therapeutic and evolutive aspects are reported and discussed.\n\n\nCONCLUSIONS\nLarge-cell primitive prostate neuroendocrine carcinoma is a rare but aggressive histological entity, which can be associated or not with an adenocarcinomatous component. Mixed forms have a better outcome, mainly when diagnosed at an early stage.",
"affiliations": "Urology Department, René Dubos Hospital, Pontoise, France.;Urology Department, René Dubos Hospital, Pontoise, France. omar.karray.88@gmail.com.;Urology Department, René Dubos Hospital, Pontoise, France.;Nuclear Medicine Department, René Dubos Hospital, Pontoise, France.;Pathology Department, René Dubos Hospital, Pontoise, France.;Pathology Department, René Dubos Hospital, Pontoise, France.;Oncology Department, René Dubos Hospital, Pontoise, France.;Centre de Radiothérapie et d'Oncologie Médicale de Pontoise, Osny, France.;Urology Department, René Dubos Hospital, Pontoise, France.;Urology Department, René Dubos Hospital, Pontoise, France.",
"authors": "Sleiman|Walid|W|;Karray|Omar|O|;Abi Abdallah|Mikael|M|;Bleichner-Perez|Sarah|S|;Kourda|Jihen|J|;Cosma-Opris|Mihaela|M|;Assouad|Sabine|S|;Riffaud|Jean-Charles|JC|;Bart|Stéphane|S|;Coloby|Patrick|P|",
"chemical_list": "D000726:Androgen Antagonists",
"country": "England",
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"doi": "10.1186/s13256-021-02830-5",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2830\n10.1186/s13256-021-02830-5\nCase Report\nLarge-cell neuroendocrine tumor of the prostate: a case report and review of the literature\nSleiman Walid 1\nKarray Omar omar.karray.88@gmail.com\n\n1\nAbi Abdallah Mikael 1\nBleichner-Perez Sarah 2\nKourda Jihen 3\nCosma-Opris Mihaela 3\nAssouad Sabine 4\nRiffaud Jean-Charles 5\nBart Stéphane 1\nColoby Patrick 1\n1 Urology Department, René Dubos Hospital, Pontoise, France\n2 Nuclear Medicine Department, René Dubos Hospital, Pontoise, France\n3 Pathology Department, René Dubos Hospital, Pontoise, France\n4 Oncology Department, René Dubos Hospital, Pontoise, France\n5 Centre de Radiothérapie et d’Oncologie Médicale de Pontoise, Osny, France\n7 5 2021\n7 5 2021\n2021\n15 25429 6 2020\n26 3 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nPrimitive neuroendocrine prostate neoplasms are rarely reported. This entity comprises carcinoïd tumors and poorly differentiated neuroendocrine tumors, mainly those of the small-cell type. Large-cell-type primitive tumors are exceptional, and only nine cases are reported in the literature. Similar to neuroendocrine tumors of the prostate, large-cell-type primitive tumors may be observed in the context of conventional adenocarcinoma during androgen deprivation therapy or as prostatic metastasis of a distant neuroendocrine tumor, mainly pulmonary neoplasms.\n\nCase presentation\n\nWe report a Caucasian case of a mixed prostatic carcinoma, with the largest component being the large-cell neuroendocine carcinoma, in a patient who underwent a total prostatectomy for a localized cancer. Diagnostic, histological, therapeutic and evolutive aspects are reported and discussed.\n\nConclusions\n\nLarge-cell primitive prostate neuroendocrine carcinoma is a rare but aggressive histological entity, which can be associated or not with an adenocarcinomatous component. Mixed forms have a better outcome, mainly when diagnosed at an early stage.\n\nKeywords\n\nNeuroendocrine carcinoma\nProstate neoplasms\nProstatectomy\nLocal neoplasm recurrences\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nThe 2016 World Health Organization’s histological classification of prostate cancer includes well-differentiated carcinoid tumors and small- or large-cell poorly differentiated tumors within the category of neuroendocrine tumors [1]. Only 20 cases of large-cell neuroendocrine prostate tumors are described in the literature, among which are nine cases of primary tumors [2]. Large-cell neuroendocrine prostate tumors are a rare histological entity whose evolutive profile and therapeutic potential differ from those of conventional adenocarcinoma. Primary prostate neuroendocrine tumors can be pure or associated with an adenocarcinomatous component. Mixed forms have better prognosis when diagnosed early at a localized stage.\n\nClinical case\n\nA 68-year-old Caucasian patient presented in September 2015 due to an elevated prostate-specific antigen (PSA) level. Past medical history included diabetes mellitus, hypertension, dyslipidemia, hyperuricemia and mild renal failure. The PSA was 6.67 ng/ml in February 2015 and 9.65 ng/ml in September 2015. Upon clinical examination, a medium-sized prostate was determined, with a palpable induration of the left lobe, clinically classified as a stage T2b cancer. Twelve ultrasound-guided prostate core biopsies were taken in October 2015. All biopsied tissue from both lobes was found to have tumor infiltration by a large-cell neuroendocrine carcinoma associated with acinar adenocarcinoma with Gleason score 7(3 + 4), with perineural invasion and without capsule infiltration. Multiparametric magnetic resonance imaging of the prostate in December 2015 showed a prostate that weighed 43 g with a suspicious lesion in the posterior peripheral zone, between the apex and the midgland of the left lobe, classified as Pi-Rads 5/5, without infiltration of seminal vesicles and without capsular invasion or pelvic adenopathy. A bone scan in November 2015 showed no bone secondaries.\n\nGiven that the majority component revealed on the biopsies was the neuroendocrine component, a 18F-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) was performed in November 2015, showing a prostate metabolic hyperfixation without suspicious distant fixation (Fig. 1).Fig. 1 18F-Fluorodeoxyglucose positron emission tomography/computed tomography: isolated metabolic uptake of the left lobe of the prostate\n\nTaking into consideration the rarity of the histological entity and the localized tumor character, we decided to carry out curative surgical treatment by radical prostatectomy with bilateral extended pelvic lymph node dissection. Surgery was performed in January 2016. Operative exploration revealed that the prostate tumor had invaded the bladder neck and trigone. Radical prostatectomy, bilateral pelvic lymph node dissection and partial cystectomy involving the bladder neck and trigone in macroscopically tumor-free limits and bilateral ureterovesical reimplantation were performed.\n\nBased on histology, we was concluded that this tumor was a bilateral mixed prostate carcinoma that had invaded 80% of the gland. The large-cell neuroendocrine component comprised 70% of the tumor and the acinar adenocarcinoma component accounted for the remaining 30%. Gleason score of the adenocarcinomatous component was 7(3 + 4). There was capsular infiltration at the base of the right lobe. The bladder neck and seminal vesicles were invaded as well as the neurovascular bands. There was also perineural invasion and vascular embolus (Fig. 2). The large-cell neuroendocrine component was confirmed by immunohistochemistry, with labeling by synaptophysin and chromogranin A, with a strong proliferative activity, as Ki67 expression was at 80% (Fig. 3).Fig. 2 Operative specimen from total prostatectomy: hematoxylin and eosin staining. Some small adenocarcinoma glands can be seen between clusters of the large-cell neuroendocrine component\n\nFig. 3 Operative specimen from total prostatectomy: immunohistochemistry. Positive labeling for chromogranin A (a) and synaptophysin (b). These two markers are positive for the neuroendocrine component and negative for the adenocarcinomatous component.\n\nAll dissected lymph nodes on the right side were negative, and one lymph node of the seven taken on the left side was metastatic, showing invasion by the large-cell neuroendocrine component. The tumor was then classified as pT4 N1 (1/13) R1. Postoperative PSA was 0.01 ng/ml. Following a multidisciplinary medical consultation, it was decided to treat the patient with chemotherapy (etoposide carboplatin [VP16]) as an adjuvant treatment, followed by radiotherapy of the prostatic bed and pelvis.\n\nA [18F]FDG PET/CT scan performed in September 2016 showed the absence of any hyper-metabolic site.\n\nChemotherapy with etoposide carboplatin (VP16) was started in February 2016, then interrupted in May 2016 following the second cycle due to renal toxicity.\n\nThe [18F]FDG PET/CT scan performed in June 2016, 6 months following surgery, showed two left latero-aortic hypermetabolic lymph nodes despite a PSA of 0.01 ng/ml. The [18F]FDG PET/CT scan in August 2016, 4 months after the end of chemotherapy, showed a significant decrease in the metabolic character of the left latero-aortic infracentimetric lymph node and the absence of a second suspicious hypermetabolic lesion; PSA was 0.01 ng/ml. Intensity-modulated radiation therapy (IMRT; 6 MV photons) of the prostatic bed was performed between November and December 2016, with 70 Gy, given in 35 sessions.\n\nThe follow-up was then planned based on the PSA level for the adenocarcinoma component and the [18F]FDG PET/CT findings for the large-cell neuroendocrine component. In July 2017 the patient presented with an elevated PSA of 2.75 ng/ml; in November 2017 the PSA was 4. 77 ng/ml. The [18F]FDG PET/CT scan in November 2017 showed bilateral supracentimetric iliac lymph nodes, poorly hypermetabolic, that were more indicative of the adenocarcinomatous component. Androgen deprivation therapy with the luteinizing hormone-releasing hormone (LHRH) agonist triptorelin was started in December 2017. The biological response was favorable; the PSA was 0.01 ng/ml and testosterone was 0.2 ng/ml 3 months after the first injection of triptorelin. The [18F]FDG PET/CT scan in June 2018, 6 months after the initiation of androgen deprivation therapy, indicated a complete metabolic response.\n\nThe follow-up was biological, with PSA measurement every 3 months for the adenocarcinomatous component and metabolic imaging with [18F]FDG PET/CT every 6 months for the large-cell neuroendocrine component. Currently, after 54 months of follow-up, the patient is still receiving androgen deprivation therapy with triptorelin with complete biological and metabolic response. At the last check-up in March 2020, PSA was 0.01 ng/ml and the [18F]FDG PET/CT scan showed a complete metabolic response.\n\nDiscussion\n\nThe first descriptions of neuroendocrine system cells are relatively recent, dating from the middle of the twentieth century. Neuroendocrine cells are usually present in prostate tissue and increasing in number after puberty. They are less frequent in acini, from which conventional adenocarcinoma of the prostate can develop. Neuroendocrine cells play a role in the growth and secretory functions of prostatic epithelium [3], and they are recognizable by the absence of androgen receptors and through labeling by certain immunohistochemical markers, such as chromogranin and synaptophysin. PSA negativity in immunohistochemistry is a fundamental criterion of neuroendocrine cell recognition [4]. It is important to note that a focal expression of PSA can be observed within neuroendocrine tumors and that high-grade acinar adenocarcinoma can also express neuroendocrine markers, thus enabling differential diagnosis with large-cell neuroendocrine tumors [2].\n\nThe incidence of neuroendocrine cells in conventional prostatic adenocarcinoma varies in the different studies that have histologically assessed primitive tumors and metastases [5].\n\nFocal neuroendocrine features in prostatic adenocarcinoma are correlated to high-grade and undifferentiated tumors. As adenocarcinomatous and neuroendocrine cells can share hybrid immunohistochemical features in some cases, it is important to consider the classical morphological aspects of neuroendocrine tumor cells. Large neuroendocrine cancer cells are usually in large nests with peripheral palisading [6].\n\nHeterogeneity in defining the neuroendocrine status in prostatic tumors can also be related to the increase in life expectancy and the awareness in detecting focal neuroendocrine foci in prostatic adenocarcinoma. Therapies based on androgen receptor signaling inhibition may also interfere with the detection of neuroendocrine features, as in the case of metastases biopsy [7, 8].\n\nTwo mechanisms are described in the pathogenesis of prostate neuroendocrine tumors. The first, most frequent, is the transdifferentiation of an acinar adenocarcinoma under long-term hormone therapy, with loss of androgen receptors. Neuroendocrine manifestations of prostate cancer are increasing because of the prolongation of survival and the use of new hormone therapies. The second mechanism is a malignant transformation of neuroendocrine cells usually present in prostatic glands [9]. This mechanism of de novo tumors is supported by carcinogenesis animal models of prostate neuroendocrine cells [10].\n\nGiven the limited number of published cases and series, the risk factors predisposing to the development of de novo neuroendocrine tumors has not been established [2]. The 2016 histological classification of tumors of the urinary and genital system described three entities of prostate neuroendocrine carcinoma: neuroendocrine differentiation of adenocarcinoma, well differentiated neuroendocrine tumors or carcinoid tumors and poorly differentiated neuroendocrine small- or large-cell tumors. The recognition of neuroendocrine tumors rests on morphological, functional and immunohistochemical criteria [1].\n\nNeuroendocrine tumors differ from adenocarcinoma by the absence of PSA secretion, resistance to hormone therapy, early metastasis and rapid progression [4]. Small-cell tumors are by far more frequent than large-cell tumors which remain exceptional. The coexistence of the two forms within the same tumor can be observed [4].\n\nLarge-cell de novo tumors are rare. The most recent review of the literature, published in 2019, lists only around 20 cases, of which 17 are about primitive prostate tumors, including seven de novo and eight following hormone therapy. Among the cases of large-cell de novo tumors, only three observations report mixed tumors with two components, neuroendocrine and adenocarcinomatous. These three cases responded favorably to hormone therapy [2]. De novo neuroendocrine tumors, either small or large cells, associated with an adenocarcinomatous component seem to have a better prognosis than pure forms because of a certain degree of hormone sensitivity. This notion of androgen dependence or resistance determines the difference in prognosis between the two forms [11]. Because of PSA secretion, mixed forms are susceptible to early diagnosis at the localized stage, providing thus the possibility of curative treatment.\n\nPure forms, not secreting PSA, are often diagnosed at an advanced stage.\n\nXiang Tu et al. report three cases of de novo large-cell pure neuroendocrine tumors, diagnosed following trans-urethral resection of the prostate, with an unfavorable course under chemotherapy [2]. Evans et al. report a similar case with a tumor classified pT3a after radical prostatectomy, with the patient presentinglocal and metastatic cerebral recurrence under adjuvant chemotherapy [5].\n\nTherapeutic possibilities are similar to thosee of lung large-cell neuroendocrine tumors and essentially involves chemotherapy given the hormone therapy resistance. The prognosis is usually unfavorable in the locally advanced and metastatic stages, with a very limited survival [12, 13].\n\nThe case we report was diagnosed at a locally advanced stage following ultrasound-guided biopsies. Considering the rarity of the histological type and the moderate renal failure that limited the possibilities of subsequent chemotherapy, we opted for radical prostatectomy rather than radiotherapy. [18]F-FDG PET/CT follow-up was justified for a better detection of neuroendocrine cell metabolism, in comparison with choline. The favorable and complete response to hormone therapy, after ganglionic recurrence, can be explained by the presence of an adenocarcinomatous component coexisting with the neuroendocrine component within the same tumor. Complete remission and relatively long survival in comparison with the previously published cases strongly depend on early diagnosis, curative initial surgical treatment and also regular imaging during the follow-up allowing an early detection and adapted treatment of lymph nodes recurrence.\n\nConclusions\n\nLarge-cell primary neuroendocrine carcinoma of the prostate is an aggressive and a rare histological entity. Curative surgery should be envisaged in localized and locally advanced forms. Hormone resistance in the pure forms limits the therapeutic arsenal for metastatic forms. The association with a hormone-sensitive adenocarcinoma component improves prognosis. The development of nuclear imaging modalities allows a better follow-up and early diagnosis of recurrence, with substantial optimized care.\n\nAcknowledgements\n\nNot applicable.\n\nAuthors' contributions\n\nWS, OK and MAA performed the surgery and conceived and designed the study. OK, MCO, JK, SBP were responsible for the acquisition of data. OK, SB, PC and SA performed the analysis and interpretation of data. WS, JCR, SB and PC gave the final approval of the version to be published. All authors read and approved the final manuscript.\n\nFunding\n\nNo funding was secured for this study.\n\nAvailability of data and materials\n\nThe authors make readily reproducible and freely available the materials described in the manuscript to any scientist wishing to use them, without breaching confidentiality. The authors make the materials described in the manuscript available for testing by reviewers in a way that preserves the reviewers’ anonymity.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNo ethics committee approval is required at our institution for a case report involving a limited number of patients.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying image. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Humphrey PA Moch H Cubilla AL Ulbright TM Reuter VE The 2016 WHO classification of tumours of the urinary system and male genital organs-part b: prostate and bladder tumours Eur Urol 2016 70 1 106 119 10.1016/j.eururo.2016.02.028 26996659\n2. Tu X Chang T Nie L Large cell neuroendocrine carcinoma of the prostate: a systematic review and pooled analysis Urol Int 2019 103 4 383 390 10.1159/000499883 30965328\n3. Abrahamsson PA Neuroendocrine differentiation in prostatic carcinoma Prostate 1999 39 135 148 10.1002/(SICI)1097-0045(19990501)39:2<135::AID-PROS9>3.0.CO;2-S 10221570\n4. Bellur S Van der Kwast T Mete O Evolving concepts in prostatic neuroendocrine manifestations: from focal divergent differentiation to amphicrine carcinoma Hum Pathol 2019 85 313 327 10.1016/j.humpath.2018.11.016 30481509\n5. Fine S Neuroendocrine tumors of the prostate Mod Pathol 2018 31 122 132 10.1038/modpathol.2017.164 28884745\n6. Epstein JI Amin MB Beltran H Proposed morphologic classification of prostate cancer with neuroendocrine differentiation Am J Surg Pathol 2014 38 6 756 767 10.1097/PAS.0000000000000208 24705311\n7. de Bono JS Logothetis CJ Molina A Abiraterone and increased survival in metastatic prostate cancer N Engl JMed 2011 364 1995 2005 10.1056/NEJMoa1014618 21612468\n8. Scher HI Fizazi K Saad F Increased survival with enzalutamide in prostate cancer after chemotherapy N Engl J Med 2012 367 1187 1197 10.1056/NEJMoa1207506 22894553\n9. Evans AJ Humphrey PA Belani J van der Kwast TH Srigley JR Large cell neuroendocrine carcinoma of prostate: a clinicopathologic summary of 7 cases of a rare manifestation of advanced prostate cancer Am J Surg Pathol 2006 30 684 693 10.1097/00000478-200606000-00003 16723845\n10. Garabedin EM Humphery PA Gordon JI A transgenic mouse model of metastatic prostate cancer originating from neuroendocrine cells Proc Natl Acad Sci USA 1998 95 15382 15387 10.1073/pnas.95.26.15382 9860977\n11. Priemer DS Montironi R Wang L Williamson SR Lopez-Beltran A Cheng L Neuroendocrine tumors of the prostate: emerging in-sights from molecular data and updates to the 2016 World Health Organization Classification Endocr Pathol 2016 27 2 123 135 10.1007/s12022-016-9421-z 26885643\n12. Tzou KY Cheng WH Lee WH Ho CH Primary large cell neuroendocrine carcinoma of the prostate in a hormone naive patient: a case report from Taiwan J Cancer Res Ther 2018 14 10 Suppl S785 S788 30249904\n13. Okoye E Choi EK Divatia M Miles BJ Ayala AG Ro JY De novo large cell neuroendocrine carcinoma of the prostate gland with pelvic lymph node metastasis: a case report with review of literature Int J Clin Exp Pathol 2014 7 12 9061 9066 25674288\n\n",
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"keywords": "Local neoplasm recurrences; Neuroendocrine carcinoma; Prostate neoplasms; Prostatectomy",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000726:Androgen Antagonists; D018278:Carcinoma, Neuroendocrine; D006801:Humans; D008297:Male; D018358:Neuroendocrine Tumors; D011471:Prostatic Neoplasms",
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"title": "Large-cell neuroendocrine tumor of the prostate: a case report and review of the literature.",
"title_normalized": "large cell neuroendocrine tumor of the prostate a case report and review of the literature"
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"abstract": "In this report, we present three cases of individuals from the same family with a diagnosis of CMT with severe tibia bone microarchitecture deterioration assessed by HR-pQCT. Charcot-Marie-Tooth disease (CMT) or hereditary neuropathy involves both motor and sensory nerves. Falls are often the first manifestation in these patients and represent an important risk factor for fracture. The reduction of mechanical input on bone inhibits bone formation by osteoblasts and accelerates bone resorption by osteoclasts, leading to disuse osteoporosis. We report three cases of individuals from the same family with a diagnosis of CMT with severe tibia bone microarchitecture deterioration assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT). This affectation was exclusive to the tibia; the radius remained undamaged, showing the consequences of the lack of mobility and mechanical stimulation. Physical activity and rehabilitation, in addition to adequate calcium and vitamin D supplementation, may play an essential role in the management of this disease.",
"affiliations": "IDIM, Libertad 836, 1st Floor, Zip code 1012, Buenos Aires, Argentina. dr.rubenabdala@gmail.com.;IDIM, Libertad 836, 1st Floor, Zip code 1012, Buenos Aires, Argentina.;IDIM, Libertad 836, 1st Floor, Zip code 1012, Buenos Aires, Argentina.;IDIM, Libertad 836, 1st Floor, Zip code 1012, Buenos Aires, Argentina.",
"authors": "Abdala|R|R|http://orcid.org/0000-0003-0442-8664;Levi|L|L|;Longobardi|V|V|;Zanchetta|M B|MB|",
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"issue": "31(12)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": "Charcot-Marie-Tooth; Disuse osteoporosis; Mechanostat; Microarchitecture",
"medline_ta": "Osteoporos Int",
"mesh_terms": "D015519:Bone Density; D001842:Bone and Bones; D009477:Hereditary Sensory and Autonomic Neuropathies; D006801:Humans; D010024:Osteoporosis; D011884:Radius; D013977:Tibia",
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"title": "Severe bone microarchitecture deterioration in a family with hereditary neuropathy: evidence of the key role of the mechanostat.",
"title_normalized": "severe bone microarchitecture deterioration in a family with hereditary neuropathy evidence of the key role of the mechanostat"
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"abstract": "BACKGROUND\nTdP is a form of polymorphic ventricular tachycardia which develops in the setting of a prolonged QT interval. There are limited data describing risk factors, treatment, and outcomes of this potentially fatal arrhythmia.\n\n\nOBJECTIVE\nOur goals were as follows: (1) to validate cases presenting with Torsade de Pointes (TdP), (2) to identify modifiable risk factors, and (3) to describe the management strategies used for TdP and its prognosis in a real-world healthcare setting.\n\n\nMETHODS\nCase-control study (with 2:1 matching on age, sex, and race/ethnicity) nested within the Genetic Epidemiology Research on Aging (GERA) cohort. Follow-up of the cohort for case ascertainment was between January 01, 2005 and December 31, 2018.\n\n\nRESULTS\nA total of 56 cases of TdP were confirmed (incidence rate = 3.6 per 100,000 persons/years). The average (SD) age of the TdP cases was 74 (13) years, 55 percent were female, and 16 percent were non-white. The independent predictors of TdP were potassium concentration <3.6 mEq/L (OR = 10.6), prior history of atrial fibrillation/flutter (OR = 6.2), QTc >480 ms (OR = 4.4) and prior history of coronary artery disease (OR = 2.6). Exposure to furosemide and amiodarone was significantly greater in cases than in controls. The most common treatment for TdP was IV magnesium (78.6%) and IV potassium repletion (73.2%). The in-hospital and 1-year mortality rates for TdP cases were 10.7% and 25.0% percent, respectively.\n\n\nCONCLUSIONS\nThese findings may inform quantitative multivariate risk indices for the prediction of TdP and could guide practitioners on which patients may qualify for continuous ECG monitoring and/or electrolyte replacement therapy.",
"affiliations": "Department of Cardiology, Kaiser Permanente San Francisco Medical Center, San Francisco, CA, USA.;Division of Research, Kaiser Permanente, Oakland, CA, USA.;Department of Cardiology, Kaiser Permanente San Francisco Medical Center, San Francisco, CA, USA.;Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.;Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.;Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.;Division of Research, Kaiser Permanente, Oakland, CA, USA.;Division of Research, Kaiser Permanente, Oakland, CA, USA.",
"authors": "Mantri|Neha|N|;Lu|Meng|M|;Zaroff|Jonathan G|JG|;Risch|Neil|N|;Hoffmann|Thomas|T|;Oni-Orisan|Akinyemi|A|;Lee|Catherine|C|;Iribarren|Carlos|C|https://orcid.org/0000-0001-5622-1839",
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"fulltext": "\n==== Front\nAnn Noninvasive Electrocardiol\nAnn Noninvasive Electrocardiol\n10.1111/(ISSN)1542-474X\nANEC\nAnnals of Noninvasive Electrocardiology\n1082-720X\n1542-474X\nJohn Wiley and Sons Inc. Hoboken\n\n34547155\n10.1111/anec.12888\nANEC12888\nOriginal Article\nOriginal Articles\nTorsade de pointes: A nested case–control study in an integrated healthcare delivery system\nMANTRI et al.\nMantri Neha MD 1\nLu Meng MD, MS 2\nZaroff Jonathan G. MD 1\nRisch Neil PhD 3\nHoffmann Thomas PhD 3 4\nOni‐Orisan Akinyemi PharmD, PhD 3\nLee Catherine PhD 2\nIribarren Carlos MD, MPH, PhD https://orcid.org/0000-0001-5622-1839\n2 Carlos.Iribarren@kp.org\n\n1 Department of Cardiology Kaiser Permanente San Francisco Medical Center San Francisco CA USA\n2 Division of Research Kaiser Permanente Oakland CA USA\n3 Institute for Human Genetics University of California, San Francisco San Francisco CA USA\n4 Department of Epidemiology and Biostatistics University of California, San Francisco San Francisco CA USA\n* Correspondence\nCarlos Iribarren MD, MPH, PhD, Division of Research, Kaiser Permanente Medical Care Program, 2000 Broadway, Oakland, CA 94612, USA.\nEmail: Carlos.Iribarren@kp.org\n\n21 9 2021\n1 2022\n27 1 10.1111/anec.v27.1 e1288829 7 2021\n21 8 2021\n© 2021 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nBackground\n\nTdP is a form of polymorphic ventricular tachycardia which develops in the setting of a prolonged QT interval. There are limited data describing risk factors, treatment, and outcomes of this potentially fatal arrhythmia.\n\nObjective\n\nOur goals were as follows: (1) to validate cases presenting with Torsade de Pointes (TdP), (2) to identify modifiable risk factors, and (3) to describe the management strategies used for TdP and its prognosis in a real‐world healthcare setting.\n\nMethods\n\nCase–control study (with 2:1 matching on age, sex, and race/ethnicity) nested within the Genetic Epidemiology Research on Aging (GERA) cohort. Follow‐up of the cohort for case ascertainment was between January 01, 2005 and December 31, 2018.\n\nResults\n\nA total of 56 cases of TdP were confirmed (incidence rate = 3.6 per 100,000 persons/years). The average (SD) age of the TdP cases was 74 (13) years, 55 percent were female, and 16 percent were non‐white. The independent predictors of TdP were potassium concentration <3.6 mEq/L (OR = 10.6), prior history of atrial fibrillation/flutter (OR = 6.2), QTc >480 ms (OR = 4.4) and prior history of coronary artery disease (OR = 2.6). Exposure to furosemide and amiodarone was significantly greater in cases than in controls. The most common treatment for TdP was IV magnesium (78.6%) and IV potassium repletion (73.2%). The in‐hospital and 1‐year mortality rates for TdP cases were 10.7% and 25.0% percent, respectively.\n\nConclusions\n\nThese findings may inform quantitative multivariate risk indices for the prediction of TdP and could guide practitioners on which patients may qualify for continuous ECG monitoring and/or electrolyte replacement therapy.\n\ncase\ncontrol study\nlong QT syndrome\nrisk factors\ntorsade de pointes\nNational Heart and Lung Institute 10.13039/501100000850 RO1HL140924 source-schema-version-number2.0\ncover-dateJanuary 2022\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.7.0 mode:remove_FC converted:07.01.2022\nMantri, N. , Lu, M. , Zaroff, J. G. , Risch, N. , Hoffmann, T. , Oni‐Orisan, A. , Lee, C. , & Iribarren, C. (2022). Torsade de pointes: A nested case–control study in an integrated healthcare delivery system. Annals of Noninvasive Electrocardiology, 27 , e12888. 10.1111/anec.12888\n==== Body\npmc1 INTRODUCTION\n\nTorsade de Pointes (TdP), first described in 1966,(La, 1966) is a potentially life‐threatening polymorphic ventricular tachycardia associated with prolongation of the QT interval on the 12‐lead electrocardiogram (ECG).(Fontaine et al., 1982; Gupta et al., 2007) Because TdP is a rare diagnosis without specific International Classification of Diseases (ICD)‐9 or ICD‐10 codes, there are limited data describing clinical risk factors and management strategies for this malignant arrhythmia.(Kay et al., 1983).\n\nThe established risk factors for TdP include older age, female sex, heart disease, electrolyte disorders (especially hypokalemia and hypomagnesemia), renal or hepatic dysfunction, bradycardia or rhythms with long pauses, treatment with more than 1 QT‐prolonging drug, and genetic predisposition.(Drew et al., 2010; Faber et al., 1994).\n\nThe goal of this study was twofold: first, to validate a case series of patients presenting with TdP and compare these patients to age‐, sex‐, and race/ethnicity‐ 2:1 matched controls in order to identify modifiable risk factors and secondly, to describe the management strategies used for TdP and the short‐term survival and long‐term survival in a real‐world healthcare setting.\n\n2 MATERIALS AND METHODS\n\n2.1 Population and study design\n\nKaiser Permanente Medical Care Program (KPMCP) of Northern California is an integrated healthcare delivery system serving approximately 4.5 million members. The membership is stable with less than 10% turnover annually overall and <3%–5% among members 65 years of age and older and/or who have a chronic condition. The program delivers comprehensive inpatient and outpatient care to its members and captures many aspects of its care using its multiple comprehensive clinical and administrative databases. Kaiser's population is ethnically and socio‐economically diverse and is broadly representative of the Northern California population.(Krieger, 1992).\n\nOur study was based on the GERA (Genetic Epidemiology Research on Aging) cohort. The goal of the GERA cohort was to create a large, multiethnic, and comprehensive population‐based resource into the genetic and environmental basis of common age‐related diseases and their treatment, and factors influencing healthy aging and longevity.(Banda et al., 2015; Kvale et al., 2015) The GERA cohort consists of a diverse cohort of 110,266 members of the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC) aged 18 and older, who participated in the KPNC Research Program on Genes, Environment, and Health (RPGEH) and provided a saliva sample for DNA analyses. The RPGEH utilizes the longitudinal electronic health records (EHR) of KPNC to obtain clinical, laboratory, imaging, and pharmacy information on all cohort members, to which personal demographic, behavioral, and health characteristics have been added through member surveys.\n\nWe used ICD‐9 code 427.1 and ICD‐10 code I47.2, augmented with natural language processing (NLP), to identify all cohort members who developed paroxysmal ventricular tachycardia between January 1, 2005, and December 31, 2018. We identified a total of 2,528 subjects with a code for paroxysmal ventricular tachycardia, and, among them, 132 had a mention of “torsade” or “torsades” in the medical record. Manual chart review, including examination of 12‐lead ECGs, telemetry strips, ambulatory ECGs, and medical documentation, was performed for these 132 patients to confirm “true” TdP events. The final cohort of patients with a confirmed TdP event by a cardiologist (N.M.) comprised 56 persons. The 76 patients without validated TdP events typically mentioned \"torsade\" within the differential diagnosis given baseline risk factors for TdP (prolonged baseline QTc, electrolyte abnormalities, use of multiple QT‐prolonging pharmacotherapies) or documented possible \"torsade\" based on inpatient telemetry monitoring. However, none of these patients had a confirmed \"torsade\" event documented in the electronic medical record by a physician. A second physician investigator (C.I.) reviewed 25 randomly selected eligible cases for review, and agreement with the first adjudicator was 100% (12 true cases out of 25). Thus, our code plus NLP algorithm to identify and validate TdP had a positive predictive value of 42% (56/132). Each of these TdP patients was matched with 2 controls with the same birth year, sex, and race/ethnicity. Moreover, control subjects were assigned an “index” date which was the hospitalization date of the corresponding matched case.\n\nIn both cases and controls, gender, date of birth, and race/ethnicity were obtained from the patient's demographic file. Diabetes was ascertained through linkage with the KPNC Diabetes Registry.(Karter, 2006) The prevalence of other comorbidities, laboratory values, body mass index (BMI), and smoking status was extracted from the EHR. A list of ICD‐9, ICD‐10, and current procedural terminology, fourth version (CPT4) codes is provided in (online‐only) Appendix SA. Baseline QTc interval (with Bazett correction), available from a Regional ECG database, was from the most recent 12‐lead ECG prior to index admission for TdP or assigned index date for controls, going back up to 5 years. Event QTc (only in cases) was determined from the baseline 12‐lead ECG available during the hospitalization where the TdP event occurred. The methodology and validity of the QT measurement at KPNC can be found elsewhere.(Iribarren et al., 2013, 2014) In brief, all ECGs in the KPNC system are obtained using cardiographs manufactured by Philips Medical Systems (Andover, Massachusetts) which have a proprietary algorithm for QT measurement.(Kligfield et al., 2006) Bazett's correction for heart rate was used because is widely utilized in clinical practice.(Bazett, 1920) Hypokalemia was defined as a potassium level of lower than 3.6 millimoles per liter (mmol/L). Hypomagnesemia was defined as a serum magnesium level of lower than 1.5 milligrams per deciliter (mg/dl). Late‐stage chronic kidney disease was defined by an estimated glomerular filtration rate(Levey et al., 2009) of less than 30 milliliter per min (ml/min) or by codes for chronic dialysis. Active prescriptions for QT‐prolonging medications (as listed in Crediblemeds.org, accessed on 9/10/2020) as well as cholesterol‐lowering drugs prescribed within a 60‐day window prior to index hospitalization for TdP cases or index date for controls were identified utilizing the KPNC outpatient pharmacy database. Discharge disposition for cases and 30‐day, 6‐month, and one‐year mortality for both cases and controls were ascertained using complimentary validated sources of mortality in KPNC.(Arellano et al., 1984).\n\nAdditional variables were obtained through electronic chart review of unstructured fields in the EHR, including concomitant surgery, congenital long QT syndrome, left ventricular ejection fraction (EF) to characterize prior history of heart failure as heart failure with preserved ejection fraction (HFpEF; EF≥45%) or heart failure with reduced ejection fraction [HFrEF; EF<45%], and left ventricular hypertrophy (LVH; defined as at least 1.2 cm posterior wall or interventricular septal wall thickness). EF data from transthoracic echocardiograms (TTEs) were available in 32 TdP cases out of 33 and in 20 controls out of 21 with prior history of heart failure. LVH data were available from TTE performed within two years prior to the index hospitalization or index date for controls in 53 cases and 65 controls. Inpatient treatment for TdP management strategies, development of sustained ventricular fibrillation, cardiac arrest, and issuance of advanced directives and do not resuscitate (DNR) orders were determined via chart review. The study was approved by the Kaiser Foundation Research Institute Institutional Review Board.\n\n2.2 Statistical analysis\n\nCase–control differences were assessed using the t test for continuous variables and the chi‐square test for categorical variables. To determine independent predictors of TdP, we used conditional logistic regression with stepwise entry of covariates and a p value threshold to stay in the model of 0.05. To retain all subjects in the model, we created a dummy variable for missing LVH. All the statistical analyses were performed with SAS version 9.4. (SAS Institute Inc., North Carolina, USA).\n\n3 RESULTS\n\nOur TdP case validation over a 14‐year period provides a population‐based estimate of 3.6 cases of TdP per 100,000 persons per year. The 56 patients with confirmed TdP were, on average, 74 years old (SD = 13 years); 25 (45%) were men and 31 (55%) women. The majority of TdP cases were white (84%), and a small portion were black/African American (3.6%), Asian & Pacific Islander (3.6%), or mixed race (8.9%) (Table 1). There were no significant differences between cases and controls in body mass index, smoking status, or cholesterol‐lowering medication use. The baseline QTc was 458 ± 40 ms in cases and 432 ± 35 ms in controls (p < .0001). Prolonged QTc (i.e., >480 ms) was present in 30 percent of cases and 10 percent of controls (p = .0008). The mean (SD) delta (event baseline) QTc in cases was 48 (53) ms. The average serum potassium level was lower in cases than in controls (3.7 vs. 4.3 mEq/L; p < .0001), and the proportion with low potassium (<3.6 mEq/L) was greater in cases than in controls (30 vs. 4.5%; p < .0001). Average magnesium concentrations did not significantly differ between TdP cases and controls, but the proportion with low magnesium was higher in cases than in controls (10 vs. 0%; p = .01).\n\nTABLE 1 Baseline characteristics of TdP cases and controls\n\n\tTdP Cases N = 56\tControls n = 112\tp\t\nAge, years\t73.6 ± 12.9\t73.7 ± 12.7\t0.98\t\nGender, (%)\t\nFemale\t31 (55.4%)\t62 (55.4%)\t1.00\t\nMale\t25 (44.6%)\t50 (44.6%)\t\nRace, n (%)\t\nWhite\t47 (83.9%)\t94 (83.9%)\t1.00\t\nBlack/African American\t2 (3.6%)\t4 (3.6%)\t\nAsian & Pacific Islander\t2 (3.6%)\t4 (3.6%)\t\nMixed race\t5 (8.9%)\t10 (8.9%)\t\nBody mass index, Kg/m2\t27.9 ± 5.9\t28.8 ± 7.6\t0.44\t\nSmoking status, n (%)\t\nCurrent\t4 (7.1%)\t5 (4.5%)\t0.55\t\nFormer\t24 (42.9%)\t57 (50.9%)\t\nNever\t26 (46.4%)\t43 (38.4%)\t\nMissing\t2 (3.6%)\t7 (6.3%)\t\nCholesterol‐lowering medication, n 9%)\t43 (76.8%)\t78 (69.6%)\t0.33\t\nBaseline QTc, ms\t458 ± 40\t432 ± 35\t<0.0001\t\nMissing baseline QTc, n (%)\t4 (7%)\t0\t\t\nBaseline QTc ≥480 ms, n (%)\t17 (30.4%)\t11 (9.8%)\t0.0008\t\nEvent QTc, ms\t504 ± 54\tNA\t\t\n∆ QTc, ms\t48 ± 53\tNA\t\t\nPotassium, mEq/L\t3.7 ± 0.8\t4.3 ± 0.5\t<0.0001\t\nPotassium <3.6 mEq/L, n (%)\t17 (30.4%)\t5 (4.5%)\t<0.0001\t\nMissing potassium, n (%)\t2 (4%)\t3 (3%)\t\t\nMagnesium, mEq/L\t1. ± 0.6\t2.0 ± 0.2\t0.36\t\nMagnesium <1.5 mg, n (%)\t5 (10.0%)\t0 (0)\t0.01\t\nMissing magnesium, n (%)\t6 (11%)\t53 (47%)\t\t\nJohn Wiley & Sons, Ltd\n\nSeveral prevalent comorbidities were found to differ between the two groups with a higher prevalence seen among the TdP cases, including the following: coronary artery disease (p = .003), HFpEF (p = .01), HFrEF (p = .0001), any cardiomyopathy (p < .0001), atrial fibrillation/flutter (p < .0001), left ventricular hypertrophy (p = .01), left bundle branch block (p = .0002), cardiac pacemaker (p = .02), automatic implantable cardioverter‐defibrillator (p = .0003), cardiac arrest (p < .0001), any valvular heart disease (p = .001), and late‐stage chronic kidney disease (p = .001) (Table 2). We also observed non‐significant trends for higher prevalence of diabetes, hypertension, stroke, HFpEF, bradycardia, pulmonary valve stenosis/regurgitation, and chronic liver disease among cases relative to controls.\n\nTABLE 2 Prevalent comorbidities of TdP cases and controls\n\nComorbidities\tTdP cases n=56\tControls n=112\tp\t\nDiabetes\t18 (32.1%)\t28 (25.0%)\t.33\t\nHypertension\t44 (78.6%)\t72 (64.3%)\t.06\t\nCoronary artery disease\t26 (46.4%)\t27 (24.1%)\t.003\t\nTransient ischemic attack\t8 (14.3%)\t12 (10.7%)\t.50\t\nIschemic stroke\t8 (14.3%)\t6 (5.4%)\t.05\t\nHemorrhagic stroke\t1 (1.8%)\t1 (0.9%)\t.62\t\nAny cerebrovascular disease\t11 (19.6%)\t15 (13.4%)\t.29\t\nHeart failure with preserved ejection fraction (HFpEF)\t16 (28.6%)\t15 (13.4%)\t.01\t\nHeart failure with reduced ejection fraction (HFrEF)\t16 (28.6%)\t5 (4.5%)\t<.0001\t\nHeart failure with unknown ejection fraction\t1 (1.7%)\t1 (0.9%)\t.80\t\nAny heart failure\t33 (58.9%)\t21 (18.7%)\t<.0001\t\nIschemic cardiomyopathy\t9 (16.1%)\t2 (1.8%)\t.0004\t\nNon‐ischemic cardiomyopathy\t14 (25.0%)\t5 (4.5%)\t<.0001\t\nAny cardiomyopathy\t16 (28.6%)\t6 (5.4%)\t<.0001\t\nBradycardia\t5 (8.9%)\t5 (4.5%)\t.25\t\nAtrial fibrillation/flutter\t34 (60.7%)\t32 (28.6%)\t<.0001\t\nParoxysmal supraventricular tachycardia\t3 (5.4%)\t5 (4.5%)\t.79\t\nLeft ventricular hypertrophy (LVH)\t16 (28.5%)\t14 (12.5%)\t.01\t\nUnknown left ventricular hypertrophy (LVH)\t3 (5.3%)\t47 (41.9%)\t<.0001\t\nLeft bundle branch block\t11 (19.6%)\t3 (2.7%)\t.0002\t\nRight bundle branch block\t2 (3.6%)\t4 (3.6%)\t1.0000\t\nAny bundle branch block\t13 (23.2%)\t7 (6.3%)\t.001\t\nCardiac pacemaker\t10 (17.9%)\t7 (6.3%)\t.02\t\nAutomatic implantable cardioverter‐defibrillator (AICD)\t8 (14.3%)\t1 (0.9%)\t.0003\t\nCardiac arrest\t19 (33.9%)\t2 (1.8%)\t<.0001\t\nMitral valve stenosis/regurgitation\t14 (25.0%)\t10 (8.9%)\t.005\t\nAortic valve stenosis/regurgitation\t13 (23.2%)\t10 (8.9%)\t.01\t\nTricuspid valve stenosis/regurgitation\t11 (19.6%)\t3 (2.7%)\t.0002\t\nPulmonary valve stenosis/regurgitation\t0 (0.0%)\t1 (0.9%)\t.48\t\nAny heart valve disease\t23 (41.1%)\t20 (17.9%)\t.001\t\nLate‐stage chronic kidney disease\t28 (50.0%)\t28 (25.0%)\t.001\t\nChronic liver disease\t5 (8.9%)\t5 (4.5%)\t.25\t\nJohn Wiley & Sons, Ltd\n\nThe ten most common QT‐prolonging prescriptions administered to TdP cases within 60 days of index hospitalization and overall percentages of “other” and “any” QT‐prolonging medications (along with corresponding prescription utilization in controls also within 60 days prior to their index date) are shown in Table 3. TdP cases were significantly more likely to have been prescribed furosemide (17.7% vs. 6.5%; p = .007), amiodarone (7.3% vs. 0.0%; p = .001), and “any” QT‐prolonging drugs (80.2% vs. 57.6%; p = .0003). On the other hand, controls were more likely to have been prescribed “other” (i.e., other than the 10 most common among cases) QT‐prolonging drugs (43.8% vs. 69.8%; p < .0001). The full list of QT‐prolonging drugs is provided as (online‐only) Appendix SB.\n\nTABLE 3 QT‐prolonging drugs* in TdP cases and controls\n\nDrug\tTdP Cases (n = 56)\tControls (n = 112)\tp\t\nFurosemide\t17 (17.7%)\t9 (6.5%)\t.007\t\nHydrochlorothiazide\t8 (8.3%)\t6 (4.3%)\t.20\t\nOmeprazole\t8 (8.3%)\t10 (7.2%)\t.75\t\nAmiodarone\t7 (7.3%)\t0 (0.0%)\t.001\t\nFamotidine\t3 (3.1%)\t7 (5.0%)\t.47\t\nMirtazapine\t3 (3.1%)\t1 (0.7%)\t0.16\t\nEscitalopram\t2 (2.1%)\t0 (0.0%)\t.08\t\nHydrocodone Bitartrate/Acetaminophen\t2 (2.1%)\t8 (5.8%)\t.17\t\nSotalol\t2 (2.1%)\t1 (0.7%)\t.35\t\nTorsemide\t2 (2.1%)\t0 (0.0%)\t.08\t\nOther\t42 (43.8%)\t97 (69.8%)\t<.0001\t\nAny\t77 (80.2%)\t80 (57.6%)\t.0003\t\n*10 most common in cases.\n\nJohn Wiley & Sons, Ltd\n\nStepwise conditional logistic regression analysis was performed to determine independent risk factors for TdP development within our 56 cases compared with the 112 matched controls. Statistically significant risk factors included the following: potassium concentration <3.6 mEq/L (OR = 10.6; p < .0001), atrial fibrillation/flutter (OR = 6.2; p < .0001), QTc >480 ms (OR = 4.4; p = .01), and prior history of coronary artery disease (OR = 2.6; p = .03) (Table 4).\n\nTABLE 4 Independent predictors of TdP by stepwise conditional logistic regression in the full sample of cases (n = 56) and controls (n = 112)\n\nIndependent Predictors\tOR (95% CI)\tp\t\nPotassium <3.6 mEq/L\t10.6 (2.54–43.9)\t<.0001\t\nAtrial fibrillation/flutter\t6.25 (2.13–18.3)\t<.0001\t\nQTc >480 ms\t4.38 (1.19–16.1)\t.01\t\nCoronary artery disease\t2.59 (1.06–6.34)\t.03\t\nJohn Wiley & Sons, Ltd\n\nTdP resulted in cardiac arrest in 44 patients (78.6%) and sustained ventricular fibrillation in 31 (55.4%) of patients. None of the cases had been admitted for surgical procedures, and two cases (3.6%) and no controls (0%) had a prior diagnosis of congenital long QT syndrome.\n\nThe most frequent treatment for TdP was intravenous magnesium sulfate (78.6%) and intravenous potassium chloride (73.2%). Anti‐arrhythmic drug therapies, including lidocaine (48.2%) and amiodarone (35.7%), were utilized less commonly. Overdrive pacing internally (transvenous pacemaker or permanent pacemaker) or externally (intravenous dopamine or isoproterenol) was utilized in 12 out of the 56 (21.4%) TdP patients. A total of 17 out of the 51 (33.3%) patients underwent cardiopulmonary resuscitation with defibrillation. Of note, five patients had an active do not resuscitate (DNR) directive within their medical record.\n\nSix out of 56 TdP patients (10.7%) died during the hospitalization. The underlying cause of death was aspiration pneumonia (n = 2), cardiogenic shock (n = 1), severe sepsis (n = 1), ventricular tachycardia (n = 1), and myocarditis (n = 1). Eight died within 1 year after discharge, yielding a cumulative mortality of 25.0% at 1 year. After hospital discharge, 1 death occurred within 30 days, 1 death between 30 days and 6 months, and 6 deaths between 6 months and 1 year. All controls were alive one year after their “index date” hospitalization.\n\n4 DISCUSSION\n\nOur study confirms that TdP is a rare occurrence (3.6 cases per 100,000 per year) with serious consequences: 55 percent developed sustained ventricular fibrillation, 11 percent died in the hospital, and 17 percent died within 12 months of discharge. Our rate (which was derived from a population‐based cohort) is lower than the incidence reported in a Belgian study (34 per 100,000 per year) that was based on patients admitted to a tertiary hospital in a 3‐year period(Vandael et al., 2017a) but higher than the incidence of drug‐induced LQTS/TdP in Berlin (0.25 per 100,000 per year in males and 0.40 per 100,000 per year in females) determined by active surveillance of 51 hospitals between 2008 and 2011.(Sarganas et al., 2014).\n\nThe independent risk factors for TdP included, in order of strength of association, hypokalemia (i.e., potassium concentration <3.6 mEq/L), prior history of atrial fibrillation/flutter, prolonged QTc (>480 ms), and prior history of coronary artery disease. Other risk factors that were significantly different between TdP cases and controls in a univariate analysis did not emerge as statistically significant predictors in the multivariate context. This could be the result of limited statistical power and the fact that these variables were often highly correlated with each other.\n\nCertain electrophysiological events are known to be associated with the development of TdP; drugs which prolong the action potential duration (APD), induce early afterdepolarizations and ectopic beats, and increase the dispersion of ventricular repolarization are more likely to result in increased risk of arrhythmia and TdP development. Prolongation of the ventricular APD by inhibition of the IKr current is the primary mechanism of Class III anti‐arrhythmic agents (i.e., dofetilide, amiodarone, and sotalol), which are often used in management of arrhythmias in heart failure patients. However, with prolongation of the APD and QT interval, these treatments are known to be arrhythmogenic, with increased risk of TdP development.(Belardinelli et al., 2003) Some clinical trials have suggested congestive heart failure to elevate the risk of TdP due to higher use of anti‐arrhythmic therapy with blocking of the IKr current, as stated above.(Roden et al., 2007) Low extracellular potassium paradoxically reduces IKr by enhanced inactivation or exaggerated competitive block by sodium leading to QT prolongation and dispersion of repolarization; prompt correction of extracellular potassium levels can quickly shorten the QT interval and associated morphologic abnormalities.(Kallergis et al., 2012) This literature is in line with our results showing exposure to two QT‐prolonging drugs occurred significantly more frequently in TdP cases than in controls: amiodarone (a Class III anti‐arrhythmic) and furosemide (a loop diuretic). The association of diuretic use with in‐hospital TdP can be explained by its correlation with congestive heart failure and electrolyte derangements, such as hypokalemia. Our results are also in line with case reports linking TdP with cardiomyopathy (Kurisu et al., 2008) and renal disease.(Patane et al., 2008).\n\nIn a scientific statement from the American Heart Association and the American College of Cardiology Foundation, Drew et al. state a gradual increase in QTc interval increases the risk of TdP development with each 10‐ms increase in QTc leading to a 5%–7% exponential increase in the risk for TdP.(Drew et al., 2010) Within our cohort, we observed an average increase of 48 ms in QTc between the baseline and the event QT among the TdP cases. This absolute increase in QTc helps to identify patients who should have continuous ECG monitoring. At present, no quantitative multivariate risk index exists for the prediction of TdP in the hospital‐based population. Several risk factors have been postulated based on pathophysiologic mechanisms and small case series; however, our real‐world and largest case–control study was able to uniquely identify several independent risk predictors which can guide practitioners on which patients may qualify for continuous QTc or ECG monitoring and/or electrolyte replacement therapy.\n\nSimilar to the case series by Kay et al, we also found pre‐existing structural heart disease, arrhythmias, hypokalemia, and QT‐prolonging medications to be commonly seen in patients who develop TdP.(Kay et al., 1983) Kay et al. found quinidine to be the most common QT‐prolonging medication; however, in recent years the use of quinidine has substantially reduced and other QT‐prolonging medications such as amiodarone and furosemide are more commonly seen. Kay et al. stated the effectiveness of drug treatment was unpredictable and unreliable since so few cases had been reported.\n\nThe most common treatment utilized for TdP was intravenous magnesium. Most patients also received IV potassium repletion, regardless of potassium levels. One‐third of patients underwent defibrillation and about one‐fifth of patients were internally or externally overdrive paced. Overdrive pacing by a transvenous pacemaker, increasing the baseline permanent pacemaker rate, or increasing the heart rate by pharmacologic means (intravenous dopamine or isoproterenol) was used in hopes of shortening the QT interval and terminating TdP. Given the known QT‐prolonging side effects of amiodarone, anti‐arrhythmic treatment with intravenous amiodarone was used less commonly.\n\nWe highlight one example from our case series describing the development and management of TdP. He is an 82‐year‐old man with history of coronary artery bypass grafting, dual‐chamber permanent pacemaker for complete heart block, ischemic cardiomyopathy with a left ventricular ejection fraction of 45%, and prostate cancer on chronic ketoconazole therapy who presented with syncope at home. Upon arrival to the emergency department, he suffered recurrent loss of consciousness and 12‐lead ECG was performed demonstrating polymorphic ventricular tachycardia (Figure 1). He was immediately treated with initiation of intravenous lidocaine, intravenous magnesium sulfate, and intravenous potassium chloride. All QT‐prolonging medications, including his chronic ketoconazole treatment, were stopped. He was successfully treated by increasing the lower rate limit on his dual‐chamber permanent pacemaker to shorten the QT interval and prevent future TdP. He was discharged from the hospital alive with no recurrent polymorphic ventricular tachycardia.\n\nFIGURE 1 Illustrative example of a 12‐lead ECG of a patient presenting with TdP\n\nWe recognize several limitations in our case–control study. First, our sample size was small given the rare nature of TdP, limiting statistical power. Second, although we leveraged a real‐world population with ethnic diversity, all patients included were insured, and thus, our results may not generalize to uninsured populations. Third, we did not consider genetic data since this is part of a separate effort and is beyond the scope of this manuscript. Fourth, we did not develop RISQ‐PATH scores because of missing hs‐CRP values.(Vandael, Vandenberk, Vandenberghe, Spriet, et al., 2017).\n\nTdP is an uncommon but potentially fatal arrhythmia due to selective potential of action potential durations in certain layers of the ventricular myocardium leading to dispersion of repolarization and a prolonged QT interval. In light of the recent COVID‐19 pandemic and the use of off‐label treatment strategies for SARS‐CoV‐2 which are known to prolong QTc, there is heightened importance of identifying risk predictors for TdP development reported showing intravenous potassium and magnesium repletion and overdrive pacing to be the most commonly utilized strategies.\n\nFurther research is needed to understand the combined effects of predisposing genetic makeup, medication effects, and clinical risk factors. Thereafter, appropriate mitigation and management strategies can be fully understood.\n\nCONFLICT OF INTEREST\n\nThe authors have no conflicts to disclose.\n\nETHICAL APPROVAL\n\nThis study was approved by the Kaiser Foundation Research Institute Institutional Review Board and the requirement for informed consent was waived.\n\nAUTHOR CONTRIBUTIONS\n\nNeha Mantri, Wrote the manuscript, approved final version. Meng Lu, Statistical analysis, approved final version. Jonathan G. Zaroff, Critical review, approved final version. Neil Risch, Critical review, approved final version. Thomas Hoffmann, Critical review, approved final version. Akinyemi Oni‐Orisan, Critical review, approved final version. Catherine Lee, Statistical methods, approved final version. Carlos Iribarren, Cowrote the manuscript, approved final version.\n\nSupporting information\n\nSupplementary Material\n\nClick here for additional data file.\n\nSupplementary Material\n\nClick here for additional data file.\n\nACKNOWLEDGEMENT\n\nThis work was supported by the National Heart, Lung, and Blood Institute (RO1HL140924; PI, Iribarren C).\n\nDATA AVAILABILITY STATEMENT\n\nNo individual data are available, but authors would contemplate reasonable requests.\n==== Refs\nREFERENCES\n\nArellano, M. G. , Petersen, G. R. , Petitti, D. B. , & Smith, R. E. (1984). The California Automated Mortality Linkage System (CAMLIS). American Journal of Public Health, 74 (12 ), 1324–1330. 10.2105/AJPH.74.12.1324 6507683\nBanda, Y. , Kvale, M. N. , Hoffmann, T. J. , Hesselson, S. E. , Ranatunga, D. , Tang, H. , Sabatti, C. , Croen, L. A. , Dispensa, B. P. , Henderson, M. , Iribarren, C. , Jorgenson, E. , Kushi, L. H. , Ludwig, D. , Olberg, D. , Quesenberry, C. P. , Rowell, S. , Sadler, M. , Sakoda, L. C. , … Risch, N. (2015). Characterizing race/ethnicity and genetic ancestry for 100,000 subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort. Genetics, 200 (4 ), 1285–1295. 10.1534/genetics.115.178616 26092716\nBazett, H. (1920). An analysis of the time‐relations of electrocardiograms. Heart, 7 , 353–370.\nBelardinelli, L. , Antzelevitch, C. , & Vos, M. A. (2003). Assessing predictors of drug‐induced torsade de pointes. Trends in Pharmacological Sciences, 24 (12 ), 619–625. 10.1016/j.tips.2003.10.002 14654302\nDrew, B. J. , Ackerman, M. J. , Funk, M. , Gibler, W. B. , Kligfield, P. , Menon, V. , Philippides, G. J. , Roden, D. M. , & Zareba, W. (2010). Prevention of torsade de pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation. Journal of the American College of Cardiology, 55 (9 ), 934–947. 10.1016/j.jacc.2010.01.001 20185054\nFaber, T. S. , Zehender, M. , & Just, H. (1994). Drug‐induced torsade de pointes. Incidence, management and prevention. Drug Safety, 11 (6 ), 463–476. 10.2165/00002018-199411060-00007 7727055\nFontaine, G. , Frank, R. , & Grosgogeat, Y. (1982). Torsades de pointes: Definition and management. Modern Concepts of Cardiovascular Disease, 51 (6 ), 103–108.\nGupta, A. , Lawrence, A. T. , Krishnan, K. , Kavinsky, C. J. , & Trohman, R. G. (2007). Current concepts in the mechanisms and management of drug‐induced QT prolongation and torsade de pointes. American Heart Journal, 153 (6 ), 891–899. 10.1016/j.ahj.2007.01.040 17540188\nIribarren, C. , Round, A. D. , Peng, J. A. , Lu, M. , Klatsky, A. L. , Zaroff, J. G. , Holve, T. J. , Prasad, A. , & Stang, P. (2014). Short QT in a cohort of 1.7 million persons: Prevalence, correlates, and prognosis. Annals of Noninvasive Electrocardiology, 19 , 490–500. 10.1111/anec.12157 24829126\nIribarren, C. , Round, A. D. , Peng, J. A. , Lu, M. , Zaroff, J. G. , Holve, T. J. , Prasad, A. , & Stang, P. (2013). Validation of a population‐based method to assess drug‐induced alterations in the QT interval: a self‐controlled crossover study. Pharmacoepidemiology and Drug Safety, 22 (11 ), 1222–1232. 10.1002/pds.3479 23857878\nKallergis, E. M. , Goudis, C. A. , Simantirakis, E. N. , Kochiadakis, G. E. , & Vardas, P. E. (2012). Mechanisms, risk factors, and management of acquired long QT syndrome: A comprehensive review. The Scientific World Journal, 2012 , 212178. 10.1100/2012/212178 22593664\nKarter, A. J. (2006). Role of self‐monitoring of blood glucose in glycemic control. Endocrine Practice: Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 12 (Suppl 1 ), 110–117. 10.4158/EP.12.S1.110\nKay, G. N. , Plumb, V. J. , Arciniegas, J. G. , Henthorn, R. W. , & Waldo, A. L. (1983). Torsade de pointes: The long‐short initiating sequence and other clinical features: Observations in 32 patients. Journal of the American College of Cardiology, 2 (5 ), 806–817. 10.1016/S0735-1097(83)80226-5 6630761\nKligfield, P. , Hancock, E. W. , Helfenbein, E. D. , Dawson, E. J. , Cook, M. A. , Lindauer, J. M. , Zhou, S. H. , & Xue, J. (2006). Relation of QT interval measurements to evolving automated algorithms from different manufacturers of electrocardiographs. American Journal of Cardiology, 98 (1 ), 88–92. 10.1016/j.amjcard.2006.01.060\nKrieger, N. (1992). Overcoming the absence of socioeconomic data in medical records: validation and application of a census‐based methodology. American Journal of Public Health, 82 (5 ), 703–710. 10.2105/AJPH.82.5.703 1566949\nKurisu, S. , Inoue, I. , Kawagoe, T. , Ishihara, M. , Shimatani, Y. , Nakama, Y. , Ohkawa, K. , Maruhashi, T. , Kagawa, E. , Dai, K. , & Aokage, T. (2008). Torsade de pointes associated with bradycardia and takotsubo cardiomyopathy. Canadian Journal of Cardiology, 24 (8 ), 640–642. 10.1016/S0828-282X(08)70653-6\nKvale, M. N. , Hesselson, S. , Hoffmann, T. J. , Cao, Y. , Chan, D. , Connell, S. , Croen, L. A. , Dispensa, B. P. , Eshragh, J. , Finn, A. , Gollub, J. , Iribarren, C. , Jorgenson, E. , Kushi, L. H. , Lao, R. , Lu, Y. , Ludwig, D. , Mathauda, G. K. , McGuire, W. B. , … Risch, N. (2015). Genotyping informatics and quality control for 100,000 subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort. Genetics, 200 (4 ), 1051–1060. 10.1534/genetics.115.178905 26092718\nLa, D. F. (1966). tachycardie ventriculaire a´ deux foyers opposes variables. Archives Des Maladies Du Coeur Et Des Vaisseaux, 59 , 263–272.4956181\nLevey, A. S. , Stevens, L. A. , Schmid, C. H. , Zhang, Y. L. , Castro, A. F. 3rd , Feldman, H. I. , Kusek, J. W. , Eggers, P. , Van Lente, F. , Greene, T. , & Coresh, J. (2009). A new equation to estimate glomerular filtration rate. Annals of Internal Medicine, 150 (9 ), 604–612. 10.7326/0003-4819-150-9-200905050-00006 19414839\nPatane, S. , Marte, F. , Di Bella, G. , Curro, A. , & Coglitore, S. (2008). QT interval prolongation, torsade de pointes and renal disease. International Journal of Cardiology, 130 (2 ), e71–e73. 10.1016/j.ijcard.2007.11.070 18255176\nRoden, D. M. , Kannankeril, P. , & Darbar, D. (2007). On the relationship among QT interval, atrial fibrillation, and torsade de pointes. Europace, 9 (Supplement 4 ), iv1–iv3. 10.1093/europace/eum165 17766319\nSarganas, G. , Garbe, E. , Klimpel, A. , Hering, R. C. , Bronder, E. , & Haverkamp, W. (2014). Epidemiology of symptomatic drug‐induced long QT syndrome and torsade de pointes in Germany. Europace, 16 (1 ), 101–108. 10.1093/europace/eut214 23833046\nVandael, E. , Vandenberk, B. , Vandenberghe, J. , Spriet, I. , Willems, R. , & Foulon, V. (2017). Development of a risk score for QTc‐prolongation: the RISQ‐PATH study. International Journal of Clinical Pharmacy, 39 (2 ), 424–432. 10.1007/s11096-017-0446-2 28281228\nVandael, E. , Vandenberk, B. , Vandenberghe, J. , Willems, R. , & Foulon, V. (2017). Cases of drug‐induced torsade de pointes: A review of Belgian cases in the EudraVigilance database. Acta Clinica Belgica, 72 (6 ), 385–390. 10.1080/17843286.2017.1300217 28335691\n\n",
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"title": "Torsade de pointes: A nested case-control study in an integrated healthcare delivery system.",
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"abstract": "Methemoglobinemia occurs as iron in heme is oxidized to its ferric state, resulting in a decreased ability of hemoglobin to bind and release oxygen. Rasburicase is a recombinant urate-oxidase enzyme used in the prevention of tumor lysis syndrome. Methemoglobinemia can occur as a rare complication of treatment with rasburicase, primarily in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Methylene blue, an agent used for treating methemoglobinemia, should be avoided in patients with G6PD deficiency. In patients with G6PD deficiency, methylene blue is inadequately reduced to its active form, which then causes the methylene blue to further the oxidize the hemoglobin to methemoglobin that can result in hemolysis.",
"affiliations": "Internal Medicine, Creighton University School of Medicine, Omaha, USA.;Internal Medicine, Creighton University School of Medicine, Omaha, USA.;Internal Medicine, Creighton University School of Medicine, Omaha, USA.;Internal Medicine, Creighton University School of Medicine, Omaha, USA.;Internal Medicine, Creighton University School of Medicine, Omaha, USA.",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.14406\nInternal Medicine\nHematology\nRasburicase-Induced Methemoglobinemia\nMuacevic Alexander\nAdler John R\nAhmed Moeed 1\nSanchez Thomas 1\nNorgbe Selinam 1\nPicking Christopher R 1\nMillner Paul G 1\n1 Internal Medicine, Creighton University School of Medicine, Omaha, USA\nMoeed Ahmed moeedahmed22@gmail.com\n10 4 2021\n4 2021\n13 4 e1440610 4 2021\nCopyright © 2021, Ahmed et al.\n2021\nAhmed 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/54196-rasburicase-induced-methemoglobinemia\nMethemoglobinemia occurs as iron in heme is oxidized to its ferric state, resulting in a decreased ability of hemoglobin to bind and release oxygen. Rasburicase is a recombinant urate-oxidase enzyme used in the prevention of tumor lysis syndrome. Methemoglobinemia can occur as a rare complication of treatment with rasburicase, primarily in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Methylene blue, an agent used for treating methemoglobinemia, should be avoided in patients with G6PD deficiency. In patients with G6PD deficiency, methylene blue is inadequately reduced to its active form, which then causes the methylene blue to further the oxidize the hemoglobin to methemoglobin that can result in hemolysis.\n\nrasburicase\nmethemoglobinemia\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nRasburicase is a recombinant urate-oxidase enzyme used in the prevention of tumor lysis syndrome in patients with malignancy. Tumor lysis syndrome (TLS) is a condition that occurs when a large number of cancer cells die within a short period, releasing their contents into the blood. When chemotherapy induces cellular death, nucleic acids are broken down, with one byproduct being uric acid. Uric acid can overwhelm the proximal tubular reabsorption capacity and cause acute kidney injury due to multiple mechanisms such as intrarenal crystallization, renal vasoconstriction, and inflammation [1,2]. The aforementioned prevention of tumor lysis syndrome is accomplished by rasburicase’s ability to convert uric acid into allantoin, which is excreted by the kidneys [3]. Methemoglobinemia can occur as a rare complication of treatment with rasburicase, primarily in patients with glucose-6-phosphare dehydrogenase (G6PD) deficiency. This occurs when an oxidizing agent, such as rasburicase, dapsone, nitrates, or methylene blue, converts iron from the ferrous (Fe2+) hemoglobin state to the ferric (Fe3+) methemoglobin state [4]. This causes a physiologic left shift in the oxygen dissociation curve leading to increased oxygen binding by red blood cells and decreased oxygen delivery to cells. G6PD-deficient individuals are more susceptible to methemoglobinemia from rasburicase.\n\nCase presentation\n\nA 72-year-old man who was recently diagnosed with high-grade neuroendocrine carcinoma of prostate, small cell type, presented to the hospital for evaluation of shortness of breath and abdominal pain. Initially, he was suspected to have pulmonary embolism after a ventilation/perfusion (V/Q) scan showed intermediate probability for pulmonary embolism and lower extremity duplex confirmed an acute deep vein thrombosis (DVT) of the right femoral and popliteal veins. Initially, the patient did not require supplemental oxygen. Anticoagulation was initiated, resulting in gross hematuria due to his bladder mass and underlying prostate cancer.\n\nGiven the diagnosis of neuroendocrine carcinoma of the prostate, he was started on chemotherapy with carboplatin and etoposide. Subsequent blood workup revealed a creatinine of 4.07 mg/dl, potassium level of 5.2 mmol/L (normal: 3.7-5.1 mmol/L), phosphorus level of 5.9 mg/dl (normal: 2.5-4.9 mg/dl), and a uric acid level of 11.5 mg/dl (normal: 2.6-7.2 mg/dl). Given the concern for tumor lysis syndrome and renal dysfunction, he was started on rasburicase. Two to three days after starting rasburicase, his oxygen saturation was measured between 70% and 80% on room air, confirmed with a normal tracing on the plethysmograph. There was a notable discrepancy between transcutaneous oximetry and arterial blood gas oxygen saturation. He had no shortness of breath, and a chest radiograph was unremarkable. He was placed on four liter per minute oxygen via nasal cannula, with improvement in SpO2. Lungs were clear to auscultation. Hemoglobin was stable. The methemoglobin level was found to be elevated at 5.1% (normal: 0.0%-1.5 %). There was high suspicion of rasburicase-induced methemoglobinemia; therefore, rasburicase was discontinued. Ascorbic acid and blood products were given, and the patient’s oxygen saturation subsequently improved to over 90% on room air. A G6PD level with a corresponding red blood cell level of 2.98 m/μl (normal 4.3-5.9 m/μl) was ordered and subsequently came back low at 36 (normal range: 127-427 units/trillion RBCs).\n\nDiscussion\n\nWhile the complication of rasburicase-induced methemoglobinemia is rare, occurring in fewer than 1% of patients, this complication can be life-threatening [5]. Common presenting symptoms include, but are not limited to, dyspnea, dizziness, cyanosis, oxygen saturation between 70% and 85% with a normal partial pressure of oxygen on arterial blood gas, “chocolate”-colored blood, seizures, and arrhythmias [6]. The normal range of methemoglobin level in the blood is between 0% and 2%; while levels above 20% can cause symptoms, levels above 70% can cause death [7].\n\nG6PD deficiency increases the risk for methemoglobinemia because this enzyme reduces glutathione which in the reduced state is a cellular buffer for oxidized molecules [8]. When hemoglobin is oxidized to methemoglobin by rasburicase, the cell’s capacity to reduce methemoglobin is overwhelmed, causing the toxic substance to build up in the body and present with symptoms [9]. Patients, especially in high-risk ethnic groups, should be tested for G6PD deficiency prior to the administration of rasburicase. Some of the factors that placed our patient at a higher risk for tumor lysis syndrome is that the patient had a solid tumor, which was responsive to the chemotherapy, as well as the fact that the patient had an existing renal dysfunction that may increase the risk of this patient progressing into tumor lysis syndrome [10]. There are fewer than 28 cases with a known rasburicase-induced methemoglobinemia in patients with a G6PD deficiency, and at least two cases of patients were found who died from complications associated with their methemoglobinemia [5,11-14]. Rasburicase should not be given to patients with a G6PD deficiency because hydrogen peroxide is produced when the rasburicase coverts the uric acid to allantoin. Patients with a G6PD deficiency are not able to detoxify the hydrogen peroxide, which then starts to oxidize the hemoglobin to methemoglobin. Methylene blue, an agent used for treating methemoglobinemia, should be avoided in patients with G6PD deficiency considering that it is inadequately reduced to its active form, which can lead to hemolysis [15]. As rasburicase-induced methemoglobinemia mainly occurs in individuals with G6PD deficiency, empirical use of methylene blue should be avoided in these individuals. One of the concerns is that the G6PD level can take days to be resulted, which increases the importance of testing the patients earlier. Initial management involves discontinuation of the offending agent with subsequent options including the administration of ascorbic acid and blood administration.\n\nConclusions\n\nLow oxygen saturation in a patient who is being given rasburicase should raise suspicion for methemoglobinemia, and these patients should be treated as being G6PD-deficient until the G6PD level is resulted. Methylene should be avoided in these patients to prevent hemolysis. Allopurinol may be considered as an alternative option in these patients.\n\nHuman Ethics\n\nWe would like to acknowledge Dr. Saad Ur Rahman for his support in this article.\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 Uric acid and cardiovascular risk N Engl J Med Feig DI Kang DH Johnson RJ 1811 1821 359 2008 18946066\n2 Tumor lysis syndrome Renal Disease in Cancer Patients Howard SC Pui CH Ribeiro RC 39 64 Amsterdam, Netherlands Elsevier Science 2014 https://www.sciencedirect.com/science/article/pii/B9780124159488000040\n3 Rasburicase (Elitek): a novel agent for tumor lysis syndrome Proc (Bayl Univ Med Cent) Ueng S 275 279 18 2005 https://www.tandfonline.com/doi/abs/10.1080/08998280.2005.11928082 16200184\n4 Methemoglobinemia: etiology, pharmacology, and clinical management Ann Emerg Med Wright RO Lewander WJ Woolf AD 646 656 34 1999 https://www.sciencedirect.com/science/article/abs/pii/S0196064499701678 10533013\n5 A perfect storm: tumor lysis syndrome with rasburicase-induced methemoglobinemia in a G6PD deficient adult J Clin Apher Montgomery KW Booth GS 62 63 32 2017 27119769\n6 Methemoglobinemia Ludlow JT Wilkerson RG Nappe TM Treasure Island, FL StatPearls Publishing 2020 https://www.ncbi.nlm.nih.gov/books/NBK537317/\n7 Methemoglobinemia West J Med Rehman HU 193 196 175 2001 11527852\n8 Glucose 6-phosphate dehydrogenase plays a key role in protection against reactive oxygen species Biochemistry Berg J Tymoczko J Stryer L 1 2 5 2002 https://evergreen-shipping.com.ph/sites/default/files/webform/pdf-biochemistry-seventh-edition-jeremy-m-berg-john-l-tymoczko-lubert-stryer-pdf-download-free-book-2008ea1.pdf\n9 Exercise in glucose-6-phosphate dehydrogenase deficiency: harmful or harmless? A narrative review Oxid Med Cell Longev Georgakouli K Fatouros IG Draganidis D Papanikolaou K Tsimeas P Deli CK Jamurtas AZ 8060193 London, UK Hindawi 2019 219 31089417\n10 Prevention and treatment of tumor lysis syndrome in the era of onco-nephrology progress. Kidney and blood pressure research Kidney Blood Press Res Matuszkiewicz-Rowinska J Malyszko J 645 660 45 2020 https://www.karger.com/Article/Abstract/509934 32998135\n11 Rasburicase-induced methemoglobinemia: case report, literature review, and proposed treatment algorithm Clin Case Rep Sherwood GB Paschal RD Adamski J 315 319 4 2016 27099716\n12 Mortality following rasburicase-induced methemoglobinemia Ann Pharmacother Bucklin MH Groth CM 1353 1358 47 2013 https://journals.sagepub.com/doi/abs/10.1177/1060028013501996 24259700\n13 Rasburicase causing severe oxidative hemolysis and methemoglobinemia in a patient with previously unrecognized glucose-6-phosphate dehydrogenase deficiency Acta Haematol Cheah CY Lew TE Seymour JF Burbury K 254 259 130 2013 https://www.karger.com/Article/Abstract/351048 23860572\n14 Rasburicase-induced methemoglobinemia in two African-American female patients: an under-recognized and continued problem Eur J Haematol Roberts DA Freed JA 83 85 94 2015 https://onlinelibrary.wiley.com/doi/abs/10.1111/ejh.12350 24750455\n15 A case of rasburicase-induced methemoglobinemia due to glucose-6-phosphate dehydrogenase deficiency treated with hyperbaric oxygen therapy Chest Richert M Ali O Stankiewicz J Augenstein C Trinidad LR 87 88 156 2019 https://journal.chestnet.org/article/S0012-3692(19)31676-9/pdf\n\n",
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"abstract": "Evidence from preclinical, epidemiological, and human studies indicates that inflammation, and in particular elevated interleukin-6 (IL-6) activity, may be related to clinical manifestations and pathophysiology of schizophrenia. Furthermore, studies in preclinical models suggest that decreasing IL-6 activity may mitigate or reverse some of these deficits. The purpose of this trial was to test whether an IL-6 receptor antibody, tocilizumab, would improve residual positive and negative symptoms and cognitive deficits in schizophrenia. We randomized 36 clinically stable, moderately symptomatic (i.e., Positive and Negative Syndrome Scale (PANSS) >60) individuals with schizophrenia to 3 monthly infusions of 8 mg/kg tocilizumab or placebo (normal saline). The primary outcome was effect at week 12 on the PANSS Total Score. Effects on the MATRICS, other PANSS subscales, Clinical Global Impression, and Global Assessment of Functioning were secondary outcomes. There were no observed treatment effects on any behavioral outcome measure. Baseline C-reactive protein (CRP) or cytokine levels did not predict treatment outcome, nor were there correlations between changes in these inflammatory markers and the measured outcomes. As expected, IL-6 and IL-8 increased, while CRP decreased, in the tocilizumab group compared with the placebo group. This study did not reveal any evidence that an IL-6 receptor antibody affects behavioral outcomes in schizophrenia. One potential explanation is the lack of capacity of this agent to penetrate the central nervous system. Additional trials of medications aimed at targeting cytokine overactivity that act directly on brain function and/or treatment in early-stage psychosis populations are needed.",
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"nlm_unique_id": "8904907",
"other_id": null,
"pages": "1317-1323",
"pmc": null,
"pmid": "29090685",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "11695949;11790516;12042193;15003440;15289276;15336511;15345767;15531402;15800151;15803162;16121756;16189509;1674062;16825309;16920078;17208413;17570481;17911480;17913903;17981263;18063801;18723840;19091984;19136031;20123911;20492850;20570110;21187298;2121800;21285702;21592521;21641581;21881215;22034110;22179732;22193671;22773376;2287938;22911828;22945416;23720576;25321611;25385788;2543584;26472628;26930525;27609240;28194003;28604733;3774930;4917967;7537419;7754524;8252293;9134598;9458910",
"title": "A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Tocilizumab, An Interleukin-6 Receptor Antibody, For Residual Symptoms in Schizophrenia.",
"title_normalized": "a randomized double blind placebo controlled clinical trial of tocilizumab an interleukin 6 receptor antibody for residual symptoms in schizophrenia"
} | [
{
"companynumb": "US-ROCHE-2118825",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BENZTROPINE MESYLATE"
},
"drugadditional": null,
... |
{
"abstract": "Vincristine was accidentally given intrathecally to a child with leukaemia, producing sensory and motor dysfunction followed by encephalopathy and death. Separate times for administering vincristine and intrathecal therapy is recommended.",
"affiliations": "Department of Paediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.",
"authors": "al Fawaz|I M|IM|",
"chemical_list": "D014750:Vincristine",
"country": "England",
"delete": false,
"doi": "10.1080/02724936.1992.11747596",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-4936",
"issue": "12(3)",
"journal": "Annals of tropical paediatrics",
"keywords": null,
"medline_ta": "Ann Trop Paediatr",
"mesh_terms": "D002493:Central Nervous System Diseases; D006801:Humans; D007223:Infant; D007278:Injections, Spinal; D008297:Male; D008508:Medication Errors; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014750:Vincristine",
"nlm_unique_id": "8210625",
"other_id": null,
"pages": "339-42",
"pmc": null,
"pmid": "1280054",
"pubdate": "1992",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Fatal myeloencephalopathy due to intrathecal vincristine administration.",
"title_normalized": "fatal myeloencephalopathy due to intrathecal vincristine administration"
} | [
{
"companynumb": "SA-PFIZER INC-12673",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "Ganciclovir-resistant (ganR) cytomegalovirus (CMV) is an emerging and important problem in solid organ transplant (SOT) recipients. Only through direct comparison of ganR- and ganciclovir-sensitive (ganS) CMV infection can risk factors and outcomes attributable specifically to ganciclovir resistance appropriately be determined.\n\n\n\nWe performed a retrospective, case-control (1:3) study of SOT recipients with genotypically confirmed ganR-CMV (n = 37) and ganS-CMV infection (n = 109), matched by donor/recipient CMV serostatus, year and organ transplanted, and clinical manifestation. We used χ2 (categorical) and Mann-Whitney (continuous) tests to determine predisposing factors and morbidity attributable to resistance, and Kaplan-Meier plots to analyze survival differences.\n\n\n\nThe rate of ganR-CMV was 1% (37/3467) overall and 4.1% (32/777) among CMV donor-positive, recipient-negative patients, and was stable over the study period. GanR-CMV was associated with increased prior exposure to ganciclovir (median, 153 vs 91 days, P < .001). Eighteen percent (3/17) of lung transplant recipients with ganR-CMV had received <6 weeks of prior ganciclovir (current guideline-recommended resistance testing threshold), and all non-lung recipients had received ≥90 days (median, 160 [range, 90-284 days]) prior to diagnosis of ganR-CMV. GanR-CMV was associated with higher mortality (11% vs 1%, P = .004), fewer days alive and nonhospitalized (73 vs 81, P = .039), and decreased renal function (42% vs 19%, P = .008) by 3 months after diagnosis.\n\n\n\nGanR-CMV is associated with longer prior antiviral duration and higher attributable morbidity and mortality than ganS-CMV. Upcoming revised CMV guidelines should incorporate organ transplant-specific thresholds of prior drug exposure to guide rational ganR-CMV testing in SOT recipients. Improved strategies for prevention and treatment of ganR-CMV are warranted.",
"affiliations": "Division of Allergy and Infectious Diseases, University of Washington.;Division of Allergy and Infectious Diseases, University of Washington.;Division of Allergy and Infectious Diseases, University of Washington.;Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center.;Division of Allergy and Infectious Diseases, University of Washington.;Division of Allergy and Infectious Diseases, University of Washington.;Division of Allergy and Infectious Diseases, University of Washington.",
"authors": "Fisher|Cynthia E|CE|;Knudsen|Janine L|JL|;Lease|Erika D|ED|;Jerome|Keith R|KR|;Rakita|Robert M|RM|;Boeckh|Michael|M|;Limaye|Ajit P|AP|",
"chemical_list": "D000998:Antiviral Agents; D015774:Ganciclovir",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/cix259",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "65(1)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "cytomegalovirus; ganciclovir resistance; outcomes; risk factors; solid organ transplant",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D005260:Female; D015774:Ganciclovir; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009017:Morbidity; D012189:Retrospective Studies; D012307:Risk Factors; D066027:Transplant Recipients; D016896:Treatment Outcome",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "57-63",
"pmc": null,
"pmid": "28369203",
"pubdate": "2017-07-01",
"publication_types": "D016428:Journal Article",
"references": "27495775;15004066;10968438;11914998;12490272;27037651;11756977;24145525;12228824;16426310;23896556;26853894;17638191;26098499;10573063;23678068;27004439;17537934;16794529;18339135",
"title": "Risk Factors and Outcomes of Ganciclovir-Resistant Cytomegalovirus Infection in Solid Organ Transplant Recipients.",
"title_normalized": "risk factors and outcomes of ganciclovir resistant cytomegalovirus infection in solid organ transplant recipients"
} | [
{
"companynumb": "US-ROCHE-1964509",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALGANCICLOVIR"
},
"drugadditional": "3",
"d... |
{
"abstract": "Denosumab is a monoclonal antibody directed against the receptor activator of nuclear factor kappa B ligand (RANKL). Denosumab has been shown to reduce the risk of skeletal-related events, including spinal cord compression, pathologic fracture and hypercalcemia of malignancy in patients with bone metastases. Hypocalcemia is a known side effect of denosumab, occurring in an estimated 8-14% of the patients. Here, we present an asymptomatic patient with stage-5 chronic kidney disease and severe hypocalcemia who had received denosumab 1 month earlier.",
"affiliations": "Department of Internal Medicine, Division of Nephrology, University of Mississippi Medical Center, Jackson, Mississippi. Electronic address: sohail3553@gmail.com.;Divison of Endocrinology, University of Mississippi Medical Center, Jackson, Mississippi.;Department of Internal Medicine, Division of Nephrology, University of Mississippi Medical Center, Jackson, Mississippi.;Divison of Endocrinology, University of Mississippi Medical Center, Jackson, Mississippi.;Division of Hospital Medicine, University of Mississippi Medical Center, Jackson, Mississippi.;Department of Internal Medicine, Division of Nephrology, University of Mississippi Medical Center, Jackson, Mississippi.;Department of Medicine, Division of Nephrology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; FMC Extracorporeal Life Support Center - Fresenius Medical Care, Esztergom, Hungary.",
"authors": "Salim|Sohail Abdul|SA|;Nair|Lakshmi Ramachandran|LR|;Thomas|Litty|L|;Garla|Vishnu|V|;Palabindala|Venkataraman|V|;Agarwal|Mohit|M|;Fülöp|Tibor|T|",
"chemical_list": "D050071:Bone Density Conservation Agents; D000069448:Denosumab; D002118:Calcium",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjms.2017.09.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9629",
"issue": "355(5)",
"journal": "The American journal of the medical sciences",
"keywords": "Alkaline phosphatase; End-stage renal disease; Hypercalcemia of malignancy; Parathyroid hormone; RANKL inhibitor",
"medline_ta": "Am J Med Sci",
"mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D002118:Calcium; D000069448:Denosumab; D006801:Humans; D006996:Hypocalcemia; D008297:Male; D051436:Renal Insufficiency, Chronic; D016896:Treatment Outcome",
"nlm_unique_id": "0370506",
"other_id": null,
"pages": "506-509",
"pmc": null,
"pmid": "29753381",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Denosumab-Associated Severe Hypocalcemia in a Patient With Chronic Kidney Disease.",
"title_normalized": "denosumab associated severe hypocalcemia in a patient with chronic kidney disease"
} | [
{
"companynumb": "US-AMGEN-USASP2017131590",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "An increased risk of impaired intelligence (IQ) has been documented in valproate-exposed children, but investigations have not previously focused on those with a clinical diagnosis of Fetal Valproate Syndrome (FVS).\n\n\n\nThis cross sectional observational study recruited individuals with a diagnosis of FVS and completed standardized assessments of intellectual abilities making comparisons to a normative comparison group. Both mean difference (MD) and prevalence of scores below the lower average range were analyzed.\n\n\n\nThe mean full-scale IQ in 31 individuals with FVS (mean age 14.97; range 6-27 years) was 19 points lower (19.55, 95% CI -24.94 to 14.15), and IQ scores <70 were present in 26%. The mean differences for verbal comprehension (21.07, 95% CI -25.84 to -16.29), working memory (19.77, 95% CI -25.00 to -14.55) and processing speed (16.87, 95% CI -22.24 to -11.50) performances were poorer than expected with the mean differences over one standard deviation from the comparison group. Sixty one percent of cases demonstrated disproportionately lower verbal comprehension ability. There were no significant group differences for IQ in high vs. moderate dose valproate or mono vs. polytherapy. There were no differences in IQ between those with and those without a major congenital malformation. The requirement for educational intervention was high at 74%.\n\n\n\nIntellectual difficulties are a central feature of FVS and are more severe in their presentation in individuals with a diagnosis of valproate embryopathy. Individuals with FVS who present with the characteristic facial presentation should be considered at high risk of cognitive difficulties regardless of the dose of valproate exposure or the presence of a major congenital malformation.",
"affiliations": "Division of Evolution and Genomic Science, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. Electronic address: Rebecca.bromley@manchester.ac.uk.;Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.;Division of Evolution and Genomic Science, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.;School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK; Clinical Sciences, Murdoch Children's Research Institute, Flemington Road, Parkville, Victoria 3052, Australia.",
"authors": "Bromley|Rebecca L|RL|;Baker|Gus A|GA|;Clayton-Smith|Jill|J|;Wood|Amanda G|AG|",
"chemical_list": "D014635:Valproic Acid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ntt.2018.11.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0892-0362",
"issue": "71()",
"journal": "Neurotoxicology and teratology",
"keywords": "Epilepsy; Fetal anticonvulsant syndrome; Fetal valproate syndrome; Intelligence; Pregnancy; Sodium valproate; Teratology",
"medline_ta": "Neurotoxicol Teratol",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000293:Adolescent; D000328:Adult; D002648:Child; D032882:Comprehension; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008607:Intellectual Disability; D008297:Male; D008570:Memory, Short-Term; D014635:Valproic Acid; D014888:Wechsler Scales; D055815:Young Adult",
"nlm_unique_id": "8709538",
"other_id": null,
"pages": "16-21",
"pmc": null,
"pmid": "30453023",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intellectual functioning in clinically confirmed fetal valproate syndrome.",
"title_normalized": "intellectual functioning in clinically confirmed fetal valproate syndrome"
} | [
{
"companynumb": "GB-IMPAX LABORATORIES, LLC-2018-IPXL-04241",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIVALPROEX SODIUM"
},
"druga... |
{
"abstract": "Sickle cell disease (SCD) is a genetic disorder resulting from a mutation in the hemoglobin (Hb) gene. Sickle cell disease results in chronic anemia and a variety of acute and chronic complications that can lead to early mortality. A child with both SCD and HIV presents a management challenge, particularly in a resource-limited setting. In this case report, we describe the case of an 18-month-old Kenyan girl with SCD and HIV who developed a severe hypersensitivity reaction to first-line antiretroviral therapy (ART). Selecting an appropriate drug substitute for a child with SCD and HIV presents a management dilemma when the available options have problematic side effect profiles or are inaccessible or inappropriate according to national guidelines. The challenges in choosing an appropriate ART regimen for a child with SCD and HIV highlight the lack of data and scarcity of treatment options for pediatric patients.",
"affiliations": "Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya.",
"authors": "Odera|Esther Brenda|EB|;Kwobah|Charles|C|;Stone|Geren|G|;Some|Faraj|F|;Vreeman|Rachel Christine|RC|",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "United States",
"delete": false,
"doi": "10.1177/2325957413508320",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-9574",
"issue": "13(2)",
"journal": "Journal of the International Association of Providers of AIDS Care",
"keywords": "HIV; antiretroviral therapy; comorbidity; sickle cell disease",
"medline_ta": "J Int Assoc Provid AIDS Care",
"mesh_terms": "D000740:Anemia; D000755:Anemia, Sickle Cell; D019380:Anti-HIV Agents; D019468:Disease Management; D018450:Disease Progression; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D015658:HIV Infections; D006295:Health Resources; D006801:Humans; D007223:Infant; D007630:Kenya",
"nlm_unique_id": "101603896",
"other_id": null,
"pages": "113-6",
"pmc": null,
"pmid": "24257463",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Sickle cell disease and HIV: a case highlighting management challenges for children in a resource-limited setting.",
"title_normalized": "sickle cell disease and hiv a case highlighting management challenges for children in a resource limited setting"
} | [
{
"companynumb": "KE-VIIV HEALTHCARE LIMITED-B0997748A",
"fulfillexpeditecriteria": "1",
"occurcountry": "KE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nGanciclovir can be used to treat a primary cytomegalovirus (CMV) infection, however it can cause side effects.\n\n\nMETHODS\nWe describe a 60-year-old immunocompromised woman with a primary CMV infection who was treated with ganciclovir. She developed an encephalopathy which resolved after discontinuation of ganciclovir.\n\n\nCONCLUSIONS\nA reversible encephalopathy as a side effect of ganciclovir.",
"affiliations": "Department of Internal Medicine, VU Medical Center, Amsterdam, the Netherlands.",
"authors": "Möhlmann|M C|MC|;Stiksma|J|J|;Kramer|M H H|MH|",
"chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D001379:Azathioprine; D015774:Ganciclovir",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "74(10)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D000998:Antiviral Agents; D001259:Ataxia; D001379:Azathioprine; D001927:Brain Diseases; D003424:Crohn Disease; D003586:Cytomegalovirus Infections; D005260:Female; D015774:Ganciclovir; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008875:Middle Aged",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "449-450",
"pmc": null,
"pmid": "27966439",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ganciclovir-induced ataxia and encephalopathy.",
"title_normalized": "ganciclovir induced ataxia and encephalopathy"
} | [
{
"companynumb": "NL-BAUSCH-BL-2017-000407",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GANCICLOVIR"
},
"drugadditional": "1",
... |
{
"abstract": "Checkpoint inhibitors are integral to non-small-cell lung cancer treatment. Existing data suggests that nutritional status may play a role in antitumor immunity.\nThis retrospective study of 106 non-small-cell lung cancer patients who started checkpoint inhibitors between 2014 and 2017 at our institution assessed relationship of nutritional parameters to overall survival (OS) and progression-free survival.\nMean age was 68.7 ± 9.2 years and 59.4% patients were male. On multivariate analysis for OS, hypoalbuminemia and significant weight loss were prognostic at p-values of 0.0005 and 0.0052, respectively. We noted a parabolic association between age and OS (p = 0.026, 0.0025).\nIn our study, some malnutrition parameters were associated with decreased OS. U-shape relationship between age and OS noted here warrants further evaluation.",
"affiliations": "St. John's University, College of Pharmacy & Health Sciences, Department of Clinical Health Professions, Queens, NY 11439, USA.;Division of Medical Oncology & Hematology, Northwell Health Cancer Institute, Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY 11042, USA.;Division of Medical Oncology & Hematology, Northwell Health Cancer Institute, Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY 11042, USA.;Biostatistics Unit, The Feinstein Institutes for Medical Research, Manhasset, NY 11021, USA.;Division of Medical Oncology & Hematology, Northwell Health Cancer Institute, Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY 11042, USA.",
"authors": "Lee|Chung-Shien|CS|https://orcid.org/0000-0003-3505-6402;Devoe|Craig E|CE|;Zhu|Xinhua|X|;Fishbein|Joanna Stein|JS|;Seetharamu|Nagashree|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/lmt-2020-0008",
"fulltext": "\n==== Front\nLung Cancer Manag\nLung Cancer Manag\nLMT\nLung Cancer Management\n1758-1966 1758-1974 Future Medicine Ltd London, UK \n\n10.2217/lmt-2020-0008\nResearch Article\nPretreatment nutritional status and response to checkpoint inhibitors in lung cancer\nhttps://orcid.org/0000-0003-3505-6402Lee Chung-Shien *12 Devoe Craig E 2 Zhu Xinhua 2 Fishbein Joanna Stein 3 Seetharamu Nagashree 2 1 St. John's University, College of Pharmacy & Health Sciences, Department of Clinical Health Professions, Queens, NY 11439, USA\n2 Division of Medical Oncology & Hematology, Northwell Health Cancer Institute, Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY 11042, USA\n3 Biostatistics Unit, The Feinstein Institutes for Medical Research, Manhasset, NY 11021, USA\n* Author for correspondence: leec3@stjohns.edu\n24 4 2020 \n6 2020 \n24 4 2020 \n9 2 LMT3110 3 2020 20 3 2020 24 4 2020 © 2020 Chung-Shien Lee2020This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported LicenseBackground:\nCheckpoint inhibitors are integral to non-small-cell lung cancer treatment. Existing data suggests that nutritional status may play a role in antitumor immunity.\n\nMaterials & methods:\nThis retrospective study of 106 non-small-cell lung cancer patients who started checkpoint inhibitors between 2014 and 2017 at our institution assessed relationship of nutritional parameters to overall survival (OS) and progression-free survival.\n\nResults:\nMean age was 68.7 ± 9.2 years and 59.4% patients were male. On multivariate analysis for OS, hypoalbuminemia and significant weight loss were prognostic at p-values of 0.0005 and 0.0052, respectively. We noted a parabolic association between age and OS (p = 0.026, 0.0025).\n\nConclusion:\nIn our study, some malnutrition parameters were associated with decreased OS. U-shape relationship between age and OS noted here warrants further evaluation.\n\nKeywords: \nimmunotherapymalnutritionnon-small-cell lung cancer\n==== Body\nPractice points\nOut of the 106 patients analyzed, 17% of patients had a low albumin (<3.5 g/dl) at baseline and 37.7% reported weight loss of 5% or more in the 6 months prior to starting immunotherapy.\n\nLow serum albumin level status, malnutrition status based on composite nutritional status, report of at least 5% weight loss within 6 months of presentation and baseline Eastern Cooperative Group performance status were each significantly associated with overall survival (OS) on univariate screen (p < 0.0001, p = 0.0001, p = 0.0003 and p = 0.0162, respectively).\n\nAge was also marginally associated with OS on univariate analysis (p = 0.06).\n\nOn multivariate analysis, an interesting U-shaped relationship was noted between age and OS.\n\nRisk of death was highest at lower ages, insignificant at ‘middle’ ages (i.e., ages 60–75 years), and at the lowest for elderly patients (i.e., >75 years of age).\n\nPatients above the estimated age of 75 years have an incrementally improved survival with every 5 year increase in age at the time of initiation of checkpoint inhibitor, whereas the risk of death increases with every 5 year increase in age from 45 to 60 years.\n\nSerum albumin less than 3.5 at baseline was associated with progression-free survival on univariate screen at p < 0.1 level (p = 0.079).\n\nOverall, 96 patients (90%) experienced an adverse event, with only three patients (2.8%) experiencing a severe event.\n\nLung cancer continues to be the most commonly diagnosed and deadliest form of cancer worldwide, accounting for approximately 1.7 million deaths in 2018 alone [1]. In the USA, there was an estimated 228,150 new cases and 142,670 deaths associated with lung cancer in 2019 [2]. Checkpoint inhibitor (CPI) therapy, referred to commonly as immunotherapy, has transformed the outcomes for advanced cancer patients over the last decade and has become an integral component of ‘standard of care’ treatment regimens for several types of cancers, including lung cancer [3]. Currently approved CPIs inhibit CTLA4, PD-1 or PD-L1. PD-1 and PD-L1 inhibitors have shown improved responses, progression-free survival (PFS) and overall survival (OS) in lung cancer patients compared with previous, ‘standard of care’ chemotherapy treatments [4–12]. However, the benefit does not extend to all patients even when enriched for extensively studied predictive markers [13]. Some patients experience no benefit at all, and some suffer from a detrimental effect on their overall health, either due to serious immune-related adverse effects [14] or the phenomenon of hyperprogression [15], in addition to an incremental increase on financial burden. Therefore, it is imperative to carefully select patients who are likely to benefit for CPI immunotherapy. Significant research efforts toward identifying optimal biomarkers that predict outcomes to CPIs are currently underway [16,17]. Two such biomarkers that have been extensively studied and shown to have some predictive value in lung cancer, include tumor expression of PD-L1 and tumor mutational burden [16,17]. However, both of these biomarkers are tissue-based and are imperfect in dichotomizing patients who benefit and those who do not. Many other biomarkers that are currently being studied require tumor tissue specimens or involve cumbersome and complicated laboratory-based testing that can only be done at highly specialized centers and will likely be of limited use due to cost constraints [18]. Hence, it would be appropriate to identify readily available clinical and laboratory parameters that might help predict response to CPIs.\n\nHypothesis-generating preclinical observations suggested that baseline nutritional status may impact antitumor immunity [19,20]. There is also clinical data showing association between malnutrition and worse outcomes from CPI [21], and paradoxically, between obesity and improved benefit from immunotherapy [22]. Optimal assessment of nutritional status however is still being debated [23]. In this retrospective study, we looked at predictive and prognostic value of several factors hypothesized to be associated with nutritional status. Our study aimed to correlate malnutrition status prior to CPI initiation, BMI serum albumin and significant weight loss at presentation with OS and PFS.\n\nMaterials & methods\nStudy design\nThis was an institutional review board approved retrospective chart review conducted at an academic medical center. Patients included in the study were adult advanced non-small-cell lung cancer (NSCLC) patients (≥18 years of age) who received CPI, specifically monoclonal antibodies to PD-1 and PD-L1 as monotherapy in any line of treatment, between January 2014 and December 2017. Patients who had received CPI previously and those with no documented baseline albumin were excluded.\n\nElectronic medical records were accessed to collect data on patient demographics, cancer details, details about immunotherapy treatment, details about prior chemotherapy regimens and smoking history. In addition, we captured data on Eastern Cooperative Group (ECOG) performance status (PS), BMI and serum albumin at the time of presentation. We also noted if there was a significant weight loss (≥5%) reported within 6 months prior to presentation. Information on adverse events and their grades was also collected. In addition, dates of death, progression and last follow-up were recorded. Study data were collected and managed using Research Electronic Data Capture (REDCap) electronic data capture tools hosted at Feinstein Institutes for Medical Research. REDCap is a secure, web-based application designed to support data capture for research studies, providing an intuitive interface for validated data entry, audit trails for tracking data manipulation and export procedures, automated export procedures for seamless data downloads to common statistical packages and procedures for importing data from external sources [24].\n\nStatistical methods\nMalnutrition status was defined as BMI <18.5 and/or serum albumin <3.5 mg/dl prior to CPI initiation. BMI was categorized and evaluated as a binary variable (obese vs nonobese) and as a three-level categorical variable: underweight/normal weight (BMI <25), overweight (BMI 25–30) and obese (BMI >30); due to few patients being classified as underweight (BMI <18), these patients were combined with those of normal weight for analysis. Serum albumin level was evaluated as a binary variable using a cutoff of <3.5 mg/dl (herein referred to as hypoalbuminemia) versus ≥3.5 mg/dl. Significant weight loss at presentation was defined as ≥5% weight loss within 6 months prior to presentation.\n\nDescriptive statistics (e.g., frequencies and proportions for categorical variables and means and standard deviations for continuous factors) were computed. OS and PFS were each analyzed by applying standard methods of survival analysis, specifically computation of Kaplan–Meier (K-M) product limit curves [25] and performance of Cox proportional hazards (PH) regression [26]. In K-M analyses, groups were compared using the log-rank test. The median survival rates for each group were obtained from the K-M/Product-Limit Estimates and their corresponding 95% CIs were computed, as appropriate. Time-to-event was measured as the number of months from initial treatment (time from first dose of immunotherapy) to the event end point (progression or death). In cases, where the event was not observed during the study time period, the number of months until last follow-up was used and subject’s survival status was classified as censored at that time point. For OS, the event end point was death and for PFS, the event was defined as either progression or death.\n\nFor all analyses, where appropriate, demographic or clinical factors that appeared to be significantly associated with each outcome in the univariate analysis at alpha level 0.1, were considered for inclusion in a multivariable Cox PH model. Appropriate functional form of continuous factors and PH assumption for models were assessed and corrected as applicable. Multivariable model selection was performed using the likelihood ratio test, or backward elimination using 5% level of significance, as appropriate, and the model with the lowest Akaike Information Criteria (AIC) [27] was chosen when comparing non-nested models. For all analyses, a result yielding p < 0.05 was considered statistically significant unless stated otherwise. All analyses were conducted using SAS version 9.4 (SAS Institute Inc., NC, USA). Immune-related adverse events of all grades and serious adverse events for the entire cohort was tabulated.\n\nResults\nA total of 115 patients were identified and 9 patients were excluded for missing baseline albumin values, leaving 106 patients included for the final analysis. Most of the patients (n = 65) had de novo Stage IV disease based on American Joint Cancer Committee (AJCC), edition 7, while 30 patients had recurrent or progressive disease after being previously treated for Stage III (n = 24), Stage II (n = 5) and Stage 1 (n = 2). For 10 patients, initial staging was not recorded. The mean age was 68.7 ± 9.2 years and 63 patients (59.4%) were male. 68% of the patients were Caucasian White, while 18, 6 and 14% were African American, Asian and unknown race, respectively. Approximately 85% of patients had anytime history of smoking, and 21.7% were active smokers at the time of treatment initiation. Based on previously established cutoffs for BMI [28], 8.5, 28.3, 38.7 and 24.5% were classified as underweight, normal, overweight and obese, respectively. 17% of patients had a low albumin (<3.5 g/dl) at baseline and 37.7% reported weight loss of 5% or more in the 6 months prior to starting immunotherapy. 23 (21.7%) of the patients were malnourished based on the composite nutritional assessment that included BMI and baseline serum albumin level. About 17, 49, 25 and 8.7% of patients had a baseline ECOG PS of 0, 1, 2 and 3, respectively. 59 (56%) patients received nivolumab, 25 (24%) received pembrolizumab, 21 (20%) received atezolizumab and 1 (0.9%) received avelumab. About 16, 64.1 and 14.2%, of patients received immunotherapy in the first-, second- and third-line setting, while 5.7% of patients had received more than three lines of prior treatment. The number of immunotherapy cycles received ranged from 1 to 36 with the median number of cycles being 6 (interquartile range: 4–12). 47 (44.3%) patients had also received thoracic radiation previously. Table 1 provides complete descriptive statistics on the subjects included in this study.\n\nTable 1. Patient demographics and characteristics.\nBaseline characteristic\tTotal (n = 106)\t\nAge (years)\t68.6 ± 9.2\t\nMale\t63 (59.4%)\t\nFemale\t43 (41.6%)\t\nRace:\n– White\n– Black\n– Asian\n– Unknown\t\n68 (64.2%)\n18 (17.0%)\n6 (5.7%)\n14 (13.2%)\t\nBMI\t25.7 ± 5.4\t\nSmoking status:\n– Yes\n– Former\t\n23 (21.7%)\n67 (63.2%)\t\nBaseline albumin\t3.9 ± 0.4\t\nBaseline albumin (<3.5 g/dl)\t18 (17%)\t\nMalnourished based CNA\t23 (21.7%)\t\nInitial ≥5% weight loss upon starting immunotherapy\t40 (37.7%)\t\nECOG PS:\n– 0\n– 1\n– 2\n– 3\t\n18 (17.3%)\n51 (49.0%)\n26 (25.0%)\n9 (8.7%)\t\n Line of therapy\n– First\n– Second\n– Third or more\t\n17 (16.0%)\n68 (64.2%)\n21 (19.8%)\t\nMorphological classification\n– Adenocarcinoma\n– Squamous\n– Small cell\t\n68 (67.3%)\n25 (24.8%)\n8 (7.9%)\t\nRadiation during immunotherapy\t10 (9.4%)\t\nNumber of cycles, median (IQR)\t4 (6–12)\t\nData represented as n (%) or mean (± SD) unless otherwise stated.\n\nCNA: Composite nutritional assessment; ECOG PS: Eastern Cooperative Group performance status; IQR: Interquartile range; SD: Standard deviation.\n\nOS\nOf 106 subjects, death was observed in 43 subjects. The median OS was 16.3 months (95% CI: 10.4–22.2). The estimated survival probability at 12 and 24 months after initiating immunotherapy were 55.2% (95% CI: 42.8–66.0) and 22.0% (95% CI: 7.4–41.4), respectively. Median OS comparisons between subsets of patients based on various nutritional assessment parameters are depicted in Table 2.\n\nTable 2. Univariate comparisons between outcomes of patients based on various nutritional parameters.\nVariables\tN\tMedian OS, months (95% CI)\tp-value\tMedian PFS, months (95% CI)\tp-value\t\nComposite nutritional status\t\nMalnutrition status\t23\t7.1 (4.8–10.4)\t0.0001\t6.3 (4.1–9.9)\t0.25\t\nNormal nutritional status\t83\t21.7 (11.9 to not estimable)\t \t8.5 (5.6–16.5)\t \t\nBMI\t\nUnderweight/Normal BMI\t50\t7.3 (5.6–15.9)\t0.4\t19.5 (9.6–23.3)\t0.98\t\nOverweight\t30\t8.5 (3.5 to not estimable)\t \tNot estimable\t \t\nObese\t26\t11.9 (6.9–17.6)\t \t9.4 (4.1–17.3)\t \t\nWeight loss\t\nWeight loss >5%\t40\t6.1 (4.0–17.6)\t0.0003\t7.4 (4.6–15.9)\t0.75\t\nNo weight loss >5%\t66\t21.7 (11.9 to not estimable)\t \t8.5 (5.6–16.5)\t \t\nAlbumin\t\n<3.5 g/dl\t18\t6.9 (2–10.4)\t0.00001\t5.2 (3.9–9.4)\t0.0792\t\n≥3.5 g/dl\t88\t19.5 (11.9–23.3)\t \t8.5 (5.6–15.9)\t \t\nOS: Overall survival; PFS: Progression-free survival.\n\nNone of the following factors: race, ethnicity, BMI, smoking status or gender, were found to be significantly associated with OS on univariate analysis. Low serum albumin level status, malnutrition status based on composite nutritional assessment, report of at least 5% weight loss within 6 months of presentation, and baseline ECOG PS were each significantly associated with OS on univariate screen (p < 0.0001, p = 0.0001, p = 0.0003, p = 0.0162, respectively). Age was also marginally associated with OS on univariate analysis (p = 0.06). Due to the multicollinearity and correlation concerns between malnutrition status and albumin, each of these factors were entered into separate multivariable Cox PH models, along with, ECOG score, age and initial ≥5% weight loss status within 6 months of initiation of CPI. The final multiple Cox PH regression model included low serum albumin level status, initial 5% weight loss and age as a quadratic term (see Figures 1 & 2, Table 3). On multivariate analysis, an interesting U-shaped relationship was noted between age and OS (Figure 2). Risk of death was highest at lower ages, insignificant at ‘middle’ ages (i.e., ages 60–75), and at the lowest for elderly patients (i.e., >75 years of age). Our observations seem to suggest that patients above the estimated age of 75 years have an incrementally improved survival with every 5-year increase in age at the time of initiation of CPI, whereas the risk of death increases with every 5-year increase in age from 45 to 60 years.\n\nFigure 1. Adjusted overall survival curves for initial significant weight loss and baseline albumin level status.\nFigure 2. Predicted overall survival curves for various patient age profiles, holding serum albumin ≥3.5 g/dl and reported ≥5% weight loss within 6 months prior to immunotherapy initiation.\nTable 3. Final cox proportional hazard model for mortality.\nParameter\tParameter Estimate\tStandard Error\tp-value\tHazard Ratio\t95% CI\t\nWas there initial (>5%) weight loss upon starting immunotherapy?\nYes vs No\t0.91\t0.32\t0.0052\t2.48\t1.31\t4.68\t\nAlbumin <3.5 g/dl\t1.37\t0.39\t0.0005\t3.95\t1.83\t8.54\t\nAge when started immunotherapy\t0.81\t0.36\t0.026\t–\t–\t–\t\nAge†\t-0.01\t0.00\t0.0249\t–\t–\t–\t\n† Hazard ratios for age are not estimated within this table, but refer to the Figure 2 for visualization of the quadratic relationship.\n\nPFS\nAmong 106 subjects, progression events were observed in 50 subjects, with five deaths occurring before progression could be observed, with the remaining 51 subjects’ observations censored. The median time of PFS was 7.4 months (95% CI: 5.6–12.1). The estimated PFS probability at 12 months after initiating immunotherapy was 39.7% (95% CI: 27.9–51.3). The estimated PFS probability at 18 months after initiating immunotherapy was 17.3% (95% CI: 11.5–39.3).\n\nNone of the following factors were found to have significant association with PFS: race, ethnicity, BMI, obesity, smoking status, gender, ECOG PS, malnutrition status, presence of at least 5% initial weight loss at presentation or age (p = 0.7, p = 0.27, p = 0.98, p = 0.96, p = 0.88, p = 0.87, p = 0.77, p = 0.25, p = 0.74 and p = 0.76, respectively). Serum albumin less than 3.5 at baseline was associated with PFS on univariate screen at p < 0.1 level (p = 0.079). Given that no factor was significantly associated with PFS other than low albumin status from univariate screen, a multivariable Cox PH model was not built.\n\nAdverse events\nOverall, 96 patients (90%) experienced an adverse event, with only three patients (2.8%) experiencing a severe event. Fatigue/weakness (54.7%), dyspnea (21.7%), rash/pruritus (16%), diarrhea/colitis (15.1%) and nausea/vomiting (13.2%) were the most common adverse events. A total of 20 patients (21.7%) discontinued CPI due to adverse events and 5 patients (4.7%) required hospital admission. The incidence of adverse events of all grades and severe adverse events are depicted in Table 4.\n\nTable 4. Adverse events for the entire subject cohort.\nAdverse events\tTotal (n = 106)\t\n \tAll grades\tGrade 3/4\t\nTotal\t96 (90.6%)\t3 (2.8%)\t\nFatigue/weakness\t58 (54.7%)\t1 (0.9%)\t\nDiarrhea/colitis\t16 (15.1%)\t0 (0%)\t\nHypophysitis\t0 (0%)\t0 (0%)\t\nThyroid\t11 (10.4%)\t0 (0%)\t\nAdrenal insufficiency\t1 (0.9%)\t0 (0%)\t\nPneumonitis\t6 (5.7%)\t2 (1.8%)\t\nRash/pruritis\t17 (16.0%)\t0 (0%)\t\nLiver\t2 (1.8%)\t0 (0%)\t\nNephropathy\t9 (8.5%)\t0 (0%)\t\nDyspnea\t23 (21.7%)\t0 (0%)\t\nEdema\t11 (10.4%)\t0 (0%)\t\nConstipation\t9 (8.5%)\t0 (0%)\t\nNausea/vomiting\t14 (13.2%)\t0 (0%)\t\nA fib\t1 (0.9%)\t0 (0%)\t\nArthralgia/myalgia\t10 (9.4%)\t0 (0%)\t\nPneumonia/upper respiratory infection\t12 (11.3%)\t0 (0%)\t\nFlu like symptoms\t2 (1.8%)\t0 (0%)\t\nHypersensitivity reaction\t1 (0.9%)\t0 (0%)\t\nOther\t10 (9.4%)\t0 (0%)\t\nDiscontinued due to adverse event\t20 (18.9%)\t\nDiscussion\nThe relationship between nutritional status and homeostasis of the immune system and anticancer immunity is a complex one and recent research into this field is shedding some light into this very intriguing association [19,20,29–32]. Advanced cancer is associated with a cancer-induced wasting syndrome, also called cancer cachexia, which results in caloric deficiency [33]. Caloric deficiency, in turn is linked to immunosuppression, increased susceptibility to infection and has been shown to be associated with cancer progression but somewhat protective against autoimmune diseases [19,31]. Obesity on the other hand is associated with an overactive immune system, auto-immunity and enhanced anticancer immunity [32,34,35]. Nutritional status has influence on T-cell metabolism and function through mediation by several inter-related cytokines such as IL-6 and TNF-α as well as stress hormones [19]. In mice models, both TNF-α and IL-6 were noted to be markedly elevated in precachexic and cachexic states of cancer patients [19,36]. One of the many possible mechanisms by which IL-6 interplays with tumor immunity is its involvement in decreasing hepatic ketogenic potential through suppression of PPARalpha [19]. Hypoketonemia which can be considered a systemic metabolic stress response resulting from precachectic and cachectic states in turn triggers a marked elevation in glucocorticoid levels, which has been in turn been shown to be associated with poor response to immunotherapy and overall poor outcomes [19]. Contrariwise, obesity has shown to be associated with improved responses to CPI in multiple recent studies [20,22,34,37,38]. The mechanistic explanation for this association is currently being elucidated but there are some hypotheses. Macrophages are the most abundant immune cells in adipose tissues and during periods of weight gain, there is an influx of inflammatory macrophages into the adipose tissue and this leads release of cytokines such as TNF-α [20,39]. Thus, obesity results in heightened inflammatory response that interferes with immune modulation, inhibits antitumor immunity and results in immune exhaustion. CPI therapy seems to reverse this process and enhance antitumor immunity.\n\nWhile there is a now general agreement that nutritional status is an important factor in predicting responses to CPI, there has been considerable variability when it comes to methods used for assessment of nutritional status [23]. Common tools include subjective quantification of weight loss by patients [40]; objective anthropometric measurements such as BMI [41,42]; skinfold thickness [43] and laboratory assessments such as serum CRP [44], and pre-treatment serum albumin [44,45] and dietary assessments such as 24-h food intake recall [46]; and body composition assessment such as lean muscle mass area calculated from axial-view computerized tomographic images of the abdomen at the level of L3 spine [47]. Combining various parameters is sometimes utilized for nutritional assessment and one of such composite measure is integration of BMI and serum albumin which has been validated in patients on hemodialysis and cancer [48]. In our study, we utilized nutritional parameters that were readily available from a retrospective chart review. We chose weight loss of 5% or more in the 6 months preceding CPI therapy, BMI, obesity, composite assessment of malnutrition using BMI and serum albumin as our primary measures of nutritional status.\n\nVelocity of weight loss has been historically used as a measure for malnutrition and the velocity of weight loss has been shown to correspond with other cancer related symptoms such as anorexia and fatigue as well as disease outcomes [40]. Weight loss by itself as a measure of nutrition is flawed since this is in many cases, this is subjective and dependent on patients’ recall. It does not discriminate between intentional and unintentional weight loss. In our study, there was a significant association between having a significant unintentional weight loss (5% or more in 6 months) and decreased OS probability.\n\nBMI has been shown to be predictive of outcomes in several disease conditions such as Type 2 diabetes [49]. It has associated with increased risk for developing certain cancers such as that of colon and endometrium [34]. Despite this, using BMI as a sole measure of nutritional status has several pitfalls: BMI cannot distinguish fat and lean masses, and it may be particularly in cancer patients may have a relative increase in body fat and fluids, and a severe decline in lean tissue [50]. In our study, BMI was not associated with OS or PFS. We did not observe improved outcomes associated with overweight and obese status in our patient population. While this might have simply been a reflection of the small size of our study population, it may also support previous reports of BMI as an inaccurate measure of nutritional status.\n\nAlbumin is a protein synthesized in the liver and has a half-life of 14–20 days, making serum albumin an easy, stable measure for nutritional status [45]. However, albumin levels are easily affected by its levels are affected by inflammation, liver dysfunction and many other conditions in addition to nutritional status. In our study, we found that the serum albumin less than 3.5 was the only factor that was possibly associated with worse OS and PFS probabilities.\n\nTheoretically, combining with BMI and albumin might be a more efficient tool to assess nutrition because they are likely to complement each other. For example, in patients with falsely elevated BMI because of increased fluids either from third-spacing or effusions, low serum albumin may point toward malnutrition. This composite measure has been validated in prior studies [43]. In our study, we used albumin cutoff of less than 3.5 and/or BMI <18.5 as a marker of malnutrition status. This composite score was significantly associated with OS in univariate screen. However, this measure was not incorporated into the final Cox-proportionate multivariable model selection, due to multicollinearity and correlation concerns if both malnutrition status and albumin were to be included. The model with low serum albumin status was chosen as having the best model fit.\n\nAn interesting and unexpected quadratic relationship between age and survival was observed in our study. This suggests that for our cohort, younger age is associated with greatest hazard of death at earlier time points, which declines with increasing age. In the middle age range of the cohort, the effect of age on survival is not meaningful. However, as age at start of therapy continues at about 75 years or older, the effect of age on survival seems to improve (risk of death decreases). To better understand the clinical background and biologic rationale of the relationship between age and clinical outcomes to CPI, we reviewed relevant literature on the use of immunotherapy in elderly patients with cancer.\n\nCounterintuitive to expectations that CPI would be ineffective in elderly patients with cancer due to immune-senescence, which is an age-related decline in the immune function [51], recent studies have shown that age is not an adverse predictive factor for responses to CPI and may in fact be a favorable predictive factor for patients on CPI. In a retrospective cohort study of 500 patients with metastatic melanoma treated with PD1 inhibitors as monotherapy, 144 patients who were ≥65 years age were selected for further analysis. They were then stratified into two age groups of 65–79 years and 80–100 years. Complete response rates were significantly higher for the older cohort of patient (48 vs 20%; p = 0.001) and overall response also trended higher as compared with the younger patients [52]. Safety analysis showed similar profiles of immune-related adverse events, and similar rates of grade 3 and 4 toxicity.\n\nAnother retrospective analysis of 246 patients focused solely on a population of patients with NSCLC who received PD-L1 inhibitors [53]. Patients in this study were divided into age groups of <60, 60–69, 70–79 and ≥80 years. The findings of this study differed a little from the aforementioned study in that patients <60 years had a less favorable survival outcome. With increasing age, outcomes improved and then worsened again after age 80. One possible explanation for the somewhat contrasting finding between these studies is the inherent differences between the patient populations in the two studies. It is possible, that elderly patients with lung cancer age have higher prevalence of co-morbid conditions [54], such as heart and lung diseases which become a source of competing mortality. Also, the age range in the former study contained very elderly individuals, well past 80 years of age. Additional methodological issues with these studies including selection bias and unmeasured confounders, might have contributed to the minor differences between the study results. A meta-analysis of nine randomized controlled clinical trials was performed on a total of 5265 patients who received CPIs for various indications, including lung cancer, melanoma and renal cancer [55]. Patients were divided into younger and older groups with an age cutoff for subgroup analysis of 65–70 years, CPI improved OS in both the younger (HR: 0.75; 95% CI: 0.68–0.82) and older (HR: 0.73; 95% CI: 0.62–0.87) groups. Since this meta-analysis included mostly melanoma randomized controlled trials, its generalizability to lung cancer is limited. Nevertheless, all these studies support activity and safety of CPI in the elderly patient population and our study echoed the same finding by demonstrating an interesting U-shape relationship between age and CPI outcomes. A plausible explanation for this rather paradoxical observation was explored in preclinical studies. In a melanoma mouse model [56], response to PD1 inhibition was significantly worse for younger (2 months) mice compared with older (10 months) ones. The study suggested that one explanation for this observation may be because of increase in immunosuppressive FOXP3+ Tregs within the tumor microenvironment and decrease in CD8+ T effector cells, which serve as the target of PDL1 inhibition in the younger mice.\n\nLimitations\nThere are several limitations to our study. First, this study was retrospective in nature. Furthermore, due to the limited sample size, it is possible that there was insufficient power to detect small, yet clinically meaningful differences in PFS probabilities for other risk factors. Third, as previously mentioned some of the limitations of using BMI as a sole measure of nutritional status, it was felt that albumin would be a good complement to assess nutritional status.\n\nConclusion\nOur study indicates that pretreatment nutritional status is associated with OS and possibly with PFS as well for patients treated with CPI therapy. Optimal measure for nutritional status is unclear but based on our single institution retrospective review, serum albumin and significant weight loss prior to starting CPI were significantly associated with OS in multivariate analysis. We noted an interesting parabolic age-response correlation for patients with NSCLC treated with CPI, and this warrants further evaluation with a larger sample size and preferably in a prospective fashion.\n\nFuture perspective\nImmunotherapy has changed the way we treat cancer and for some, long, durable responses have been shown. However, this benefit does not extend to all patients, with some patients experiencing no benefit at all and some suffering from a detrimental effect on their overall health either due to serious immune-related adverse effects. It is essential to carefully select patients who are likely to benefit for CPI immunotherapy. Significant research efforts toward identifying optimal biomarkers that predict outcomes to CPIs are currently underway. Nutritional status may play a role in antitumor immunity, but is still being debated. Further research will provide additional, much needed insight on this topic.\n\nAcknowledgments\nThe authors would like to thank R Sin for her assistance with data collection.\n\nAuthor contributions\n\nAll authors contributed to the study design and putting together the manuscript.\n\nFinancial & competing interests disclosure\n\nN Seetharamu has served on the advisory boards for Genentech and AstraZeneca in the last year. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.\n\nNo writing assistance was utilized in the production of this manuscript.\n\nOpen access\n\nThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. 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Lancet Oncol. \n17 (11 ), 1497 –1508\n (2016 ).27745820 \n13. Shukuya T , Carbone DP \nPredictive markers for the efficacy of anti-PD-1/PD-L1 antibodies in lung cancer\n. J. Thorac. Oncol. \n11 (7 ), 976 –988\n (2016 ).26944305 \n14. Postow MA , Sidlow R , Hellmann MD \nImmune-related adverse events associated with immune checkpoint blockade\n. N. Engl. J. Med. \n378 (2 ), 158 –168\n (2018 ).29320654 \n15. Fuentes-Antrás J , Provencio M , Díaz-Rubio E \nHyperprogression as a distinct outcome after immunotherapy\n. Cancer Treat. Rev. \n70 , 16 –21\n (2018 ).30053725 \n16. Samstein RM , Lee CH , Shoushtari AN \n\nTumor mutational load predicts survival after immunotherapy across multiple cancer types\n. Nat. Genet. \n51 (2 ), 202 –206\n (2019 ).30643254 \n17. Jacquelot N , Roberti MP , Enot DP \n\nPredictors of responses to immune checkpoint blockade in advanced melanoma\n. Nat. Commun. \n8 (1 ), 592 (2017 ).28928380 \n18. Otoshi T , Nagano T , Tachihara M , Nishimura Y \nPossible biomarkers for cancer immunotherapy\n. Cancers (Basel) \n11 (7 ), 935 (2019 ).\n19. Flint TR , Janowitz T , Connell CM \n\nTumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity\n. Cell Metab. \n24 (5 ), 672 –684\n (2016 ).27829137 \n20. Wang Z , Aguilar EG , Luna JI \n\nParadoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade\n. Nat. Med. \n25 (1 ), 141 –151\n (2019 ). 30420753 • Indicates a paradoxical impact of obesity on cancer and that obesity is associated with increased efficacy of program death-1/program death ligand-1 blockade in tumor-bearing mice and clinical cancer patients.\n\n\n21. Coss CC , Clinton SK , Phelps MA \nCachectic cancer patients: immune to checkpoint inhibitor therapy?\n\nClin. Cancer Res. \n24 (23 ),5787 \n5789\n (2018 ). 30018117 • Cachectic cancer patients exhibit poorer response to immunotherapy.\n\n\n22. Murphy WJ , Longo DL \nThe surprisingly positive association between obesity and cancer immunotherapy efficacy\n. JAMA \n321 (13 ), 1247 –1248\n (2019 ).30882850 \n23. Andreoli A , De Lorenzo A , Cadeddu F , Iacopino L , Grande M \nNew trends in nutritional status assessment of cancer patients\n. Eur. Rev. Med. Pharmacol. Sci. \n15 (5 ), 469 –480\n (2011 ).21744742 \n24. Harris PA , Taylor R , Thielke R , Payne J , Gonzalez N , Conde JG \nResearch electronic data capture (REDCap)-A metadata-driven methodology and workflow process for providing translational research informatics support\n. J. Biomed. Inform. \n42 (2 ), 377 –381\n (2009 ).18929686 \n25. Efron B \nLogistic regression, survival analysis, and the kaplan–meier curve\n. J. Am. Stat. Assoc. \n83 (402 ), 414 –425\n (1988 ).\n26. Cai J , Zeng D \nCox proportional hazard model\n. : Wiley Encyclopedia of Clinical Trials . D'agostino R , Massaro J , Sullivan L (). John Wiley & Sons, Inc , NJ, USA (2008 ).\n27. Cavanaugh JE \nUnifying the derivations for the Akaike and corrected Akaike information criteria\n. Stat. Probab. Lett. \n33 (2 ), 201 –208\n (1997 ).\n28. Flegal KM , Kit BK , Graubard BI \nBody mass index categories in observational studies of weight and risk of death\n. Am. J. Epidemiol. \n180 (3 ), 288 –296\n (2014 ).24893710 \n29. Soldati L , Di Renzo L , Jirillo E , Ascierto PA , Marincola FM , De Lorenzo A \nThe influence of diet on anti-cancer immune responsiveness\n. J. Transl. Med. \n16 (1 ), 75 (2018 ).29558948 \n30. Zitvogel L , Pietrocola F , Kroemer G \nNutrition, inflammation and cancer\n. Nat. Immunol. \n18 (8 ), 843 –850\n (2017 ).28722707 \n31. Pae M , Meydani SN , Wu D \nThe role of nutrition in enhancing immunity in aging\n. Aging Dis. \n3 (1 ), 91 –129\n (2012 ).22500273 \n32. Valdés-Ramos R , Benítez-Arciniega AD \nNutrition and immunity in cancer\n. Br. J. Nutr. \n98 (S1 ), S127 –S132\n (2007 ).17922950 \n33. Thoresen L , Frykholm G , Lydersen S \n\nNutritional status, cachexia and survival in patients with advanced colorectal carcinoma. Different assessment criteria for nutritional status provide unequal results\n. Clin. Nutr. \n32 (1 ), 65 –72\n (2013 ).22695408 \n34. Wolin KY , Carson K , Colditz GA \nObesity and cancer\n. Oncologist \n15 (6 ), 556 –565\n (2010 ).20507889 \n35. Versini M , Jeandel PY , Rosenthal E , Shoenfeld Y \nObesity in autoimmune diseases: not a passive bystander\n. Autoimmun. Rev. \n13 (9 ), 981 –1000\n (2014 ).25092612 \n36. Landskron G , De La Fuente M , Thuwajit P , Thuwajit C , Hermoso MA \nChronic inflammation and cytokines in the tumor microenvironment\n. J. Immunol. Res. \n2014 ) (Epub ahead of print ).\n37. Canter RJ , Le CT , Beerthuijzen JMT , Murphy WJ \nObesity as an immune-modifying factor in cancer immunotherapy\n. J. Leukoc. Biol. \n104 (3 ), 487 –497\n (2018 ).29762866 \n38. Lysaght J \nThe ‘obesity paradox’ in action with cancer immunotherapy\n. Nat. Rev. Endocrinol. \n15 , 132 –133\n (2019 ).30670818 \n39. Mirsoian A , Bouchlaka MN , Sckisel GD \n\nAdiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice\n. J. Exp. Med. \n211 (12 ), 2373 –2383\n (2014 ).25366964 \n40. Gioulbasanis I , Baracos VE , Giannousi Z \n\nBaseline nutritional evaluation in metastatic lung cancer patients: mini nutritional assessment versus weight loss history\n. Ann. Oncol. \n22 (4 ), 835 –841\n (2011 ).20937647 \n41. Cortellini A , Bersanelli M , Buti S \n\nA multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable\n. J. Immunother. Cancer \n7 (1 ), 57 (2019 ).30813970 \n42. Ibrahimi S , Mukherjee S , Roman D , King C , Machiorlatti M , Aljumaily R \nEffect of body mass index and albumin level on outcomes of patients receiving anti PD-1/PD-L1 therapy\n. J. Clin. Oncol. \n36 (Suppl. 5 ), 213 (2018 ).\n43. Kalantar-Zadeh K , Kleiner M , Dunne E , Lee GH , Luft FC \nA modified quantitative subjective global assessment of nutrition for dialysis patients\n. Nephrol. Dial. Transplant. \n14 (7 ), 1732 –1738\n (1999 ).10435884 \n44. Banh L \nSerum proteins as markers of nutrition: what are we treating?\n\nPract. Gastroenterol. \n30 (10 ), 46 –64\n (2006 ).\n45. Don BR , Kaysen G \nSerum albumin: relationship to inflammation and nutrition\n. Semin. Dial. \n17 (6 ), 432 –437\n (2004 ).15660573 \n46. Castell GS , Serra-Majem L , Ribas-Barba L \nWhat and how much do we eat? 24-hour dietary recall method\n. Nutr. Hosp. \n31 (Suppl. 3 ), 46 –48\n (2015 ).25719770 \n47. Vandewoude MFJ , Alish CJ , Sauer AC , Hegazi RA \nMalnutrition-sarcopenia syndrome: is this the future of nutrition screening and assessment for older adults?\n\nJ. Aging Res. \n2012 ) (Epub ahead of print ).\n48. Leinig CE , Moraes T , Ribeiro S \n\nPredictive value of malnutrition markers for mortality in peritoneal dialysis patients\n. J. Ren. Nutr. \n21 (2 ), 176 –183\n (2011 ).21193323 \n49. Narayan KMV , Boyle JP , Thompson TJ , Gregg EW , Williamson DF \nEffect of BMI on lifetime risk for diabetes in the U.S\n. Diabetes Care \n30 (6 ), 1562 –1566\n (2007 ).17372155 \n50. Baracos VE , Reiman T , Mourtzakis M , Gioulbasanis I , Antoun S \nBody composition in patients with non-small cell lung cancer: a contemporary view of cancer cachexia with the use of computed tomography image analysis\n. Am. J. Clin. Nutr. \n91 (4 ), S1133 –S1137\n (2010 ).\n51. Kanesvaran R , Cordoba R , Maggiore R \nImmunotherapy in older adults with advanced cancers: implications for clinical decision-making and future research\n. Am. Soc. Clin. Oncol. Educ. B \n38 , 400 –414\n (2018 ). • Describes the role of immunotherapy in older adults with lung cancer, bladder cancer and lymphomas.\n\n\n52. Ben-Betzalel G , Steinberg-Silman Y , Stoff R \n\nImmunotherapy comes of age in octagenarian and nonagenarian metastatic melanoma patients\n. Eur. J. Cancer \n108 , 61 –68\n (2019 ). 30648631 • Increasing age within the elderly patients group may predict a better response to therapy and comparable survival in patients of very old age in the metastatic melanoma setting.\n\n\n53. Lichtenstein MRL , Nipp RD , Muzikansky A \n\nImpact of age on outcomes with immunotherapy in patients with non–small cell lung cancer\n. J. Thorac. Oncol. \n14 (3 ), 547 –552\n (2019 ). 30476576 •• In non-small-cell lung cancer patients treated with immunotherapy, outcomes improved with increasing age and then worsened again after age 80.\n\n\n54. Dutkowska AE , Antczak A \nComorbidities in lung cancer\n. Adv. Respir. Med. \n84 (3 ), 186 –192\n (2016 ).\n55. Nishijima TF , Muss HB , Shachar SS , Moschos SJ \nComparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis\n. Cancer Treat. Rev. \n45 , 30 –37\n (2016 ).26946217 \n56. Kugel CH , Douglass SM , Webster MR \n\nAge correlates with response to anti-PD1, reflecting age-related differences in intratumoral effector and regulatory T-cell populations\n. Clin. Cancer Res. \n24 (21 ), 5347 –5356\n ( 2018 ).29898988\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1758-1966",
"issue": "9(2)",
"journal": "Lung cancer management",
"keywords": "immunotherapy; malnutrition; non-small-cell lung cancer",
"medline_ta": "Lung Cancer Manag",
"mesh_terms": null,
"nlm_unique_id": "101588392",
"other_id": null,
"pages": "LMT31",
"pmc": null,
"pmid": "32346405",
"pubdate": "2020-04-24",
"publication_types": "D016428:Journal Article",
"references": "26712084;24901008;28722707;29558948;30620402;15660573;26412456;17922950;25092612;22695408;30207593;30643254;30670818;28928380;18929686;21193323;26946217;27829137;30882850;25719770;30476576;20164322;30231397;27238182;30813970;29898988;30785829;30280635;29357948;22500273;25366964;25891174;10435884;17372155;30648631;30018117;30053725;20937647;29320654;24893710;27745820;21744742;31277279;30420753;26028407;26944305;29762866;20507889;23024863",
"title": "Pretreatment nutritional status and response to checkpoint inhibitors in lung cancer.",
"title_normalized": "pretreatment nutritional status and response to checkpoint inhibitors in lung cancer"
} | [
{
"companynumb": "US-ROCHE-2609587",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Von Willebrand disease (VWD) is the most common congenital bleeding disorder and is due to quantitative or qualitative defects of von Willebrand factor (VWF). Acquired defects of VWF, termed acquired von Willebrand syndrome (AVWS), are due to a host of different mechanisms. Autoantibody-mediated AVWS may be associated with lymphoproliferative or immunological disorders, such as systemic lupus erythematosus (SLE). A large majority of AVWS cases are type 1 or type 2A-like and patients tend to have a mild to moderate bleeding tendency. We report a case of severe autoimmune AVWS in a woman with SLE who presented with clinical and laboratory features of type 3 VWD (undetectable VWF antigen, ristocetin cofactor activity, and VWF multimers). A mixing study demonstrated an inhibitor to VWF (6BU/mL). Her bleeds were managed with antifibrinolytics, recombinant activated factor VII, and activated prothrombin complex concentrate. She was initially treated with steroids and intravenous immunoglobulin therapy. However, her bleeding symptoms continued until she was treated with rituximab, and her VWF parameters normalized. She relapsed two years later due to non-compliance with her immunosuppressive medications and expired another two years later secondary to complications of sepsis and uremic pericarditis. This case emphasizes the importance of aggressive initial therapy of SLE to reduce secondary complications, frequent patient monitoring, and continued treatment of the underlying autoimmune disorder in patients with AVWS.",
"affiliations": "Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9072, USA. Electronic address: cgavva@gmail.com.;Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9030, USA.;Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9030, USA.;Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9030, USA.;Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9072, USA.",
"authors": "Gavva|Chakri|C|;Patel|Prapti|P|;Shen|Yu-Min|YM|;Frenkel|Eugene|E|;Sarode|Ravi|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.transci.2017.04.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-0502",
"issue": "56(3)",
"journal": "Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis",
"keywords": "Acquired von Willebrand syndrome; Rituximab; Systemic lupus erythematosus",
"medline_ta": "Transfus Apher Sci",
"mesh_terms": "D000328:Adult; D001327:Autoimmune Diseases; D005260:Female; D006801:Humans; D016019:Survival Analysis; D055815:Young Adult; D014842:von Willebrand Diseases",
"nlm_unique_id": "101095653",
"other_id": null,
"pages": "431-433",
"pmc": null,
"pmid": "28512017",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of autoimmune severe acquired von Willebrand syndrome (type 3-like).",
"title_normalized": "a case of autoimmune severe acquired von willebrand syndrome type 3 like"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2017-00530",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "Lipoic acid (alpha lipoic acid, thioctic acid) is a popular over-the-counter antioxidant and insulin-mimetic supplement under investigation in a variety of conditions including multiple sclerosis, diabetes, and schizophrenia. Unfortunately, high-grade proteinuria was an unexpected adverse event specific to the treatment arm of our clinical trial investigating lipoic acid supplementation in patients with multiple sclerosis. This observation led to detection of similar patients in our nephrology practice. Here, we describe four biopsy-proven cases of neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy following lipoic acid supplementation and a fifth suspected case. Discontinuation of lipoic acid and supportive therapy resulted in remission.",
"affiliations": "Neurology Division, Portland VA Medical Center, Portland, Oregon, USA. Electronic address: spainr@ohsu.edu.;Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, Oregon, USA.;Department of Pathology and Larboratory Medicine, The Robert Larner, M.D. College of Medicine at the University of Vermont, Burlington, Vermont, USA.;Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon, USA.;Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon, USA.;Department of Neurological Sciences, The Robert Larner, M.D. College of Medicine at the University of Vermont, Burlington, Vermont, USA.;Division of Nephrology and Hypertension, The Robert Larner, M.D. College of Medicine at the University of Vermont, Burlington, Vermont, USA.;Research Division, Portland VA Medical Center, Portland, Oregon, USA.;Department of Medicine, Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, Oregon, USA.",
"authors": "Spain|Rebecca I|RI|;Andeen|Nicole K|NK|;Gibson|Pamela C|PC|;Samuels|Mary H|MH|;Morris|Cynthia D|CD|;Solomon|Andrew J|AJ|;Solomon|Richard|R|;Waslo|Carin|C|;Avasare|Rupali S|RS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.kint.2021.10.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0085-2538",
"issue": "100(6)",
"journal": "Kidney international",
"keywords": "albuminuria; glomerulonephritis; kidney biopsy; kidney pathology; lipoic acid; membranous nephropathy; nephrotic syndrome; proteinuria",
"medline_ta": "Kidney Int",
"mesh_terms": null,
"nlm_unique_id": "0323470",
"other_id": null,
"pages": "1208-1213",
"pmc": null,
"pmid": "34662650",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "25394321;33833079;33849930;30086435;26142398;20110379;33866674;6247989;33086555;33952630;28680916;21784892;21775755;31901340;21323563;21784898;31061139;17586737;32828756;306574;18559961;32200340",
"title": "Lipoic acid supplementation associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy.",
"title_normalized": "lipoic acid supplementation associated with neural epidermal growth factor like 1 nell1 associated membranous nephropathy"
} | [
{
"companynumb": "US-ORGANON-O2112USA001634",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LOSARTAN POTASSIUM"
},
"drugadditional": "4",... |
{
"abstract": "OBJECTIVE\nThe aim of the study was to explore the extent of thrombocytopenia (TCP), anaemia and leucopenia in patients with hepatitis C and evaluate how they impact the management of antiviral therapy, the attainment of sustained virological response (SVR), and some therapy-related adverse events.\n\n\nMETHODS\nThe Scottish Hepatitis C Clinical Database was used in this retrospective study. The prevalence of TCP, anaemia and leucopenia was evaluated. The impact of the three deficiencies on antiviral therapy management, serious adverse events and SVR attainment was assessed in patients who received therapy.\n\n\nRESULTS\nThe prevalence of TCP, anaemia and leucopenia was 18.5, 0.9 and 0.2% among 4907 treated patients at baseline, increasing to 72, 25.8 and 5.4% during treatment, respectively. Dose reduction occurred in 29.3% of the patients without TCP; this percentage was higher in those with baseline TCP (53%) and in those who acquired it during treatment (35%). Similar results were found for anaemia and leucopenia. Baseline TCP (odds ratio=0.67, P<0.001) and baseline anaemia (odds ratio=0.43, P=0.03) were identified as risk factors associated with lower SVR rate; acquired TCP and anaemia were not associated with reduced SVR.\n\n\nCONCLUSIONS\nBaseline TCP or anaemia increased the risk of dose cessation. Patients who acquired TCP, anaemia or leucopenia during treatment did not exhibit compromised SVR rates, whereas patients with TCP or anaemia at baseline did. The potential benefit of growth factors in maintaining SVR rate is likely to be confined to those with baseline TCP or anaemia rather than to those who acquire it during therapy, where dose reduction does not appear to reduce the chance of SVR.",
"affiliations": "aDundee Epidemiology and Biostatistics Unit, University of Dundee bDivision of Cardiovascular and Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee cSchool of Health and Life Sciences, Glasgow Caledonian University dHealth Protection Scotland eWalton Liver Clinic, Glasgow Royal Infirmary fGartnavel General Hospital, Glasgow gCrosshouse Hospital, Kilmarnock hDepartment of Hepatology, Stirling Community Hospital, Stirling iAberdeen Royal Infirmary, Aberdeen jRoyal Infirmary Edinburgh, Edinburgh kMonklands Hospital, Lanarkshire, UK.",
"authors": "Wang|Huan|H|;Innes|Hamish|H|;Hutchinson|Sharon J|SJ|;Goldberg|David J|DJ|;Allen|Samuel|S|;Barclay|Stephen T|ST|;Bramley|Peter|P|;Fox|Raymond|R|;Fraser|Andrew|A|;Hayes|Peter C|PC|;Kennedy|Nicholas|N|;Mills|Peter R|PR|;Dillon|John F|JF|",
"chemical_list": "D000998:Antiviral Agents",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000000556",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "28(4)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D000740:Anemia; D000998:Antiviral Agents; D016208:Databases, Factual; D005260:Female; D006526:Hepatitis C; D006801:Humans; D007970:Leukopenia; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D012606:Scotland; D013921:Thrombocytopenia; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "398-404",
"pmc": null,
"pmid": "26695428",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The prevalence and impact of thrombocytopenia, anaemia and leucopenia on sustained virological response in patients receiving hepatitis C therapy: evidence from a large 'real world' cohort.",
"title_normalized": "the prevalence and impact of thrombocytopenia anaemia and leucopenia on sustained virological response in patients receiving hepatitis c therapy evidence from a large real world cohort"
} | [
{
"companynumb": "GB-ROCHE-1744878",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INTERFERON ALFA-2A"
},
"drugadditional": null,
... |
{
"abstract": "This article reports the successful use of C1 esterase inhibitor in the treatment of capillary leak syndrome. The coincidence of exposure to latex during surgery and medication with ramipril led to prolonged shock complicated by secondary hyperfibrinolysis, capillary leak syndrome and multiple organ failure. Initial treatment according to relevant guidelines failed to stabilize the condition. Treatment was only successful after administration of 1,500 IU of human C1 esterase inhibitor.",
"affiliations": "Klinik für Anästhesiologie und Intensivmedizin, HELIOS-Kliniken Schwerin, Schwerin, Deutschland. ronald.seidel@helios-kliniken.de",
"authors": "Seidel|R|R|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D050718:Complement C1 Inhibitor Protein; D017257:Ramipril",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00101-012-2092-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2417",
"issue": "61(11)",
"journal": "Der Anaesthesist",
"keywords": null,
"medline_ta": "Anaesthesist",
"mesh_terms": "D000758:Anesthesia; D000806:Angiotensin-Converting Enzyme Inhibitors; D001014:Aortic Aneurysm; D019559:Capillary Leak Syndrome; D050718:Complement C1 Inhibitor Protein; D004211:Disseminated Intravascular Coagulation; D004342:Drug Hypersensitivity; D006801:Humans; D007431:Intraoperative Complications; D020315:Latex Hypersensitivity; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure; D017257:Ramipril; D012769:Shock",
"nlm_unique_id": "0370525",
"other_id": null,
"pages": "954-7",
"pmc": null,
"pmid": "23135769",
"pubdate": "2012-11",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": "20866113;20496014;20008204;20818888;21695090;22080632;19767078;21884533;20602665;20806108;21345278;20447725",
"title": "Successful use of C1 esterase inhibitor in capillary leak syndrome.",
"title_normalized": "successful use of c1 esterase inhibitor in capillary leak syndrome"
} | [
{
"companynumb": "PHHY2013DE059494",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFUROXIME"
},
"drugadditional": null,
"drug... |
{
"abstract": "The PROPKD score has been proposed to stratify the risk of progression to end-stage renal disease in autosomal dominant polycystic kidney disease (ADPKD) subjects. We aimed to assess its prognostic value in a genotyped subgroup of subjects from the Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (TEMPO3/4) trial.\n\n\n\nIn the post hoc analysis, PKD1 and PKD2 were screened in 770 subjects and the PROPKD score was calculated in mutation-positive subjects (male: 1 point; hypertension <35 years: 2 points; first urologic event <35 years: 2 points; nontruncating PKD1 mutation: 2 points; truncating PKD1 mutation: 4 points). Subjects were classified into low-risk (LR; 0-3 points), intermediate-risk (IR; 4-6 points) and high-risk (HR; 7-9 points) groups.\n\n\n\nThe PROPKD score was calculated in 749 subjects (LR = 132, IR = 344 and HR = 273); age was inversely related to risk (LR = 43.6 years, IR = 39.5 years, HR = 36.2 years; P < 0.001). Subjects from the HR group had significantly higher height-adjusted total kidney volume (TKV) and rates of TKV growth. While baseline renal function was similar across all risk groups, the rate of estimated glomerular filtration rate (eGFR) decline significantly increased from LR to HR in the placebo group. Tolvaptan treatment effectiveness to reduce TKV growth was similar in all three risk categories. While tolvaptan significantly slowed eGFR decline in the IR (tolvaptan = -2.34 versus placebo = -3.33 mL/min/1.73 m2/year; P = 0.008) and HR groups (tolvaptan = -2.74 versus placebo = -3.94 mL/min/1.73 m2/year; P = 0.002), there was no difference in the LR group (tolvaptan = -2.35 versus placebo = -2.50 mL/min/1.73 m2/year; P = 0.72). Excluding the LR subjects from the analysis improved the apparent treatment effect of tolvaptan on eGFR decline.\n\n\n\nThis study confirms the prognostic value of the PROPKD score and suggests that it could reduce costs and enhance endpoint sensitivity by enriching future study populations for rapidly progressing ADPKD subjects.",
"affiliations": "Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA.;Otsuka PDC, Rockville, MD, USA.;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA.;Institute of Nephrology, University of Zurich, Zurich, Switzerland.;Department of Nephrology, University Medical Center of Groningen, Groningen, The Netherlands.;Tufts Medical Center, Boston, MA, USA.;Division of Nephrology, University of Chicago, Chicago, IL, USA.;Otsuka PDC, Rockville, MD, USA.;Otsuka PDC, Rockville, MD, USA.;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA.;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA.;European University of Western Brittany, CHU Brest, Brest, France.;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA.;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA.",
"authors": "Cornec-Le Gall|Emilie|E|;Blais|Jaime D|JD|;Irazabal|Maria V|MV|;Devuyst|Olivier|O|;Gansevoort|Ron T|RT|;Perrone|Ron D|RD|;Chapman|Arlene B|AB|;Czerwiec|Frank S|FS|;Ouyang|John|J|;Heyer|Christina M|CM|;Senum|Sarah R|SR|;Le Meur|Yannick|Y|;Torres|Vicente E|VE|;Harris|Peter C|PC|",
"chemical_list": "D065092:Antidiuretic Hormone Receptor Antagonists; D050396:TRPP Cation Channels; C087882:polycystic kidney disease 1 protein; C099714:polycystic kidney disease 2 protein; D000077602:Tolvaptan",
"country": "England",
"delete": false,
"doi": "10.1093/ndt/gfx188",
"fulltext": "\n==== Front\nNephrol Dial TransplantNephrol. Dial. TransplantndtNephrology Dialysis Transplantation0931-05091460-2385Oxford University Press 10.1093/ndt/gfx188gfx188ORIGINAL ARTICLESClinical ResearchCan we further enrich autosomal dominant polycystic kidney disease clinical trials for rapidly progressive patients? Application of the PROPKD score in the TEMPO trial Cornec-Le Gall Emilie 12Blais Jaime D 3Irazabal Maria V 1Devuyst Olivier 4Gansevoort Ron T 5Perrone Ron D 6Chapman Arlene B 7Czerwiec Frank S 3Ouyang John 3Heyer Christina M 1Senum Sarah R 1Le Meur Yannick 2Torres Vicente E 1Harris Peter C 11 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA2 European University of Western Brittany, CHU Brest, Brest, France3 Otsuka PDC, Rockville, MD, USA4 Institute of Nephrology, University of Zurich, Zurich, Switzerland5 Department of Nephrology, University Medical Center of Groningen, Groningen, The Netherlands6 Tufts Medical Center, Boston, MA, USA7 Division of Nephrology, University of Chicago, Chicago, IL, USACorrespondence and offprint requests to: Emilie Cornec-Le Gall; E-mail: emilie.cornec-legall@chu-brest.fr4 2018 19 7 2017 19 7 2017 33 4 645 652 07 2 2017 13 4 2017 © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nThe PROPKD score has been proposed to stratify the risk of progression to end-stage renal disease in autosomal dominant polycystic kidney disease (ADPKD) subjects. We aimed to assess its prognostic value in a genotyped subgroup of subjects from the Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (TEMPO3/4) trial.\n\nMethods\nIn the post hoc analysis, PKD1 and PKD2 were screened in 770 subjects and the PROPKD score was calculated in mutation-positive subjects (male: 1 point; hypertension <35 years: 2 points; first urologic event <35 years: 2 points; nontruncating PKD1 mutation: 2 points; truncating PKD1 mutation: 4 points). Subjects were classified into low-risk (LR; 0–3 points), intermediate-risk (IR; 4–6 points) and high-risk (HR; 7–9 points) groups.\n\nResults\nThe PROPKD score was calculated in 749 subjects (LR = 132, IR = 344 and HR = 273); age was inversely related to risk (LR = 43.6 years, IR = 39.5 years, HR = 36.2 years; P < 0.001). Subjects from the HR group had significantly higher height-adjusted total kidney volume (TKV) and rates of TKV growth. While baseline renal function was similar across all risk groups, the rate of estimated glomerular filtration rate (eGFR) decline significantly increased from LR to HR in the placebo group. Tolvaptan treatment effectiveness to reduce TKV growth was similar in all three risk categories. While tolvaptan significantly slowed eGFR decline in the IR (tolvaptan = −2.34 versus placebo = −3.33 mL/min/1.73 m2/year; P = 0.008) and HR groups (tolvaptan = −2.74 versus placebo = −3.94 mL/min/1.73 m2/year; P = 0.002), there was no difference in the LR group (tolvaptan = −2.35 versus placebo = −2.50 mL/min/1.73 m2/year; P = 0.72). Excluding the LR subjects from the analysis improved the apparent treatment effect of tolvaptan on eGFR decline.\n\nConclusion\nThis study confirms the prognostic value of the PROPKD score and suggests that it could reduce costs and enhance endpoint sensitivity by enriching future study populations for rapidly progressing ADPKD subjects.\n\nautosomal dominant polycystic kidney diseasegeneticsPKD1PKD2TEMPO 3/4Otsuka Pharmaceutical10.13039/501100007132\n==== Body\nINTRODUCTION\nAutosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of end-stage renal disease (ESRD) worldwide [1], with a prevalence of renal replacement therapy (RRT) calculated at 91.1 per million in Europe [2]. The course of ADPKD varies considerably among individuals, with some reaching ESRD before 40 years of age and others living a normal lifespan without requiring RRT. Two principal genes, PKD1 and PKD2, are involved in ∼72–77% and ∼13–18% of cases, respectively [3–8]. A third gene, GANAB, has recently been described, which causes milder polycystic kidney disease but in some cases severe polycystic liver disease [9]. Genetic variability strongly influences the severity of ADPKD, with PKD1 truncating mutations typically associated with an earlier age at ESRD (median age ∼58 years) than PKD1 nontruncating mutations (∼67 years) and PKD2 mutations (∼79 years) [3].\n\nSubstantial progress in understanding the pathogenesis of ADPKD has triggered the development of new therapeutic strategies [10]. Tolvaptan, a vasopressin 2 receptor antagonist, was demonstrated to slow the rate of total kidney volume (TKV) growth and the rate of kidney function decline in the Tolvaptan Efficacy and Safety in Autosomal Dominant Polycystic Kidney Disease (TEMPO) trial [11]. A post hoc analysis suggested clinically similar beneficial effects of tolvaptan in ADPKD across chronic kidney disease (CKD) Stages 1–3, as defined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [12].\n\nTwo major factors have made the design of clinical trials in ADPKD particularly challenging. First, the significant variability of renal disease severity complicates the evaluation of candidate drugs, as nonselected cohorts are highly heterogeneous. Second, the loss of kidney function [evaluated by estimated glomerular filtration rate (eGFR)] usually happens gradually, when irreversible structural damage has occurred and intervention is unlikely to be successful. Consequently, classic clinical endpoints such as doubling of serum creatinine or onset of ESRD are difficult to study in a placebo-controlled trial of reasonable length. Ideally, patients at risk of rapid progression should be selected and treatment should be initiated early to maximize the chance of detecting therapeutic effects in a limited population size [13].\n\nSeveral approaches have been developed to assess the severity and the prognosis of ADPKD. Previous studies from the Consortium for Radiologic Imaging Study of PKD (CRISP) provided a strong rationale for the prognostic value of TKV, including height adjusted (HtTKV), in ADPKD [14–19]. The Mayo imaging classification (MIC) was developed to predict the rate of decline of eGFR according to the HtTKV at a given age [20]. The authors recommended enriching clinical trials with patients who present with typical imaging presentations and higher HtTKV/age, specifically imaging categories 1C–1E. Aside from the imaging-based prognostic strategies, a different approach was developed in the French cohort Genkyst, which aims to include all the consenting ADPKD patients from the western part of France, irrespective of their disease severity. The Predicting Renal Outcome in Polycystic Kidney Disease (PROPKD) score, based on clinical and genetic data, was shown to stratify the risk of progression to ESRD [4]. The authors suggested enriching clinical trials with subjects classified as high risk by the PROPKD score.\n\nIn this post hoc analysis involving a subgroup of subjects from the TEMPO 3/4 trial with genetic data available, we first aimed to assess the prognostic value of the PROPKD score. Our second objective was to investigate whether risk stratification using the PROPKD score in the TEMPO 3/4 trial, by excluding subjects from the low-risk group, where progression of TKV and eGFR would be expected to be slowest, may have further enriched the population for subjects with rapidly progressing ADPKD enhancing discriminative ability.\n\nMATERIALS AND METHODS\nStudy design\nThis is a post hoc exploratory analysis of TEMPO 3/4, a prospective, randomized, double-blinded trial in 1445 ADPKD adult patients (18–50 years) with an estimated creatinine clearance (Cockroft and Gault) >60 mL/min and a TKV >750 mL/min. The participants were randomized in a 2:1 ratio to receive tolvaptan or placebo [11, 21].\n\nStudy participants\nTEMPO 3/4 participants with available genetic analysis were included in this study, namely subjects enrolled in the open-label extension trial TEMPO 4/4 who consented to provide a blood sample for DNA analysis [22]. The PROPKD score was calculated in all the subjects in whom a mutation of PKD1 or PKD2 was identified (n = 749).\n\nMolecular analysis of the PKD1 and PKD2 genes\nThe entire coding regions of the PKD1 and PKD2 genes and their flanking intronic regions were screened by Sanger sequencing, followed if negative by the detection of gross rearrangements using multiplex ligation-dependent probe amplification [23, 24].\n\nCalculation of the PROPKD\nThe PROPKD score, ranging from 0 to 9 points, was calculated in the mutation-positive subjects as the sum of the following factors: being a male: 1 point; hypertension onset before age 35 years: 2 points; first urologic event before age 35 years (including cyst infection, gross hematuria and/or flank pain related to cysts): 2 points; PKD2 mutation: 0 points; nontruncating mutation of PKD1: 2 points; truncating mutation of PKD1: 4 points (Supplementary data, Table S1). Subjects were classified into low-risk (LR; 0–3 points), intermediate-risk (IR; 4–6 points) and high-risk (HR; 7–9 points) groups (Supplementary data, Table S1) [4]. For subjects <35 years of age who had not developed hypertension and/or urological events, a score of 0 was allocated to these clinical variables and the score calculated as the sum of the remaining factors.\nTable 1 Baseline characteristics\n\n(A) Comparison of the baseline characteristics in the three PROPKD risk groups\t\n\tLR PROPKD 1–3\tIR PROPKD 4–6\tHR PROPKD 7–9\tP-values\t\n\t(n = 132)\t(n = 344)\t(n = 273)\tLR to IR\tIR to HR\tLR to HR\t\nAge (years), mean (SD)\t43.6 (5.3)\t39.5 (6.6)\t36.3 (6.8)\t<0.0001\t<0.0001\t<0.0001\t\nCaucasian, n (%)\t124 (93.9)\t339 (98.5)\t259 (94.9)\t0.01\t0.7\t0.003\t\nMale, n (%)\t80 (60.6)\t101 (29.3)\t209 (76.6)\t<0.0001\t<0.0001\t0.002\t\nAge at diagnosis of ADPKD (years), mean (SD)\t35.4 (8.6)\t26.7 (8.9)\t23.6 (7.7)\t<0.0001\t<0.0001\t<0.0001\t\nHTN, n (%)\t108 (81.8%)\t277 (80.5%)\t252 (92.3%)\t0.80\t<0.0001\t0.003\t\nAge at diagnosis of HTN, (years), mean (SD)\t38.3 (5.77)\t33.1 (7.9)\t26.5 (6.5)\t<0.0001\t<0.0001\t<0.0001\t\nMedian TKV (mL) (IQR)\t1367 (838–1896)\t1338 (916–1759)\t1682 (1181–2182)\t0.15\t<0.0001\t0.002\t\nMedian HtTKV (mL/m), (IQR)\t785 (492–1077)\t784 (545–1022)\t947 (663–1231)\t0.28\t<0.0001\t0.005\t\neGFRCKD-EPI (mL/min/1.73 m2, mean (SD)\t84.8 (21.1)\t83.4 (20.9)\t82.3 (23.1)\t0.56\t0.49\t0.32\t\nGenotype, n (%)\t\n PKD1 truncating\t0 (0.0)\t219 (63.7)\t240 (87.9)\t<0.0001\t<0.0001\t<0.0001\t\n PKD1 nontruncating\t53 (40.2)\t111 (32.2)\t33 (12.1)\t0.11\t<0.0001\t<0.0001\t\n PKD2\t79 (59.8)\t14 (4.1)\t0 (0.0)\t<0.0001\t0.304\t<0.0001\t\nMayo imaging class, n (%)\t\n Class 2\t10 (7.6)\t7 (2)\t1 (0.4)\t0.097\t0.0831\t<0.0001\t\n Class 1B\t17 (12.9)\t35 (10.2)\t6 (2.2)\t0.41\t<0.0001\t<0.0001\t\n Class 1C\t62 (47)\t151 (43.9)\t70 (25.6)\t0.61\t0.0119\t0.003\t\n Class 1D\t36 (27.2)\t113 (32.8)\t117 (42.9)\t0.27\t<0.0001\t<0.0001\t\n Class 1E\t7 (5.3)\t36 (10.5)\t76 (27.8)\t0.11\t<0.0001\t<0.0001\t\n Missing\t0\t2 (0.6)\t3 (1.1)\t\t\t\t\n(B) Comparison of the baseline characteristics in the tolvaptan-(T) and placebo (P)-treated patients within each PROPKD risk group\t\n\tLR PROPKD 1–3\tIR PROPKD 4–6\tHR PROPKD 7–9\t\n\tT (n = 79)\tP (n = 53)\tT (n = 226)\tP (n = 118)\tT (n = 167)\tP (n = 106)\t\nAge (years), mean (SD)\t43.7 (5.0)\t43.5 (5.8)\t39.2 (6.7)\t40.2 (6.5)\t36.3 (6.4)\t36.1 (7.3)\t\nCaucasian, n (%)\t75 (94.9)\t49 (92.5)\t222 (98.2)\t117(99.2)\t157 (94)\t102 (96.2)\t\nMale, n (%)\t50 (63.3)\t30 (56.6)\t74 (32.7)\t27 (22.9)\t135* (80.8)\t74* (69.8)\t\nTKV (mL), median (IQR)\t1574*\t1241*\t1330\t1352\t1699\t1677\t\n(1009–2138)\t(943–1538)\t(905–1754)\t(950–1754)\t(1163–2235)\t(1216–2138)\t\nHtTKV (mL/m), median (IQR)\t917*\t705*\t756\t793\t952\t939\t\n(596–1238)\t(538–871)\t(520–991)\t(553–1032)\t(666–1238)\t(663–1215)\t\neGFRCKD-EPI, mean mL/min/1.73 m2 (SD)\t81.1* (18.5)\t90.3* (23.6)\t83.7 (20.7)\t82.9 (21.4)\t82.0 (22.5)\t82.8 (24.1)\t\nHTN, hypertension; IQR, interquartile range.\n\n* P-value between T and P < 0.05.\n\n\n\nOutcome measure\nTwo endpoints of the TEMPO 3/4 trial were considered in this analysis: the primary outcome measure, which was the annual rate of change in TKV over time, and the secondary outcome measure, the rate of kidney function decline.\n\nStatistical analyses\nAnnualized TKV growth rate was calculated in each risk subgroup by regressing logarithm-transformed kidney volume data against time and then displaying regression slope exponentials. All eGFR values presented were calculated using the CKD-EPI formula [25]. The rate of eGFR decline was obtained in each risk subgroup by regressing eGFR from steady-state after baseline (i.e. Week 3 and beyond) against time by subject. Treatment effects for both endpoints corresponded to the difference between the slopes of tolvaptan and placebo.\n\nRESULTS\nDescription of the study population and comparison of risk groups defined by the PROPKD score at baseline\nMolecular analysis of PKD1 and PKD2 was conducted in 770 subjects. The mutation detection rate was high, with mutations identified in 749 subjects (97.3%; 583 different mutations), of whom 61.3% had a truncating PKD1 mutation, 26.3% had a nontruncating PKD1 mutation and 12.4% had a PKD2 mutation. A majority of the mutations identified were private, the two most frequent variants were the missense c.8311G>A (p.Glu2771Lys) and the frameshifting deletion c.5014_5015delAG (p.Arg1672fs97X), each identified in 2% of the subjects (n = 15). Baseline and demographic characteristics in these 749 tolvaptan- and placebo-treated subjects were well-balanced overall and similar to baseline characteristics in the TEMPO 3/4 trial (Supplementary data, Table S2). After calculation of the PROPKD score in the 749 mutation-positive patients, most subjects were categorized to the more severe risk groups [n = 132 (17.6%) in LR, 344 (45.9%) in IR and 273 (36.5%) in HR], with the mean age inversely related to risk (LR = 43.6 years, IR = 39.5 years, HR = 36.3 years; P < 0.001) (Table 1).\nTable 2 Rate of change in TKV and eGFR by PROPKD risk categories\n\n(A) Analysis in the 749 individuals included in the post hoc analysis\t\nVariable\tLR\tIR\tHR\t\n\tT\tP\tT\tP\tT\tP\t\n\t(n = 79)\t(n = 53)\t(n = 226)\t(n = 118)\t(n = 167)\t(n = 106)\t\nRate of TKV growth (%/year)\t2.80\t5.11\t2.30\t4.72\t4.15\t6.75\t\nP-value\t0.0022\t<0.0001\t<0.0001\t\nRelative treatment effect (%)\t45.8\t51.8\t38.2\t\n\tT\tP\tT\tP\tT\tP\t\n(n = 79)\t(n = 52)\t(n = 214)\t(n = 115)\t(n = 159)\t(n = 103)\t\nRate of eGFRCKD-EPI decline (mL/min/1.73 m2)\t−2.35\t−2.50\t−2.34\t−3.33\t−2.74\t−3.94\t\nP-value\t0.72\t0.008\t0.002\t\nRelative treatment effect (%)\t6.9\t30.3\t30.6\t\n(B) Subgroup analysis in patients from MICs C, D and E (n = 668)\t\nVariable\tLR\tIR\tHR\t\nT\tP\tT\tP\tT\tP\t\n(n = 65)\t(n = 40)\t(n = 196)\t(n = 104)\t(n = 160)\t(n = 103)\t\nRate of TKV growth (%/year)\t2.71\t5.36\t2.47\t5.08\t4.27\t6.9\t\nP-value\t0.0010\t<0.0001\t<0.0001\t\nRelative treatment effect (%)\t50.4\t52.2\t38.1\t\n\tT\tP\tT\tP\tT\tP\t\n(n = 65)\t(n = 39)\t(n = 186)\t(n = 101)\t(n = 152)\t(n = 100)\t\nRate of eGFRCKD-EPI decline (mL/min/1.73 m2)\t−2.55\t−2.58\t−2.47\t−3.53\t−2.74\t−4.11\t\nP-value\t0.91\t0.009\t0.0003\t\nRelative treatment effect (%)\t2.3\t30.5\t33.7\t\nP, placebo; T, tolvaptan.\n\n\n\nAt baseline, while HtTKV was significantly higher in the HR group than in the IR and LR groups (respective median values of 947, 784 and 785 mL/m; P < 0.005), eGFR was similar in the three groups (Table 1, panel A).\n\nPatients with no mutation detected\nWhile age and eGFR at baseline were similar in the 21 patients with no mutation detected (NMD) and the 749 mutation-positive subjects, median baseline TKV (1167 mL) and HtTKV (648 mL/m) were lower (P-values 0.015 and 0.018, respectively) and these subjects were more frequently classified at lower risk by the MIC (Class 2 or 1B) (38.1% versus 10.2%; P = 0.009).\n\nRate of TKV growth and PROPKD risk categories\nRate of TKV growth was significantly higher in subjects classified in the HR group than those in the IR and LR groups for both treatment arms. Indeed, in placebo-treated subjects, the rate of TKV growth in the HR group was 32–43% higher than in the LR and IR groups, whereas in the tolvaptan-treated subjects, TKV growth in the HR group was 48–80% higher than in the LR and IR groups (Table 2, panel A). In the LR group, TKV at baseline was significantly higher in the tolvaptan- versus placebo-treated subjects (Table 1, panel B). However, TKV growth was significantly lower in tolvaptan- versus placebo-treated subjects in each of the risk groups. Treatment effect was similar in the three risk groups (Table 2, panel A).\n\nRate of eGFR decline and PROPKD risk categories\nIn the placebo-treated subjects, the eGFR decline was greater from the HR to the LR groups. While tolvaptan significantly reduced the rate of renal function decline in the IR and HR groups, with relative treatment effects of 30.3% and 30.6%, there was no significant difference between the tolvaptan- and placebo-treated subjects in the LR group (Table 2, panel A). In the latter group, however, the eGFR at baseline was significantly higher in the placebo-treated group (Table 1, panel B).\n\nEffect of the exclusion of subjects from the LR group on the outcome measures\nWe investigated the effect of excluding subjects from the LR group [n = 132 (17.6%)]. While this exclusion did not change the tolvaptan-mediated decrease in TKV growth rate (Figure 1A), there was a nonsignificant trend of increased treatment effect on the rate of eGFR decline (treatment effect 30.6% after exclusion of LR versus 27.1%). In the three combined groups, tolvaptan reduced the rate of eGFR decline from −3.40 to −2.48 mL/min/1.73 m2/year (P = 0.0001). Excluding subjects in the LR group from the analysis increased this difference (−3.62 to −2.51 mL/min/1.73 m2/year; P < 0.0001) (Figure 1B).\n\n\nFIGURE 1 (A) Rate of TKV growth in the LR group, in the combined HR and IR group and in the three combined groups. (B) Rate of eGFR decline in the LR group, in the combined HR and IR group and in the three combined groups. Error bars represent the standard error of the mean.\n\nStability of PROPKD risk groups in subjects <35 years of age during the trial follow-up\nThe clinical variables included in the PROPKD score, i.e. hypertension and urological events, are set as binary variables occurring before 35 years (2 points) or not (0 points). Among the 749 mutation-positive subjects, 168 were <35 years of age, almost exclusively in the more severe groups (7 in LR, 61 in IR, 100 in HR). Fourteen of these subjects changed risk category after 3 years of follow-up: 3 from LR to IR and 11 from IR to HR (Figure 2).\n\n\nFIGURE 2 Classification remains stable in most patients over time. Flowchart representing the classification of the 749 subjects in the three PROPKD risk groups at baseline and after 3 years of follow-up. Fourteen of these subjects changed risk category after 3 years of follow-up: 3 from LR to IR and 11 from IR to HR as a consequence of a diagnosis of hypertension in 10 subjects and the occurrence of a first urological event in 6 subjects.\n\nCombination of the MIC and PROPKD approaches\nTo investigate whether the PROPKD score and the MIC could be used as complementary enrichment strategies, we studied the distribution of LR, IR and HR subjects in the different classes of the MIC. As expected, HR subjects were more represented in the more severe classes (1C, 1D and 1E; Table 1, panel A and Figure 3). While 75.7% of subjects were defined at higher risk of significant progression by both methods (Group 1, i.e. IR and HR by the PROPKD and MIC groups 1C, 1D and 1E), only 3.6% were defined at low risk of progression by both methods (Group 2), 14.1% were considered at higher risk only by the MIC (Group 3) and 6.6% only by the PROPKD score (Group 4). Consistent with the entry criteria of the TEMPO trial, a majority of the subjects classified at lower risk by each method were >35 years of age (96% for the MIC and 94% for the PROPKD). Inversely, subjects from Group 1 had similar baseline kidney function but were significantly younger than patients from Group 3 and Group 4 [mean age 37 versus 43 and 43 years, respectively (P < 0.001)]. The proportion of subjects from MIC Class 1C was significantly higher in the discordant Group 3 than in the concordant Group 1 (59% versus 39.3%; P < 0.001). Similarly, the proportion of subjects from the PROPKD IR group was higher in the discordant Group 4 than in the concordant Group 1 (85.7% versus 40%; P < 0.001). This suggests an overall milder disease in these two discordant subgroups. The most frequent missense variant, p.Glu2771Lys, was more frequently identified in the discordant Group 3 than in the rest of the cohort (5.7% versus 1.4%; P = 0.004).\n\n\nFIGURE 3 Distribution of LR, IR and HR groups in each category of the MIC model.\n\nTo evaluate whether the PROPKD further improved the imaging stratification in Classes 1C, 1D and 1E, we excluded subjects classified as Class 2 (n = 18) and 1B (n = 58). In subjects from Classes 1C, 1D and 1E, while tolvaptan reduced TKV growth in each of the three PROPKD risk groups, it was associated with significantly slower renal function decline in the IR and HR groups, but not in the LR group (Table 2, panel B).\n\nDISCUSSION\nDesigning optimal clinical trials in ADPKD is a difficult task given the lifelong progression of the disease and the high variability of its severity. Inclusion criteria in the TEMPO trial combined volume and age thresholds in individuals with preserved kidney function, thus enriching for patients with rapidly progressive ADPKD. Reflecting this enrichment, when compared with the Genkyst cohort, PKD1 truncating mutations were more frequent in TEMPO patients (61.3% versus 53%) and PKD2 mutations less frequent (12.4% versus 20.2%).\n\nThe PROPKD score was developed in a population-based cohort representative of the wide spectrum of disease severity in adult ADPKD. Herein, we confirm the prognostic value of the PROPKD score in a genotyped subgroup of subjects from the TEMPO trial. Indeed, subjects from the HR group, although younger, had higher HtTKVs at baseline and higher rates of TKV growth. While subjects from the three risks groups had similar average eGFR at baseline, we observed increasingly steeper rates of eGFR decline from the LR to the HR group. This study provides strong validation of the prognostic value of the PROPKD score for two reasons. First, it demonstrates that the PROPKD score stratifies the risk for disease progression even in ADPKD patients selected to have rapidly progressive disease. Second, although the PROPKD score was developed to predict age at ESRD, we show here that it also predicts rates of eGFR decline and TKV growth.\n\nOur second objective was to investigate whether excluding subjects from the LR group defined by the PROPKD score may have enhanced the discriminative ability of the TEMPO trial. As a result of the TEMPO entry criteria, a higher proportion of subjects was classified in the HR (36.5%) and IR groups (45.9%) when compared with the Genkyst cohort, where the HR and IR groups represented 14% and 46.7% of the subjects, respectively [4]. In this post hoc analysis, exclusion of the 132 LR group subjects (17.6%) slightly maximized the difference in the rate of eGFR decline between the tolvaptan- and the placebo-treated subjects. The treatment effect on the rate of TKV growth was similar in the three risk groups.\n\nThis analysis demonstrates that the PROPKD score can be used to enrich clinical trial cohorts for rapidly progressive patients, and complement enrichment from TKV criteria, to increase the chances of observing significant differences in the rate of kidney function decline. Such strategies in future trials may allow cost reductions by decreasing the number of subjects to recruit while maximizing the chance of positive results. While the high cost of a comprehensive analysis of PKD genes has long been a disincentive, the current widespread use of next-generation sequencing allows significant cost reductions and is likely to facilitate access to genetic testing [26–30].\n\nTwo recent studies evaluating an enrichment strategy using the MIC have been published [31, 32]. The first post hoc analysis was conducted in early disease in the HALT-PKD study, a randomized controlled trial that studied the effect of rigorous versus standard blood pressure control on rates of TKV increase and eGFR decline in ADPKD subjects ages 15–49 years with preserved renal function (eGFR > 60 mL/min/1.73 m2) at inclusion [33]. Treatment was more beneficial in subjects from Classes 1D and 1E, both in terms of TKV increase and eGFR decrease. This cohort of subjects was more heterogeneous in terms of disease severity than in the TEMPO 3/4 trial. Analysis of the PROPKD score performance in that population would be interesting, but age at the first urological event was not systematically collected. The second post hoc analysis was conducted in the TEMPO trial [32]. Exclusion of Class 2A and 1B subjects resulted in a slightly higher treatment effect on TKV and eGFR slopes, although nonsignificant. Interestingly in our study, 105 subjects from MICs 1C–1E were categorized in the PROPKD LR group. Subjects in this subgroup were significantly older and more frequently classified as MIC 1C, suggesting an overall milder disease in this discordant subgroup. In subgroup analysis including only the 668 subjects from MICs 1C–1E, the rate of eGFR decline was lower in the LR than in the IR and HR groups. And while treatment was associated with a slower renal function decline in the HR and IR groups, there was no difference from placebo in the LR group. This suggests that combining imaging, genetics and clinical criteria in a single scoring system may be of interest to develop future prognostic tools in ADPKD. Such an approach will allow evaluation of the relative contributions of the different predictors and provide accurate prognostic information earlier: before the occurrence of significant volume enlargement and/or hypertension or a urological event. Meanwhile, the use of both tools seems particularly interesting in patients at intermediate risk, for instance using PROPKD to reclassify subjects from MIC 1C and MIC to reclassify subjects from the PROPKD IR group, depending on which prognosis tool was used first.\n\nTolvaptan is now available in Canada, Japan, Europe, South Korea and Switzerland and a position statement for the use of tolvaptan has recently been issued by a European group of experts [34]. One of the objectives of this group was to define the definition of ‘evidence of rapid disease progression’. Besides historical kidney growth and eGFR decline, demonstrated by sequential imaging or creatinine measurements, the authors suggested that subjects from MICs 1C–1E or from the PROPKD HR group were likely to have rapid progression. Taking into account the results of the present study, subjects from the PROPKD IR group should also be considered at risk for rapid progression, although we must keep in mind that these subjects met the inclusion criteria for the TEMPO trial and so potentially had more rapid progression than nonpreselected IR group subjects.\n\nThis study has some limitations. First, this is a post hoc analysis, which was run in a subgroup of the TEMPO trial, and a sample for genetic analysis was collected on only ∼53% of subjects. As a consequence, the LR group was quite small and baseline characteristics between placebo- and tolvaptan-treated patients differed significantly in this subgroup. Reassuringly, baseline characteristics in the genotyped subgroup were similar to the full TEMPO 3/4 cohort [11]. Second, while disease severity is overall milder in patients with nontruncating variants, a handful of missense variants has been shown in vitro to be fully penetrant, including p.Glu2771Lys, which disrupts cleavage of polycystin 1 at the G-protein coupled receptor proteolytic site [35, 36], and was more frequent in subjects considered at higher risk only by the MIC. Attributing four points (truncating mutation) rather than two points (nontruncating mutation) for the genetic component of the PROPKD score in the ∼2% of ADPKD patients harboring this mutation would improve their prognostic assessment. In the future, the development of functional assays will allow more refined variant classification. Moreover, in 21 patients no mutation of PKD1 or PKD2 was identified and thus the PROPKD score could not been calculated. Aside from missed mutations in the complex PKD1 gene, or in the intronic portions of both genes, missense variants of unknown significance or mosaic cases may explain some of these genetically unresolved cases, which is suggested by the higher proportion of subjects from MIC 2, i.e. with segmental, asymmetric or lopsided imaging presentation. Mutations in GANAB are unlikely to be involved here, as none of the 20 GANAB patients reported so far would have met the age and TKV inclusion criteria of the TEMPO 3/4 trial [9]. Nevertheless, the mutation detection rate was particularly high in this cohort, with only 2.7% of the subjects having NMD, compared with 7–10% in other recent ADPKD cohorts [3, 4, 7, 24]. A potential explanation is that subjects with NMD tend to have milder disease [7] and were hence less likely to be included in the TEMPO trial. Last, due to the scoring criteria, the PROPKD score can increase in subjects <35 years of age if they develop hypertension or experience a first urological event. Therefore, excluding young LR group subjects from studies and treatment has the risk of removing a few subjects with rapidly progressive disease. The follow-up analysis in the TEMPO trial timeframe is reassuring, as only three subjects moved from the LR to the IR group.\n\nIn conclusion, the PROPKD score is an efficient strategy to enrich future randomized control trials cohorts for rapidly progressive patients. Ultimately, the combination of imaging and genetic-based approaches will likely enhance our capacity to predict renal outcomes and tailor therapeutic approaches to individual ADPKD patients.\n\nSupplementary Material\nSupplementary Data Click here for additional data file.\n\n ACKNOWLEDGEMENTS\nWe thank the patients involved in the TEMPO 3/4 trial for their participation and contribution.\n\nFUNDING\nThe trial was funded by Otsuka Pharmaceutical, Tokyo, Japan and Otsuka Pharmaceutical Development and Commercialization, Rockville, MD, USA. An Otsuka grant also funded mutation analysis of the TEMPO population at the Mayo Translational PKD Center. E.C.-L.G. was funded by an American Society of Nephrology Foundation Kidney Research Fellowship.\n\nSUPPLEMENTARY DATA\n\nSupplementary data are available online at http://ndt.oxfordjournals.org.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n==== Refs\nREFERENCES\n1 \nChebib FT , Torres VE. \nAutosomal dominant polycystic kidney disease: core curriculum 2016 . Am J Kidney Dis 2016 ; 67 : 792 –810 26530876 \n2 \nSpithoven EM , Kramer A , Meijer E \n\nRenal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe: prevalence and survival—an analysis of data from the ERA-EDTA Registry . Nephrol Dial Transplant 2014 ; 29(Suppl 4) : iv15 –iv25 25165182 \n3 \nCornec-Le Gall E , Audrezet MP , Chen JM \n\nType of PKD1 mutation influences renal outcome in ADPKD . J Am Soc Nephrol 2013 ; 24 : 1006 –1013 23431072 \n4 \nCornec-Le Gall E , Audrezet MP , Rousseau A \n\nThe PROPKD score: a new algorithm to predict renal survival in autosomal dominant polycystic kidney disease . J Am Soc Nephrol 2016 ; 27 : 942 –951 26150605 \n5 \nCornec-Le Gall EC-L , Audrézet M-P , Le Meur Y \n\nGenetics and pathogenesis of autosomal dominant polycystic kidney disease: twenty years on . Hum Mutat 2014 ; 35 : 1393 –1406 25263802 \n6 \nHarris PC , Rossetti S. \nMolecular diagnostics for autosomal dominant polycystic kidney disease . Nat Rev Nephrol 2010 ; 6 : 197 –206 20177400 \n7 \nHeyer CM , Sundsbak JL , Abebe KZ \n\nPredicted mutation strength of nontruncating PKD1 mutations aids genotype–phenotype correlations in autosomal dominant polycystic kidney disease . J Am Soc Nephrol 2016 ; 27 : 2872 –2884 26823553 \n8 \nHwang YH , Conklin J , Chan W \n\nRefining genotype–phenotype correlation in autosomal dominant polycystic kidney disease . J Am Soc Nephrol 2016 ; 27 : 1861 –1868 26453610 \n9 \nPorath B , Gainullin VG , Cornec-Le Gall E \n\nMutations in GANAB, encoding the glucosidase IIα subunit, cause autosomal-dominant polycystic kidney and liver disease . Am J Hum Genet 2016 ; 98 : 1193 –1207 27259053 \n10 \nOng AC , Devuyst O , Knebelmann B \n\nAutosomal dominant polycystic kidney disease: the changing face of clinical management . Lancet 2015 ; 385 : 1993 –2002 26090645 \n11 \nTorres VE , Chapman AB , Devuyst O \n\nTolvaptan in patients with autosomal dominant polycystic kidney disease . N Engl J Med 2012 ; 367 : 2407 –2418 23121377 \n12 \nTorres VE , Higashihara E , Devuyst O \n\nEffect of tolvaptan in autosomal dominant polycystic kidney disease by CKD stage: results from the TEMPO 3:4 trial . Clin J Am Soc Nephrol 2016 ; 11 : 803 –811 26912543 \n13 \nGrantham JJ. \nRationale for early treatment of polycystic kidney disease . Pediatr Nephrol 2015 ; 30 : 1053 –1062 25022529 \n14 \nBhutani H , Smith V , Rahbari-Oskoui F \n\nA comparison of ultrasound and magnetic resonance imaging shows that kidney length predicts chronic kidney disease in autosomal dominant polycystic kidney disease . Kidney Int 2015 ; 88 : 146 –151 25830764 \n15 \nChapman AB , Bost JE , Torres VE \n\nKidney volume and functional outcomes in autosomal dominant polycystic kidney disease . Clin J Am Soc Nephrol 2012 ; 7 : 479 –486 22344503 \n16 \nEuropean Medicines Agency . Total Kidney Volume (TKV) as a prognostic biomarker for use in clinical trials evaluating patients with autosomal dominant polycystic kidney disease (ADPKD). 2015 \nhttp://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2015/11/WC500196569.pdf.\n17 \nUS Food and Drug Administration . biomarker qualification review for total kidney volume. 2015. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/UCM458496.pdf (6 April 2017, date last accessed).\n18 \nGrantham JJ , Torres VE. \nThe importance of total kidney volume in evaluating progression of polycystic kidney disease . Nat Rev Nephrol 2016 ; 12 : 667 –677 27694979 \n19 \nGrantham JJ , Torres VE , Chapman AB \n\nVolume progression in polycystic kidney disease . N Engl J Med 2006 ; 354 : 2122 –2130 16707749 \n20 \nIrazabal MV , Rangel LJ , Bergstralh EJ \n\nImaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials . J Am Soc Nephrol 2015 ; 26 : 160 –172 24904092 \n21 \nTorres VE , Meijer E , Bae KT \n\nRationale and design of the TEMPO (tolvaptan efficacy and safety in management of autosomal dominant polycystic kidney disease and its outcomes) 3–4 study . Am J Kidney Dis 2011 ; 57 : 692 –699 21333426 \n22 \nTorres VE , Chapman AB , Devuyst O \n\nMulticenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial . Nephrol Dial Transplant. 2017; https://clinicaltrials.gov/ct2/show/NCT01214421 (6 April 2017, date last accessed)\n23 \nConsugar MB , Wong WC , Lundquist PA \n\nCharacterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome . Kidney Int 2008 ; 74 : 1468 –1479 18818683 \n24 \nRossetti S , Consugar MB , Chapman AB \n\nComprehensive molecular diagnostics in autosomal dominant polycystic kidney disease . J Am Soc Nephrol 2007 ; 18 : 2143 –2160 17582161 \n25 \nLevey AS , Stevens LA , Schmid CH \n\nA new equation to estimate glomerular filtration rate . Ann Intern Med 2009 ; 150 : 604 –612 19414839 \n26 \nEisenberger T , Decker C , Hiersche M \n\nAn efficient and comprehensive strategy for genetic diagnostics of polycystic kidney disease . PLoS One 2015 ; 10 : e0116680 25646624 \n27 \nRossetti S , Hopp K , Sikkink RA \n\nIdentification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing . J Am Soc Nephrol 2012 ; 23 : 915 –933 22383692 \n28 \nTan Y-C , Blumenfeld JD , Anghel R \n\nNovel method for genomic analysis of PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease . Hum Mutat 2009 ; 30 : 264 –273 18837007 \n29 \nTrujillano D , Bullich G , Ossowski S \n\nDiagnosis of autosomal dominant polycystic kidney disease using efficient PKD1 and PKD2 targeted next-generation sequencing . Mol Genet Genomic Med 2014 ; 2 : 412 –421 25333066 \n30 \nYang T , Meng Y , Wei X \n\nIdentification of novel mutations of PKD1 gene in Chinese patients with autosomal dominant polycystic kidney disease by targeted next-generation sequencing . Clin Chim Acta 2014 ; 433 : 12 –19 24582653 \n31 \nIrazabal MV , Abebe KZ , Bae KT \n\nPrognostic enrichment design in clinical trials for autosomal dominant polycystic kidney disease: the HALT-PKD clinical trial . Nephrol Dial Transplant 2017 ; 32 : 1857 –1865 27484667 \n32 \nIrazabal MV , Blais JD , Perrone RD \n\nPrognostic enrichment design in clinical trials for ADPKD: the TEMPO 3:4 clinical trial . Kidney Int Rep 2016 ; 1 : 213 –220 29142926 \n33 \nSchrier RW , Abebe KZ , Perrone RD \n\nBlood pressure in early autosomal dominant polycystic kidney disease . N Engl J Med 2014 ; 371 : 2255 –2266 25399733 \n34 \nGansevoort RT , Arici M , Benzing T \n\nRecommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice . Nephrol Dial Transplant 2016 ; 31 : 337 –348 26908832 \n35 \nGarcia-Gonzalez MA , Jones JG , Allen SK \n\nEvaluating the clinical utility of a molecular genetic test for polycystic kidney disease . Mol Genet Metab 2007 ; 92 : 160 –167 17574468 \n36 \nQian F , Boletta A , Bhunia AK \n\nCleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations . Proc Natl Acad Sci USA 2002 ; 99 : 16981 –16986 12482949\n\n",
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"journal": "Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association",
"keywords": null,
"medline_ta": "Nephrol Dial Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D065092:Antidiuretic Hormone Receptor Antagonists; D002986:Clinical Trials as Topic; D018450:Disease Progression; D005260:Female; D015321:Gene Rearrangement; D005919:Glomerular Filtration Rate; D006801:Humans; D006973:Hypertension; D007668:Kidney; D008297:Male; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D050396:TRPP Cation Channels; D000077602:Tolvaptan; D055815:Young Adult",
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"pubdate": "2018-04-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "25263802;17582161;22383692;20177400;26823553;23431072;28444221;26150605;23121377;19414839;21333426;17574468;25165182;18818683;26912543;25333066;26908832;27484667;26453610;12482949;27694979;24582653;16707749;29142926;27259053;25399733;18837007;24904092;26530876;22344503;25646624;26090645;25830764;25022529",
"title": "Can we further enrich autosomal dominant polycystic kidney disease clinical trials for rapidly progressive patients? Application of the PROPKD score in the TEMPO trial.",
"title_normalized": "can we further enrich autosomal dominant polycystic kidney disease clinical trials for rapidly progressive patients application of the propkd score in the tempo trial"
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"abstract": "Raynaud's phenomenon is a rare side effect of CGRP monoclonal antibodies. These molecular treatments are a relatively new class of drugs for the prevention of migraine. It is likely that we will see this side effect more often in the future. Patients with a background of Raynaud's phenomenon may experience worsening of their symptoms if started on these treatments.",
"affiliations": "Department of Human Genetics and Molecular Biology Bharathiar University Coimbatore India.;Mater Misericordiae University Hospital Dublin Ireland.;Beaumont Hospital Dublin Ireland.;Beaumont Hospital Dublin Ireland.",
"authors": "Manickam|Agaath Hedina|AH|https://orcid.org/0000-0001-5263-7407;Buture|Alina|A|;Tomkins|Esther|E|;Ruttledge|Martin|M|",
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"doi": "10.1002/ccr3.4625",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4625\nCCR34625\nCase Report\nCase Reports\nRaynaud's phenomenon secondary to erenumab in a patient with chronic migraine\nMANICKAM et al.\nManickam Agaath Hedina https://orcid.org/0000-0001-5263-7407\n1 hedina03@gmail.com\n\nButure Alina 2\nTomkins Esther 3\nRuttledge Martin 3\n1 Department of Human Genetics and Molecular Biology Bharathiar University Coimbatore India\n2 Mater Misericordiae University Hospital Dublin Ireland\n3 Beaumont Hospital Dublin Ireland\n* Correspondence\nAgaath Hedina Manickam, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore‐641046, Tamilnadu, India.\nEmail: hedina03@gmail.com\n\n16 8 2021\n8 2021\n9 8 10.1002/ccr3.v9.8 e0462512 6 2021\n28 3 2021\n06 7 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nRaynaud's phenomenon is a rare side effect of CGRP monoclonal antibodies. These molecular treatments are a relatively new class of drugs for the prevention of migraine. It is likely that we will see this side effect more often in the future. Patients with a background of Raynaud's phenomenon may experience worsening of their symptoms if started on these treatments.\n\nRaynaud's phenomenon is a rare side effect of CGRP monoclonal antibodies. These molecular treatments are a relatively new class of drugs for the prevention of migraine. It is likely that we will see this side effect more often in the future. Patients with a background of Raynaud's phenomenon may experience worsening of their symptoms if started on these treatments.\n\nCGRP monoclonal antibodies\nchronic migraine\nerenumab\nRaynaud's phenomenon\nsource-schema-version-number2.0\ncover-dateAugust 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.5 mode:remove_FC converted:16.08.2021\nManickamAH, ButureA, TomkinsE, RuttledgeM. Raynaud's phenomenon secondary to erenumab in a patient with chronic migraine. Clin Case Rep. 2021;9 :e04625. 10.1002/ccr3.4625\n\nFunding information\n\nThis manuscript has not received financial support\n==== Body\n1 INTRODUCTION\n\nA 45‐year‐old woman with chronic migraine undergoing treatment with the calcitonin gene‐related peptide (CGRP) monoclonal antibody, erenumab 70 mg monthly subcutaneous injections developed Raynaud's phenomenon (RP). The patient subsequently discontinued the treatment due to severe symptoms of RP, a rare side effect associated with CGRP monoclonal antibodies.\n\nChronic migraine (CM) is a debilitating neurological disorder with a prevalence of 0.5%–5% in the general population.1 It is associated with a significant negative impact on quality of life (QOL) and mental health.2 Monoclonal antibodies targeting the CGRP pathway have been shown to be effective in episodic and chronic migraine. These molecular treatments work by binding either to the CGRP receptor or the CGRP ligand.3 Raynaud's phenomenon (RP) is characterized by brief reduction of blood flow to the extremities due to vasoconstriction.4, 5 The relationship of RP and migraine is previously documented. Zahavi et al. reported RP in association with migraine in 26% (29/111) of patients.4 RP secondary to administration of migraine‐specific therapies, such as CGRP monoclonal antibodies, has been recently reported in a few cases.\n\n2 CASE\n\nWe present the case of a 45‐year‐old right‐handed woman who developed chronic daily headache (CDH) with migraine features in 2018. She had migraine in her teens, often associated with her menstrual cycle. There is no history of migraine aura. The headaches progressively increased in frequency and severity in her 30's. In January 2018, after a viral infection, she developed unremitting headache with associated migraine symptoms and chronic daily headache (CDH). The pain is usually holocranial. She also has bilateral facial pain. With worsenings, there is associated phonophobia, aggravation by physical activity and severe fatigue. The patient denied photophobia, nausea, vomiting, and cranial autonomic symptoms. Poor sleep and physical activity worsen the headaches. The clinical examination was normal, including fundoscopy. Her routine blood tests including full blood count, biochemical profile, renal, liver, thyroid function, vitamin B12, and folate were within the normal limits. MRI brain and MR venogram (MRV) of the intracranial vessels were unremarkable. The patient has a previous history of varicose vein surgery and panic attacks. There is no history of rheumatological disease. She had sinus surgery in 2009, with no improvement in her headache and associated migraine symptoms. Her other medication consists of duloxetine 30mg daily, paracetamol PRN, and naproxen PRN.\n\nA diagnosis of chronic daily headache (CDH) with migraine features was made in 2018, and she was started on prophylactic medication. She had failed five migraine prophylactic drugs due to side effects and/or lack of efficacy: propranolol (minimal benefit), amitriptyline (weight gain), topiramate (some benefit, but significant cognitive impairment at doses above 50 mg twice daily), flunarizine (intolerable side effects), and venlafaxine (worsening of headaches). Therefore, as per national and international guidelines, she was started on erenumab 70 mg, a monthly subcutaneous injection. The patient reported 40% improvement in headache severity and overall migraine symptoms but with no crystal clear days.\n\nTwo weeks after the second injection of erenumab, she developed intermittent blue discoloration of both hands, which worsened over a period of 7–8 months on erenumab treatment (see Figure 1). There was no associated pain or sensory disturbance. The symptoms were worse in cold weather and improved in the summertime. Hand movements also improved the symptoms. The patient had never experienced such symptoms prior to erenumab administration. A diagnosis of RP secondary to erenumab was made. The patient initially declined discontinuation of erenumab, as she feared worsening of headaches and associated symptoms. However, she discontinued treatment after 8 months due to the side effect of RP, both voluntarily and on medical advice. The RP symptoms have improved by approximately 70% and she is now off erenumab for more than 1 year. The patient is currently having Botox treatment (PREEMPT Protocol) and is due to her fourth round of injections. There is an improvement of approximately 40%–50% in terms of headache and migraine severity. She has not tried an alternative CGRP monoclonal antibody.\n\nFIGURE 1 Raynaud's phenomenon secondary to erenumab in a patient with chronic migraine\n\n3 DISCUSSION\n\nThe overall global prevalence of RP is approximately 10% in women (partly due to hormonal variations) and 4%–14% in men.4 Migraine and RP were found to co‐exist in 26% (29 of 111) of migraine patients in one study.4 Although the pathophysiology of RP is not well‐understood, a combination of neuronal and vascular factors (including intravascular anomalies) are known to play a role.6 Vasoconstriction is believed to be a major feature of RP and can be triggered by external stimuli, including cold water or weather. RP can also be triggered mainly by neural‐mediated changes.4 There are two main types: primary RP, which is a benign condition, and secondary RP, which is associated with several connective tissue diseases, in particular systemic sclerosis.5 The underlying mechanism in primary RP is considered to be a “local fault” in the thermoregulatory vessels without evidence of structural alteration or injury to vessels while the secondary RP are acquired conditions including those that can cause vascular injury.6\n\nCalcitonin gene‐related peptide is a ubiquitous 37 amino acid neuropeptide found in two isoforms: α‐CGRP (mainly localized to the peripheral nervous system) and β‐CGRP (predominantly localized to enteric nervous system). Both isoforms are efficient vasodilators.2, 3, 7 Evidence suggests that the presence of increased CGRP in sites undergoing inflammatory response.7 Elevated CGRP levels are observed in saliva, CSF, and serum during migraine attacks and reduce after these bouts subside.2 Targeting the CGRP receptor with monoclonal antibodies is effective in the management of migraine.3, 7 It is believed that activation of the trigeminovascular system by migraine‐specific triggers causes vasodilation of cranial blood vessels, thereby activating sensory nerve fibers of the trigeminal system.2, 3 Pain is conveyed to the brainstem where several different neurotransmitters including CGRP and substance P are released and bind to the functional receptors causing neuronal inflammation, degranulation of mast cells, and leakage of blood vessels.2, 7\n\nAlthough the CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) were found to be safe and effective in clinical trials, more data are emerging regarding their safety profile and potential side effects in clinical practice.3 RP is becoming a relatively rare recognized side effect of CGRP monoclonal antibodies in patients with migraine.4 It has been recently reported in three patients (two women‐ 33 years & 45 years and one man‐ 65 years) undergoing CGRP monoclonal antibody treatment. Two patients were treated with monoclonal antibodies against the ligand (fremanezumab and galcanezumab) and in one case, the monoclonal antibody targeted the receptor (erenumab).4 There is a consensus now that the most likely mechanism by which CGRP monoclonal antibodies cause RP is primarily due to vasoconstriction, but this can only occur in conjunction with several other factors, including genetic and hormonal influences. CGRP monoclonal antibodies, therefore, antagonize CGRP's role as a potent vasodilator in this context.2, 3 When administered, erenumab binds to the functional receptor, subsequently blocking its function.3, 4 This prevents the cascade of reactions within the cell responsible for vasodilation, presumably leading to the development of RP in a small number of cases.3, 4\n\nIn summary, we report a case of chronic daily headache with migraine features who developed RP after receiving treatment with a CGRP receptor antagonist, further supporting the theory that RP is now a recognized rare side effect of CGRP monoclonal antibodies. This side effect information did not emerge from clinical trials. The presence of significant or debilitating RP in a small proportion of patients with migraine who are treated with CGRP monoclonal antibodies has clinical implications, including the necessity for cessation of treatment in some patients. Furthermore, this class of drugs could exacerbate the symptoms of RP in patients with a previous history of this condition. A previous background history of RP secondary to connective tissue disease might prevent patients from initiating these new class of migraine preventative medications.\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHOR CONTRIBUTIONS\n\nAHM: drafted the manuscript; AB: neurologist involved in patient's care; ET: headache specialist nurse involved in patient's care; MR: primary neurologist involved in patient's care and decisions regarding diagnosis and management. All authors contributed to chart review and data collection. All authors revised the draft manuscript and approved the final version.\n\nCONSENT STATEMENT\n\nPublished with written consent of the patient.\n\nACKNOWLEDGEMENTS\n\nWe thank the patient for her consent and help in preparation of this case report.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are available from the authors upon reasonable request.\n==== Refs\nREFERENCES\n\n1 BuseDC, ManackAN, FanningKM, et al. Chronic migraine prevalence, disability, and sociodemographic factors: results from the American migraine prevalence and prevention study. Headache. 2012;52 :1456‐1470.22830411\n2 DurhamPL. Calcitonin gene‐related peptide (CGRP) and migraine. Headache. 2006;46 (Suppl 1 );S3‐S8.16927957\n3 EdvinssonL, HaanesKA, WarfvingeK, et al. CGRP as the target of new migraine therapies—successful translation from bench to clinic. Nat Rev Neurol. 2018;14 :338‐350.29691490\n4 EvansRW. Raynaud's phenomenon associated with calcitonin gene‐related peptide monoclonal antibody antagonists. Headache. 2019;59 :1360‐1364.31310337\n5 RuaroB, SmithV, SulliA, et al. Innovations in the assessment of primary and secondary Raynaud’s phenomenon. Front Pharmacol. 2019;10 :360.31073287\n6 HerrickAL, WigleyFM. Raynaud's phenomenon. Best Pract Res Clin Rheumatol. 2020;34 (1 ):101474.32007400\n7 DurhamPL. CGRP‐receptor antagonists—a fresh approach to migraine therapy? N Engl J Med. 2004;350 :1073‐1075.15014178\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "9(8)",
"journal": "Clinical case reports",
"keywords": "CGRP monoclonal antibodies; Raynaud's phenomenon; chronic migraine; erenumab",
"medline_ta": "Clin Case Rep",
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"title": "Raynaud's phenomenon secondary to erenumab in a patient with chronic migraine.",
"title_normalized": "raynaud s phenomenon secondary to erenumab in a patient with chronic migraine"
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"abstract": "A healthy 32-year-old female patient required an extraction of the right maxillary third molar. Lidocaine containing 1:80,000 epinephrine for right posterior superior alveolar nerve block was administered in the mucobuccal fold above the third molar to be extracted at our hospital. After few minutes of posterior superior alveolar block anesthesia, patient felt double vision. The condition was subsequently diagnosed as transient diplopia due to temporary paralysis of lateral rectus muscle due to involvement of the VI cranial nerve. The patient recovered in 30 minutes and the treatment was performed successfully. This article discusses the possible scientific explanation for this phenomenon.",
"affiliations": "Balaji Dental and Craniofacial Hospital, Teynampet, Chennai, Tamil Nadu, India.",
"authors": "Balaji|S M|SM|",
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"journal": "Indian journal of dental research : official publication of Indian Society for Dental Research",
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"medline_ta": "Indian J Dent Res",
"mesh_terms": "D020222:Abducens Nerve Injury; D000328:Adult; D000766:Anesthesia, Dental; D004172:Diplopia; D005260:Female; D006801:Humans; D007049:Iatrogenic Disease; D008437:Maxilla; D008442:Maxillary Nerve; D008964:Molar, Third; D009407:Nerve Block; D014081:Tooth Extraction",
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"title": "Transient diplopia in dental outpatient clinic: an uncommon iatrogenic event.",
"title_normalized": "transient diplopia in dental outpatient clinic an uncommon iatrogenic event"
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"abstract": "BACKGROUND\nSymptoms of spasmodic dysphonia (SD) are usually managed successfully with botulinum toxin injections. Vocal tremor (VT), which accompanies SD, has a poor response to this treatment.\n\n\nMETHODS\nWe report a case of a female with SD and VT who became symptom-free for 10 months after the intake of a single dose of sodium oxybate (Xyrem®). The long-term treatment effect correlated with attenuated brain activity in the key regions of dystonic brain network.\n\n\nCONCLUSIONS\nOur case demonstrates that the novel treatment of sodium oxybate may hold promise for SD patients, especially those who have associated VT.",
"affiliations": "Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, , United States of America ; Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, , United States of America.;Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, , United States of America.",
"authors": "Simonyan|Kristina|K|;Frucht|Steven J|SJ|",
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"fulltext": "\n==== Front\nTremor Other Hyperkinet Mov (N Y)Tremor Other Hyperkinet Mov (N Y)TOHMTremor and Other Hyperkinetic Movements2160-8288Columbia University Libraries/Information Services tre-03-206-4731-1Case ReportsLong-term Effect of Sodium Oxybate (Xyrem®) in Spasmodic Dysphonia with Vocal Tremor Sodium Oxybate Treatment in SD with TremorSimonyan Kristina 12*Frucht Steven J. 11 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, , United States of America2 Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, , United States of AmericaLouis Elan D. Columbia University, United States of America*To whom correspondence should be addressed. E-mail: kristina.simonyan@mssm.edu2013 9 12 2013 3 tre-03-206-4731-19 10 2013 8 11 2013 2013Simonyan et alThis is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommerical–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original author and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed.Background\nSymptoms of spasmodic dysphonia (SD) are usually managed successfully with botulinum toxin injections. Vocal tremor (VT), which accompanies SD, has a poor response to this treatment.\n\nCase Report\nWe report a case of a female with SD and VT who became symptom-free for 10 months after the intake of a single dose of sodium oxybate (Xyrem®). The long-term treatment effect correlated with attenuated brain activity in the key regions of dystonic brain network.\n\nDiscussion\nOur case demonstrates that the novel treatment of sodium oxybate may hold promise for SD patients, especially those who have associated VT.\n\nFocal dystoniatreatmentbrain modulation\n==== Body\nIntroduction\nSpasmodic dysphonia (SD), or laryngeal dystonia, is a primary focal dystonia characterized by selective loss of voluntary voice control during speaking due to uncontrolled spasms in the laryngeal muscles. Voice tremor (VT) is characterized by rhythmic alterations in pitch and loudness during vowel production and inability to sustain a vowel for more than a few seconds. Combined SD/VT is a chronic debilitating condition, which often extends beyond vocal communication impairment and causes significant occupational disability and life-long social isolation. While symptoms of the adductor type of SD can be managed with botulinum toxin injections for an average period of 3–4 months, VT has less predictable and poor results.1–3 Based on a trial-and-error approach, some patients with SD and VT receive oral medications, such as propranolol, primidone, clonazepam, and lorazepam, which typically provide only mild short-term benefits.1,4\n\nCase report\nWe report the case of a 38-year-old female with SD and VT who became symptom-free for 10 months after the intake of a single dose of sodium oxybate (Xyrem®). About 1.5 years prior to her visit with us, she developed a strained, strangled voice with a mild tremor. Voice breaks improved during singing at high pitches, laughing, and whispering. Alcohol intake improved her voice by increasing the volume and decreasing the tremor; however, symptoms returned after the effect of alcohol had worn off. She was diagnosed with adductor SD and VT 6 months after symptom onset by an experienced laryngologist based on fiberoptic nasolaryngoscopy and videostroboscopy, which revealed hyper-adduction and regular symmetrical vibration of the vocal folds. Voice and speech therapy were not beneficial. From the time of diagnosis up to the treatment with sodium oxybate, the patient has received six botulinum toxin injections bilaterally into the thyroarytenoid muscles (1.5 units/each) every 3 months, which were reportedly 90% effective for SD symptoms for a period of 8 weeks; VT symptoms remained unaffected.\n\nAt the time of the visit, the patient was at the end of her botulinum toxin treatment cycle. Her voice was mildly tremulous with straining, strangulations, and moderate breaks on vowels. Her neurological examinations did not reveal any dystonic postures in other body parts; slight action tremor of the hands was observed. After obtaining written informed consent for drug administration and follow-up magnetic resonance imaging (MRI), which was approved by the Institutional Review Board of Mount Sinai School of Medicine, the patient received 1.0 g of sodium oxybate (Xyrem®) by mouth in the outpatient clinic as part of an ongoing clinical research study. A clear audible improvement of her voice was observed starting 20 minutes after drug intake and was marked by an increase in the projecting volume without voice breaks or tremor. On the visual analog scale from 1 (normal) to 10 (most difficult), the patient indicated that the effort of speaking, crying, and shouting decreased from 9 to 2. Treatment-related transient dizziness improved within 60 minutes of drug intake. No adverse events, such as excessive sleepiness, depression, cardiopulmonary problems, cognitive impairment, or treatment-emergent suicidality, were observed. Five hours after drug intake, the patient was cognitively alert and stable, and her speech was not associated with voice breaks or tremor. During follow-up phone calls on the day after the visit and in the following 8 months, her voice remained without SD-characteristic breaks or tremor. Her evaluation by us at 8 months and by her laryngologist at 9 months after initial drug intake revealed no signs of dystonic posture or tremor and there was a normal laryngeal function with no evidence of adductor SD or VT. During this period, the patient did not receive any additional treatment with either botulinum toxin injections or sodium oxybate. She remained symptom-free for a total of 10 months, before recurrence of SD voice breaks following a stressful event. The patient took the second dose of 1.0 g of sodium oxybate and received benefits for 2 months. The third intake of sodium oxybate (1.0 g) improved her voice for 24 hours with some benefits lasting up to 1 week. At the time of submission of this case, the effects of the most recent drug intake (1.0 g) have lasted for over 1 month.\n\nTo examine the central effects of sodium oxybate, we performed a functional MRI (fMRI) before the initial drug intake and about 90 minutes after the first drug intake as part of the ongoing research study. Anatomical MRI was within the normal ranges without any gross abnormalities. Pre-treatment fMRI was conducted before the initial drug intake when the patient’s voice was fully symptomatic. Sentence production showed bilaterally increased brain activity in the sensorimotor cortical regions, basal ganglia, and cerebellum (Figure 1A), which was in line with abnormal brain activity found in larger studies in SD patients.5,6 Post-treatment fMRI, which was conducted 90 minutes after the drug intake when the patient had improved voice symptoms, showed significantly attenuated brain activity in the primary sensorimotor cortex (right>left), putamen, and cerebellum (Figure 1B). Because of unusually lengthy drug benefits in this patient, we re-examined the effects of the initial dose of sodium oxybate on brain activity at 8 months, when she was still asymptomatic. The brain activity during speech production remained attenuated in the basal ganglia and cerebellum with further normalization of activity in the bilateral sensorimotor cortices compared with the first post-treatment scan (Figure 1C).\n\nFigure 1 Brain Activity During Production of English Sentences Containing a Large Number of Vowels.\nBefore treatment with sodium oxybate (A), 90 minutes after treatment (B), and 8 months after treatment (C). Brain activity is shown on the inflated brain surfaces in the standard Talairach–Tournoux space and on the series of axial slices. The color bar represents t score.\n\nDiscussion\nOur observation demonstrates that sodium oxybate significantly improved voice symptoms in an ethanol-responsive SD/VT patient. Although the limitation of this report is that such a lengthy effect of sodium oxybate was observed in one patient only, another four patients (two with abductor SD and two with isolated VT) who participated in our study have reported treatment benefits lasting over 24 hours and up to 2 weeks after intake of 1.0 g of sodium oxybate. This duration of drug benefits is much longer than typical effects of sodium oxybate on dystonia and tremor of about 3.5–4 hours.7,8 In the single patient reported here, a long-term effect of sodium oxybate on SD/VT symptoms appeared to be associated with a decrease (normalization) of brain overactivity in the key regions within the dystonic brain network, possibly due to direct modulation of abnormally increased5,6 brain activation during symptom production. This may be due to the ability of sodium oxybate to mediate gamma-aminobutic acid (GABA)-B receptor activation and metabolize into GABA,9 the levels of which are known to be deficient in patients with dystonia.10,11 It has been suggested that GABA-ergic deficiencies in dystonia may contribute to the loss of inhibition and thus to the generation of dystonic movements.12 Conversion of sodium oxybate into GABA might have directly increased GABA levels and stabilized the balance between excitation and inhibition within the sensorimotor system.\n\nA limitation of the study is that it was designed as an open-label trial and hence the placebo effects of the drug cannot be ruled out. Although the possibility exists that a sustained voice improvement in this patient could be due to a placebo or psychogenic cause, the nature of her voice disturbance, voice recordings, time course of improvement with the drug, and correlation with imaging measures argue for a biological cause. While we did not expect to see such long-term effects in patients with SD and/or VT, this patient’s experience suggests that sodium oxybate may be a promising pharmacological agent for treatment of ethanol-responsive SD and VT patients. Further study of its clinical and central effects is warranted.\n\nAcknowledgments\nWe thank Frank Macaluso, Heather Alexander, Amanda Pechman, and Melissa Choy for help with data acquisition.\n\nFunding: National Institute on Deafness and other Communication Disorders, National Institutes of Health grant R01DC012545 to K.S. ClinicalTrials.gov Identifier: NCT01961297.\n\nFinancial Disclosure: None.\n\nConflict of Interests: The authors report no conflict of interest.\n==== Refs\nReferences\n1 Sulica L Louis ED Clinical characteristics of essential voice tremor: a study of 34 cases Laryngoscope 2010 120 516 528 10.1002/lary.20702 20066728 \n2 Gurey LE Sinclair CF Blitzer A A new paradigm for the management of essential vocal tremor with botulinum toxin Laryngoscope 2013 123 2497 2501 23553653 \n3 Brin MF Blitzer A Stewart C Laryngeal dystonia (spasmodic dysphonia): observations of 901 patients and treatment with botulinum toxin Adv Neurol 1998 78 237 252 9750921 \n4 Ludlow CL Adler CH Berke GS et al Research priorities in spasmodic dysphonia Otolaryngol Head Neck Surg 2008 139 495 505 10.1016/j.otohns.2008.05.624 18922334 \n5 Simonyan K Ludlow CL Abnormal activation of the primary somatosensory cortex in spasmodic dysphonia: an fMRI study Cereb Cortex 2010 20 2749 2759 10.1093/cercor/bhq023 20194686 \n6 Ali SO Thomassen M Schulz GM et al Alterations in CNS activity induced by botulinum toxin treatment in spasmodic dysphonia: an H215O PET study J Speech Lang Hear Res 2006 49 1127 1146 10.1044/1092-4388(2006/081) 17077220 \n7 Frucht SJ Bordelon Y Houghton WH Reardan D A pilot tolerability and efficacy trial of sodium oxybate in ethanol-responsive movement disorders Mov Disord 2005 20 1330 1337 10.1002/mds.20605 15986420 \n8 Frucht SJ Houghton WC Bordelon Y Greene PE Louis ED A single-blind, open-label trial of sodium oxybate for myoclonus and essential tremor Neurology 2005 65 1967 1969 10.1212/01.wnl.0000188670.38576.bd 16382538 \n9 Crunelli V Ernri Z Leresche N Unravelling the brain targets of gamma-hydroxybutyric acid Curr Opin Pharmacol 2006 6 44 52 10.1016/j.coph.2005.10.001 16368267 \n10 Levy LM Ziemann U Chen R Cohen LG Rapid modulation of GABA in sensorimotor cortex induced by acute deafferentation Ann Neurol 2002 52 755 761 10.1002/ana.10372 12447929 \n11 Marjanska M Lehericy S Valabregue R et al Brain dynamic neurochemical changes in dystonic patients: a magnetic resonance spectroscopy study Movement Disord 2013 28 201 209 10.1002/mds.25279 23239076 \n12 Hallett M Neurophysiology of dystonia: the role of inhibition Neurobiol Dis 2011 42 177 184 10.1016/j.nbd.2010.08.025 20817092\n\n",
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"journal": "Tremor and other hyperkinetic movements (New York, N.Y.)",
"keywords": "Focal dystonia; brain modulation; treatment",
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"title": "Long-term Effect of Sodium Oxybate (Xyrem®) in Spasmodic Dysphonia with Vocal Tremor.",
"title_normalized": "long term effect of sodium oxybate xyrem in spasmodic dysphonia with vocal tremor"
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"abstract": "BACKGROUND\nCandida parapsilosis is a common agent of fungaemia, but few outbreaks of Candida parapsilosis infection have been reported in China.\n\n\nOBJECTIVE\nTo elaborate an outbreak of nosocomial Candida parapsilosis sensu stricto fungaemia in a neonatal intensive care unit (NICU) of a comprehensive hospital in China from July to October 2017.\n\n\nMETHODS\nEpidemics and characteristics of fungaemia cases were investigated. Surveillance samples were collected. Vitek 2 Compact System, internal transcribed spacer sequencing, and random amplified polymorphic DNA (RAPD) typing were conducted to identify the isolates. Antifungal susceptibility test was performed for all bloodstream isolates.\n\n\nRESULTS\nSixteen neonates were diagnosed as Candida parapsilosis sensu stricto fungaemia during this period. Presenting symptoms included leucopenia, thrombocytopenia, and respiratory crackles. Fifteen cases were cured whereas one case who suffered from severe concomitant diseases died. The isolates were susceptible to fluconazole, amphotericin B, itraconazole, voriconazole, and 5-fluorocytosine. A total of 313 surveillance samples were collected, and Candida parapsilosis sensu stricto was identified from 16 environmental samples and one sample from an ultrasonographer's hand. The colonized locations included wiping cloths, faucets, sinks, operating table, puddles in the bathroom, a ventilator, and an ultrasonic probe. The RAPD patterns of all the Candida parapsilosis sensu stricto isolates from bloodstream and surveillance samples were identical. The outbreak was controlled after a series of infection control measures.\n\n\nCONCLUSIONS\nContaminated environment was associated with this outbreak. Close attention to immunocompromised patients, thorough environmental disinfection and hand hygiene should be strengthened in NICU.",
"affiliations": "Department of Laboratory, Army General Hospital, PLA, Beijing, China.;Department of Laboratory, Army General Hospital, PLA, Beijing, China.;Department of Infection Control, Army General Hospital, PLA, Beijing, China.;Department of Laboratory, Army General Hospital, PLA, Beijing, China.;Department of Laboratory, Army General Hospital, PLA, Beijing, China.;Department of Laboratory, Army General Hospital, PLA, Beijing, China.;Department of Extremely Preterm Neonatal Intensive Care Unit, Army General Hospital, PLA, Beijing, China.;Department of Laboratory, Army General Hospital, PLA, Beijing, China. Electronic address: liujie_sci@163.com.",
"authors": "Qi|L|L|;Fan|W|W|;Xia|X|X|;Yao|L|L|;Liu|L|L|;Zhao|H|H|;Kong|X|X|;Liu|J|J|",
"chemical_list": "D000935:Antifungal Agents; D004271:DNA, Fungal; D021903:DNA, Ribosomal Spacer",
"country": "England",
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"medline_ta": "J Hosp Infect",
"mesh_terms": "D000935:Antifungal Agents; D000074429:Candida parapsilosis; D058387:Candidemia; D002681:China; D016000:Cluster Analysis; D003428:Cross Infection; D004271:DNA, Fungal; D021903:DNA, Ribosomal Spacer; D004196:Disease Outbreaks; D004783:Environmental Microbiology; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D008297:Male; D008826:Microbial Sensitivity Tests; D017720:Molecular Epidemiology; D016533:Mycological Typing Techniques; D010802:Phylogeny; D019105:Random Amplified Polymorphic DNA Technique; D017422:Sequence Analysis, DNA",
"nlm_unique_id": "8007166",
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"title": "Nosocomial outbreak of Candida parapsilosis sensu stricto fungaemia in a neonatal intensive care unit in China.",
"title_normalized": "nosocomial outbreak of candida parapsilosis sensu stricto fungaemia in a neonatal intensive care unit in china"
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"abstract": "The standard modality of administration of rFVIIa to patients with FVIII and FIX inhibitors is the intermittent infusion every 2 to 6 hours. No untoward local or systemic effects have been reported; laboratory data of activation of coagulation were reported in the presence of coexistent problems (sepsis, septic shock) or with high doses. We treated four patients with FVIII inhibitor with rFVIIa administered by continuous infusion by a central vein catheter, monitoring the signs of systemic activation of the hemostatic system. The F(1+2) prothrombin fragments and the D-dimer increased after the bolus, and remained above the baseline values throughout the treatment period. These variations observed during the infusion period were not accompanied by clinical events.",
"affiliations": "Hemostasis and Thrombosis Unit, Niguarda Hospital, Milan, Italy. md9821@mclink.it",
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"title": "The continuous infusion of recombinant activated factor VIIa (rFVIIa) in patients with factor VIII inhibitors activates the coagulation and fibrinolytic systems without clinical complications.",
"title_normalized": "the continuous infusion of recombinant activated factor viia rfviia in patients with factor viii inhibitors activates the coagulation and fibrinolytic systems without clinical complications"
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"abstract": "Optimal management of EGFR-mutated NSCLC with leptomeningeal (LM) disease progression through EGFR tyrosine kinase inhibitor remains unclear. We present a 39-year-old man with EGFR-mutated NSCLC and LM disease progression through osimertinib 80 mg daily, with subsequent durable radiographic and symptomatic response to systemic pemetrexed in combination with osimertinib. This builds on the limited data evaluating LM disease response to systemic pemetrexed and lends further support to consideration of this treatment strategy.",
"affiliations": "Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington.;Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington.",
"authors": "Merkhofer|Cristina M|CM|;Baik|Christina S|CS|",
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"delete": false,
"doi": "10.1016/j.jtocrr.2021.100177",
"fulltext": "\n==== Front\nJTO Clin Res Rep\nJTO Clin Res Rep\nJTO Clinical and Research Reports\n2666-3643\nElsevier\n\nS2666-3643(21)00036-9\n10.1016/j.jtocrr.2021.100177\n100177\nCase Report\nDurable Response of Leptomeningeal Disease With Osimertinib and Pemetrexed in EGFR-Mutated Metastatic NSCLC: A Case Report\nMerkhofer Cristina M. MD, MHS cmerkhof@fredhutch.org\nab∗\nBaik Christina S. MD, MPH ab\na Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington\nb Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington\n∗ Corresponding author. Address for correspondence: Cristina M. Merkhofer, MD, MHS, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North – M3-B232, Seattle, WA 98109-1024. cmerkhof@fredhutch.org\n25 4 2021\n6 2021\n25 4 2021\n2 6 10017712 3 2021\n9 4 2021\n16 4 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nOptimal management of EGFR-mutated NSCLC with leptomeningeal (LM) disease progression through EGFR tyrosine kinase inhibitor remains unclear. We present a 39-year-old man with EGFR-mutated NSCLC and LM disease progression through osimertinib 80 mg daily, with subsequent durable radiographic and symptomatic response to systemic pemetrexed in combination with osimertinib. This builds on the limited data evaluating LM disease response to systemic pemetrexed and lends further support to consideration of this treatment strategy.\n\nKeywords\n\nPemetrexed\nEGFR mutation\nNon–small cell lung cancer\nLeptomeningeal disease\nCase report\n==== Body\npmcIntroduction\n\nLeptomeningeal (LM) disease is a late complication of NSCLC associated with substantial morbidity and a poor prognosis. Although osimertinib and other EGFR tyrosine kinase inhibitors (TKIs) have activity against LM disease, the best treatment approach after LM disease progression through TKI is unclear. Systemic or intrathecal chemotherapy, or dose escalation of osimertinib from 80 mg daily to 160 mg daily is often used, but clinical benefit in this population has not been clearly defined. Retrospective data suggest that systemic pemetrexed has activity against LM disease. We report a case of a patient with EGFR-mutated NSCLC with LM disease who experienced remarkably durable disease control on pemetrexed and osimertinib after disease progression on osimertinib monotherapy.\n\nCase Presentation\n\nA 39-year-old man with no smoking history developed a left neck mass, cough, dyspnea, and chest pain in late 2015. Initial computed tomography of the head and chest and positron emission tomography scan in June 2016 revealed innumerable metastases throughout the cerebellum and cerebral hemispheres bilaterally, supraclavicular and hilar adenopathy, diffuse pulmonary nodules, and multiple osseous lesions. Biopsy of a right pulmonary mass and mediastinal lymph nodes revealed lung adenocarcinoma, with an EGFR exon 19 deletion on molecular profiling. Given the large burden of parenchymal brain metastases, he completed whole-brain radiation before starting erlotinib in June 2016 (Fig. 1).Figure 1 Case timeline. Timeline of all antineoplastic therapies administered from date of initial lung cancer diagnosis to present (February 2021), relative to timing of LM disease development and radiographic response. LM, leptomeningeal.\n\nHe experienced good radiographic and symptomatic response to erlotinib until March 2017, when he presented after a syncopal episode. He noted new-onset dizziness, blurred vision, changes in his ability to articulate his thoughts, and full-body stiffness with arthralgias and myalgias in the preceding month. A magnetic resonance imaging (MRI) of the brain revealed numerous new subcentimeter parenchymal metastases bilaterally and extensive LM enhancement along the superior cerebellar folia, brainstem, and fifth, seventh and eighth cranial nerve complexes (Fig. 1). An MRI of the cervical, thoracic, and lumbar spine revealed diffuse LM seeding along the spinal cord and nerve roots. Cerebrospinal fluid (CSF) cytology results revealed rare atypical cells, suggestive of metastatic adenocarcinoma. An EGFR p.T790M mutation was not detected in CSF circulating tumor DNA (ctDNA), although there were low levels of ctDNA. Computed tomography imaging revealed stable systemic disease. He continued erlotinib and started intrathecal methotrexate in April 2017. This was changed to intrathecal liposomal cytarabine after he developed aseptic meningitis attributed to methotrexate. He developed an enlarging left supraclavicular lymph node in July 2017, and a biopsy of this revealed an EGFR p.T790M mutation. He discontinued erlotinib and intrathecal chemotherapy and started osimertinib 80 mg daily in August 2017, with good radiologic and symptomatic response.\n\nIn May 2019, he developed near-syncope, back stiffness, and diplopia. An MRI brain revealed new LM enhancement along the cerebellar hemispheres bilaterally, and he started carboplatin and pemetrexed in June 2019. Osimertinib was discontinued but quickly resumed due to a flare of his neurologic symptoms, which improved soon after restarting. He switched to maintenance pemetrexed after four cycles of carboplatin and pemetrexed. A lumbar puncture in August 2019 revealed rare atypical cells concerning for malignancy, which were positive for an EGFR exon 19 deletion, negative for an EGFR p.T790M mutation, and positive for a two- to four-gene MET copy gain on University of Washington OncoPlex Single Gene Mutational Analysis. Subsequently, the patient had complete resolution of neurologic symptoms and his systemic disease has remained stable on imaging since January 2018. In September 2019, an MRI brain revealed radiographic resolution of LM disease and an MRI spine showed decreased diffuse LM disease. The patient remains on osimertinib 80 mg daily and maintenance pemetrexed as of February 2021, with ongoing radiologic and clinical responses (Fig. 2).Figure 2 MRI brain scans before and after starting carboplatin and pemetrexed. An MRI of the brain from June 2019 (A) showed progressive leptomeningeal disease on osimertinib monotherapy, before the start of carboplatin and pemetrexed. The most recent MRI of the brain from December 2020 (B) revealed sustained radiographic response of leptomeningeal disease on osimertinib 80 mg daily and maintenance pemetrexed. MRI, magnetic resonance imaging.\n\nDiscussion\n\nWe present a case of EGFR-mutated NSCLC with LM disease progression through osimertinib monotherapy, now with a durable response to systemic pemetrexed in combination with osimertinib. We elected to start pemetrexed-based systemic therapy on LM disease progression due to evidence of activity against both parenchymal brain metastases and LM disease in patients with EGFR-mutated NSCLC. Although we initially planned to switch to chemotherapy alone, we quickly resumed osimertinib to address a neurologic symptom flare. The AURA3 trial showed a 31% intracranial response rate to combination platinum and pemetrexed chemotherapy in EGFR-mutated NSCLC.1 Retrospective data also suggest that the combination of osimertinib and chemotherapy after progression through previous EGFR TKI provides effective control of parenchymal brain metastases.2 Most of these patients received a regimen including pemetrexed, although the study did not specifically evaluate the effectiveness of combination osimertinib and pemetrexed-based chemotherapy for brain metastases.\n\nData on LM disease response to pemetrexed with or without an EGFR TKI are limited. A retrospective review of 110 patients with EGFR-mutated advanced NSCLC treated with EGFR TKI found that median overall survival after LM disease development was longer with receipt of pemetrexed versus no pemetrexed (13.7 versus 4.0 mo, p = 0.008) and with continuation of EGFR TKI relative to discontinuation (16.9 versus 3.0 mo, p < 0.001).3 Another retrospective study of 30 patients with NSCLC and LM disease found that the receipt of a modern systemic treatment regimen including pemetrexed, bevacizumab or a TKI at or during LM diagnosis was associated with a decreased risk of death relative to receipt of a regimen without at least one of those systemic agents (hazard ratio = 0.24, p = 0.007).4 Of the 16 patients who received a modern treatment regimen, nine (56%) had a known or suspected EGFR mutation. A study of six patients with new LM disease and NSCLC previously well controlled on gefitinib, five (83%) of whom had a sensitizing EGFR mutation, reported a 67% cerebral response rate to the combination of cisplatin, pemetrexed, and erlotinib.5 Most patients on these studies were not treated with osimertinib, and their interpretation is limited by small study size, potential selection bias, and heterogeneous treatment approaches.\n\nConclusions\n\nOur patient’s durable radiographic and symptomatic response to systemic pemetrexed in combination with osimertinib for recurrent LM disease lends further support to use of this treatment strategy for LM disease in EGFR-mutated NSCLC. This case also illustrates the potential value of using CSF ctDNA in evaluating for resistance alterations of LM disease. Prospective studies are needed to better characterize the efficacy of this combination at a population level.\n\nAcknowledgments\n\nThe Fred Hutchinson Institutional Review Board does not require informed consent for case reports, but the authors did obtain verbal consent from the patient authorizing use and disclosure of his health information.\n\nCite this article as: Merkhofer CM, Baik CS. Durable response of leptomeningeal disease with osimertinib and pemetrexed in EGFR-mutated metastatic NSCLC: a case report. JTO Clin Res Rep. 2021;2:100177.\n\nDisclosure: Dr. Baik receives research funding from 10.13039/100006483 AbbVie , 10.13039/100006436 Celgene , Eli Lilly Oncology, Pfizer, Rain Therapeutics, Spectrum Pharmaceuticals, and Turning Point Therapeutics and personal consulting fees from 10.13039/100004325 AstraZeneca , Blueprint Medicines, 10.13039/501100002973 Daiichi-Sankyo , and Takeda Pharmaceuticals. Dr. Merkhofer declares no conflict of interest.\n==== Refs\nReferences\n\n1 Wu Y.L. Ahn M.J. Garassino M.C. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3) J Clin Oncol 36 2018 2702 2709 30059262\n2 White M.N. Piotrowska Z. Stirling K. Combining osimertinib with chemotherapy in EGFR-mutant NSCLC at progression [e-pub ahead of print]. Clin Lung Cancer https://doi.org/10.1016/j.cllc.2021.01.010 accessed March 2, 2021\n3 Choi M. Keam B. Ock C.Y. Pemetrexed in the treatment of leptomeningeal metastasis in patients with EGFR-mutant lung cancer Clin Lung Cancer 20 2019 e442 e451 31010639\n4 Riess J.W. Nagpal S. Iv M. Prolonged survival of patients with non-small-cell lung cancer with leptomeningeal carcinomatosis in the modern treatment era Clin Lung Cancer 15 2014 202 206 24524822\n5 Yang H. Yang X. Zhang Y. Erlotinib in combination with pemetrexed/cisplatin for leptomeningeal metastases and cerebrospinal fluid drug concentrations in lung adenocarcinoma patients after gefitinib failure Target Oncol 10 2015 135 140 24985049\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-3643",
"issue": "2(6)",
"journal": "JTO clinical and research reports",
"keywords": "Case report; EGFR mutation; Leptomeningeal disease; Non–small cell lung cancer; Pemetrexed",
"medline_ta": "JTO Clin Res Rep",
"mesh_terms": null,
"nlm_unique_id": "101769967",
"other_id": null,
"pages": "100177",
"pmc": null,
"pmid": "34590025",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": "31010639;24985049;30059262;24524822;33610453",
"title": "Durable Response of Leptomeningeal Disease With Osimertinib and Pemetrexed in EGFR-Mutated Metastatic NSCLC: A Case Report.",
"title_normalized": "durable response of leptomeningeal disease with osimertinib and pemetrexed in egfr mutated metastatic nsclc a case report"
} | [
{
"companynumb": "US-ACCORD-242533",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nClozapine is a second-generation antipsychotic that has been shown to reduce suicidal ideation and suicidal behaviors in patients with schizophrenia. However, it is underutilized because of its serious side effects.\n\n\nMETHODS\nWe describe 3 patients with a history of suicide ideation and attempts who were successfully treated and maintained in the community without suicidal tendencies while taking clozapine. All 3 patients, men in their 20s, discontinued clozapine because of side effects and subsequently committed suicide. We also review the literature on clozapine's effects on suicidality.\n\n\nRESULTS\nIn these 3 cases, suicide followed abrupt discontinuation of clozapine or transition to another antipsychotic.\n\n\nCONCLUSIONS\nThis case series is the first of its kind to document the risk of suicide when clozapine is discontinued. The decision to discontinue clozapine should be made carefully, especially because clozapine is considered the treatment of last resort for patients with treatment-resistant schizophrenia and suicidal ideation. We stress the importance of minimizing the risk of abrupt clozapine discontinuation and recommend further evaluation of suicide ideation and attempts when clozapine is discontinued.",
"affiliations": "University of Maryland/Sheppard Pratt Psychiatry, Department of Psychiatry, Psychiatry Residency Program, Baltimore, MD USA.",
"authors": "Patchan|Kathleen M|KM|;Richardson|Charles|C|;Vyas|Gopal|G|;Kelly|Deanna L|DL|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1040-1237",
"issue": "27(4)",
"journal": "Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists",
"keywords": null,
"medline_ta": "Ann Clin Psychiatry",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D012306:Risk; D012559:Schizophrenia; D013405:Suicide; D055815:Young Adult",
"nlm_unique_id": "8911021",
"other_id": null,
"pages": "253-6",
"pmc": null,
"pmid": "26554366",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8463447;21849905;17017827;19955390;10890315;24435842;17170061;24708834;10505585;6433395;12126596;22544020;7840350;10789357;9345668;19595447;10385477;9712207;8075909;12511175;23104931",
"title": "The risk of suicide after clozapine discontinuation: Cause for concern.",
"title_normalized": "the risk of suicide after clozapine discontinuation cause for concern"
} | [
{
"companynumb": "US-AUROBINDO-AUR-APL-2021-048380",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPROPION HYDROCHLORIDE"
},
"drugaddit... |
{
"abstract": "Endothelial cell malignancies are extremely rare in childhood. New identification of genetic abnormalities (WWTR1:CAMTA1 translocation) helps to recognize potential therapeutic targets. Little is known about treatment and outcome of these patients.\n\n\n\nClinical course, treatment, and outcome in patients with endothelial cell malignancies treated within the Cooperative Weichteilsarkom Studiengruppe (CWS) trials CWS-91, -96, -2002P, and the Soft-Tissue Sarcoma Registry (SoTiSaR) were analyzed (1991-2019).\n\n\n\nPatients had angiosarcoma (AS) (n = 12), malignant epithelioid hemangioendothelioma (EHE) (n = 16), and kaposiform hemangioendothelioma (KHE) (n = 13). The median age was 5.39 years (range, 0.8-17.34); 33 patients had localized disease (LD), and 8 patients had metastatic disease. Therapy consisted of chemotherapy (CHT) (AS n = 8, EHE n = 9, KHE n = 5), interferon or new agent therapy (EHE n = 5, 2 KHE n = 2), microscopically or macroscopically complete resection (AS n = 3, EHE n = 6, KHE n = 3), and radiotherapy (AS n = 6, EHE n = 2, KHE n = 1). Two patients (KHE) had watch-and-wait strategy resulting in stable disease. Complete remission (CR) was achieved in AS (10/12; 83%), EHE (10/16; 63%), and KHE (5/13; 38%). The five-year EFS and OS for patients with AS was 64% (± 29 CI 95%) and 80% (± 25, CI 95%), with EHE 62% (± 24, CI 95%) and 78% (± 23, CI 95%), with KHE 33% (± 34, CI 95%) and 92% (± 15, CI 95%), respectively. Complete resection was a significant prognostic factor for AS, LD for EHE.\n\n\n\nEndothelial cell malignancies in childhood have a fair outcome with multimodal treatment. New treatment options are needed for metastic disease.",
"affiliations": "Klinikum Stuttgart, Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany.;Klinikum Stuttgart, Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany.;Section of Pediatric Pathology, Department of Pathology, Kiel Pediatric Tumor Registry, Kiel, Germany.;Division of Pediatric Hematology and Oncology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University of Munich, Munich, Germany.;Department of Pediatrics, Hematology, Oncology and Endocrinology, Medical University of Gdansk, Gdansk, Poland.;Department of Pediatric Surgery, University Children's Hospital Marburg, Marburg, Germany.;Klinikum Stuttgart, Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany.;Klinikum Stuttgart, Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Olgahospital, Institute of Radiology, Stuttgart, Germany.;Klinikum Stuttgart, Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany.;Klinikum Stuttgart, Institute of Radiotherapy, Stuttgart, Germany.;Klinikum Stuttgart, Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany.;Department of Pediatric Oncology, University of Zurich, Zurich, Switzerland.;Department of Women's and Children`s Health, University of Uppsala, Children's University Hospital, Uppsala, Sweden.;Department of Pediatric Surgery and Urology, University Children's Hospital, Tuebingen, Germany.;Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Faculty of Medicine, University of Freiburg, Germany.;Universitätsklinik für Kinderheilkunde, Hämatologie und Onkologie, Inselspital, Universitätsspital Bern, Switzerland.;Department for Children and Adolescents, University of Frankfurt, Frankfurt am Main, Germany.",
"authors": "Sparber-Sauer|Monika|M|0000-0001-9551-2399;Koscielniak|Ewa|E|;Vokuhl|Christian|C|0000-0002-4138-4536;Schmid|Irene|I|;Bien|Ewa|E|;Seitz|Guido|G|0000-0001-9280-1451;Hallmen|Erika|E|;von Kalle|Thekla|T|;Scheer|Monika|M|0000-0002-0665-6268;Münter|Marc|M|;Bielack|Stefan S|SS|;Niggli|Felix|F|;Ljungman|Gustaf|G|;Fuchs|Joerg|J|;Hettmer|Simone|S|0000-0003-1709-4448;Rössler|Jochen|J|;Klingebiel|Thomas|T|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28095",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "67(3)",
"journal": "Pediatric blood & cancer",
"keywords": "CWS Group; angiosarcoma; children; endothelial cell malignancies; epithelioid hemangioendothelioma; kaposiform hemangioendothelioma",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006390:Hemangioendothelioma; D018323:Hemangioendothelioma, Epithelioid; D006394:Hemangiosarcoma; D006801:Humans; D007223:Infant; D059885:Kasabach-Merritt Syndrome; D008297:Male; D009364:Neoplasm Recurrence, Local; D012042:Registries; D012189:Retrospective Studies; D012509:Sarcoma; D012514:Sarcoma, Kaposi; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28095",
"pmc": null,
"pmid": "31814291",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Endothelial cell malignancies in infants, children and adolescents: Treatment results of three Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.",
"title_normalized": "endothelial cell malignancies in infants children and adolescents treatment results of three cooperative weichteilsarkom studiengruppe cws trials and one registry"
} | [
{
"companynumb": "NVSC2019DE066714",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PAZOPANIB"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nAlthough consensus guidelines for pretreatment evaluation and monitoring of propranolol therapy in patients with infantile hemangiomas (IH) have been formulated, little is known about the cardiovascular side effects.\n\n\nOBJECTIVE\nWe sought to analyze cardiovascular evaluations in patients with IH at baseline and during treatment with an oral beta-blocker.\n\n\nMETHODS\nData from 109 patients with IH were retrospectively analyzed. Patient and family history, pretreatment electrocardiogram (ECG), heart rate, and blood pressure were evaluated before initiation of beta-blocker therapy. Blood pressure and standardized questionnaires addressing side effects were evaluated during treatment.\n\n\nRESULTS\nQuestionnaire analyses (n = 83) identified 3 cases with a family history of cardiovascular disease in first-degree relatives. ECG findings were normal in each case and no serious complication of therapy occurred. ECG abnormalities were found in 6.5% of patients but there were no contraindications to beta-blocker therapy and no major complications. Hypotension in 9 patients did not require therapy adjustment. In all, 88 parents (81%) reported side effects during beta-blocker treatment.\n\n\nCONCLUSIONS\nThe relatively small patient cohort is a limitation.\n\n\nCONCLUSIONS\nPretreatment ECG is of limited value for patients with an unremarkable cardiovascular history and a normal heart rate and blood pressure. Hypotension may occur during treatment.",
"affiliations": "Department of Pediatric Dermatology and Allergology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; Center for Congenital Vascular Anomalies Utrecht, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: m.f.raphael-2@umcutrecht.nl.;Department of Pediatric Plastic Surgery, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; Center for Congenital Vascular Anomalies Utrecht, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Pediatric Dermatology and Allergology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Pediatric Dermatology and Allergology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; Center for Congenital Vascular Anomalies Utrecht, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Pediatric Cardiology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Pediatric Dermatology and Allergology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; Center for Congenital Vascular Anomalies Utrecht, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Pediatric Dermatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.;Department of Pediatric Cardiology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; Center for Congenital Vascular Anomalies Utrecht, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.",
"authors": "Raphael|Martine F|MF|;Breugem|Corstiaan C|CC|;Vlasveld|Florine A E|FA|;de Graaf|Marlies|M|;Slieker|Martijn G|MG|;Pasmans|Suzanne G M A|SG|;Breur|Johannes M P J|JM|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D011433:Propranolol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": "72(3)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": "beta-blocker therapy; cardiovascular side effects; infantile hemangioma; treatment evaluation",
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D002318:Cardiovascular Diseases; D002675:Child, Preschool; D015331:Cohort Studies; D016903:Drug Monitoring; D004562:Electrocardiography; D005260:Female; D006391:Hemangioma; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011433:Propranolol; D012189:Retrospective Studies; D012878:Skin Neoplasms",
"nlm_unique_id": "7907132",
"other_id": null,
"pages": "465-72",
"pmc": null,
"pmid": "25592625",
"pubdate": "2015-03",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Is cardiovascular evaluation necessary prior to and during beta-blocker therapy for infantile hemangiomas?: A cohort study.",
"title_normalized": "is cardiovascular evaluation necessary prior to and during beta blocker therapy for infantile hemangiomas a cohort study"
} | [
{
"companynumb": "NL-ALVOGEN-2015AL000552",
"fulfillexpeditecriteria": "2",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATENOLOL"
},
"drugadditional": null,
... |
{
"abstract": "Statins have been linked to myasthenia gravis (MG) in recent case reports. However, MG is not currently listed as an adverse drug reaction (ADR) in the summary of product characteristics.\n\n\n\nWe performed case/noncase analyses in VigiBase® (the World Health Organization international database of suspected ADR) to identify a signal of MG (expressed as the reporting odds ratio [ROR] and its 95% confidence interval [CI]) for statins.\n\n\n\nA total of 3967 reports mentioned MG. Of these, 169 were suspected to be statin-induced. A disproportionality signal was found for MG and statins use (ROR [95%CI] = 2.66 [2.28-3.10]).\n\n\n\nThe present disproportionality analysis revealed a possible drug safety signal linking MG and statins. This potential signal is weak, and is offset by the cardiovascular benefits of statins. Clinicians should be aware of this potential ADR, because it may require consideration of statin withdrawal or treatment of MG.",
"affiliations": "Regional Pharmacovigilance Centre, Division of Clinical Pharmacology, Amiens University Hospital, Amiens, France.;Regional Pharmacovigilance Centre, Division of Clinical Pharmacology, Amiens University Hospital, Amiens, France.;Regional Pharmacovigilance Centre, Division of Clinical Pharmacology, Amiens University Hospital, Amiens, France.;Regional Pharmacovigilance Centre, Division of Clinical Pharmacology, Amiens University Hospital, Amiens, France.",
"authors": "Gras-Champel|Valerie|V|;Batteux|Benjamin|B|;Masmoudi|Kamel|K|;Liabeuf|Sophie|S|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1002/mus.26637",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-639X",
"issue": "60(4)",
"journal": "Muscle & nerve",
"keywords": "adverse drug reaction; disproportionality; myasthenia; pharmacovigilance; statin",
"medline_ta": "Muscle Nerve",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D016208:Databases, Factual; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis; D060735:Pharmacovigilance; D014944:World Health Organization",
"nlm_unique_id": "7803146",
"other_id": null,
"pages": "382-386",
"pmc": null,
"pmid": "31298743",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Statin-induced myasthenia: A disproportionality analysis of the WHO's VigiBase pharmacovigilance database.",
"title_normalized": "statin induced myasthenia a disproportionality analysis of the who s vigibase pharmacovigilance database"
} | [
{
"companynumb": "FR-ACCORD-164583",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ROSUVASTATIN"
},
"drugadditional": "3",
"dru... |
{
"abstract": "A 20-year-old man with a rare neurodegenerative disease developed hypermetabolic symptoms with dyskinesia after a third ventriculostomy for hydrocephalus. The initial presentation was concerning for an acute dystonic reaction after metoclopramide was administered for nausea. He concurrently developed hypermetabolic symptoms, including hyperthermia, tachycardia, and a lactic acidosis. The diagnosis was broadened to include neuroleptic malignant syndrome, serotonin syndrome, and malignant hyperthermia. Although perhaps less intellectually satisfying but more true to clinical reality, we did not isolate a single diagnosis but treated effectively all 3 with dantrolene sodium and benzodiazepine.",
"affiliations": "From the Department of Anesthesiology and Pain Medicine, Seattle Children's, Seattle, Washington.;Department of Neurology/Division of Pediatric Neurology, Neuroscience Institute, Seattle Children's/University of Washington, Seattle, Washington.;From the Department of Anesthesiology and Pain Medicine, Seattle Children's, Seattle, Washington.",
"authors": "Holland|Erica L|EL|;Saneto|Russell P|RP|;Knipper|Emily K|EK|",
"chemical_list": "D000932:Antiemetics; D065127:Dopamine D2 Receptor Antagonists; C000598644:Leukoencephalopathy Brain Calcifications and Cysts; D008787:Metoclopramide",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000001212",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "14(7)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000140:Acidosis, Lactic; D000328:Adult; D000932:Antiemetics; D002114:Calcinosis; D020863:Central Nervous System Cysts; D065127:Dopamine D2 Receptor Antagonists; D020820:Dyskinesias; D005076:Exanthema; D006801:Humans; D006849:Hydrocephalus; D056784:Leukoencephalopathies; D008297:Male; D008305:Malignant Hyperthermia; D008787:Metoclopramide; D019636:Neurodegenerative Diseases; D011184:Postoperative Period; D013577:Syndrome; D014696:Ventriculostomy; D055815:Young Adult",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "e01212",
"pmc": null,
"pmid": "32371820",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypermetabolic Syndrome and Dyskinesia After Neurologic Surgery for Labrune Syndrome: A Case Report.",
"title_normalized": "hypermetabolic syndrome and dyskinesia after neurologic surgery for labrune syndrome a case report"
} | [
{
"companynumb": "US-MYLANLABS-2021M1000515",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": "3",
... |
{
"abstract": "Calcineurin inhibitor-induced pain syndrome is an entity recognized in patients on immunosuppressive therapy after transplantation. Diagnosis is characterized by onset of pain beginning in the setting of an elevated calcineurin-inhibitor trough level. Reducing the medication dose relieves symptoms. Imaging findings can be nonspecific, including bone marrow edema and periosteal reaction. We present the unique case of calcineurin inhibitor-induced pain syndrome in a child and review the imaging findings.",
"affiliations": "Department of Radiology, Columbia University Medical Center, Morgan Stanley Children's Hospital, 3959 Broadway, CHONY 3N, New York, NY, 10032, USA. rsa2121@cumc.columbia.edu.;Department of Radiology, Columbia University Medical Center, Morgan Stanley Children's Hospital, 3959 Broadway, CHONY 3N, New York, NY, 10032, USA.;Department of Radiology, Columbia University Medical Center, Morgan Stanley Children's Hospital, 3959 Broadway, CHONY 3N, New York, NY, 10032, USA.;Department of Radiology, Columbia University Medical Center, Morgan Stanley Children's Hospital, 3959 Broadway, CHONY 3N, New York, NY, 10032, USA.",
"authors": "Ayyala|Rama S|RS|;Arnold|Staci D|SD|;Bhatia|Monica|M|;Dastgir|Jahannaz|J|",
"chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00247-016-3644-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0449",
"issue": "46(11)",
"journal": "Pediatric radiology",
"keywords": "Bone marrow transplant; Calcineurin inhibitor-induced pain syndrome; Child; Magnetic resonance imaging; Radiography",
"medline_ta": "Pediatr Radiol",
"mesh_terms": "D018771:Arthralgia; D016026:Bone Marrow Transplantation; D065095:Calcineurin Inhibitors; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D008279:Magnetic Resonance Imaging; D013577:Syndrome; D016559:Tacrolimus; D017086:beta-Thalassemia",
"nlm_unique_id": "0365332",
"other_id": null,
"pages": "1618-21",
"pmc": null,
"pmid": "27324395",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "17217441;23615775;8153313;18785910;1922263;11263551;26069740;19318596",
"title": "Imaging findings in a child with calcineurin inhibitor-induced pain syndrome after bone marrow transplant for beta thalassemia major.",
"title_normalized": "imaging findings in a child with calcineurin inhibitor induced pain syndrome after bone marrow transplant for beta thalassemia major"
} | [
{
"companynumb": "US-ASTELLAS-2016US044466",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "Clinical trials on childhood acute promyelocytic leukemia (APL) report early death (ED) rates of 3-8%, but predictors of thrombohemorrhagic (TH)-ED are not well understood. In a retrospective study, we aimed to determine the incidence and predictors of TH-ED in childhood APL. Data were analyzed from children and adolescents with t(15;17)-positive APL (n = 683) who started treatment with all-trans retinoic acid (ATRA) and chemotherapy in different international studies. Demographic data; initial white blood cell (WBC), peripheral blood (PB) blast, and platelet counts; hemoglobin value; coagulation parameters; morphologic variant (M3 or M3v); and induction details were analyzed. Early death was defined as death occurring within 30 days of presentation. The incidence of ED was 4.7% (32 of 683 patients). Predictors of TH-ED were identified by univariable and multivariable Cox proportional hazard regression analyses (n = 25). In univariable analysis, high WBC (>10 × 109/L) (P < 0.001) and high PB blast (>30 × 109/L) (P < 0.001), M3v (P < 0.01), and black ethnicity (P < 0.001) were independent predictors of TH-ED. In multivariable analysis, high WBC count (P < 0.01) and obesity (i.e., body mass index ≥95th percentile for age) (P = 0.03) were predictors of TH-ED. Initial high WBC counts and obesity are likely predictors of TH-ED in childhood APL. The efficacy of novel drugs for APL-associated coagulopathy or of frontline arsenic trioxide and ATRA combination regimens in reducing ED rates in childhood APL remains to be established.",
"affiliations": "Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada. oussama.abla@sickkids.ca.;Division of Leukemia/Lymphoma, Department of Oncology, St. Jude Children's Research Hospital, Memphis, USA.;Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.;Department of Hematology, Hospital Universitari i Politecnic La Fe, Valencia, and Centro de Investigación Biomédica en Red de Cáncer, Instituto Carlos III, Madrid, Spain.;Department of Paediatric Haematology and Oncology, Hannover Medical School, Hannover, Germany.;Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada.;Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada.;Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada.;Division of Hematology/Oncology, Children's Hospital and Research Center Oakland, Oakland, USA.;Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, USA.;Department of Paediatrics, Aarhus University Hospital, Aarhus, Denmark.;Department of Pediatric Oncology/Hematology, University Medical Center, Amsterdam, Netherlands.;Department of Oncology, The Children's Hospital at Westmead, Westmead, Australia.;Pediatric Hematology-Oncology Department, Instituto Carlos III, Madrid, Spain.;Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, USA.;Department of Pediatric Hematology-Oncology, IRCCS Ospedale Bambino Gesù, Rome, Italy.;Department of Haematology-Oncology, University of Essen, Duisburg, Germany.;Department of Biomedicine and Prevention, University Tor Vergata, Rome, Italy.;Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada.;Department of Hematology, Hospital Universitari i Politecnic La Fe, Department of Medicine, University of Valencia, Valencia, Spain.",
"authors": "Abla|Oussama|O|http://orcid.org/0000-0001-7446-6274;Ribeiro|Raul C|RC|;Testi|Anna Maria|AM|;Montesinos|Pau|P|;Creutzig|Ursula|U|;Sung|Lillian|L|;Di Giuseppe|Giancarlo|G|;Stephens|Derek|D|;Feusner|James H|JH|;Powell|Bayard L|BL|;Hasle|Henrik|H|;Kaspers|Gertjan J L|GJL|;Dalla-Pozza|Luciano|L|;Lassaletta|Alvaro|A|;Tallman|Martin S|MS|;Locatelli|Franco|F|;Reinhardt|Dirk|D|;Lo-Coco|Francesco|F|;Hitzler|Johann|J|;Sanz|Miguel A|MA|",
"chemical_list": "D014212:Tretinoin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-017-3042-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "96(9)",
"journal": "Annals of hematology",
"keywords": "APL; Children; Early death; Predictors",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D004211:Disseminated Intravascular Coagulation; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015473:Leukemia, Promyelocytic, Acute; D007958:Leukocyte Count; D008297:Male; D009765:Obesity; D012307:Risk Factors; D014178:Translocation, Genetic; D014212:Tretinoin",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1449-1456",
"pmc": null,
"pmid": "28597167",
"pubdate": "2017-09",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Predictors of thrombohemorrhagic early death in children and adolescents with t(15;17)-positive acute promyelocytic leukemia treated with ATRA and chemotherapy.",
"title_normalized": "predictors of thrombohemorrhagic early death in children and adolescents with t 15 17 positive acute promyelocytic leukemia treated with atra and chemotherapy"
} | [
{
"companynumb": "CA-CHEPLA-C20170369",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRETINOIN"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nA case of detectable systemic vancomycin levels after oral vancomycin administration but not after intracolonic administration in a patient with colonic discontinuity and severe Clostridium difficile infection (CDI) is reported.\n\n\nCONCLUSIONS\nA 63-year-old woman who had recently undergone pancreas-kidney transplantation developed severe CDI after 13 days of meropenem therapy for presumed urosepsis. Meropenem was stopped immediately, and treatment with oral vancomycin (250 mg every 6 hours) was started. Due to fulminant C. difficile colitis with signs of toxic megacolon and abdominal compartment syndrome, an emergency left hemicolectomy (Hartmann's procedure) was performed. Ten days after initiation of oral vancomycin therapy, the serum vancomycin concentration was 16.7 mg/L. After oral dose reduction to 125 mg every 6 hours, the measured serum vancomycin concentrations stayed above 10 mg/L. CDI therapy was terminated after 16 days. Eight days later, as sigmoidoscopy of the Hartmann rectal stump still showed pseudomembranes, intracolonic vancomycin application in the Hartmann rectal stump was started; 7-9 days after initiation of intracolonic therapy, the serum vancomycin concentration remained undetectable. The observed patterns of vancomycin exposure and absorption in this case suggest that the sigmoid colon is not the site of resorption of intracolonically applied vancomycin.\n\n\nCONCLUSIONS\nA patient with severe CDI and Hartmann rectal stump after hemicolectomy was treated with vancomycin. After oral vancomycin therapy, significant enteral absorption was observed, while levels stayed undetectable during intracolonic administration alone.",
"affiliations": "Division of Infectious Diseases, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.;Division of Infectious Diseases, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.;Division of Infectious Diseases, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany katja.dewith@uniklinikum-dresden.de.",
"authors": "Wilke|Katja|K|;Helbig|Sina|S|;de With|Katja|K|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp170200",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "75(9)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": "Clostridium difficile; intracolonic; retention enemas; systemic exposure; vancomycin",
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000284:Administration, Oral; D000900:Anti-Bacterial Agents; D016360:Clostridioides difficile; D003015:Clostridium Infections; D003106:Colon; D005260:Female; D006801:Humans; D007408:Intestinal Absorption; D008875:Middle Aged; D012720:Severity of Illness Index; D014640:Vancomycin",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "e189-e193",
"pmc": null,
"pmid": "29691261",
"pubdate": "2018-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Serum vancomycin concentrations after oral and intracolonic vancomycin administration in a patient with colonic discontinuity and severe Clostridium difficile infection.",
"title_normalized": "serum vancomycin concentrations after oral and intracolonic vancomycin administration in a patient with colonic discontinuity and severe clostridium difficile infection"
} | [
{
"companynumb": "DE-ROCHE-2133252",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nDalbavancin is approved for acute bacterial skin and skin structure infections (ABSSSIs) but offers a potential treatment option for complicated invasive gram-positive infections. Importantly, dalbavancin's real benefits may be in treating complicated infections in vulnerable patient populations, such as persons who inject drugs (PWID).\n\n\nMETHODS\nA multicenter retrospective analysis was performed from March 2014 to April 2017 to assess 30- and 90-day clinical cure and adverse drug events (ADEs) in adult patients who received ≥ 1 dose of dalbavancin for a non-ABSSSI indication.\n\n\nRESULTS\nDuring the study period, 45 patients received dalbavancin, 28 for a non-ABSSSI indication. The predominant infections treated included osteomyelitis (46%), endovascular infection (25%) and uncomplicated bacteremia (14%). Half of the patients had positive Staphylococcus aureus in cultures, 29% methicillin resistant and 21% methicillin susceptible. Most patients were prescribed dalbavancin as sequential treatment with a median of 13.5 days of prior antibiotic therapy. The most common reason for choosing dalbavancin over standard therapy use was PWID (54%). Seven patients were lost to follow-up at day 30. Of the remaining evaluable patients, 30-day clinical cure was achieved in 15/21 (71%) patients. The most common reason for failure was lack of source control (4/6, 67%). At day 90, relapse occurred in two patients. Three patients had a potential dalbavancin-associated ADE: two patients with renal dysfunction and one patient with pruritus.\n\n\nCONCLUSIONS\nThis study demonstrates a possible role for dalbavancin in the treatment of non-ABSSSI invasive gram-positive infections in select vulnerable OPAT patients.",
"affiliations": "Division of Infectious Disease, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA. jabork@som.umaryland.edu.;University of Maryland School of Pharmacy, Baltimore, MD, USA.;Division of Infectious Disease, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.;Division of Infectious Disease, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.;Department of Pharmacy, VA Maryland Health Care System, Baltimore, MD, USA.;Division of Infectious Disease, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.;Division of Infectious Disease, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.",
"authors": "Bork|Jacqueline T|JT|;Heil|Emily L|EL|;Berry|Shanna|S|;Lopes|Eurides|E|;Davé|Rohini|R|;Gilliam|Bruce L|BL|;Amoroso|Anthony|A|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40121-019-0247-0",
"fulltext": "\n==== Front\nInfect Dis Ther\nInfect Dis Ther\nInfectious Diseases and Therapy\n2193-8229\n2193-6382\nSpringer Healthcare Cheshire\n\n31054088\n247\n10.1007/s40121-019-0247-0\nOriginal Research\nDalbavancin Use in Vulnerable Patients Receiving Outpatient Parenteral Antibiotic Therapy for Invasive Gram-Positive Infections\nBork Jacqueline T. jabork@som.umaryland.edu\n\n14\nHeil Emily L. 2\nBerry Shanna 1\nLopes Eurides 1\nDavé Rohini 3\nGilliam Bruce L. 1\nAmoroso Anthony 14\n1 0000 0001 2175 4264 grid.411024.2 Division of Infectious Disease, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD USA\n2 0000 0001 2175 4264 grid.411024.2 University of Maryland School of Pharmacy, Baltimore, MD USA\n3 0000 0000 9558 9225 grid.417125.4 Department of Pharmacy, VA Maryland Health Care System, Baltimore, MD USA\n4 0000 0000 9558 9225 grid.417125.4 Department of Medicine, VA Maryland Health Care System, Baltimore, MD USA\n3 5 2019\n3 5 2019\n6 2019\n8 2 171184\n9 3 2019\n© The Author(s) 2019\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\nIntroduction\n\nDalbavancin is approved for acute bacterial skin and skin structure infections (ABSSSIs) but offers a potential treatment option for complicated invasive gram-positive infections. Importantly, dalbavancin’s real benefits may be in treating complicated infections in vulnerable patient populations, such as persons who inject drugs (PWID).\n\nMethods\n\nA multicenter retrospective analysis was performed from March 2014 to April 2017 to assess 30- and 90-day clinical cure and adverse drug events (ADEs) in adult patients who received ≥ 1 dose of dalbavancin for a non-ABSSSI indication.\n\nResults\n\nDuring the study period, 45 patients received dalbavancin, 28 for a non-ABSSSI indication. The predominant infections treated included osteomyelitis (46%), endovascular infection (25%) and uncomplicated bacteremia (14%). Half of the patients had positive Staphylococcus aureus in cultures, 29% methicillin resistant and 21% methicillin susceptible. Most patients were prescribed dalbavancin as sequential treatment with a median of 13.5 days of prior antibiotic therapy. The most common reason for choosing dalbavancin over standard therapy use was PWID (54%). Seven patients were lost to follow-up at day 30. Of the remaining evaluable patients, 30-day clinical cure was achieved in 15/21 (71%) patients. The most common reason for failure was lack of source control (4/6, 67%). At day 90, relapse occurred in two patients. Three patients had a potential dalbavancin-associated ADE: two patients with renal dysfunction and one patient with pruritus.\n\nConclusions\n\nThis study demonstrates a possible role for dalbavancin in the treatment of non-ABSSSI invasive gram-positive infections in select vulnerable OPAT patients.\n\nKeywords\n\nDalbavancin\nOutpatient parenteral antibiotic therapy\nSubstance use disorder\nissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\n\nInvasive gram-positive infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA), are a therapeutic challenge and significant burden on the health care system [1–3]. Often, optimal treatment requires long-term intravenous antibiotic therapy, which poses a particular challenge for treating patients classified as vulnerable or high-risk for complications such as persons who inject drugs (PWID) or those who lack social support such as the elderly, homeless or patients with an underlying psychiatric illness [4, 5]. These patients are at higher risk for drug-related adverse events (ADEs), line-associated complications, nonadherence and hospital re-admission [6, 7].\n\nDalbavancin, a novel second-generation lipoglycopeptide antibiotic with an extended half-life was approved by the Food and Drug Administration in 2014 for acute gram-positive bacterial soft tissue and skin structure infections (ABSSSIs). Dalbavancin’s half-life of approximately 14 days has the potential to obviate the need for long-term intravenous access [8].\n\nThere are limited data on the use of dalbavancin for indications other than 1–2 doses for treatment of ABSSSI. Case reports have demonstrated success in treating more complicated infections such as MRSA pneumonia, osteomyelitis and endovascular infections [9–11]. Dalbavancin for treatment of catheter-related bloodstream infections demonstrated efficacy in a small phase 2 open-label study with overall success of 87% (95% CI 73.2–100%) [12]. Recently, a randomized control trial for dalbavancin in the treatment of osteomyelitis versus standard of care demonstrated clinical efficacy with overall success of 97% (95% CI 89.6–99.6%) [13]. In addition, both studies demonstrated safety with mild ADEs that were similar to comparators.\n\nHerein, we describe characteristics and outcomes of off-label use of dalbavancin for invasive gram-positive infections as primarily sequential treatment in patients with high risk for complications.\n\nMethods\n\nStudy Location, Design and Eligibility\n\nThe study was conducted at the University of Maryland Medical Center (UMMC), a 750-bed acute tertiary care center in Baltimore, MD, and the VA Maryland Health Care System (VAMHCS), an acute care facility comprised of a 137-bed inpatient unit and 2 long-term care facilities. Patients were identified from the Antibiotic Stewardship Program clinical management database at UMMC and from the outpatient parenteral antibiotic therapy (OPAT) program at the VAMHCS. All adult patients who received at least one dose of dalbavancin for a non-ABSSSI indication between March 2014 and April 2017 were included in the review. During this study period, all dalbavancin prescriptions were made at the clinical discretion of the Infectious Diseases (ID) physicians evaluating the patient.\n\nData Extraction and Definitions\n\nCharts were primarily reviewed by one reviewer and adjudicated by the research team, consisting of three ID physicians and two ID pharmacists. Charts were abstracted for patient characteristics (demographics, comorbidities, length of hospital stay), infection characteristics (type of infection, microbiologic data) and treatment characteristics (indication for dalbavancin, prior antibiotic received, number of doses of dalbavancin). Type of infection was defined by the ID physician at the bedside. Each case was probed for the exact reason for dalbavancin over standard therapy, which included: PWID, any history of substance use (drug use by any route and alcohol abuse), homelessness, lack of home support, and patient refusal for intravenous access or institutional placement.\n\nThe primary outcome was the proportion of patients with defined clinical cure 30 days after completion of the planned dalbavancin course (i.e., end date), termed “30-day clinical cure.” Secondary outcomes included the proportion of patients without recurrent or persistent infection 90 days after completion of planned dalbavancin, termed “90-day clinical cure,” and ADEs.\n\nClinical cure was defined as a composite of the following factors: resolution of clinical signs of infection (erythema, swelling, pain), absence of fever, normalization of inflammatory markers (C-reactive protein, erythrocyte sedimentation rate), normalization of the white count, source control defined as removal or drainage of the foci of infection, resolution of radiographic signs of infection and/or microbiologic clearance of organisms. If there was readmission to the hospital for infection, clinical failure was assumed regardless of the above factors.\n\nPatients who did not meet criteria for clinical cure were defined as clinical failure and further characterized as failure due to one of the following: (1) death, (2) intolerance or adverse event, (3) lack of access to subsequent dalbavancin, (4) lack of source control and (5) worsening signs of infection or relapse infection. Lack of source control was defined based on retained hardware or device, surgical margins that were not clear, positive cultures from a proximal specimen or undrained abscess.\n\nAdverse events were defined as any untoward experience that was likely to be associated with dalbavancin based on the specific ADE and temporal relationship with dalbavancin.\n\nData Analysis\n\nDescriptive statistics were performed for all data in total for both facilities. Outcome analysis for 30-day clinical cure and 90-day clinical cure was evaluated in total on an “as-treated” basis, excluding patients lost to follow-up. In addition, an “intention-to-treat” analysis for 30- and 90-day clinical cure for each infection type was also performed, including patients lost to follow-up. All analyses were performed using Microsoft Excel software (Redmond, WA).\n\nThe study was approved with a waiver of informed consent in an expedited review by the University of Maryland, Baltimore, Institutional Review Board, which oversees both UMMC and VAMHCS facilities. This study was also performed in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.\n\nResults\n\nA total of 45 patients received dalbavancin at UMMC and VAMHCS from March 2014 to March 2017. Twenty-eight patients met the inclusion criteria for further review (Fig. 1). Table 1 describes the overall patient characteristics. Most patients were male, and the median age was 52 years old. Underlying substance use disorder (SUD) (68%) was the most common comorbidity followed by hepatitis C (25%) and diabetes mellitus (21%). The most common indications for antibiotics included osteomyelitis (46%), endovascular infection (25%) and uncomplicated bacteremia (14%). PWID (54%) was the predominant reason for dalbavancin (over standard therapy) followed by patient refusal of long-term intravenous access (25%). Dalbavancin was initiated in 22 patients (79%) in the inpatient and 6 patients (21%) in the outpatient setting. The median number of doses, including loading doses, in total was three. Median duration of prior antibiotic was 13.5 days. Sixty-eight percent (19/28) were on prior antibiotics for 1 week or longer before switching to dalbavancin. Twenty-eight percent (8/28) had completed ≥ 50% of the therapy prior to dalbavancin.Fig. 1 Patient selection. ABSSSI acute bacterial skin and skin structure infections\n\nTable 1 Patient characteristics\n\n\tUMMC (%)\tVAMHCS (%)\tTotal (%)\t\nTotal n\t12\t16\t28\t\nMedian age (years, IQR)\t39.5\t59.5\t52 (21.5)\t\nMale\t10 (83)\t16 (100)\t26 (93)\t\nComorbidities\t\t\t\t\n Substance abuse\t9 (75)\t10 (63)\t19 (68)\t\n DM\t0 (0)\t6 (40)\t6 (21)\t\n Hepatitis C\t4 (33)\t3 (19)\t7 (25)\t\n Vascular\t0 (0)\t4 (25)\t4 (14)\t\n Cardiovascular\t1 (8)\t3 (19)\t4 (14)\t\n Malignancy\t1 (8)\t1 (6)\t2 (7)\t\n CKD\t0 (0)\t2 (13)\t2 (7)\t\n HIV\t0 (0)\t1 (6)\t1 (4)\t\nInfection\t\t\t\t\n Osteomyelitis\t3 (25)\t10 (63)\t13 (46)\t\n Endovascular\t4 (33)\t2 (13)\t6 (21)\t\n Bacteremia\t3 (25)\t1 (6)\t4 (14)\t\n Othera\t2 (17)\t3 (19)\t5 (18)\t\nCulture\t\t\t\t\n MRSA\t6 (50)\t2 (13)\t8 (29)\t\n MSSA\t3 (25)\t3 (19)\t6 (21)\t\n CoNS\t1 (8)\t3 (19)\t4 (14)\t\n Mixed GPO\t0 (0)\t8 (50)\t8 (29)\t\n Not available\t2 (17)\t3 (19)\t5 (18)\t\nReason for dalbavancin\t\t\t\t\n PWID\t9 (75)\t7 (44)\t16 (57)\t\n Patient refusal of PICC\t2 (17)\t2 (13)\t4 (14)\t\n Otherb\t1 (8)\t5 (31)\t6 (21)\t\n Substance usec\t0 (0)\t2 (13)\t2 (7)\t\nLocation of initiation of dalbavancin\t\t\t\t\n Inpatient\t11 (92)\t11 (69)\t22 (79)\t\n Outpatient\t1 (8)\t5 (33)\t6 (21)\t\n Median dalbavancin doses (IQR)\t1.5\t5.5\t3 (4.5)\t\n Median LOPA (days, IQR)\t9\t15\t13.5 (16)\t\n Median LOS (days, IQR)\t10\t7\t8 (12.5)\t\nVAMHCS VA Maryland Health Care System, UMMC University of Maryland Medical Center, DM diabetes mellitus, HIV human immunodeficiency virus, CKD chronic kidney disease, MSSA methicillin susceptible S. aureus, MRSA methicillin-resistant S. aureus, CoNS coagulase-negative staphylococcus, GPO gram-positive organisms, PWID persons who inject drugs, LOPA length of prior antibiotic, LOS length of stay\n\naMRSA pneumonia, septic arthritis, prosthetic joint infection, cardiac device infection, pyelonephritis\n\nbLack of home support, homelessness, not documented\n\ncNon-injectable substance\n\nMRSA and mixed gram-positive organisms were the most common cultures targeted followed by methicillin-susceptible S. aureus (MSSA) and coagulase-negative staphylococci (CoNS) (Table 1). Mixed gram-positive organisms included Enterococcus faecalis, MRSA, MSSA and CoNS. One patient had Propionibacterium acnes isolated. In six patients, dalbavancin was used in combination with an oral fluoroquinolone to treat a concomitant gram-negative organism, three of which were for definitive therapy against Pseudomonas aeruginosa (n = 2) and Escherichia coli (n = 1), in addition to one requiring oral metronidazole to cover Bacteroides fragilis. In the remaining three patients, an oral fluoroquinolone was used as part of empiric therapy.\n\nOutcomes\n\nTwenty-eight patients received off-label use of dalbavancin for an invasive gram-positive infection. The “as-treated” analysis included 21 patients and excluded 7 patients who were lost to follow-up at the 30-day outcome. Outcomes are presented in Table 2. There were 15 patients (71%) with clinical cure at day 30. The most common reason for failure was lack of source control (4/6, 67%). Of the 15 patients who had clinical cure at day 30, 2 (one with pyelonephritis and one with cardiac-device infection) had relapse of infection, both due to lack of source control prior to 90 days. The patient with pyelonephritis had recrudescent infection with CoNS with evidence of a retained stone that was later removed. The patient with cardiac-device infection had debridement with cultures revealing CoNS and Corynebacterium spp. He went on to receive an extended course of intravenous daptomycin due to retained cardiac wires.Table 2 As-treated outcomes for all indications\n\n\tUMMC (%)\tVAMHCS (%)\tTotal (%)\t\n30 days\t\n Follow-up\t7 (58)\t14 (88)\t21 (75)\t\n Cure\t5 (71)\t10 (71)\t15 (71)\t\n Failure\t2 (29)\t4 (29)\t6 (29)\t\nAdverse eventsa\t\n Renal\t1 (14)\t1 (7)\t2 (10)\t\n Pruritus\t1 (14)\t0 (0)\t1 (5)\t\naOf total patients evaluable at day 30\n\nThe “intention-to-treat” 30- and 90-day clinical cure analysis included all 28 patients stratified by infection type. Outcomes for each infection are presented in Fig. 2. Thirteen patients were treated for osteomyelitis with a 30-day clinical cure rate of 46% (6/13). Of the five failures, four were considered to be due to lack of source control and one due to lack of access to subsequent dalbavancin. All 30-day failures continued on to 90-day failures, including one patient without source control who failed at 90 days because of an unrelated death. There were no additional failures at 90 days; however, three additional patients were lost to follow-up. Six patients were treated for endovascular infections with a 30-day clinical cure rate of 50% (3/6). The one failure was due to possible ADE secondary to acute kidney injury (AKI). Four patients were treated for uncomplicated bacteremia with a 30-day clinical cure of 75% (3/4). There was one patient within each infection type for septic arthritis, pyelonephritis and cardiac device infection with 100% 30-day clinical cure. The patients with a prosthetic joint infection and MRSA pneumonia could not be evaluated because of loss to follow-up, but they both received all planned doses of dalbavancin via home infusion and infusion clinic, respectively.Fig. 2 Intention-to-treat outcomes by indication. MRSA methicillin-resistant S. aureus\n\nSeven (25%) patients were lost to follow-up at 30 days. Only 1/7 (14%) patients failed to complete the intended course of therapy, receiving one out of four of the intended doses. The remaining patients either completed therapy while inpatient (n = 3) or completed therapy as an outpatient with home infusions (n = 3). Six of the 7 patients with loss to follow-up were patients with SUD, and 6/19 (32%) of patients with SUD were lost to follow-up. Of the patients with SUD who were followed up, 10/13 (77%) had clinical cure at day 30.\n\nThere were 3/21 (14%) patients with a documented ADE. Two patients had AKI that developed subsequent to dalbavancin administration. The first patient, treated with dalbavancin for osteomyelitis, was a 72-year-old male with multiple cardiac comorbidities (coronary artery disease, peripheral vascular disease, cardiomyopathy) including chronic kidney disease with creatinine 1.68 mg/dl prior to dalbavancin. After one administered dose of dalbavancin at 1000 mg, his creatinine increased by 10%, and the decision was made to hold any further dalbavancin doses. Despite holding dalbavancin, his creatinine continued to rise (peaked at 2.5 mg/dl), and AKI was considered multifactorial, but most likely secondary to diuresis and/or cardiorenal syndrome. The patient ultimately died from decompensated heart failure. The second patient was a 36-year-old pregnant female treated with dalbavancin for an endovascular infection. AKI developed subsequent to the third dose of dalbavancin, a 500-mg continuation dose. The creatinine increased by 50% from baseline and continued to rise after discontinuation of dalbavancin. The patient underwent renal biopsy for her progressive renal failure and was found to have acute tubular necrosis secondary to IgA nephropathy. The third patient, treated for osteomyelitis, reported generalized pruritus and rash immediately after he finished the first dalbavancin infusion.\n\nDiscussion\n\nThis study evaluated clinical outcomes of dalbavancin use for non-ABSSI indications in two different medical centers with high prevalence of SUD (68%). Dalbavancin successfully treated 15/28 of patients with invasive gram-positive infections, though 7 patients were lost to follow-up, conferring a 71% (15/21) success rate in the treatment of evaluable patients.\n\nThere is significant interest in the use of dalbavancin for off-label indications. Dalbavancin offers the potential for line-sparing treatment, which can facilitate outpatient treatment of serious infections, enable hospital discharge for patients disqualified from facility placement and long-term intravenous access due to active substance use, and prevent line-related complications. Several published case reports demonstrate clinical success of dalbavancin for off-label indications including the treatment of septic phlebitis with secondary MRSA bacteremia, MRSA pneumonia and Corynebacterium striatum native septic arthritis [9, 10, 14]. Most recently, larger case series and comparative studies have been published and are described in Table 3. Dalbavancin treatment success ranged from 71 to 92%, but populations and infectious syndromes were fairly heterogenous [12, 13, 15–20]. For comparison, daptomycin real-world experience from a large registry of 6075 patients and mixed infection revealed a clinical success of 81% [21].Table 3 Summary of non-FDA approved or real-world experience with Dalbavancin studies in adult patients\n\nCitation (year)\tStudy design\tInfection(s)\tStudy population\tDose and duration\tTreatment response\tAdverse drug events\t\nRaad et al. (2005) [12]\tPhase 2 randomized, controlled, open label trial, 13 sites\tCatheter-related bloodstream infections\n\n23% MSSA\n\n20% MRSA\n\n50% CoNS\n\n\tUnited States\n\nInitial treatment\n\nExcluded renal and liver dysfunction, immune suppression, complicated infections\n\nN = 26 (23 in mITT)\n\n\t1000 mg, 1 week later 500 mg\tEOT mITT 20/23 (87%) vs. vancomycin 14/28 (50%)\tHypotension (21%), constipation (18%), diarrhea (21%), anemia (18%)\t\nRappo et al. (2018) [13]\tPhase 2 randomized, open-label, comparator-controlled, parallel-group\tOsteomyelitis (first episode)\n\n54% MSSA\n\n6% MRSA\n\n20% CoNS\n\n\tUkraine\n\nInitial treatment\n\nDM (14% in Dalbavancin group vs. 50% SOC)\n\nNo SUD\n\nN = 70 (67 included due to follow-up)\n\n\t1500 mg\n\n2 doses, 1 week apart\n\n\tClinical cure at day 42: 65/67 (97%) vs. 7/8 (88%) SOC\tNone related to dalbavancin, but 14.3% treatment emergent AE, anemia and bleeding\t\nTobudic et al. (2018) [15]\tCase series\tInfective endocarditis: 16 native valve, 6 prosthetic valve, 5 cardiac device\n\n29% S. aureus\n\n26% Streptococcus\n\n13% Enterococcus\n\n\tAustria\n\nSequential treatment\n\nN = 31 (27 included, due to missing data)\n\n\t1000 mg loading, 500 mg maintenance weekly, Median duration 6 weeks (range 1–30 weeks)\tClinical and microbiologic success 6 months after completed therapy 25/27 (93%)\t1 patient with nausea\n\n1 patient with 2.5-fold increase in creatinine\n\n\t\nBouza et al. (2019) [16]\tCase series, 29 sites\tMixed infections: PJI, ABSSSI, OM, IE most common\n\n35% CoNS\n\n23% MRSA\n\n18% MSSA\n\n18% Enterococcus\n\n\tSpain\n\nBoth initial and sequential treatment\n\nimmune suppressed (28%)\n\nDM 23%\n\nN = 69\n\n\t1500 mg weekly × 2 or 1000 mg × 1 followed by 500 every week, median duration 3 weeks (range 1–24)\tClinical success at 30 days after completion in 58/69 (84%)\n\n(92% for OM, 86% for IE and 75% CRBSI)\n\nNo issues with follow-up or missing data reported\n\n\t2 patients with renal dysfunction; also rash, nausea\t\nWunsch et al. (2019) [17]\tCase series, 3 sites\tMixed infections: ABSSSI, PJI, OM, IE, CRBSI\n\n33% CoNS\n\n16% MSSA\n\n8% MRSA\n\n\tAustria\n\nBoth initial and sequential treatment\n\nN = 101 (7 excluded for follow-up or serious ADE)\n\n\tVariable, 1500 mg weekly or 1000 mg X1, followed by 500 mg every week, median 3 doses (range 1–32), regimens varied\tClinical success at 90 days after completion was 84/94 (89%)\n\n(92% for IE, 85% for OM, 93% for PJI)\n\n\t3%, anaphylaxis, fatigue, vertigo\t\nBrysom-Cohn et al. (2019) [18]\tCase series\tS. aureus-related infections: IE, OM, bacteremia, septic arthritis\n\n88% MRSA\n\n\tUnites States\n\nBoth initial and sequential treatment\n\nPWID\n\nN = 32 (17 completed course, 22 where ultimately evaluable)\n\n\tVariable, 1500 mg or 1000 mg × 1, followed by 500 mg or 1000 mg every week, median duration 1 dose (range 1–5)\tClinical success at 1 year follow-up\n\n18/22 (81%)\n\n\tNone reported\t\nMorata et al. (2019) [19]\tCase series, 30 sites\tBone and joint infections\n\n22% S. aureus\n\n47% CoNS\n\n\tSpain\n\nBoth initial and sequential treatment\n\nDM (16%)\n\nN = 64 (1 lost to follow-up)\n\n\tVariable 1500 mg or 1000 mg × 1, followed by 500 mg or 1000 mg every week, median of 5 doses (IQR 3–7)\tClinical success during or after treatment 45/63 (71%), highest when implant removed (76% vs. 65%)\t3 GI distress, 1 rash, 1 increase in creatinine, none stopped because of AE\t\nAlmangour et al. (2019) [20]\tCase series, 3 sites\tOsteomyelitis\n\nMRSA 48%\n\nMSSA 39%\n\n\tUnites States\n\nBoth initial and sequential treatment\n\nDM (32%)\n\nIVDU (32%)\n\nN = 34 (3 lost to follow-up)\n\n\tVariable 1500 mg or 1000 mg × 1 followed by 500 mg or 1000 mg every week, median 3 (range 1–14)\tClinical success at EOT was 28/31 (90%)\tNone reported\t\nEOT end of treatment, SOC standard of care, ADE adverse drug event, AE adverse event, MSSA methicillin susceptible S. aureus, MRSA methicillin-resistant S. aureus, CoNS coagulase negative S. aureus, mITT modified intention to treat, DM diabetes mellitus, SUD substance use disorder, AE adverse event, PJI prosthetic joint infection, ABSSSI acute bacterial skin and skin structure infection, OM osteomyelitis, IE infective endocarditis, CRBSI catheter-related bloodstream infection, IVDU intravenous drug use\n\nTable 4 Proposed criteria for use for dalbavancin\n\n(A) Infection determinants\t1. Invasive infection with gram-positive organism that is microbiologically proven or highly suspected based on previous culturesa,b\n\nOR\n\n2. Skin and soft tissue infection that would otherwise require an extended course of intravenous antibiotic therapyc,b\n\nAND\n\n\t\n(B) Drug determinants\t3. Allergy/intolerance to standard therapy with vancomycin, daptomycin, ceftaroline or linezolid\n\n4. Drug toxicity or interactions that prohibit use of vancomycin, daptomycin, ceftaroline or linezolid\n\nOR\n\n\t\n(C) Social determinants\t6. Recent or active intravenous drug use—history or active\n\n7. Lack of support at home\n\n8. Homelessness\n\n9. Recent or active alcohol abuse\n\n10. Nonadherence to medical care\n\n\t\naThis includes: methicillin susceptible S. aureus, methicillin-resistant S. aureus, Streptococcal spp. and vancomycin-susceptible Enterococcus\n\nbAttention to source control must be made\n\ncSevere cellulitis, failure of high-level oral antibiotics (i.e., linezolid), contraindication to oral options (i.e., concomitant selective serotonin receptor inhibitor and linezolid) and malabsorption/lack of enteral access\n\nThere are published failures and shortcomings of dalbavancin. In one case report, dalbavancin was used for MRSA endocarditis, which resulted in infection relapse and breakthrough bacteremia with vancomycin-intermediate S. aureus (VISA) [22]. The development of VISA was thought to be related to sub-inhibitory dalbavancin exposure and high inoculum infection. Comparatively, in vitro studies have demonstrated increased MICs of S. aureus and CoNS in the presence of sub-inhibitory dalbavancin [23]. It is unclear how this translates to clinical use of dalbavancin, specifically if dosing strategies should be revised based on etiology, but further studies are needed to evaluate the risk of relapse infection in high inoculum infections.\n\nOsteomyelitis was the most common infection type encountered in our study with the lowest 30-day clinical cure (46%), equally owing to the poor follow-up and failures. Lack of source control was the primary reason for failure, as documented by persistently positive margins, wound dehiscence and persistent elevation of inflammatory markers. Dalbavancin has been shown to have high concentrations through day 14 in bone in rat studies, which is promising for clinical application [11]. Rappo et al. performed a randomized clinical trial of dalbavancin in first-episode osteomyelitis treatment and found that patients treated with dalbavancin (1500 mg, 2 doses 1 week apart) had clinical cure at day 42 in 65/67 (97%) versus 7/8 (88%) in standard-of-care patients [13]. These are encouraging data for expanding options for treating osteomyelitis. However, this study had few patients with diabetes mellitus in the dalbavancin group (14.3%) and no patients with underlying substance use disorder. Furthermore, all patients had some degree of debridement. The outcomes of our study suggest that dalbavancin may be a suitable option for osteomyelitis; however, as with many antimicrobials in the setting of osteomyelitis, it is more likely to fail if concomitant source control is not achieved [24].\n\nLow clinical cure rates were also seen for endovascular infections (50%) owing to one patient with failure and two patients who were lost to follow-up; however, there were no relapse infections at day 90. Clinical success was high (93%) in a comparable study in Italy looking at 27 patients with infective endocarditis [15]. Dalbavancin has been shown to have in vitro activity against biofilms of Staphylococci, and there are data to suggest that dalbavancin may be an effective agent in frequent biofilm infections such as endocarditis [25].\n\nA potential niche for dalbavancin is as an alternative therapeutic option to long-term intravenous access and institutional placement. However, if patients fail to return for maintenance dosing or fail to follow up to assess for clinical response as treatment is ongoing, dalbavancin will fall short in filling this therapeutic niche. Brysom-Cohn et al. focused only on the PWID population and described a high loss to follow-up with only 53% (17/32) completing treatment, comparable to our SUD population follow-up of 32% (6/19); however, most of our patients completed the intended treatment course. Nonetheless, these patients had infectious etiologies that traditionally require long-term intravenous antibiotic therapy (> 2 weeks) such as osteomyelitis. As such, the lack of follow-up is problematic given the absence of observation for clinical cure, drug toxicities and recrudescent infection that would determine extension, discontinuation or re-initiation of therapy. It is, therefore, important to recognize nonadherence with therapy and loss to follow-up as significant barriers to successful use of dalbavancin.\n\nSUD and PWID were the most common comorbidities and reason for dalbavancin, respectively. PWIDs are an especially vulnerable patient population that carries a high morbidity risk and places a significant burden on the health care system [26]. Most of the patients lost to follow-up had SUD. Despite this setback, 77% of the clinically evaluable patients with active or history of SUD achieved clinical cure. Thus, dalbavancin offers an alternative treatment option for high-risk patient populations who otherwise are poor candidates for conventional parenteral therapy, provided they followed with treatments. There is much needed improvement in PWID outcomes by applying a multi-disciplinary and co-location strategy that has been successfully used in the treatment of coincident opioid use disorder with hepatitis C and/or HIV infection [27].\n\nIn this study, dalbavancin mostly functioned as a bridge to discharge patients who otherwise would have stayed in the hospital receiving parenteral antibiotics. When compared with a study evaluating the health care cost and utilization of patients with MRSA infection, the length of stay for our study population was lower (8.0 days versus 22.4 days) [28]. Although no formal cost analysis was done, the data from these two centers suggest that this strategy may potentially help to alleviate some health care costs including costs of hospital stay and prolonged subacute rehabilitation stays. Despite these obvious cost savings, access to dalbavancin for off-label use does present a challenge; obtaining insurance coverage can be time consuming and, at times, may lead to interruption in therapy. This was exemplified by one case for which a patient received one dose of the two planned doses of dalbavancin because of a gap in insurance coverage.\n\nThe two cases of nephrotoxicity raise some concerns about renal toxicity with use of dalbavancin. However, conclusions regarding this relationship cannot be made based on these two complicated cases with other contributing causes of AKI. A cumulative effect of doses greater than two and up to seven were otherwise well tolerated. There was no evidence of hepatotoxicity or cytopenias. These study results reinforce that weekly outpatient laboratory monitoring, to include renal function, is recommended.\n\nBased on our experience with dalbavancin at these two different medical centers, we offer criteria for use (Table 4) that have been adapted into our clinical decision support by antimicrobial stewardship and OPAT programs. Dalbavancin offers alternative treatment for select circumstances that should be carefully considered. Infection determinants are required for dalbavancin candidacy, followed by either a drug determinant (i.e., drug-drug interaction with an alternative) or social determinant (i.e., PWID). By following these criteria for use, inappropriate prescribing of dalbavancin can be limited. Implementation and validation of these proposed criteria for use need to be conducted.\n\nThis study has several advantages, including a predominant representation of the PWID and SUD population and the high prevalence of MRSA. We also provide an example of criteria for use that can be adapted by other institutions and summary of the literature. However, due to the small sample size and study design, the overall generalizability is low. There are several other limitations of our study. As a retrospective study, there can be information bias leading to differential misclassification. There is no comparator group, and therefore we are unable to make any conclusions regarding effectiveness against standard of care. Additionally, most patients were on standard of care therapy before starting dalbavancin with the majority completing at least 1 week of antibiotics prior to dalbavancin. Clinical response during that time was not evaluated in our study. Thus, the impact of dalbavancin on clinical cure could not be evaluated separately from the clinical benefits provided by previous antimicrobials. Retention of care was another limitation of our study. Notably, patients at UMMC had higher loss to follow-up at 30 days compared with VAHMCS (42% versus 12%). This may be in part because OPAT at UMMC is newly established and has less coordinated care and oversight compared with VAHMCS. The difference in coordinated care and follow-up between the two OPAT programs further highlights the importance of OPAT programs for all long-term parenteral antibiotic therapies including dalbavancin. Multidisciplinary OPAT coordination is an integral component of successful dalbavancin treatment in these high-risk patients.\n\nConclusion\n\nIn conclusion, this study describes two centers’ experience with dalbavancin, suggesting a possible role for dalbavancin in the treatment of non-ABSSSI invasive gram-positive infections. In carefully selected patients and with OPAT oversight, we propose dalbavancin as an alternative to long-term daily intravenous antibiotic therapy in invasive gram-positive infections, but more experience and investigation are needed.\n\nAcknowledgements\n\nFunding\n\nNo funding or sponsorship was received for this study or publication of this article.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole and have given their approval for this version to be published.\n\nPrior Presentation\n\nThis work was presented previously at ASM Microbe 2018 in Atlanta, GA, 7 June 2018 (poster).\n\nDisclosures\n\nJacqueline T. Bork, Emily L. Heil, Shanna Berry, Eurides Lopes, Rohini Davé, Bruce L. Gilliam and Anthony Amoroso have nothing to disclose.\n\nCompliance with Ethics Guidelines\n\nThe study was approved with a waiver of informed consent in an expedited review by the University of Maryland, Baltimore, Institutional Review Board, which oversees both UMMC and VAMHCS facilities. This study was also performed in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\n\nEnhanced digital features\n\nTo view enhanced digital features for this article go to 10.6084/m9.figshare.8006438.\n==== Refs\nReferences\n\n1. Noskin GA Rubin RJ Schentag JJ Kluytmans J Hedblom EC Smulders M The burden of Staphylococcus aureus infections on hospitals in the United States Arch Intern Med 2005 165 1756 1761 10.1001/archinte.165.15.1756 16087824\n2. 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Molina Collada J Rico Nieto A de Bustamante Díaz Ussia M Balsa Criado A Artritis séptica de rodilla nativa por Corynebacterium striatum Reumatol Clín 2017 14 301 302 10.1016/j.reuma.2017.01.013 28283311\n15. Tobudic S Forstner C Burgmann H Lagler H Ramharter M Steininger C Dalbavancin as primary and sequential treatment for gram-positive infective endocarditis: 2-year experience at the General Hospital of Vienna Clin Infect Dis 2018 67 795 798 10.1093/cid/ciy279 29659732\n16. Bouza E Valerio M Soriano A Morata L Carus EG Rodríguez-González C Dalbavancin in the treatment of different gram-positive infections: a real-life experience Int J Antimicrob Agents 2018 51 571 577 10.1016/j.ijantimicag.2017.11.008 29180276\n17. Wunsch S Krause R Valentin T Prattes J Janata O Lenger A Multicenter clinical experience of real life Dalbavancin use in gram-positive infections Int J Infect Dis 2019 81 210 214 10.1016/j.ijid.2019.02.013 30794940\n18. Bryson-Cahn C, Beieler AM, Chan JD, Harrington RD, Dhanireddy S. Dalbavancin as secondary therapy for serious Staphylococcus aureus infections in a vulnerable patient population. Open Forum Infect Dis. 2019 [cited 2019 Mar 6]; 6. Available from: https://academic.oup.com/ofid/article/6/2/ofz028/5304406.\n19. Morata L, Cobo J, Fernández-Sampedro M, Vasco PG, Ruano E, Lora-Tamayo J, et al. Safety and efficacy of prolonged use of dalbavancin in bone and joint infections. Antimicrob Agents Chemother. 2019;AAC.02280-18, aac;AAC.02280-18v1.\n20. Almangour TA Perry GK Terriff CM Alhifany AA Kaye KS Dalbavancin for the management of gram-positive osteomyelitis: effectiveness and potential utility Diagn Microbiol Infect Dis 2019 93 213 218 10.1016/j.diagmicrobio.2018.10.007 30396697\n21. Gonzalez-Ruiz A Gargalianos-Kakolyris P Timerman A Sarma J José González Ramallo V Bouylout K Daptomycin in the clinical setting: 8-year experience with gram-positive bacterial infections from the EU-CORE(SM) registry Adv Ther 2015 32 496 509 10.1007/s12325-015-0220-6 26108157\n22. Steele JM Seabury RW Hale CM Mogle BT Unsuccessful treatment of methicillin-resistant Staphylococcus aureus endocarditis with dalbavancin J Clin Pharm Ther 2018 43 101 103 10.1111/jcpt.12580 28628223\n23. Kim A Kuti JL Nicolau DP Review of dalbavancin, a novel semisynthetic lipoglycopeptide Expert Opin Investig Drugs 2007 16 717 733 10.1517/13543784.16.5.717\n24. Spellberg B Lipsky BA Systemic antibiotic therapy for chronic osteomyelitis in adults Clin Infect Dis 2012 54 393 407 10.1093/cid/cir842 22157324\n25. Fernández J Greenwood-Quaintance KE Patel R In vitro activity of dalbavancin against biofilms of staphylococci isolated from prosthetic joint infections Diagn Microbiol Infect Dis 2016 85 449 451 10.1016/j.diagmicrobio.2016.05.009 27241369\n26. Collier MG Doshani M Asher A Using population based hospitalization data to monitor increases in conditions causing morbidity among persons who inject drugs J Community Health 2018 43 598 603 10.1007/s10900-017-0458-9 29305727\n27. Treloar C Rance J Grebely J Dore GJ Client and staff experiences of a co-located service for hepatitis C care in opioid substitution treatment settings in New South Wales, Australia Drug and Alcohol Depend 2013 133 529 534 10.1016/j.drugalcdep.2013.07.023\n28. Nelson RE Jones M Liu CF Samore MH Evans ME Graves N The impact of healthcare-associated methicillin-resistant Staphylococcus aureus infections on post-discharge healthcare costs and utilization Infect Control Hosp Epidemiol 2015 36 534 542 10.1017/ice.2015.22 25715806\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2193-6382",
"issue": "8(2)",
"journal": "Infectious diseases and therapy",
"keywords": "Dalbavancin; Outpatient parenteral antibiotic therapy; Substance use disorder",
"medline_ta": "Infect Dis Ther",
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"nlm_unique_id": "101634499",
"other_id": null,
"pages": "171-184",
"pmc": null,
"pmid": "31054088",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "15668859;16087824;17461743;18251665;18462089;20864497;21208910;22157324;23932843;25715806;26108157;26183753;26518048;27241369;28283311;28628223;28638844;28706403;29180276;29305727;29659732;29766017;30396697;30551156;30648126;30794940;30838225;30858217",
"title": "Dalbavancin Use in Vulnerable Patients Receiving Outpatient Parenteral Antibiotic Therapy for Invasive Gram-Positive Infections.",
"title_normalized": "dalbavancin use in vulnerable patients receiving outpatient parenteral antibiotic therapy for invasive gram positive infections"
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"abstract": "During the coronavirus disease 2019 (Covid-19) pandemic, several physicians have questioned pursuing belatacept in kidney-transplant patients in order to reduce the risk of nosocomial transmission during the monthly infusion. The effect of the conversion from belatacept to another immunosuppressive regimen is underreported. The aim of the present retrospective study was to assess the effect on kidney function and the clinical outcome of the conversion from belatacept to another regimen.\nWe have identified 44 maintenance kidney transplantation patients from five French kidney transplantation centers who were converted from belatacept to another regimen either because of a complication (n = 28) or another reason (patients' request or belatacept shortage, n = 13). The follow-up after the conversion from belatacept was 27.5 ± 25.3 months.\nOverall, mean estimated glomerular filtration rate (eGFR) decreased from 44.2 ± 16 ml/min per 1.73 m2 at conversion from belatacept to 35.7 ± 18.4 ml/min per 1.73 m2 at last follow-up (P = 0.0002). eGFR significantly decreased in patients who had been given belatacept at transplantation as well as in those who had been converted to belatacept earlier. The decrease was less significant in patients who had stopped belatacept without having experienced any complications. Finally, eGFR decreased more severely in patients who were converted to calcineurin inhibitors (CNIs), compared to those who received mammalian target of rapamycin inhibitor (mTORi). Few patients also developed diabetes and hypertension.\nThus, transplantation physicians should avoid stopping belatacept when not clinically required.",
"affiliations": "Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.;Service de néphrologie-Transplantation, Hôpital Necker, AP-HP, Paris et Université Paris Descartes, Paris.;Service de néphrologie, dialyse et transplantation rénale, FHU INCREASE, CHU de Besançon, Besançon, France.;Service de néphrologie, dialyse et transplantation rénale, CHU de Rouen, Rouen, France.;Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.;Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.;Service de néphrologie, dialyse et transplantation rénale, FHU INCREASE, CHU de Besançon, Besançon, France.;Service de néphrologie-Transplantation, Hôpital Necker, AP-HP, Paris et Université Paris Descartes, Paris.;Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.",
"authors": "Gouin|Anna|A|;Sberro-Soussan|Rebecca|R|;Courivaud|Cécile|C|;Bertrand|Dominique|D|;Del Bello|Arnaud|A|;Darres|Amandine|A|;Ducloux|Didier|D|;Legendre|Christophe|C|;Kamar|Nassim|N|",
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"doi": "10.1016/j.ekir.2020.09.036",
"fulltext": "\n==== Front\nKidney Int Rep\nKidney Int Rep\nKidney International Reports\n2468-0249 Elsevier \n\nS2468-0249(20)31552-7\n10.1016/j.ekir.2020.09.036\nClinical Research\nConversion From Belatacept to Another Immunosuppressive Regimen in Maintenance Kidney-Transplantation Patients\nGouin Anna 1 Sberro-Soussan Rebecca 2 Courivaud Cécile 3 Bertrand Dominique 4 Del Bello Arnaud 15 Darres Amandine 1 Ducloux Didier 3 Legendre Christophe 2 Kamar Nassim kamar.n@chu-toulouse.fr156∗ 1 Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France\n2 Service de néphrologie-Transplantation, Hôpital Necker, AP-HP, Paris et Université Paris Descartes, Paris\n3 Service de néphrologie, dialyse et transplantation rénale, FHU INCREASE, CHU de Besançon, Besançon, France\n4 Service de néphrologie, dialyse et transplantation rénale, CHU de Rouen, Rouen, France\n5 INSERM U1043, IFR–BMT, CHU Purpan, Toulouse, France\n6 Université Paul Sabatier, Toulouse, France\n∗ Correspondence: Nassim Kamar, Department of Nephrology and Organ Transplantation, CHU Rangueil, TSA 50032, 31059 Toulouse Cedex 9, France. kamar.n@chu-toulouse.fr\n06 10 2020 \n12 2020 \n06 10 2020 \n5 12 2195 2201\n4 6 2020 22 8 2020 15 9 2020 © 2020 International Society of Nephrology. Published by Elsevier Inc.2020International Society of NephrologyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nDuring the coronavirus disease 2019 (Covid-19) pandemic, several physicians have questioned pursuing belatacept in kidney-transplant patients in order to reduce the risk of nosocomial transmission during the monthly infusion. The effect of the conversion from belatacept to another immunosuppressive regimen is underreported. The aim of the present retrospective study was to assess the effect on kidney function and the clinical outcome of the conversion from belatacept to another regimen.\n\nMethods\nWe have identified 44 maintenance kidney transplantation patients from five French kidney transplantation centers who were converted from belatacept to another regimen either because of a complication (n = 28) or another reason (patients’ request or belatacept shortage, n = 13). The follow-up after the conversion from belatacept was 27.5 ± 25.3 months.\n\nResults\nOverall, mean estimated glomerular filtration rate (eGFR) decreased from 44.2 ± 16 ml/min per 1.73 m2 at conversion from belatacept to 35.7 ± 18.4 ml/min per 1.73 m2 at last follow-up (P = 0.0002). eGFR significantly decreased in patients who had been given belatacept at transplantation as well as in those who had been converted to belatacept earlier. The decrease was less significant in patients who had stopped belatacept without having experienced any complications. Finally, eGFR decreased more severely in patients who were converted to calcineurin inhibitors (CNIs), compared to those who received mammalian target of rapamycin inhibitor (mTORi). Few patients also developed diabetes and hypertension.\n\nConclusions\nThus, transplantation physicians should avoid stopping belatacept when not clinically required.\n\nGraphical abstract\nKeywords\nbelataceptcalcineurin inhibitorconversiondonor-specific antibodykidney functionsafety\n==== Body\nSee Commentary on Page 2123\n\n\n\nAlthough CNI-based immunosuppression has dramatically improved the outcome of kidney transplantation, its use is responsible for nephrotoxicity and increased risk for tumoral proliferation. This has prompted transplantation physicians to try using CNI-free regimens. An mTORi CNI-free regimen was used in de novo and maintenance kidney transplantation patients.1, 2, 3 It was associated with significantly improved kidney function in patients who tolerated this therapy compared to those who remained on CNI-based therapy.1, 2, 3 However, mTOR inhibitor CNI-free regimens were associated with an increased risk of occurrence of acute rejection and de novo donor-specific anti–human leukocyte antibodies (DSAs).4, 5, 6 Thus, they are now rarely used. Conversely, CNI-avoiding regimens based on the use of belatacept were confirmed to be effective in preventing acute rejection and safe after kidney transplantation.7,8 In de novo kidney transplantation patients, long-term use of belatacept was associated with better kidney function and an increase in patient and graft survivals compared to patients who were given cyclosporin A–based immunosuppression.9 In maintenance kidney transplantation patients, several studies, including a phase II trial and a large retrospective real-life study, have shown that the conversion from CNI to belatacept leads to an improvement in kidney function.10,11\n\nTo our knowledge, the effect on kidney function and the clinical outcome of the conversion from belatacept to another regimen has not been assessed. Thus, this was the aim of the present retrospective study.\n\nPatients and Methods\nWe have identified 44 maintenance kidney transplantation patients from five French kidney transplantation centers who were converted from belatacept: Besançon University Hospital (n = 10), Necker University Hospital (Paris, France) (n = 15), Rouen University Hospital (n = 1), and Toulouse University Hospital (France) (n = 18). Conversion was conducted between December 2006 and June 2018. The 44 patients had been given belatacept + mycophenolic acid (MPA) + steroids (S) (n = 37), belatacept + MPA (n = 2), or belatacept + mTORi S (n = 5) for 14 (2–137) months. Fourteen patients (31.8%) had been given de novo belatacept at transplantation, and 30 patients had been converted at 7.2 (0.6 to 223) months from CNI to belatacept for impaired kidney function and/or histology (n = 29) or post-transplantation diabetes mellitus (n = 1). All 14 de novo kidney transplantation patients were given belatacept + MPA + S. For the 30 patients who were converted to belatacept, initial immunosuppression was based on CNI + MPA + S (n = 11), CNI + MPA + mTORi + S (n = 2), or CNI + mTORi + S (n = 3). The patients’ characteristics at and before conversion from belatacept to other immunosuppressive regimens are presented in Table 1. No specific antimicrobial prophylaxis was given after conversion from belatacept.Table 1 Patients’ characteristicsa\n\nVariables\tNumbers\t\nCharacteristics at transplantation\tN = 44\t\n Recipients’ sex: male\t27 (61.4)\t\n Deceased donor\t36 (81.8)\t\n Rank of transplantation (first/second)\t41/3\t\n Initial kidney disease\t\t\n Glomerulopathy\t18 (40.9)\t\n Interstitial nephropathy\t7 (15.9)\t\n Diabetes mellitus and/or nephroangiosclerosis\t4 (9.1)\t\n Genetic disease\t7 (15.9)\t\n Other\t8 (18.2)\t\n EBV serostatus\t\t\n Donor positive/recipient positive\t42 (95.4)\t\n Donor negative/recipient positive\t1 (2.3)\t\n Donor positive/recipient negative\t1 (2.3)\t\nImmunologic recipient status\t\t\n Anti-HLA antibodies at kidney transplantation\t8 (18.2)\t\n Donor-specific antibodies at kidney transplantation\t5 (11.4)\t\n Donor-specific antibodies at conversion to belatacept\t4 (9.3)\t\nStart of belatacept\t\t\n Age upon starting belatacept (years)\t54.8 ± 13\t\n De novo belatacept/conversion to belatacept\t14 (13.6)/30 (68.2)\t\n Time from transplantation to conversion to belatacept (months)\t7.2 (0.6 to 223)\t\n Induction therapy at transplantation\t\t\n Anti-interleukin 2 receptor blocker\t34 (77.3)\t\n Polyclonal antibodies\t6 (13.6)\t\n None\t4 (9.1)\t\n Calcineurin inhibitors before conversion to belatacept\tn = 30\t\n Cyclosporine A\t3 (10)\t\n Tacrolimus\t27 (90)\t\n mTORi-based therapy before conversion to belatacept\t5 (16.7)\t\n MPA before conversion to belatacept\t27 (90)\t\n Steroids before conversion to steroids\t30 (100)\t\nEBV, Epstein-Barr virus; HLA, human leukocyte antibody; MPA, mycophenolic acid; mTORi, mammalian target of rapamycin inhibitor.\n\na Values shown are n (%) unless otherwise stated.\n\n\n\nKidney parameters were assessed at conversion to belatacept (in the 30 patients who were converted to belatacept) 6 and 3 months before the conversion from belatacept, at conversion from belatacept, and at 3, 6, and 12 months after conversion, as well as at the last follow-up. eGFR was estimated using the abbreviated Modification of the Diet in Renal Disease formula. In all centers, DSAs were assessed yearly or in case of impaired kidney function and/or increased proteinuria. Efficacy and safety parameters were assessed after the conversion from belatacept until last follow-up (i.e., 27.5 ± 25.3 months [median 20 (6–138) months]).\n\nAccording to French law (Loi Jardé), anonymous retrospective studies do not require Institutional Review Board approval. In each center, patients were identified and data were obtained from the local database, and then electronic medical records were shared by all institutions.\n\nStatistical Analyses\nReported values represent either means (±SD) or medians (ranges). Proportions were compared by the chi square test or Fisher exact test. The nonparametric Friedman test for serial measurements was used to compare quantitative variables. The Student t test was used to compare quantitative variables. A P < 0.05 was considered statistically significant.\n\nResults\nConversion From Belatacept\nBelatacept was stopped in 44 patients. The descriptions of baseline characteristics for all patients as well as their outcomes are presented in Supplementary Table S1. They had been given belatacept for 14 (2–137) months. Their mean age at conversion from belatacept was 57 ± 12.6 months. The reasons for stopping belatacept are detailed in Table 2 and Supplementary Table S1. In 28 patients (63.6%), it was stopped because of a complication; in 13 patients, it was ceased without patients having experienced any complications; and in the last 3 patients, belatacept was interrupted because no improvement in kidney function was observed. In 34 patients, belatacept was replaced by a CNI-based regimen, and 10 patients were given an mTORi-CNI-free–based regimen. Post-conversion from belatacept immunosuppression was as follows: CNI + MPA ± S (n = 21, 47.7%), CNI + mTORi ± S (n = 7, 15.9%), CNI + azathioprine ± S (n = 3, 6.8%), CNI + S (n = 3, 6.8%), mTORi + MPA ± S (n = 8, 18.2%), and mTORi + azathioprine ± S (n = 2, 4.6%). Tacrolimus was the most commonly used CNI after belatacept cessation (94%). Its median trough level was 6 (4 to 8) ng/ml. Everolimus was the most commonly used mTORi after belatacept cessation. Its median trough level was 3 (2 to 6) ng/ml when associated with CNI and 5 (4 to 8) ng/ml when given without CNI.Table 2 Reasons for conversion from belatacept\n\nReasoning\tN = 44\t\nConversion for a complication\tn = 28\t\n Infectionsa\t15\t\n CMV\t13\t\n Human herpes virus 8\t1\t\n BK virus\t1\t\n Acute rejection\t7\t\n T-cell–mediated rejection\t5\t\n Antibody-mediated rejection\t1\t\n Mixed T-cell and antibody-mediated rejection\t1\t\n T-cell–mediated rejection and CMV infection\t1\t\n Colon cancer\t2\t\n T-lymphoma and human papilloma virus infection\t1\t\n No improvement in kidney function and recurrent CMV infection\t1\t\n No improvement in kidney function and BK virus infection\t1\t\nConversion without a complication\tn = 13\t\n Belatacept shortage\t5\t\n Patients’ request\t7\t\n Improvement in kidney function\t1\t\nNo improvement in kidney function after conversion to belatacept\tn = 3\t\nCMV, cytomegalovirus.\n\na Among patients who were converted from belatacept because of a complication, CMV replication persisted in patients having resistant CMV infection (n = 3) whereas no CMV replication recurrence occurred in the nine remaining patients. All other viruses were cleared after conversion from belatacept.\n\n\n\nKidney Function Outcome\nOverall, in the whole population (N = 44), eGFR decreased after belatacept cessation (P = 0.0002). Mean eGFR decreased from 44.2 ± 16 ml/min per 1.73 m2 at conversion from belatacept to 39.3 ± 18.5 ml/min per 1.73 m2 at 12 months post-conversion (P = 0.01), and 35.7 ± 18.4 ml/min per 1.73 m2 at last follow-up (P = 0.0002) (Figure 1a). eGFR decreased in 29 patients (66%), remained stable in 8 patients (18%), and improved in 7 patients (16%). Proteinuria remained unchanged (i.e., 0.09 [0 to 2.1] g/d at conversion from belatacept vs. 0.13 [0 to 1.7] g/d at last follow-up; P = 0.27).Figure 1 Outcome of kidney function before and after conversion from belatacept. (a) In the whole population (n = 44). (b) In de novo kidney transplantation patients who were given belatacept (n = 14). (c) In maintenance kidney transplantation patients who were converted to belatacept earlier (n = 30). (d) In patients who stopped belatacept without experiencing a complication (n = 13). eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease.\n\n\n\nBecause some patients were given belatacept at transplantation (de novo patients) whereas others were converted to belatacept mainly because of impaired kidney function and/or histology, and because in some patients belatacept was ceased due to complications that can negatively impact kidney function, we have analyzed the outcome of different subgroups of patients separately.\n\nDe novo Kidney-Transplantation Patients Who Were Given Belatacept\nFourteen patients who were given belatacept immediately after transplantation stopped it 12.5 (3 to 137) months later. The mean follow-up after conversion from belatacept was 41.5 ± 38.4 months. eGFR decreased after belatacept cessation (P = 0.054). Mean eGFR decreased from 51.4 ± 16.6 ml/min per 1.73 m2 at conversion from belatacept to 44.5 ± 18.6 ml/min per 1.73 m2 at 12 months post-conversion (P = 0.03), and 43.3 ± 19.4 ml/min per 1.73 m2 at last follow-up (P = 0.03) (Figure 1b).\n\nMaintenance Kidney Transplantation Patients Who Were Converted to Belatacept\nThirty patients were converted to belatacept at 7.2 (0.6 to 223) months. The mean follow-up after conversion from belatacept was 21 ± 13.1 months. eGFR decreased after belatacept was stopped (P = 0.0009). Mean eGFR initially improved from 32.4 ± 13.6 ml/min per 1.73 m2 at conversion to belatacept to 40.8 ± 14 ml/min per 1.73 m2 at conversion from belatacept (P = 0.004). Thereafter, it decreased to 36.9 ± 18.7 ml/min per 1.73 m2 at 12 months post-conversion from belatacept (P = 0.035) and 32.1 ± 17.4 ml/min per 1.73 m2 at last follow-up (P = 0.0002) (Figure 1c).\n\nPatients Who Stopped Belatacept Without Experiencing a Complication\nThirteen patients stopped belatacept because of the shortage of belatacept that occurred 3 years ago (n = 5), upon their request (n = 7), or because kidney function had improved after the initiation of belatacept given because of prolonged delayed graft function (n = 1). The mean follow-up after conversion from belatacept was 27.9 ± 21.9 months. Overall, no significant change was observed in eGFR (P = 0.3). Mean eGFR decreased from 56.4 ± 15.6 ml/min per 1.73 m2 at conversion from belatacept to 47.7 ± 20 ml/min per 1.73 m2 at last follow-up (P = 0.07) (Figure 1d).\n\nPatients Who Were Converted From Belatacept to CNIs\nThirty-four patients were converted from belatacept to a CNI-based regimen. eGFR decreased after belatacept cessation (P = 0.001). Mean eGFR decreased from 44.1 ± 15.3 ml/min per 1.73 m2 at conversion from belatacept to 38.9 ± 19.5 ml/min per 1.73 m2 at 12 months post-conversion (P = 0.006) and 34.8 ± 18.9 ml/min per 1.73 m2 at last follow-up (P < 0.0001) (Figure 2a).Figure 2 Outcome of kidney function before and after conversion from belatacept. (a) In patients who were converted from belatacept to calcineurin inhibitors (n = 34). (b) In patients who were converted from belatacept to mTORi (n = 10). eGFR, estimated glomerular filtration rate; mTORi, mammalian target of rapamycin inhibitor.\n\n\n\nPatients Who Were Converted from Belatacept to mTORi\nTen patients were converted from belatacept to an mTORi-based regimen. No significant change in eGFR was observed after belatacept stop (P = 0.17). Mean eGFR decrease was at 44.6 ± 17.4 ml/min per 1.73 m2 at conversion from belatacept, 40.7 ± 16.8 ml/min per 1.73 m2 at 12 months post-conversion (P = 0.22), and 38.5 ± 18.3 ml/min per 1.73 m2 at last follow-up (P = 0.2) (Figure 2b).\n\nImmunological and Kidney Allograft Outcomes After Conversion From Belatacept\nOnly one patient, who was given CNI + MPA + S, developed a de novo DSA (2.3%) 6 months after conversion from belatacept that led to antibody-mediated rejection and graft loss. Another patient who had a DSA at conversion to belatacept developed chronic antibody-mediated rejection. A third patient experienced a T-cell–mediated rejection 16 months after conversion from belatacept. Thus, overall, 3 patients (6.8%) developed an acute rejection after belatacept cessation. Four patients (9.1%) lost their graft during follow-up: the first patient because of chronic antibody-mediated rejection, the second patient due to the development of the acute antibody-mediated rejection, the third one due to poor kidney function and severe interstitial fibrosis/tubular atrophy, and the last patient because of a cardiorenal syndrome. After the exclusion of patients who presented an acute rejection and/or a graft loss (n = 5), eGFR significantly decreased in the remaining 39 patients from 46.1 ± 14.6 ml/min per 1.73 m2 at conversion to 39.3 ± 16.2 ml/min per 1.73 m2 at last follow-up (P = 0.0002).\n\nClinical Outcomes After Conversion From Belatacept\nDuring follow-up, 10 patients (22.3%) experienced an infectious episode: cytomegalovirus replication (n = 3), flu (n = 2), norovirus infection (n = 1), pneumocystis jiroveci pneumonitis (n = 1), pyelonephritis (n = 2), and arthritis (n = 1).\n\nEight patients (18.2%) developed de novo cancer after conversion from belatacept: 6 patients developed skin cancer 4 to 66 months after conversion form belatacept; one patient presented lung cancer 11 months after conversion from belatacept; and one patient developed an Epstein-Barr virus–positive cerebral post-transplant lymphoproliferative disease 12 months after the conversion from belatacept.\n\nTwo patients (4.5%) developed de novo diabetes mellitus 1 and 3 months after belatacept cessation.\n\nTwo patients (4.5%) developed de novo hypertension 1 and 3 months after the conversion from belatacept, whereas a worsening of hypertension defined by adding antihypertension medications was observed in 10 other patients (22.7%).\n\nFinally, 6 patients (13.6%) died during follow-up with a functioning graft. The causes for death were colon cancer (n = 1), lung cancer (n = 1), cerebral post-transplant lymphoproliferative disease (n = 1), stroke (n = 1), vascular dementia (n = 1), and acute respiratory distress syndrome due to flu virus (n = 1).\n\nDiscussion\nThe effect of the conversion from belatacept to another immunosuppressive regimen is underreported. The aim of the present retrospective study was to assess the effect on kidney function and the clinical outcome of the conversion from belatacept to another regimen. Our findings were threefold: (1) the conversion from belatacept to another regimen was associated with a decrease in eGFR of ∼8 ml/min per 1.73 m2; (2) the decrease was less significant in patients who were converted from belatacept for a reason that was not a complication, and in those who were converted to an mTORi-based CNI-free regimen; and (3) some patients developed diabetes and hypertension after conversion from belatacept.\n\nIn maintenance kidney transplantation patients, a phase II randomized controlled study showed an improvement in kidney function at 1 year in patients converted to belatacept (that was administrated with MPA and S) compared to those who were maintained on CNI (7 ± 11.99 ml/min per 1.73 m2).12 This gain was maintained at 3 years (i.e., +1.9 ml/min per 1.73 m2 per year).10 In a large retrospective real-life European multicenter study that included 219 maintenance kidney transplantation patients, mean eGFR significantly increased from 32 ± 16.4 ml/min per 1.73 m2 at conversion to belatacept to 38 ± 20 ml/min per 1.73 m2 at 21.9 ± 20.2 months later.11 In the present study, we observed another way that eGFR decreases by ∼8 ml/min per 1.73 m2 after conversion from belatacept. This decrease was observed in patients who had received belatacept at transplantation and in those who had been converted to belatacept earlier because of impaired kidney function and/or histology.\n\nIn nearly two-thirds of patients, belatacept was stopped because of a complication, mainly because of a viral infection. It was recently shown that cytomegalovirus infection is the main opportunistic infection observed in belatacept-treated kidney transplantation patients.13,14 Conversely, in 30% of patients, belatacept was stopped either at the patients’ request or because of belatacept shortage. In these patients in whom belatacept was stopped without having experienced any complication, eGFR also decreased from 56.4 ± 15.6 ml/min per 1.73 m2 at conversion from belatacept to 47.7 ± 20 ml/min per 1.73 m2 at last follow-up (P = 0.07). Because of the small number of patients, the decrease in eGFR was not statistically significant. An improvement in eGFR was observed in 7 patients after belatacept cessation. Most of them were converted because of a complication. Thus, we speculate that the improvement is related to the resolution of the complication.\n\nThe improvement in kidney function after stopping CNI was often attributed to the loss of CNI-associated intrarenal vasoconstriction.15 In the present study, in patients converted from belatacept to CNI, eGFR decreased from 44.1 ± 15.3 ml/min per 1.73 m2 to 34.8 ± 18.9 ml/min per 1.73 m2 at last follow-up (P < 0.0001), whereas in those converted from belatacept to an mTORi-based CNI-free regimen, no significant change in eGFR was observed (i.e., 44.6 ± 17.4 ml/min per 1.73 m2 at conversion from belatacept and 38.5 ± 18.3 ml/min per 1.73 m2 at last follow-up; P = 0.2). Thus, after belatacept cessation, a lesser eGFR decrease was observed in patients who stopped it without having experienced a complication and in patients who were given mTORi without CNI. Although the risk of de novo DSAs is increased in kidney transplantation patients who receive the latter combination,4,5 several studies have shown improved kidney function in patients given an mTORi-based therapy compared to those on CNI-based immunosuppression.\n\nThe use of belatacept was associated with a decreased risk of metabolic syndrome, post-transplant diabetes mellitus, and hypertension.16,17 In the present study, some patients developed de novo diabetes and de novo hypertension in the first 3 months after conversion from belatacept.\n\nThere are several limitations for the present study. It is retrospective uncontrolled study that included a small number of patients. The evolution of eGFR should be interpreted with caution because in 28 of 44 patients, belatacept was stopped because of a complication that could have had a negative impact on kidney function. Finally, we acknowledge the lack of kidney allograft histology at conversion from belatacept and at last follow-up.\n\nIn summary, ceasing belatacept is associated with a significant decrease in kidney function.\n\nDisclosure\nDD has received grants from Astellas and Neovii. CL has received lecture fees from Astellas, Novartis, Chiesi, CSL Behring, and Hansa Medical, and travel grants from Astellas, CSL Behring, and Alexion. NK has received lecture fees from Astellas, Novartis, Gilead, Neovii, MSD, Octapharma, and Amgen, and travel grants from Astellas, CSL Behring, Novartis, and Alexion. All the other authors declared no competing interests.\n\nAuthor Contributions\nAG collected the data from Toulouse, pooled the data from all centers, and wrote the paper. RS-S and CL collected the data from Necker Hospital and reviewed the paper. CC and DD collected the data from Besançon Hospital and reviewed the paper. DB collected the data from Rouen Hospital and reviewed the paper. ADB and AD reviewed the paper. NK designed the study, did the statistical analyses, and wrote the paper.\n\nSupplementary Material\nSupplementary File (PDF)\n \n\nSupplementary File (PDF)\n\nSupplementary Table S1. Clinical course of all 44 patients who were included in the study.\n==== Refs\nReferences\n1 Flechner S.M. Kurian S.M. Solez K. De novo kidney transplantation without use of calcineurin inhibitors preserves renal structure and function at two years Am J Transplant 4 2004 1776 1785 15476476 \n2 Campistol J.M. Eris J. Oberbauer R. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation J Am Soc Nephrol 17 2006 581 589 16434506 \n3 Budde K. Becker T. Arns W. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial Lancet 377 2011 837 847 21334736 \n4 Liefeldt L. Brakemeier S. Glander P. Donor-specific HLA antibodies in a cohort comparing everolimus with cyclosporine after kidney transplantation Am J Transplant 12 2012 1192 1198 22300538 \n5 Kamar N. Del Bello A. Congy-Jolivet N. Incidence of donor-specific antibodies in kidney transplant patients following conversion to an everolimus-based calcineurin inhibitor-free regimen Clin Transplant 27 2013 455 462 23621682 \n6 Rostaing L. Hertig A. Albano L. Fibrosis progression according to epithelial-mesenchymal transition profile: a randomized trial of everolimus versus CsA Am J Transplant 15 2015 1303 1312 25808994 \n7 Vincenti F. Charpentier B. Vanrenterghem Y. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study) Am J Transplant 10 2010 535 546 20415897 \n8 Durrbach A. Pestana J.M. Pearson T. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study) Am J Transplant 10 2010 547 557 20415898 \n9 Vincenti F. Rostaing L. Grinyo J. Belatacept and long-term outcomes in kidney transplantation N Engl J Med 374 2016 333 343 26816011 \n10 Grinyo J.M. Del Carmen Rial M. Alberu J. Safety and efficacy outcomes 3 years after switching to belatacept from a calcineurin inhibitor in kidney transplant recipients: results from a phase 2 randomized trial Am J Kidney Dis 69 2017 587 594 27889299 \n11 Darres A. Ulloa C. Brakemeier S. Conversion to belatacept in maintenance kidney transplant patients: a retrospective multicenter european study Transplantation 102 2018 1545 1552 29570163 \n12 Rostaing L. Massari P. Garcia V.D. Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study Clin J Am Soc Nephrol 6 2011 430 439 21051752 \n13 Bertrand D. Chavarot N. Gatault P. Opportunistic infections after conversion to belatacept in kidney transplantation Nephrol Dial Transplant 35 2020 336 345 32030416 \n14 Karadkhele G. Hogan J. Magua W. CMV high-risk status and posttransplant outcomes in kidney transplant recipients treated with belatacept Am J Transplant 2020 10.1111/ajt.16132 \n15 Shihab F.S. Cyclosporine nephropathy: pathophysiology and clinical impact Semin Nephrol 16 1996 536 547 9125798 \n16 Vanrenterghem Y. Bresnahan B. Campistol J. Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies) Transplantation 91 2011 976 983 21372756 \n17 Rostaing L. Neumayer H.H. Reyes-Acevedo R. Belatacept-versus cyclosporine-based immunosuppression in renal transplant recipients with pre-existing diabetes Clin J Am Soc Nephrol 6 2011 2696 2704 21921152\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2468-0249",
"issue": "5(12)",
"journal": "Kidney international reports",
"keywords": "belatacept; calcineurin inhibitor; conversion; donor-specific antibody; kidney function; safety",
"medline_ta": "Kidney Int Rep",
"mesh_terms": null,
"nlm_unique_id": "101684752",
"other_id": null,
"pages": "2195-2201",
"pmc": null,
"pmid": "33305112",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
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"title": "Conversion From Belatacept to Another Immunosuppressive Regimen in Maintenance Kidney-Transplantation Patients.",
"title_normalized": "conversion from belatacept to another immunosuppressive regimen in maintenance kidney transplantation patients"
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"abstract": "Adoptive immunotherapy against viral infections is a promising treatment option for patients after hematopoietic stem cell transplantation. However, the generation of virus-specific T cells is either cost-intensive or time-consuming. We developed the first GMP-compliant protocol to generate donor-derived adenovirus (HAdV), cytomegalovirus, and Epstein-Barr virus-specific T-cell lines (TCLs) within 12 days by the use of overlapping polypeptides derived from different viruses in combination with IL-15. Two patients after undergoing haploidentical hematopoietic stem cell transplantation with HAdV viremia displaying rising viral loads despite treatment with cidofovir received 1×10 donor-derived short-term expanded HAdV-specific TCLs per kg body weight. In both patients, HAdV-specific T cells could be detected by IFN-γ-ELISpot 30 and 22 days postinfusion, and resulted in complete clearance or >1.5 log reduction of viral load within 15 and 18 days, respectively. This protocol facilitates rapid and cost-effective generation of virus-specific TCLs, which appear to provide an effective treatment option.",
"affiliations": "Departments of *Clinical Cell Biology and FACS Core Unit †Quality Management ∥Molecular Microbiology, Children´s Cancer Research Institute (CCRI) ‡St. Anna Children´s Hospital #Department of Stem Cell Transplantation, St. Anna Children´s Hospital Departments of §Pediatrics ¶Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria **Institute of Pathology, Charité Unversitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.",
"authors": "Geyeregger|René|R|;Freimüller|Christine|C|;Stemberger|Julia|J|;Artwohl|Michaela|M|;Witt|Volker|V|;Lion|Thomas|T|;Fischer|Gottfried|G|;Lawitschka|Anita|A|;Ritter|Julia|J|;Hummel|Michael|M|;Holter|Wolfgang|W|;Fritsch|Gerhard|G|;Matthes-Martin|Susanne|S|",
"chemical_list": "D010455:Peptides",
"country": "United States",
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"doi": "10.1097/CJI.0000000000000034",
"fulltext": null,
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"issn_linking": "1524-9557",
"issue": "37(4)",
"journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)",
"keywords": null,
"medline_ta": "J Immunother",
"mesh_terms": "D000258:Adenovirus Infections, Human; D000260:Adenoviruses, Human; D002675:Child, Preschool; D017809:Fatal Outcome; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016219:Immunotherapy, Adoptive; D007223:Infant; D008297:Male; D010455:Peptides; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes; D013602:T-Lymphocytes, Cytotoxic; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "9706083",
"other_id": null,
"pages": "245-9",
"pmc": null,
"pmid": "24714358",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "First-in-man clinical results with good manufacturing practice (GMP)-compliant polypeptide-expanded adenovirus-specific T cells after haploidentical hematopoietic stem cell transplantation.",
"title_normalized": "first in man clinical results with good manufacturing practice gmp compliant polypeptide expanded adenovirus specific t cells after haploidentical hematopoietic stem cell transplantation"
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"abstract": "BACKGROUND\nTo analyze the effectiveness and the safety of Sofosbuvir-based regimens to treat patients with chronic hepatitis C virus (HCV) infection and chronic kidney disease (CKD).\n\n\nMETHODS\nA retrospective, observational study in patients with chronic HCV infection and CKD treated with Sofosbuvir-based regimens was performed. Liver fibrosis, comorbidities, HCV genotype and sustained virological resposnse (SVR) at 12th week post-treatment were evaluated. Kidney function was accessed by serum creatinine and glomerular filtration rate (GFR). The assumed level of significance was 5 %.\n\n\nRESULTS\nThirty-five patients were treated. The mean age was 52.1±10.9 years, 19 (54.3 %) were women, 32 (91.4 %) were already kidney transplanted and 3 (8.6 %) were on hemodialysis. The SVR by intention to treat was 88.6 %. The mean GFR was 65.8±28.6 and 63.7±28.3ml/min pre- and post-treatment respectively (p>0.05). Treatment was interrupted in 1 (2.85 %) patient due to anemia and in 2 (5.7 %) due to loss of kidney function.\n\n\nCONCLUSIONS\nSofosbuvir-based regimens are effective to treat HCV in patients with CKD. In patients with mild CKD this type of therapy seems to be safe.",
"affiliations": "Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Aelgre, RS, Brazil. Electronic address: giovanadrossato@gmail.com.;Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Aelgre, RS, Brazil. Electronic address: cristianev@ufcspa.edu.br.;Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Aelgre, RS, Brazil. Electronic address: paulorlalmeida@terra.com.br.",
"authors": "Rossato|Giovana|G|;Tovo|Cristiane Valle|CV|;Almeida|Paulo Roberto Lerias de|PRL|",
"chemical_list": "D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D007166:Immunosuppressive Agents; D011759:Pyrrolidines; D003404:Creatinine; D014633:Valine; C549273:daclatasvir; D000069474:Sofosbuvir",
"country": "Brazil",
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"doi": "10.1016/j.bjid.2019.10.011",
"fulltext": "\n==== Front\nBraz J Infect Dis\nBraz J Infect Dis\nThe Brazilian Journal of Infectious Diseases\n1413-8670\n1678-4391\nElsevier\n\nS1413-8670(19)30477-5\n10.1016/j.bjid.2019.10.011\nOriginal Article\nTreatment of chronic hepatitis C in patients with chronic kidney disease with Sofosbuvir-basead regimes\nRossato Giovana giovanadrossato@gmail.com\n\nTovo Cristiane Valle cristianev@ufcspa.edu.br\n⁎\nAlmeida Paulo Roberto Lerias de paulorlalmeida@terra.com.br\n\nUniversidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Aelgre, RS, Brazil\n⁎ Corresponding author at: Rua Sarmento Leite 245, Porto Alegre 90050-170, Brazil. cristianev@ufcspa.edu.br\n21 11 2019\nJan-Feb 2020\n21 11 2019\n24 1 2529\n7 7 2019\n27 10 2019\n© 2020 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U.\n2020\nSociedade Brasileira de Infectologia\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nBackground\n\nTo analyze the effectiveness and the safety of Sofosbuvir-based regimens to treat patients with chronic hepatitis C virus (HCV) infection and chronic kidney disease (CKD).\n\nMethods\n\nA retrospective, observational study in patients with chronic HCV infection and CKD treated with Sofosbuvir-based regimens was performed. Liver fibrosis, comorbidities, HCV genotype and sustained virological resposnse (SVR) at 12th week post-treatment were evaluated. Kidney function was accessed by serum creatinine and glomerular filtration rate (GFR). The assumed level of significance was 5 %.\n\nResults\n\nThirty-five patients were treated. The mean age was 52.1 ± 10.9 years, 19 (54.3 %) were women, 32 (91.4 %) were already kidney transplanted and 3 (8.6 %) were on hemodialysis. The SVR by intention to treat was 88.6 %. The mean GFR was 65.8 ± 28.6 and 63.7 ± 28.3 ml/min pre- and post-treatment respectively (p > 0.05). Treatment was interrupted in 1 (2.85 %) patient due to anemia and in 2 (5.7 %) due to loss of kidney function.\n\nConclusion\n\nSofosbuvir-based regimens are effective to treat HCV in patients with CKD. In patients with mild CKD this type of therapy seems to be safe.\n\nKeywords\n\nHemodialysis\nKidney transplantion\nDirect-acting antiviral\nSofosbuvir\nDaclatasvir\n==== Body\npmcIntroduction\n\nThe prevalence of hepatitis C virus (HCV) infection in patients with end-stage renal disease (ESRD) is clearly higher than the observed in the general population.1 In Brazil, 1.38 % of the population is infected with HCV,2 and in patients on dialysis, the prevalence of this infection ranges from 4.2%–8% depending on the renal replacement therapy center.3\n\nHCV infection in patients with chronic kidney disease (CKD) is associated with a more rapid progression of liver disease, increased mortality due to complications of cirrhosis, loss of renal graft and glomerulonephritis, thus contributing to a worse prognosis in these patients.4 Despite the relationship between HCV and the progression of CKD, the vast majority of patients with CKD remained untreated, because they are historically a difficult to treat population due to the frequent adverse effects associated with medications used to treat HCV.5, 6 In addition to the complexity of the treatment, the use of Interferon in renal transplant recipients is associated with a high risk of graft rejection (15%–100%) and has been contraindicated in this set.7\n\nThe advent of direct-acting antivirals (DAA) dramatically changed the treatment of HCV, including the special population of patients with CKD. In 2015, the use of Sofosbuvir (SOF) based regimens was approved in Brazil.8 Renal transplant patients and patients on hemodialysis have been treated with DAA since then, but the importance of individualizing the treatment due to the risk of loss of kidney function was also emphasized.\n\nThe objective of the present study was to analyze the effectiveness and the safety of Sofosbuvir-based regimens to treat patients with CKD.\n\nMaterial and methods\n\nA retrospective, observational study was performed in all cronically infected patients with HCV and CKD at various stages treated with SOF-based regimens at the Gastroenterology/Hepatology outpatient clinic of the Santa Casa Hospital, Porto Alegre, a tertiary reference hospital from southern Brazil, from June 2016 to March 2018.\n\nThe age, sex, liver fibrosis, comorbidities, HCV genotype and sustained virological response (SVR) at 12th week post-treatment were evaluated.\n\nKidney function was accessed by serum creatinine and GFR calculated using the Cockroff-Gault formula before, after treatment and 3 months after the end of treatment.5 Chronic kidney disease was classified at different stages according to criteria established by Kidney Disease Improving Global Outocomes (KDIGO).5 Kidney transplantation prior to treatment and the use of immunosuppressants were also registered.\n\nChronic HCV infection was defined as the persistence of HCV-RNA for a period of at least six months. Molecular diagnosis HCV were performed by polymerase chain reaction (PCR) - Real-time using the Extraction and Amplification Method: COBAS® AmpliPrep / COBAS® TaqMan® HCV Quantitative Test, v2.0 (Roche).\n\nPatients were considered to have cirrhosis based on clinical, image, laboratory or histologic parameters (METAVIR score).9\n\nTreatment with DAA was performed according to the Brazilian Public Health system (2015),8 which recommended that patients with CKD and kidney transplant patients should be treated with a non-interferon-alpha regimen and, if possible, without ribavirin.\n\nIn the statistical analysis, the quantitative variables were described by mean and standard deviation (if normal distribution) or median and interquartile range (if asymmetric distribution). The normality of the continuous variables was evaluated by the Shapiro-Wilk test. Categorical variables were described by absolute and relative frequencies. To compare means before and after treatment, the paired t-student test was applied. In case of asymmetry, the Wilcoxon test was used. For the categorical variables, the McNemar test was applied. To compare means between the three moments, the analysis of variance (ANOVA) for repeated measures was applied. In case of asymmetry or ordinal variables, the Friedman test was used. The association between numerical and ordinal variables was evaluated by the Spearman correlation coefficient. The significance level adopted was 5 % (p < 0.05) and the analyzes were performed in the SPSS program version 21.0. The study was approved by the Research Ethics of local Committee (number 1838479).\n\nResults\n\nThirty-five patients were analyzed. There was a light predominance of females 19 (54.3 %), the mean age was 52.1 ± 10.1 years (34–70 years), 32 (91.4 %) were previously submitted to renal transplants and 3 (8.6 %) patients were on hemodialysis (Table 1).Table 1 Clinical characteristics of patients with HCV and CKD (n = 35).\n\nTable 1Clinical characteristics\t\t\nAge; years; m ± DP [range]\t52.1 ± 109 [34–70]\t\nSex,female; n (%)\t19 (54.3)\t\nHBV coinfection; n (%)\t02 (5.7)\t\nKidney transplant recipientes; n (%)\t32 (91.4)\t\n\n\n\t\nCKD staging (Crcl; mL/min); n (%)\t\t\n 1 (Crcl> 90)\t06 (17.1 %)\t\n 2 (Crcl 89–60)\t13 (37.1 %)\t\n 3 (Crcl 59–30)\t12 (37.1 %)\t\n 4 (Crcl 29–15)\t01 (2.9 %)\t\n 5 (Crcl <15 ou hemodialysis)\t03 (8.6 %)\t\n\n\n\t\nHCV Genotypes; n (%)\t\t\n 1a\t16 (457)\t\n 1b\t06 (17.1)\t\n 2\t03 (8.6)\t\n 3\t09 (25.7)\t\n 3 and 4\t01 (2.9)\t\n\n\n\t\nComorbidities\t\t\n Systemic arterial hypertersion\t18 (51.4)\t\n Diabetes mellitus\t11 (31.4)\t\n Cardiac failure\t03 (8.6)\t\n Arrhythmia\t04 (11.4)\t\nCirrhosis; n (%)\t08 (22.8)\t\n CTP A\t04(11.4)\t\n CTP B\t04 (11.4)\t\n CTP C\t00 (0)\t\nLiver fibrosis (elastography); n (%)\t12 (34.3)\t\n F0\t03 (8.6)\t\n F1\t03 (8.6)\t\n F2\t01 (2.9)\t\n F3\t01 (2.9)\t\n F4\t04 (11.4)\t\nCDK = chronic kidney disease; CTP = Child Turcotte- Pugh escore; CrCl: Creatinine clearance; HBV: Hepatitis B virus; HCV: Hepatitis C vírus.\n\nConsidering the stages of CKD, 16 (45.7 %) were stage 3 or worse. Regarding the etiology of kidney failure, 24 (68.6 %) had no diagnosis, and systemic lupus erythomatous was found in 3 (8.6 %) patients. Glomerulonephritis focal segmental scleroderma (GESF), diabetes mellitus (DM), systemic arterial hypertension, polycystic kidney disease, Alport syndrome, chronic pyelonephritis and Bor syndrome were responsible for the etiology in a few patients (8; 22.8 %). HCV genotype 1 was the most prevalent (22; 62.8 %) (Table 1).\n\nCoinfection with hepatitis B virus (HBV) was found in 2 patients (5.7 %). There was observed the reactivation of HBV in one of these, immediatly post-treatment of HCV. This was a renal transplant, genotype 1 patient, using Tenofovir since 2012, with undetectable HBV viral load pre-treatment. The patient presented SVR after HCV treatment, and after HBV reactivation. Entecavir was associated with Tenofovir.\n\nIn the evaluation of liver fibrosis, no patient underwent liver biopsy. Transient hepatic elastography (THE) was performed in 12 (34.2 %) patients, showing absence or mild/significant fibrosis (F0-F1-F2) in 7 (58.3 %) and advanced fibrosis (F3-F4) in 5 (41.7 %) patients. Cirrhosis was diagnosed by THE in 4 (11.4 %) patients, and by clinical presentation (portal hypertension with ascites and esophageal varices) in 4 (11.4 %). Among the 8 cirrhotics, 5 (14.2 %) were Child-Turcotte-Pugh (CTP) A and 3 (8.6 %) CTP B (Table 1).\n\nThe prevalent comorbidities were systemic hypertension in 18 (51.4) patients, diabetes mellitus in 11 (31.4 %), heart failure in 3 (8.6 %) and cardiac arrhythmia in 4 (11.4 %) (Table1).\n\nOf the 35 patients who underwent HCV treatment, 33 (94.2 %) were treated with Sofosbuvir and Daclatasvir, of whom 8 (24.2 %) received Ribavirin. The 2 (5.7 %) patients with HCV genotype 2 were treated with Sofosbuvir and Ribavirin (Table 2). Full dose of Sofosbuvir was used in 33 (94.2 %) patients, and half dose (1 tablet on alternate days) in 2 (5.7 %) patients.Table 2 Medications used in the treatment of patients with HCV and CKD (n = 35).\n\nTable 2Treatment of HCV\tN (%)\t\nSofosbuvir + Daclatasvir 12 weeks\t27 (77.1)\t\nSofosbuvir + Daclatasvir + Ribavirin 12 weeks\t03 (8.6)\t\nSofosbuvir + Daclatasvir + Ribavirin 24weeks\t03 (8.6)\t\nSofosbuvir + Ribavirin 12 weeks\t02 (5.7)\t\nHCV = hepatitis C virus.\n\nThirty-two (91.4 %) patients were receiving immunosuppressants because they were kidney transplant recipients. Immunosuppressive regimens were not modified during HCV treatment. There was a predominance of Prednisone associated with Mycophenolate Mofetil and Tacrolimus in 15 (42.9 %) patients (Table 3).Table 3 Imunosuppressants in CKD submitted to renal transplantation (n = 32).\n\nTable 3Imunosuppressants\tn (%)\t\nPrednisone, MMF and FK\t15 (42.9)\t\nPrednisone and MMF\t06 (17.1)\t\nPrednisone, MMF and CYA\t04 (11.4)\t\nPrednisone AZA and CYA\t03 (8.6)\t\nPrednisone and FK\t02 (5.7)\t\nPrednisone + CYA + Sirolimo\t02 (5.7)\t\nAZA: Azathioprine; CYA: cyclosporin; FK: Tracolimus; MMF: Mycophenolate mofetil.\n\nThe treatment was suspended in 3 (8.6 %) patients, being 1 (2.8 %) due to anemia and 2 (5.8 %) due to a significant loss of kidney function. The patient who discontinued treatment for symptomatic anemia (hemoglobin drop) was cirrhotic on hemodialysis using Sofosbuvir, Daclatasvir and Ribavirin. The two patients worsening kidney function were cirrhotic Child-Turcotte-Pugh B, renal transplanted, in the advanced stages of CKD stage 3 (GFR 41 mL/min) and stage 4 (GFR 27 mL/min), worsening to GFR 29 ml/min and 25 mL min, respectively.\n\nWhen the median creatinine and GFR were analyzed, there was no statistically significant difference before and after treatment with Sofosbuvir (Table 4). And also, there was no statistically significant difference when analyzed the CKD according to the different stages (Fig. 1).Table 4 Comparison of creatinine and glomerular filtration rate (GFR) pre, post and three months after treatment.\n\nTable 4Variables\tPre\tPost\t3 m after EOT\tP\t\nCreatinine (mg/dL); Median (P25–P75)\t1.27 (0.94–1.57)\t1.23 (0.92–1.70)\t1.28 (0.92–1.92)\t0.573a\t\nGFR (mL/min); Median ± SD\t65.8 ± 28.6\t63.7 ± 28.3\t64.4 ± 29,8\t0.241b\t\nM = months; treat = treatment; GFR = Glomerular filtration rate; SD = standard deviation; EOT = end of treatment.\n\na Friedman test.\n\nb Analysis of variance (ANOVA) for repeated measures.\n\nFig. 1 Comparation between the stages of CKD pre, post and 3 months after the end of treatment. (p = 0459 McNemar test).\n\nFig. 1\n\nSVR was evaluated in 32 patients who completed the treatment, and 31 (88.6 %) achieved SVR 12 in an intention to treat analysis; per protocol 96.9 %. Only 1 (2.8 %) presented HCV recurrence after treatment.\n\nDiscussion\n\nIn the present study, a series of cases of patients with CKD and HCV were treated with Sofosbuvir-based regimens, successfully achieving SVR and without GFR decline. Most of the patients were renal transplant patients, non-cirrhotic patients with HCV genotype 1, and the most commonly used treatment regimen was the association of Sofosbuvir and Daclatasvir for 12 weeks.\n\nHepatitis C virus often has a negative impact on the survival of post-renal transplant patients due to the increased risk of graft loss due to rejection and disease infection, post-transplant diabetes, cancer and rapid progression of liver fibrosis.10\n\nAlthough eradication of HCV is of paramount importance, renal transplant recipients have always represented a special population difficult to treat. Currently, the use of DAA has been an important step in the treatment of HCV infection due to rates of SVR ranging from 60 % to 100 % according to genotype and degree of hepatic dysfunction.11\n\nManys studies in the literature that evaluate the use of DAA in CKD presented with encouraging results. Desnoyer et al.12 observed that Sofosbuvir was well tolerated in 13 dialysis patients. However, SVR12 was 100 % in patients who used Sofosbuvir full dose and 60 % in those who received three times a week. Saxena et al., (n = 19, being 5 on hemodialysis) observed, in the TARGET study, no difference in the SVR regardless of kidney function. However, patients with GFR < 30 ml/min experienced more anemia and worsened kidney function after using Sofosbuvir.13 Studies on kidney transplant recipients treated with DAAs stand out with 100 % SVR12.14, 15, 16 This study confirms that Sofosbuvir-based therapies are effective in patients with CKD. In this series of 35 cases, the SVR12 was reached in 31 (88.6 %) patients. Only one patient (2.8 %) developed HCV recurrence after treatment; he was genotype 1a, under hemodialysis, presented fibrosis F1 evaluated by THE and was treated with Sofosbuvir, Daclastavir and Ribavirin for 12 weeks.\n\nTreatment of hepatitis C with new DAA may represent a risk for reactivation of hepatitis B virus in co-infected patients with HCV. A systematic review and meta-analysis found 17 studies involving 1621 patients being 242 with HBV and 1379 with resolved hepatitis B (HBsAg-negative and anti- HBc-positive). All were treated with different regimens containing DAA against HCV. The reacivation of HBV was observed in 24 % (IC95 % 19–30 %) in patients with chronic HBV infection and 1.4 % (0.8–2.4 %) in those with resolved HBV infection.17 In the present study, 2 (5.7 %) patients were HBsAg positive, and one reactivated HBV during use de DAA.\n\nTo know the drug interactions of DAA is of fundamental importance, particularly the interaction between protease inhibitors and calcineurin inhibitors or mammalian target of rapamycin (mTOR). Simeprevir, a second-generation antiviral that inhibits the protease coded by the HCV NS3/4A region, has potential drug interaction with Tacrolimus, Sirolimus and Everolimus.18\n\nSofosbuvir (polymerase inhibitor encoded by the HCV NS5B region) and Daclatasvir (HCV NS5A region-encoded polymerase inhibitor) have a low risk of interaction with immunosuppressants and have pangenotypic action. In this study, the vast majority of patients were renal transplant patients (n = 33; 94.3 %).\n\nAll patients were treated with Sofosbuvir based regimes. Renal transplant patients were using immunosuppressants, 8 (25.0 %) used schedules with Ciclosporin, and 17 (48.5 %) with Tacrolimus. There was no need for more frequent control of the levels of immunosuppression due to the lack of drug interaction with these DAA. This study showed that treatment with Sofosbuvir was well tolerated in patients with mild CKD, although 3 (8.6 %) patients discontinued therapy.\n\nA pontential limitation of the present study the fact that it is retrospective and included a small number of patients in more advanced stages of CKD.\n\nIn conclusion, this study suggests that tratament HCV in patients with CKD is efetive, and in patients with mild CKD this type of therapy seems to be safe.\n\nConflicts of interest\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors declare no conflicts of interest.\n==== Refs\nReferences\n\n1 Jadoul M. Bieber B.A. Martin P. Akiba T. Nwankwo C. Arduino J.M. Goodkin D.A. Pisoni R.L. Prevalence, incidence, and risk factors for hepatitis C virus infection in hemodialysis patients Kidney Int 4 2019 939 947\n2 Pereira L.M.M.B. Martelli C.M. Moreira R.C. Merchan-Hamman E. Stein A.T. Cardoso R.M.A. Prevalence and risk factors of hepatitis C virus infection in Brazil, 2005 through 2009: a cross-sectional study BMC Infect Dis 1 2013 60\n3 Sesso R.C. Lopes A.A. Thomé F.S. Lugon J.R. Martins C.T. Brazilian Chronic Dialysis Census 2014 J Bras Nefrol 38 2016 54 61 27049365\n4 Chen Y.C. Li C.Y. Tsai S.J. Chen Y.C. Anti-hepatitis C virus therapy in chronic kidney disease patients improves long-term renal and patient survivals World J Clin case 11 2019 1270 1281\n5 Gordon C.E. Berenguer M.C. Doss W. Fabrizi F. Izopet J. Jha V. Prevention, diagnosis, evaluation, and treatment of hepatitis C virus infection in chronic kidney disease: synopsis of the kidney disease: Improving Global Outcomes 2018 Clinical Practice Guideline Ann Intern Med 171 2019 496 504 31546256\n6 Saadoun D. Resche Rigon M. Pol S. Thibault V. Blanc F. Pialoux G. PegIFNa/ribavirin/protease inhibitor combination in severe hepatitis C virus-associated mixed cryoglobulinemia vasculitis J Hepatol 62 2015 24 30 25135864\n7 Sise M.E. Backman E.S. Wenger J.B. Wood B.R. Sax P.E. Chung R.T. Short and long-term effects of telaprevir on kidney function in patients with hepatitis C virus infection: a retrospective cohort study PLoS One 10 2015 1 11\n8 Ministry of Health Department of Health Surveillance Department of STD AIDS and Viral Hepatitis Clinical protocol and therapeutic guidelines for hepatitis C and coinfections 2015 Brasília: Ministry of Health\n9 Bedossa P. Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group Hepatology 24 1996 289 293 8690394\n10 Cohen- Bucay A. Gordon C.E. Francis J.M. Non- immunological complications following Kidney transplantion F1000Res 8 2019 194\n11 Bunchrntavakul C. Maneerattanaporn M. Chavalitdhamrong D. Management of patients with hepatitis C infection and renal disease World J Hepatol 7 2015 213 225 25729476\n12 Desnoyer A. Pospai D. Lê M.P. Gervais A. Heurgué-Berlot A. Laradi A. Pharmacokinetics, safety and efficacy of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C J Hepatol 65 2016 40 47 26952005\n13 Saxena V. Koraishy F.M. Sise M.E. Lim J.K. Schmidt M. Chung R.T. Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function Liver Int 36 2016 807 816 26923436\n14 Sawinski D. Kaur N. Ajeti A. Trofe-Clark J. Lim M. Bleicher M. Successful treatment of hepatitis C in renal transplant recipients with direct-acting antiviral agents Am J Transplant 16 2016 1588 1595 26604182\n15 Kamar N. Marion O. Rostaing L. Cointault O. Ribes D. Lavayssière L. Efficacy and safety of sofosbuvir-based antiviral therapy to treat hepatitis C virus infection after kidney transplantation Am J Transplant 16 2016 1474 1479 26587971\n16 Beinhardt S. Al Zoairy R. Ferenci P. Kozbial K. Freissmuth C. Stern R. DAA-based antiviral treatment of patients with chronic hepatitis C in the pre- and post kidney transplantation setting Transpl Int 29 2016 999 1007 27203857\n17 Mücke M.M. Backus L.I. Mücke V.T. Coppola N. Preda C.M. Yeh M.L. Hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C: a systematic review and meta-analysis Lancet Gastroenterol Hepatol 3 2018 172 180 29371017\n18 www.hep-druginteractions.org [Internet]. Liverpool: HEP Drug Interactions; c2018 [cited 2017 Aug 11]. Available from: www.hep-druginteractions.org.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1413-8670",
"issue": "24(1)",
"journal": "The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases",
"keywords": "Daclatasvir; Direct-acting antiviral; Hemodialysis; Kidney transplantion; Sofosbuvir",
"medline_ta": "Braz J Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000998:Antiviral Agents; D002219:Carbamates; D003404:Creatinine; D005260:Female; D005919:Glomerular Filtration Rate; D019698:Hepatitis C, Chronic; D006801:Humans; D007093:Imidazoles; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D051436:Renal Insufficiency, Chronic; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012720:Severity of Illness Index; D000069474:Sofosbuvir; D018709:Statistics, Nonparametric; D000072230:Sustained Virologic Response; D016896:Treatment Outcome; D014633:Valine",
"nlm_unique_id": "9812937",
"other_id": null,
"pages": "25-29",
"pmc": null,
"pmid": "31760038",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Treatment of chronic hepatitis C in patients with chronic kidney disease with Sofosbuvir-basead regimes.",
"title_normalized": "treatment of chronic hepatitis c in patients with chronic kidney disease with sofosbuvir basead regimes"
} | [
{
"companynumb": "BR-GILEAD-2019-0439957",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SOFOSBUVIR"
},
"drugadditional": null,
... |
{
"abstract": "Metformin, an oral antidiabetic agent, is considered the preferred first-line therapy for patients with type II diabetes. Between 2010 and 2012, it has been estimated that 14 million Americans were administered an oral antidiabetic agent, suggesting the extensive use of metformin among the diabetic population. There have been few case reports implicating metformin in causing hemolytic anemia. We present a case of a 53-year-old white male who developed hemolytic anemia after the initiation of treatment with metformin 500 mg twice daily. The patient experienced a 1.5 g/dL decrease in hemoglobin from baseline and a 2.8 mg/dL increase in total bilirubin within 1 day of treatment. Laboratory results confirmed that the patient was also glucose-6-phosphate dehydrogenase deficient. The hemolytic anemia resolved on discontinuation of metformin. Although this adverse effect seems to be rare, it is important to consider its seriousness. Clinicians should be advised to closely monitor patients newly started on metformin.",
"affiliations": "1Pharmacy Department, James J. Peters VA Medical Center, Bronx, NY; and 2Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY.",
"authors": "Ruggiero|Nicole A|NA|;Kish|Troy D|TD|;Lee|Mikyung L|ML|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000194",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "23(2)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000743:Anemia, Hemolytic; D005955:Glucosephosphate Dehydrogenase Deficiency; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D008875:Middle Aged",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e575-8",
"pmc": null,
"pmid": "25756470",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metformin-Induced Hemolytic Anemia in a Patient With Glucose-6-Phosphate Dehydrogenase Deficiency.",
"title_normalized": "metformin induced hemolytic anemia in a patient with glucose 6 phosphate dehydrogenase deficiency"
} | [
{
"companynumb": "US-IPCA LABORATORIES LIMITED-E2B_00000019",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "INSULIN GLARGINE"
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{
"abstract": "Bone marrow necrosis (BMN) is an extremely rare condition characterized by necrosis of the myeloid tissue and medullary stroma leaving an amorphous eosinophilic background and ill-defined necrotic cells in the hematopoietic bone marrow. Several conditions are associated with BMN, including sickle cell disease, metastatic carcinoma, and hematologic malignancies. It is also associated with the use of antineoplastic drugs, such as fludarabine, interferon alpha, and imatinib. Blinatumomab is a CD19/CD3 bispecific T-cell engager antibody which redirects autologous CD3-positive T cells to CD19-positive lymphoblasts creating a cytolytic synapse leading to blastic cells. Cytokine release syndrome, cerebral nervous system toxicities, and febrile neutropenia are the most frequent adverse effects of blinatumomab. Here, we report an adolescent boy with relapse/resistant acute lymphoblastic leukemia developing BMN following blinatumomab therapy. To our knowledge, this is the first case report on BMN following blinatumomab treatment.",
"affiliations": "Departments of Pediatric Hematology/Oncology.;Departments of Pediatric Hematology/Oncology.;Departments of Pediatric Hematology/Oncology.;Departments of Pediatric Hematology/Oncology.;Pathology, University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, Turkey.",
"authors": "Yarali|Nese|N|;Isik|Melek|M|;Arman-Bilir|Ozlem|O|;Guzelkucuk|Zeliha|Z|;Oguz-Erdogan|Ayse Selcen|AS|",
"chemical_list": "D018033:Antibodies, Bispecific; D000074322:Antineoplastic Agents, Immunological; C510808:blinatumomab",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001532",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "42(3)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D018033:Antibodies, Bispecific; D000074322:Antineoplastic Agents, Immunological; D001853:Bone Marrow; D006801:Humans; D008297:Male; D009336:Necrosis; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e167-e169",
"pmc": null,
"pmid": "31219910",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bone Marrow Necrosis in a Patient Following Blinatumomab Therapy.",
"title_normalized": "bone marrow necrosis in a patient following blinatumomab therapy"
} | [
{
"companynumb": "TR-BAXTER-2019BAX026029",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
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"drugadditional": "3",
... |
{
"abstract": "Acute inflammatory demyelinating polyneuropathy or Guillain-Barré syndrome is well recognized as a presenting feature of human immunodeficiency virus (HIV) seroconversion and, to a lesser extent, as a complication of HIV infection, particularly immune reconstitution. Acute motor axonal neuropathy (AMAN) is much rarer in this setting. A case is presented of acute motor neuropathy, with features most consistent with AMAN in the setting of congenital HIV and prolonged non-compliance with antiretroviral treatment. The case throws new light on the pathogenesis of this condition. Macrophage activation is proposed as fundamental; the patient was predisposed by HIV as well as the use of granulocyte colony-stimulating factor and AMAN was then precipitated by a bacterial infection.",
"affiliations": "Department of Neurology , Barrow Neurological Institute , Phoenix, AZ , USA.",
"authors": "Dardis|Christopher|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/omcr/omv009",
"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcromcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omv009omv009130012001100Case ReportsAcute motor axonal neuropathy in a patient with prolonged CD4 depletion due to HIV: a local variant of macrophage activation syndrome? Dardis Christopher *Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA* Correspondence address. Department of Neurology, Barrow Neurological Institute, Phoenix, Phoenix, AZ, USA. Tel: +44-602-406-6262; Fax: +01-602-406-6260; E-mail: christopherdardis@gmail.com2 2015 26 2 2015 2015 2 200 202 27 11 2014 29 1 2015 © The Author 2015. Published by Oxford University Press.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAcute inflammatory demyelinating polyneuropathy or Guillain-Barré syndrome is well recognized as a presenting feature of human immunodeficiency virus (HIV) seroconversion and, to a lesser extent, as a complication of HIV infection, particularly immune reconstitution. Acute motor axonal neuropathy (AMAN) is much rarer in this setting. A case is presented of acute motor neuropathy, with features most consistent with AMAN in the setting of congenital HIV and prolonged non-compliance with antiretroviral treatment. The case throws new light on the pathogenesis of this condition. Macrophage activation is proposed as fundamental; the patient was predisposed by HIV as well as the use of granulocyte colony-stimulating factor and AMAN was then precipitated by a bacterial infection.\n==== Body\nINTRODUCTION\nAcute inflammatory demyelinating polyneuropathy (AIDP) has long been associated with human immunodeficiency virus (HIV). Presentation, treatment and outcomes are similar to those in patients without HIV, although colony-stimulating factor (CSF) pleocytosis is more common and the initial presentation may be more severe with and take longer to resolve [1]. Screening for HIV is advised in those with AIDP in endemic areas. Cases have been reported as occurring as part of the immune reconstitution syndrome, including in children with congenitally acquired HIV.\n\nThere are only four recorded cases of AMAN occurring in a patient with HIV. These are summarized in Table 1. Based on cases to date, it had been suggested that AMAN occurs before the stage of profound immune suppression; the current case makes this highly unlikely.\nTable 1: Reported cases of HIV and AMAN\n\nCase\tHIV\tStage\tCD4 count\tRecent infection\tReference\t\n1\tAcquired\tNew\t150\tNo\t[2]\t\n2\tUnknown\tChronic\t440\tNo\t[3]\t\n3\tUnknown\tChronic\t350\tNo\t\n4\tCongenital\tChronic\t540\tDysentery\t[4]\t\nCurrent\tCongenital\tChronic\t5\tE. coli pyelonephritis\t\t\n\n\nCASE REPORT\nA 22-year-old lady with congenitally acquired HIV presented with generalized weakness and numbness of the body for almost 2 weeks. She had been discharged from another institution 2 weeks before following the treatment of an episode of pyelonephritis. Blood cultures grew Escherichia coli, and she underwent a 14-day course of treatment with ciprofloxacin. Two days after discharge she noted tingling and numbness affecting the hands and legs. Later that day, her legs gave way while she was standing at a bus stop. These symptoms progressed to the point where she was not able to support herself sitting up and had needed to move in with her partner for help with her activities of daily living.\n\nShe had been repeatedly non-compliant with HAART for her HIV, which was multidrug resistant. She had been taking filgrastim [a granulocyte colony-stimulating factor (G-CSF) analogue] for neutopenia. Her last CD4 count prior to admission was 3 months ago and was 1/µl. On this admission, it was 5. It had always been <10 since she had first attended here 21 months prior to this. She had a prior episode of Pneumocystis pneumonia. aged 17.\n\nHer initial examination showed generalized weakness, particularly proximally and particularly of the legs. Reflexes were initially preserved, but were absent even with reinforcement 10 days later. There were no sensory signs. She had mild fine nystagmus in all directions of gaze. No ophthalmoplegia or ataxia was present.\n\nHer initial complete blood count, coagulation profile, comprehensive metabolic profile, Mg2+, lactate, CK, B12 and TSH were all normal apart from her hemoglobin/hematocrit of 10 g/deciliter/ 29% which was normocytic. Her lumbar puncture showed a protein of 95 mg/dl with no cells and normal glucose. MRI of the spine with contrast showed diffuse, symmetric enhancement of multiple ventral nerve roots.\n\nNerve conduction studies performed 1 week after admission are summarized in Table 2. These show diffuse motor neuropathy in the legs, with no involvement of the arms or of sensory nerves. The only evidence of demyelination was in the right peroneal nerve. While this does not meet the formal criteria for AMAN as proposed by the Guillain-Barré Syndrome Trial Group, the pattern is in keeping with this rather than AIDP [5]. Electomyography showed increased spontaneous activity and decreased motor unit amplitudes in the legs.\nTable 2: Nerve conduction studies\n\n\tVelocity (m/s)\tAmplitude (mV)\tLatency (ms)\t\nL median nerve\t50 (>48)\t\t\t\nL peroneal\t38 (>50)\t2.1 (>2.5)\t\t\nR peroneal motor\t\t0.3 (>2.5)\t10.4 (<5.5)\t\nR tibial motor\t\t4.3 (>2.9)\t6.2 (<6.0)\t\nL tibial motor\t\t4.4 (>2.9)\t6.7 (<6.0)\t\nL superficial peroneal sensory\t\t\t3.8 (<2.4)\t\nF waves\t\t\t\t\nL median\t\t\t25 (<31)\t\nL&R peroneal\t\t\tAbsent\t\nR tibial\t\t\t52 (<58)\t\nL ulnar\t\t\t29 (<31)\t\nFigures in parentheses show reference values.\n\nFindings are typical of a predominantly axonal neuropathy.\n\n\n\nShe was given a 5-day course of intravenous immunoglobulin (ivIg). There was no initial sign of clinical improvement and she was discharged to rehabilitation. We were unable to contact her for follow-up in our clinic as planned.\n\nDISCUSSION\nThe CD4 count reported here is the lowest reported for a patient with an acute motor neuropathy. The neuropathy is all the more striking in that it is predominantly axonal.\n\nIn the largest series of patients with HIV and AIDP, 10 in total, the two lowest CD4 counts at time of presentation were 55 and 118/µl [6]. Another series of six patients showed the lowest CD4 count to be 46.\n\nWhat light does this throw on pathophysiology? The key event here appears to be macrophage activation, precipitated by a recent infection and with the use of G-CSF as a predisposing factor.\n\nWhile it is already recognized that patients with HIV can develop AIDP at any stage of the disease process, our patient provides evidence that the same is true for AMAN. Furthermore, the precipitating event does not appear to be solely the result of a change in CD4 levels. Varying levels (and changes in levels) of CD4 at the time of diagnosis suggest that these cells are not crucial to the pathogenesis. CD4 depletion in animal models has been shown to result in other organ-specific autoimmune conditions, although not AIDP or AMAN [7].\n\nBoth AIDP and AMAN are thought to be mediated by activated macrophages, targeting either the myelin sheaths or the nodes of Ranvier, respectively [8]. Macrophages become ‘classically activated’ following the stimulus of IFN-γ (primarily); local tissue destruction results. Macrophages serve as a reservoir for HIV and its intracellular presence allows them to ‘auto-activate’, in part by secreting IFN-γ in response to viral protein gp120 exposure [9].\n\nWidespread systemic mobilization is known as ‘macrophage activation syndrome’ (MAS). This often follows infection in immunosupressed patients and is characterized by an increase in circulating IFN-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF). One case has been reported as occurring in a patient with HIV following infection with Nocardia, also with a low CD4 count (53/µl) [10].\n\nIf AMAN and AIDP are organ-specific variants of MAS, then markers of this process should be elevated and could be measured in such patients (IFN-γ is available commercially and may be expected to fall with resolution of the neuropathy). Confirmation would provide a rationale for use of steroids in addition to ivIg. There are also reports of dramatic benefit from the use of anakinra (a recombinant IL-1 receptor antagonist) in MAS; monocyte–granulocyte apheresis is another therapeutic possibility. Given the rarity of this condition, treatments will necessarily continue to be individualized.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n==== Refs\nREFERENCES\n1 Schleicher GK Black A Mochan A Richards GA Effect of human immunodeficiency virus on intensive care unit outcome of patients with Guillain-Barré syndrome Crit Care Med 2003 31 1848 50 12794429 \n2 Wagner JC Bromberg MB HIV infection presenting with motor axonal variant of Guillain-Barré Syndrome J Clin Neuromuscul Dis 2007 9 303 5 18090683 \n3 Goldstein JM Azizi SA Booss J Vollmer TL Human immunodeficiency virus-associated motor axonal polyradiculoneuropathy Arch Neurol 1993 50 1316 9 8257309 \n4 Jadhav S Agrawal M Rathi S Acute motor axonal neuropathy in HIV infection Indian J Pediatr 2014 81 193 24057968 \n5 Hadden RD Cornblath DR Hughes RA Zielasek J Hartung HP Toyka KV Electrophysiological classification of Guillain-Barré syndrome: clinical associations and outcome. Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group Ann Neurol 1998 44 780 8 9818934 \n6 Brannagan TH III Zhou Y HIV-associated Guillain-Barré syndrome J Neurol Sci 2003 208 39 42 12639723 \n7 Shevach EM Regulatory T cells in autoimmunity Annu Rev Immunol 2000 18 423 49 10837065 \n8 Hughes RAC Cornblath DR Guillain-Barre Syndrome Lancet 2005 366 1653 66 16271648 \n9 Herbein G Gras G Khan KA Abbas W Macrophage signaling in HIV-1 infection Retrovirology 2010 7 34 20380698 \n10 Simon F Koninck JC Vaylet F Samson T Falque L Herve V [Thoracic nocardiasis associated with macrophage activation syndrome] Rev Mal Respir 2001 18 59 62 14639178\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2053-8855",
"issue": "2015(2)",
"journal": "Oxford medical case reports",
"keywords": null,
"medline_ta": "Oxf Med Case Reports",
"mesh_terms": null,
"nlm_unique_id": "101642070",
"other_id": null,
"pages": "200-2",
"pmc": null,
"pmid": "25988079",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports",
"references": "9818934;24057968;12794429;18090683;10837065;14639178;12639723;20380698;16271648;8257309",
"title": "Acute motor axonal neuropathy in a patient with prolonged CD4 depletion due to HIV: a local variant of macrophage activation syndrome?",
"title_normalized": "acute motor axonal neuropathy in a patient with prolonged cd4 depletion due to hiv a local variant of macrophage activation syndrome"
} | [
{
"companynumb": "US-AMGEN-USASP2015108760",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": null,
... |
{
"abstract": "Primary effusion lymphoma (PEL) is a rare non-Hodgkin lymphoma subtype primarily seen in human immunodeficiency virus (HIV)-infected individuals with low CD4(+) cell counts and elevated HIV viral loads. It has always been associated with human herpesvirus type 8 (HHV-8) and in 80% of cases has also been associated with Epstein-Barr virus (EBV). Less commonly, PEL has presented in patients with advanced age and other conditions associated with an altered immunity, including malignancy, liver cirrhosis, and immunosuppressive medications. It is a tumor of B-cell lineage; however, it shows a \"null\" phenotype, rarely expressing pan-B cell surface antigens. It will usually express CD45, CD30, CD38, CD138, and MUM1 and is characterized by lymphomatous effusions in body cavities but not lymphadenopathy. It is an aggressive lymphoma, with an average median survival of < 1 year. HHV-8-associated large B-cell lymphoma (HHV-8-LBL) is a second variant of PEL that is both solid and extracavitary. It has immunoblastic and/or anaplastic morphologic features and a distinct immunohistochemical staining pattern. It could also have a different clinical presentation than that of classic PEL.\n\n\n\nWe describe the case of a 57-year-old HIV-infected man who presented with a slow-growing and asymptomatic abdominal mass. Examination of an excisional biopsy specimen showed malignant large cells with prominent cytoplasm that were positive for pan-B cell antigen CD20, HHV-8, and EBV and negative for CD138, CD10, BCL-6, CD3, and CD30. The Ki-67 labeling index was 90%. The diagnosis was stage IIIA HHV-8-LBL, and he was treated with 6 cycles of R-EPOCH (rituximab, etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone) infusion chemotherapy. At 12 months after treatment, he was in complete remission. We also performed a Medline and Embase search to better understand the clinical findings of our patient and the unique attributes of HHV-8-LBL. Focusing our search on English language studies, we identified 83 cases of HHV-8-LBL without an effusion component. We compared these 83 cases with 118 reported cases of classic PEL.\n\n\n\nThe median age of the patients with HHV-8-LBL was 41 years (range, 24-77), and 96% of the cases were associated with HIV. The median age of the patients with classic PEL was 41 years (range, 26-86), and 96% of the cases were associated with HIV. Of those with HHV-8-LBL, 31 of 61 (51%) had a pre-existing diagnosis of acquired immunodeficiency syndrome (AIDS) and 47 of 63 (75%) were coinfected with EBV. In contrast, 69 of 96 patients (72%) with classic PEL had a pre-existing AIDS diagnosis and 40 of 49 (82%) were coinfected with EBV. The mean CD4(+) count of the HHV-8-LBL patients was 256 cells/μL (range, 18-1126 cells/μL) compared with 139 cells/μL (range, 2-557 cells/μL) in the classic PEL patients. The median survival time for both groups was similar at 5.5 months (range, 25 days to ≥ 25 months) for patients with HHV-8-LBL and 4 months (range, 2 days to ≥ 113 months) for those with classic PEL. More patients with HHV-8-LBL were alive at the last follow-up point (59% vs. 18%). The percentage of patients achieving complete remission was 54% (30 of 56) and 36% (32 of 89) for HHV-8-LBL and classic PEL, respectively.\n\n\n\nOur patient's high CD4(+) cell count, the lack of a pre-existing AIDS diagnosis, and the excellent response to chemotherapy highlights that HHV-8-LBL might have distinct clinical features and possibly a better response to chemotherapy than classic PEL. HHV-8-LBL should be included in the differential diagnosis of HIV patients with solid lesions. It is essential that patients' Centers for Disease Control and Prevention HIV clinical status and HIV viral load at the diagnosis of PEL and HHV-8-LBL be reported and that the reported clinical results include longer term follow-up data. Only then will a more complete clinical picture of this little-appreciated and little-understood PEL variant be defined.",
"affiliations": "School of Medicine, New York Medical College, Valhalla, NY.;Section of Hematology and Oncology, Virginia Mason Medical Center, Seattle, WA.;Section of Hematology and Oncology, Virginia Mason Medical Center, Seattle, WA.;Section of Hematology and Oncology, Virginia Mason Medical Center, Seattle, WA; Division of Hematology, University of Washington, Seattle, WA. Electronic address: david.aboulafia@virginiamason.org.",
"authors": "Foster|William R|WR|;Bischin|Alina|A|;Dorer|Russell|R|;Aboulafia|David M|DM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "16(6)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "AIDS; HHV-8-LBL; HIV-associated non-Hodgkin lymphoma; Human immunodeficiency virus; Nonserous PEL",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001402:B-Lymphocytes; D001706:Biopsy; D060085:Coinfection; D015658:HIV Infections; D006566:Herpesviridae Infections; D019288:Herpesvirus 8, Human; D018451:Homosexuality, Male; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D054685:Lymphoma, Primary Effusion; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000072078:Positron Emission Tomography Computed Tomography; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "311-21",
"pmc": null,
"pmid": "27234438",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D016454:Review",
"references": "20150647;19287457;16099881;24525514;21541215;12827623;15800785;8695812;23136597;23424065;12203218;22790853;24076781;11308402;12748248;15105661;25843730;17991301;9335459;18854561;24917369;10706463;22011447;20484888;15681470;14581418;15370268;25027567;10435572;16231856;25843729;15994147;22591071;12015867;11895764;24614140;22497739;15744337;16189148;24400343;23899073;22264773;25139766;15489644;20348880;17554754;18663051;25364646;10658913;17522245;11920242",
"title": "Human Herpesvirus Type 8-associated Large B-cell Lymphoma: A Nonserous Extracavitary Variant of Primary Effusion Lymphoma in an HIV-infected Man: A Case Report and Review of the Literature.",
"title_normalized": "human herpesvirus type 8 associated large b cell lymphoma a nonserous extracavitary variant of primary effusion lymphoma in an hiv infected man a case report and review of the literature"
} | [
{
"companynumb": "US-ROCHE-1788216",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Compartment syndrome presents with a slow onset of pain. Anything that causes an increased intra-compartmental pressure can lead to surgical emergency. A 45-year-old male presents to the emergency department with prolonged syncope. The patient is unable to recall the previous night except for using oxycodone. Patient medical history is significant for ischemic cardiomyopathy and myocardial infarction. Physical exam showed left arm pain and swelling, decreased sensation to light touch, and decreased range of motion. The left forearm was cool to touch with decreased pulses. Blood urea nitrogen/creatinine ratio was 47/4.0, white blood cell was 15.1, troponin was 34.2, and creatine kinase was immeasurable. Electrocardiogram showed non-specific T-wave abnormalities. Computed tomography showed left hemithoracic musculature enlargement. The patient's symptoms continued to worsen. The patient underwent emergency fasciotomy to relieve intra-compartmental pressure. Compartment syndrome of the deltoid is rare and yielded less than ten cases in our literature review. Although compartment syndrome usually affects the forearm, one must consider its possibility in any anatomical location.",
"affiliations": "a Department of Emergency Medicine , Campbell University School of Osteopathic Medicine , Buies Creek , NC , USA.;a Department of Emergency Medicine , Campbell University School of Osteopathic Medicine , Buies Creek , NC , USA.;a Department of Emergency Medicine , Campbell University School of Osteopathic Medicine , Buies Creek , NC , USA.;a Department of Emergency Medicine , Campbell University School of Osteopathic Medicine , Buies Creek , NC , USA.",
"authors": "Harrison|Andrew|A|;Sumner|Michael|M|;Sobecki|Jeffrey|J|;Christiansen|Gregory|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/21548331.2016.1216237",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2154-8331",
"issue": "44(4)",
"journal": "Hospital practice (1995)",
"keywords": "Compartment syndrome; deltoid compartment syndrome; emergency medicine; rhabdomyolysis; surgical emergencies",
"medline_ta": "Hosp Pract (1995)",
"mesh_terms": null,
"nlm_unique_id": "101268948",
"other_id": null,
"pages": "224-226",
"pmc": null,
"pmid": "27447677",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Compartment syndrome of the deltoid: a case report of a common presentation in a rare location.",
"title_normalized": "compartment syndrome of the deltoid a case report of a common presentation in a rare location"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-121642",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXYCODONE"
},
"druga... |
{
"abstract": "There are few published data on the efficacy and safety of prednisolone in preterm infants with bronchopulmonary dysplasia (BPD).\n\n\n\nTo describe the use of chronic prednisolone therapy in a population of infants with severe BPD, examine potential benefits on respiratory status, and document potential effects on growth.\n\n\n\nSingle-center retrospective cohort study.\n\n\n\nPreterm infants who had received ≥30 days of prednisolone for the treatment of severe BPD.\n\n\n\nWeekly changes in Pulmonary Severity Score (PSS), as well as weekly changes in weight, length, and head circumference during prednisolone therapy.\n\n\n\nForty-three infants (mean birth weight 729 g; mean gestational age 26 weeks) were identified. The average age at start of prednisolone treatment was 42.5 ± 5.9 weeks; while the median duration and median cumulative dose of prednisolone therapy were 67 (IQR 57-107) days and 61.3 (IQR 39.9-93.3) mg/kg, respectively. PSS decreased after 1 week of prednisolone therapy (mean difference, 0.19; 95% Cl, 0.01 to 0.37; p = 0.03). No further reduction in PSS was noted despite continued treatment. Length z-scores decreased after 4 weeks of continued treatment (mean difference 0.6; 95% CI 0.01 to 1.1; P = 0.04), while weight and head circumference did not change.\n\n\n\nIn one of the first reports on prednisolone therapy for severe BPD, we describe that long-term prednisolone is associated with modest short-term improvement in PSS, but impairs linear growth. Our results suggest a risk-benefit profile of prednisolone that does not favor long-term use in infants with severe BPD.",
"affiliations": "Department of Pharmacy, Children's Mercy Kansas City, 2401 Gillham Road, Kansas City, MO 64108, USA. Electronic address: aelinafelter@cmh.edu.;School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA; Division of Neonatology, Department of Pediatrics, Children's Mercy Kansas City, 2401 Gillham Road, Kansas City, MO 64108, USA; Center for Infant Pulmonary Disorders, Children's Mercy Kansas City, 2401 Gillham Road, Kansas City, MO 64108, USA. Electronic address: accuna@cmh.edu.;School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA. Electronic address: clpt5@mail.umkc.edu.;School of Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA. Electronic address: a163q615@kumc.edu.;School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA; Division of Neonatology, Department of Pediatrics, Children's Mercy Kansas City, 2401 Gillham Road, Kansas City, MO 64108, USA; Center for Infant Pulmonary Disorders, Children's Mercy Kansas City, 2401 Gillham Road, Kansas City, MO 64108, USA. Electronic address: wtruog@cmh.edu.;School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA; Division of Neonatology, Department of Pediatrics, Children's Mercy Kansas City, 2401 Gillham Road, Kansas City, MO 64108, USA. Electronic address: vsampath@cmh.edu.;Department of Pharmacy, Children's Mercy Kansas City, 2401 Gillham Road, Kansas City, MO 64108, USA. Electronic address: aoschman@cmh.edu.",
"authors": "Linafelter|Alaina|A|;Cuna|Alain|A|;Liu|Cynthia|C|;Quigley|Anastasia|A|;Truog|William E|WE|;Sampath|Venkatesh|V|;Oschman|Alexandra|A|",
"chemical_list": "D005938:Glucocorticoids; D011239:Prednisolone",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.earlhumdev.2019.06.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0378-3782",
"issue": "136()",
"journal": "Early human development",
"keywords": "Bronchopulmonary dysplasia; Corticosteroids; Growth; Outcome; Prednisolone; Prematurity",
"medline_ta": "Early Hum Dev",
"mesh_terms": "D001997:Bronchopulmonary Dysplasia; D002657:Child Development; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D008297:Male; D011239:Prednisolone",
"nlm_unique_id": "7708381",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "31265946",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Extended course of prednisolone in infants with severe bronchopulmonary dysplasia.",
"title_normalized": "extended course of prednisolone in infants with severe bronchopulmonary dysplasia"
} | [
{
"companynumb": "PHHY2019US173268",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Drug-induced scleroderma-like lesion is a condition in which administration of a drug induces skin sclerotic lesions similar to systemic sclerosis or morphea. The clinical manifestations of drug-induced scleroderma-like lesion can be divided into two types: scleroderma-like lesions and morphea-like plaques. A wide variety of drugs can cause drug-induced scleroderma-like lesion. Bleomycin, L-tryptophan, vinyl chloride, and phytonadione (vitamin K1) have been reported, but in recent years, cases due to chemotherapeutic agents, such as taxane-based agents, gemcitabine, and tegafur-uracil, and immune checkpoint inhibitors have increased. Drug-induced scleroderma-like lesion differs from systemic sclerosis in that it does not include Raynaud's phenomenon, nail-fold capillary abnormality, organ involvement, such as reflux esophagitis, interstitial pneumonia, renal crisis, or anti-nuclear Abs. On the other hand, there are reports of cases in which Raynaud's phenomenon, positive conversion of anti-nuclear Abs, and development of skin sclerosis from the fingers developed after initiation of the drug. Whether the skin sclerosis improves after discontinuation of the drug depends on the patient. In patients with severe skin sclerosis, functional impairment, such as flexion contracture of the fingers, may occur, and systemic therapy, such as steroids, may be necessary. When treating patients with skin sclerosis, it is important to keep in mind the possibility that the sclerotic lesion may be induced by a drug.",
"affiliations": "Department of Molecular Pathology of Skin, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: yasuhito@med.kanazawa-u.ac.jp.",
"authors": "Hamaguchi|Yasuhito|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.alit.2021.08.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1323-8930",
"issue": null,
"journal": "Allergology international : official journal of the Japanese Society of Allergology",
"keywords": "Drug; Fibrosis; Morphea; Scleroderma; Skin sclerosis",
"medline_ta": "Allergol Int",
"mesh_terms": null,
"nlm_unique_id": "9616296",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34465533",
"pubdate": "2021-08-28",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Drug-induced scleroderma-like lesion.",
"title_normalized": "drug induced scleroderma like lesion"
} | [
{
"companynumb": "JP-PFIZER INC-202101208677",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditiona... |
{
"abstract": "Tachycardia and supraventricular tachyarrhythmias often impair cardiovascular capacity in patients with decompensated heart failure (dHF) treated with inotropes. Normalization of heart rhythm or rate typically improves diastolic filling and stroke volume (SV). Thus, isochronal administration of an ultra-short-acting and highly selective β1-blockers, such as landiolol, along with inotropic calcium-sensitizer medications, such as levosimendan, could benefit patients with dHF.We present a case series of three patients with severe dHF and low ejection fraction who were successfully treated with a combination of landiolol and levosimendan. The co-administration of landiolol and levosimendan was well tolerated, improved cardiac function, normalized SV, and enabled the reduction of norepinephrine dosing in all patients. Additionally, the combination improved the vectorcardiographic spatial QRS-T angle and decreased the corrected QT interval. All patients were successfully discharged from the intensive care unit (ICU).A combination of levosimendan and landiolol was safe and well-tolerated. This combination may be a new option for successful treatment of patients with acute dHF complicated by sinus or supraventricular tachycardias.",
"affiliations": "Department of Anaesthesiology and Intensive Care Medical University of Lublin.;Department of Anaesthesiology and Intensive Care Medical University of Lublin.;Department of Anaesthesiology and Intensive Care Medical University of Lublin.;Department of Molecular Medicine and Surgery, Karolinska Institute.;Department of Nephrology, Institute of Medical Science, Jan Kochanowski University of Kielce.",
"authors": "Dabrowski|Wojciech|W|;Siwicka-Gieroba|Dorota|D|;Piasek|Ewa|E|;Schlegel|Todd T|TT|;Jaroszynski|Andrzej|A|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D009025:Morpholines; D000077464:Simendan; C077049:landiolol; D014508:Urea",
"country": "Japan",
"delete": false,
"doi": "10.1536/ihj.19-420",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1349-2365",
"issue": "61(2)",
"journal": "International heart journal",
"keywords": "Cardiac tachyarrhthmias; Corrected QT interval; Critically ill; Sepsis; Spatial QRS-T angle",
"medline_ta": "Int Heart J",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D000368:Aged; D002316:Cardiotonic Agents; D004359:Drug Therapy, Combination; D005260:Female; D006333:Heart Failure; D006801:Humans; D008297:Male; D009025:Morpholines; D000077464:Simendan; D013610:Tachycardia; D014508:Urea",
"nlm_unique_id": "101244240",
"other_id": null,
"pages": "384-389",
"pmc": null,
"pmid": "32132321",
"pubdate": "2020-03-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Combination of Landiolol and Levosimendan in Patients with Decompensated Heart Failure.",
"title_normalized": "successful combination of landiolol and levosimendan in patients with decompensated heart failure"
} | [
{
"companynumb": "PL-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-245286",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drug... |
{
"abstract": "As survival rates for children with acute lymphoblastic leukemia (ALL) improve, awareness of treatment complications becomes important. Osteonecrosis (ON) is a serious disabling complication in treated ALL patients. The aim of the study was to define the frequency of ON identified by magnetic resonance imaging (MRI) and to study the risk factors for ON.\n\n\n\nThe frequency of ON was evaluated retrospectively in 858 patients with ALL who were diagnosed at Children's Cancer Hospital of Egypt from January 2009 to December 2012. Patients were treated with St Jude Total Therapy Study XV.\n\n\n\nOf 858 patients evaluated, 665 were eligible for the study and 65 (9.7%) developed ON. The cumulative 5-year incidence of ON was 11.96% (SE, 0.131%). Of 154 patients aged 10 years and older, 40 (26%) developed ON. The mean age of patients with ON was 10.7 years. The prognostic factors with a significant relationship with ON were age 10 years and older (P = 0.0001) and intermediate-/high-risk group (P = 0.0001). However, gender did not have a significant relationship. At the onset of ON, the mean cumulative dexamethasone dose was 796 mg/m2 , and the mean total corticosteroid dose, calculated as prednisolone equivalence, was 6,431 mg/m2 . Out of 43 patients who developed ON while on corticosteroid therapy, 36 (84%) required dexamethasone dose modification and/or discontinuation.\n\n\n\nThe frequency of ON among the studied patients was 9.7%. Risk factors with a significant association with ON were older age and more intensive corticosteroid therapy.",
"affiliations": "Lecturer of Pediatric Oncology and Hematology, National Cancer Institute (NCI), Cairo University, Egypt, Consultant of Pediatric Oncology and Hematology, Children Cancer Hospital, Egypt.;Consultant of Pediatric Oncology and Hematology Children Cancer Hospital, Egypt.;Professor of Radiodiagnosis, National Cancer Institute (NCI), Cairo University, Egypt, Consultant of Radiodiagnosis, Children Cancer Hospital, Egypt.;Professor of Orthopedic Surgery, Kasr Al Eeiny, Cairo University, Egypt, Consultant of Orthopedic Surgery, Children Cancer Hospital, Egypt.;Board Certified Oncology Pharmacist, Children Cancer Hospital, Egypt.;Clinical Pharmacy, Children Cancer Hospital, Egypt.;Professor of Clinical Pathology, National Cancer Institute (NCI), Cairo University, Egypt, Consultant of Clinical Pathology, Children Cancer Hospital, Egypt.;Assistant Professor of Clinical Pathology, National Cancer Institute (NCI), Cairo University, Egypt, Consultant of Clinical Pathology, Children Cancer Hospital, Egypt.;Clinical Research, Children Cancer Hospital, Egypt.;Professor of Pediatric Oncology and Hematology, National Cancer Institute (NCI), Cairo University, Egypt, Consultant of Pediatric Oncology and Hematology Children Cancer Hospital, Egypt.",
"authors": "Ali|Nesreen|N|0000-0002-9770-6290;Gohar|Seham|S|;Zaky|Iman|I|;Elghoneimy|Ahmed|A|;Youssef|Sarah|S|;Sameer|Gehad|G|;Yassin|Dina|D|;Salem|Sherine|S|;Magdi|Hadeel|H|;Sidhom|Iman|I|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27440",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "66(1)",
"journal": "Pediatric blood & cancer",
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"title": "Osteonecrosis in children with acute lymphoblastic leukemia: A report from Children's Cancer Hospital Egypt (CCHE).",
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"abstract": "We report on the emergence and clinical relevance of an unusual BCR-ABL1 kinase domain mutational status in a 2-year-old female with p210-BCR-ABL Philadelphia chromosome-positive acute lymphoblastic leukaemia. We detected three BCR-ABL1 clones determined by the presence of the E255V, D276G and F317L mutations. We point out the usefulness of searching for mutated populations that survive tyrosine-kinase inhibitor therapy and the role of their clonal selection over time in relation to therapeutic intervention.",
"affiliations": "Paediatric Haematology Section, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CSIC/Universidad de Sevilla, Sevilla, Spain.",
"authors": "Molinos-Quintana|Agueda|A|;Aquino|Virginia|V|;Montero|Isabel|I|;Pérez-de Soto|Concepción|C|;García-Lozano|Raúl|R|;Pérez-Simón|José Antonio|JA|;Pérez-Hurtado|José María|JM|",
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"abstract": "We describe a case of Omenn syndrome displaying exudative erythroderma and other characteristic features, including alopecia, absent B and naïve T cells, hyper immunoglobulin E levels, and eosinophilia. A pathogenic recombination-activating RAG1 homozygous genetic mutation confirmed the diagnosis. She required frequent antibiotics at both treatment and prophylactic doses, which alone did not control her erythroderma, but her high risk of infection precluded the use of systemic agents such as cyclosporine, which would further suppress her already severely compromised immune system. Thrice-weekly topical dilute hypochlorite compresses, combined with skin acidification with a low pH emollient, were initiated to control inflammation and for cutaneous bacterial prophylaxis. She demonstrated a marked improvement in her erythroderma within days after treatment initiation. Further improvement continued with the addition of systemic corticosteroids, with resolution of erythroderma after her first dose. This case reveals for the first time that dilute topical hypochlorite and skin pH restoration holds promise to control severe dermatitis associated with immunodeficiency and inflammatory syndromes with minimal side effects.",
"affiliations": "Department of Dermatology, Case Western Reserve University, Cleveland, Ohio; margaret.wat@uhhospitals.org.;Department of Dermatology, Case Western Reserve University, Cleveland, Ohio.;Department of Dermatology, Case Western Reserve University, Cleveland, Ohio.;Department of Dermatology, Case Western Reserve University, Cleveland, Ohio.;Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and.;Department of Dermatology, Case Western Reserve University, Cleveland, Ohio.",
"authors": "Wat|Margaret|M|;Olicker|Arielle|A|;Meyerson|Howard|H|;Nedorost|Susan|S|;Paller|Amy S|AS|;Cooper|Kevin|K|",
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"mesh_terms": "D000279:Administration, Cutaneous; D000305:Adrenal Cortex Hormones; D003873:Dermatitis, Exfoliative; D003879:Dermatologic Agents; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006997:Hypochlorous Acid; D007231:Infant, Newborn; D016511:Severe Combined Immunodeficiency; D063465:Skin Cream; D017192:Skin Diseases, Bacterial",
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"title": "Topical Hypochlorite and Skin Acidification Improves Erythroderma of Omenn Syndrome.",
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"abstract": "Pheochromocytoma (PCC) is a rare catecholamine-secreting tumor that arises from chromaffin cells of the adrenal medulla which are derived from the neural crest. This report illustrates a 51-year-old Caucasian male with a history of hypertension diagnosed two years ago who presented to the hospital due to acute onset of right testicular pain of 3-day duration. Laboratory results and imaging revealed a presumptive diagnosis of PCC. The patient had undergone robot-assisted laparoscopic right adrenalectomy 14 days after being diagnosed with PCC due to perioperative management with phenoxybenzamine. The final pathology report revealed a PCC. At follow-up two weeks after discharge, the patient reported complete resolution of his testicular pain.",
"affiliations": "Department of Internal Medicine, HCA Healthcare/USF Morsani College of Medicine GME: Medical Center of Trinity, Trinity, FL, USA.;Department of Internal Medicine, HCA Healthcare/USF Morsani College of Medicine GME: Medical Center of Trinity, Trinity, FL, USA.;Department of Internal Medicine, HCA Healthcare/USF Morsani College of Medicine GME: Medical Center of Trinity, Trinity, FL, USA.;Department of Internal Medicine, HCA Healthcare/USF Morsani College of Medicine GME: Medical Center of Trinity, Trinity, FL, USA.;Department of Internal Medicine, HCA Healthcare/USF Morsani College of Medicine GME: Medical Center of Trinity, Trinity, FL, USA.",
"authors": "Patel|Jinal K|JK|https://orcid.org/0000-0002-1429-595X;Reddy|Varun|V|;Stepman|Gauthier|G|;Angelo|Debra|D|;Frunzi|Johnathan|J|",
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"fulltext": "\n==== Front\nCase Rep Endocrinol\nCase Rep Endocrinol\nCRIE\nCase Reports in Endocrinology\n2090-6501\n2090-651X\nHindawi\n\n10.1155/2021/6699409\nCase Report\nPheochromocytoma Presenting as Testicular Pain: An Unusual Case Report\nhttps://orcid.org/0000-0002-1429-595X\nPatel Jinal K. jinal.patel@hcahealthcare.com\n\nReddy Varun\nStepman Gauthier\nAngelo Debra\nFrunzi Johnathan\nDepartment of Internal Medicine, HCA Healthcare/USF Morsani College of Medicine GME: Medical Center of Trinity, Trinity, FL, USA\nAcademic Editor: Osamu Isozaki\n\n2021\n14 4 2021\n2021 669940918 12 2020\n7 3 2021\n29 3 2021\nCopyright © 2021 Jinal K. Patel et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nPheochromocytoma (PCC) is a rare catecholamine-secreting tumor that arises from chromaffin cells of the adrenal medulla which are derived from the neural crest. This report illustrates a 51-year-old Caucasian male with a history of hypertension diagnosed two years ago who presented to the hospital due to acute onset of right testicular pain of 3-day duration. Laboratory results and imaging revealed a presumptive diagnosis of PCC. The patient had undergone robot-assisted laparoscopic right adrenalectomy 14 days after being diagnosed with PCC due to perioperative management with phenoxybenzamine. The final pathology report revealed a PCC. At follow-up two weeks after discharge, the patient reported complete resolution of his testicular pain.\n\nHCA Healthcare\n==== Body\n1. Introduction\n\nPheochromocytoma (PCC) is a rare catecholamine-secreting tumor that arises from chromaffin cells of the adrenal medulla [1–4]. Histologically, chromaffin cells are derived from the neural crest during development [1–4]. In 2017, the World Health Organization (WHO) classified PCC as an adrenal tumor and extraadrenal tumor as paraganglioma; since both types of tumor cannot be differentiated on histological findings [1–4]. The incidence of PCC and paraganglioma ranges between 2 and 8 per million, whereas the incidence of PCC is approximately 500–1600 cases per year [5]. PCC may occur at any age; however, it is more commonly seen in the 3rd to 5th decade of life [3]. Typically, patients present with a triad of severe headache, sweating, and palpitations which occur in waves as a result of excess hormone release [1–3]. Furthermore, half of the patients can have paroxysmal hypertension. Less common symptoms include flushing, tremor, chest pain, weight loss, constipation, diarrhea, and warmth or heat intolerance [2]. The diagnosis of PCC is a combination of urine and serum analysis showing excess catecholamines and localization of the tumor by computerized tomography (CT) and magnetic resonance imaging (MRI) [1–4, 6]. Here, we present a case of a 51-year-old Caucasian male with PCC presenting as testicular pain.\n\n2. Case Presentation\n\nA 51-year-old Caucasian male with a past medical history of hypertension (diagnosed two years ago, treated with lisinopril 10 mg daily), nephrolithiasis, presented to the hospital with a 3-day complaint of right testicular pain. The pain radiated to the right flank, was intermittent, sharp, 5/10 in severity, aggravated with movement, and alleviated with rest. The pain in the scrotum had not improved, which caused him to present to the emergency department. He denied having hypertensive episodes, headaches, sweating, flushing, and palpitations.\n\nAn initial evaluation in the emergency department revealed the following vitals: temperature of 98.6 F, heart rate of 81 beats per minute, blood pressure (BP) of 137/96 mmHg, and oxygen saturation of 97% on room air. Initial laboratory results revealed mild leukocytosis with a white blood cell (WBC) count of 12,900 cells/mL. Due to the patient having acute scrotal pain and elevated WBC count, testicular etiologies such as testicular torsion, epididymitis, varicocele, hydrocele, or chronic testicular pain were ruled out with a thorough physical examination and testicular ultrasound (US). A CT of the abdomen and pelvis without contrast revealed a large right suprarenal mass. A follow-up CT abdomen with adrenal protocol revealed a 5.1 cm enhancing right adrenal mass, which was further detailed with an MRI with contrast (Figure 1). With findings of an adrenal gland mass on imaging, urine and serum analyses (Tables 1 and 2) were obtained, which revealed elevated catecholamines consistent with possible PCC. The patient was discharged home as he required perioperative blood pressure management with phenoxybenzamine. The patient was brought back to the hospital 14 days later for transperitoneal robot-assisted laparoscopic right adrenalectomy due to having multiple back surgeries. He was transferred to the intensive care unit (ICU) postoperatively for close monitoring of hemodynamics. The final pathology report revealed a PCC, 6.2 cm in size, with no evidence of necrosis, capsular invasion, or extension into periadrenal adipose tissue. The patient was discharged home on postoperative day three and to follow-up with hematology and oncology for surveillance and possible adjuvant chemotherapy. At follow-up two weeks after discharge, the patient reported complete resolution of his testicular pain.\n\n3. Discussion\n\nTesticular pain with acute onset warrants emergent evaluation with a thorough history and physical examination as well as urinalysis and imaging [7, 8]. For example, testicular torsion is a medical emergency, which presents as a high-riding testicle, which is confirmed with a scrotal US and can result in loss of testes if there is a delay of care [7–9]. In our patient, we were able to rule out potential medical emergencies with examination, urinalysis, and imaging as stated above. While less common, extrascrotal etiologies can cause testicular pain due to common nerve root pathways (T10-T12, L1-L2, and S2–S4) [10]. Thus, pathologies such as ureteral calculi, back pain, aortic aneurysm, intervertebral disc prolapse, hernias, and other intrabdominal pathologies that share common nerve pathways may present as acute testicular pain [10], which was the case of our patient.\n\nOur case is unique, as there have not been reported cases previously of PCC presenting as testicular pain. On the other hand, Cheungpasitporn et al. reported a case of adrenocortical carcinoma that presented as varicocele and renal vein thrombosis [11].\n\nThe majority of PCC are initially discovered as incidentalomas, while others are suspected in patients presenting with the typical symptoms as mentioned in the introduction or secondary cause of hypertension [12]. Our patient likely did not have the typical presentation of PCC as his hypertension was treated with lisinopril for the past 2 years, which likely masked his symptoms of catecholamine excess. In our case, the patient did not have evidence of acute testicular etiology as stated above, which warranted further investigation with a CT of the abdomen and pelvis as the patient had a history of renal calculi. There was no evidence of nephrolithiasis; however, there was an incidental finding of an adrenal mass. When an adrenal mass is found incidentally, the next step in management is to determine if it is malignant or functioning, which can be determined with laboratory tests and imaging studies [1–4]. PCC has increased attenuation on unenhanced CT scan revealing greater than 20 Hounsfield units (HU), with a delay in contrast medium washout [13, 14]. Our patient's CT scan measured 64 HU prior to contrast administration, which enhanced heterogeneously following contrast injection with delay in contrast medium washout. Also, PCC shows high signal intensity on T2-weighted MRI [13, 14]. Our patient's MRI demonstrated a slightly increased T2 signal and heterogeneous enhancement. Due to the imaging findings, PCC was higher on the differential and requires further investigation with biochemical assay [1–6, 15]. A 24-hour urinary metanephrine and plasma metanephrines were positive for excess catecholamines (Tables 1 and 2), further supporting the presumptive diagnosis of PCC. We later obtained a CT of the chest and MRI of the brain for staging, which was negative for metastatic disease. Once the diagnosis of PCC is confirmed, the next step in management is surgical resection [2, 16]. Our patient had undergone robot-assisted laparoscopic right adrenalectomy.\n\nWhile surgical resection of the tumor is usually definitive, it is associated with high mortality risk if not managed medically first [15]. Physical manipulation of the adrenal gland during surgery can cause a sudden release of catecholamines and cause intraoperative hypertensive emergency [15–17]. Thus, in the perioperative period, it is important to start patients on adrenergic blocking agents 10–14 days prior to surgery to decrease intraoperative hypertensive crisis [15–17]. Initial treatment consists of alpha-blockade with medications like phenoxybenzamine [17]. Our patient in the perioperative period was treated with phenoxybenzamine beginning 14 days prior to surgery. Alpha-blockage prevents peripheral vascular constriction and subsequently causes reflexive tachycardia. Beta-blockers are initially avoided, as blocking this initial reflex can cause dangerous hypertension due to unopposed alpha blockade. Once an adequate alpha-blockade has been achieved, which can be indicated by postural hypotension, a beta-blocker can be added. Our patient did report postural hypotension but was not treated with a beta-blocker. On the other hand, increased salt and fluid intake can be recommended to expand the intravascular volume and maintain BP preoperatively, which was done in our patient. After appropriate perioperative management is achieved, the final step in management is adrenalectomy. A patient may have the option of undergoing an open approach, laparoscopic or robotic-assisted laparoscopy adrenalectomy [16, 18, 19]. Comparing the different surgical approaches, robotic-assisted approach has been shown to decrease blood loss and have shorter hospital course when compared to open and laparoscopic approach [19]. In robotic-assisted adrenalectomy, patients may undergo transperitoneal or retroperitoneal laparoscopic adrenalectomy [16, 18]. Ultimately, our patient had undergone transperitoneal robot-assisted laparoscopic right adrenalectomy as he had multiple previous back surgeries. After surgical removal of the adrenal gland, patients should be monitored closely in the ICU due to potential complications of abrupt decline in catecholamine levels after tumor resection [20]. Finally, patients should be followed up with an MRI for recurrence for at least 10 years even after complete resection [6].\n\n4. Conclusion\n\nPhysicians should be aware that testicular tenderness needs further evaluation if a thorough history and physical exam do not reveal a cause. Furthermore, the combination of testicular pain and hypertension should raise suspicion for PCC, even in the absence of the typical symptoms for PCC.\n\nAcknowledgments\n\nThis research was supported in part by the HCA Healthcare and/or an HCA Healthcare affiliated entity.\n\nConsent\n\nThe patient provided informed consent.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 T2-Weighted MRI of the abdomen: slight increased T2 signal and heterogeneous enhancement of the right adrenal gland (arrows).\n\nTable 1 Urine analysis.\n\nUrine analysis\tResults\tReference range\t\nEpinephrine\t24 ug/L\tUndefined\t\nEpinephrine in 24 hours\t58\t0–20 ug/24 hr\t\nNorepinephrine\t128 ug/L\tUndefined\t\nNorepinephrine in 24 hours\t307\t0–135 ug/24 hr\t\nMetanephrine\t562 ug/L\tUndefined\t\nMetanephrine in 24 hours\t1345\t45–290 ug/24 hr\t\nNormetanephrine\t4520 ug/L\tUndefined\t\nNormetanephrine in 24 hours\t10848\t82–500 ug/24 hr\t\nDopamine\t112 ug/L\tUndefined\t\nDopamine in 24 hours\t269\t0–510 ug/24 hr\t\n\nTable 2 Serum analysis.\n\nSerum analysis\tResults\tReference range\t\nCarcinoembryonic antigen\t2.1\t0.0–0.5 ng/mL\t\nRenin activity\t3.010\t0.167–5.380 ng/mL/hr\t\nAldosterone\t1.1\t0.0–30.0 ng/dL\t\nDHEA sulfate\t151.0\t80.0–560.0 ng/dL\t\nAM cortisol\t2.29\tAM: 4.30–22.40 mcg/dL\t\nPM: 3.09–16.66 mcg/dL\t \t \t\nACTH\t8.9\t7.2–63.3 pg/mL\t\nPlasma metanephrine\t510\t0–62 pg/mL\t\nPlasma normetanephrine\t5648\t0–145 pg/mL\t\nDHEA: dihydroepiandrosterone, ACTH: adrenocorticotropic hormone.\n==== Refs\n1 Neumann H. P. H. Young W. F. Eng C. Pheochromocytoma and paraganglioma New England Journal of Medicine 2019 381 6 552 565 10.1056/nejmra1806651 2-s2.0-85070618547\n2 Reisch N. Peczkowska M. Januszewicz A. Neumann H. P. Pheochromocytoma: presentation, diagnosis and treatment Journal of Hypertension 2006 24 12 2331 2339 10.1097/01.hjh.0000251887.01885.54 2-s2.0-33750592253 17082709\n3 Farrugia F.-A. charalampopoulos A. Pheochromocytoma Endocrine Regulations 2019 53 3 191 212 10.2478/enr-2019-0020 2-s2.0-85072141432 31517632\n4 Sbardella E. Grossman A. B. Pheochromocytoma: an approach to diagnosis Best Practice & Research Clinical Endocrinology & Metabolism 2020 34 2 p. 101346 10.1016/j.beem.2019.101346\n5 Aygun N. Pheochromocytoma and paraganglioma: from epidemiology to clinical findings SiSli Etfal Hastanesi Tip Bulteni/The Medical Bulletin of Sisli Hospital 2020 54 10.14744/semb.2020.18794\n6 Nölting S. Ullrich M. Pietzsch J. Current management of pheochromocytoma/paraganglioma: a guide for the practicing clinician in the era of precision medicine Cancers 2019 11 10 1505 1527 10.3390/cancers11101505 2-s2.0-85073549059\n7 Gordhan C. G. Sadeghi-Nejad H. Scrotal pain: evaluation and management Korean Journal of Urology 2015 56 1 3 11 10.4111/kju.2015.56.1.3 2-s2.0-84920986257 25598931\n8 Wright S. Hoffmann B. Emergency ultrasound of acute scrotal pain European Journal of Emergency Medicine 2015 22 1 2 9 10.1097/MEJ.0000000000000123 2-s2.0-84920274591 24910960\n9 Sharp V. J. Kieran K. Arlen A. M. Testicular torsion: diagnosis, evaluation, and management American Family Physician 2013 88 12 835 840 24364548\n10 Patel A. P. Anatomy and physiology of chronic scrotal pain Translational Andrology and Urology 2017 6 S1 p. S51 10.21037/tau.2017.05.32 2-s2.0-85019553799\n11 Cheungpasitporn W. Horne J. M. Howarth C. B. Adrenocortical carcinoma presenting as varicocele and renal vein thrombosis: a case report Journal of Medical Case Reports 2011 5 1 1 5 10.1186/1752-1947-5-337 2-s2.0-79960885338 21205286\n12 Whelton P. K. Carey R. M. Aronow W. S. Detection, evaluation, and management of high blood pressure in adults a report of the american college of cardiology/American heart association task force on clinical Pratice guidelines Hypertension 2017 71 10.1161/HYP.0000000000000065 2-s2.0-85061038737\n13 Leung K. Stamm M. Raja A. Low G. Pheochromocytoma: the range of appearances on ultrasound, CT, MRI, and functional imaging American Journal of Roentgenology 2013 200 2 370 378 10.2214/AJR.12.9126 2-s2.0-84873608247 23345359\n14 Wang F. Liu J. Zhang R. CT and MRI of adrenal gland pathologies Quantitative Imaging in Medicine and Surgery 2018 8 8 p. 853 10.21037/qims.2018.09.13 2-s2.0-85055688734\n15 Brouwers F. M. Lenders J. W. M. Eisenhofer G. Pacak K. Pheochromocytoma as an endocrine emergency Reviews in Endocrine and Metabolic Disorders 2003 4 2 121 128 10.1023/A:1022981801344 2-s2.0-0038374790 12766539\n16 Patel D. Surgical approach to patients with pheochromocytoma Gland Surgery 2020 9 1 32 42 10.21037/gs.2019.10.20 32206597\n17 Naranjo J. Dodd S. Martin Y. N. Perioperative management of pheochromocytoma Journal of Cardiothoracic and Vascular Anesthesia 2017 31 4 1427 1439 10.1053/j.jvca.2017.02.023 2-s2.0-85017139268 28392094\n18 Arezzo A. Bullano A. Cochetti G. Transperitoneal versus retroperitoneal laparoscopic adrenalectomy for adrenal tumours in adults Cochrane Database of Systematic Reviews 2018 12 12 p. CD011668 10.1002/14651858.CD011668.pub2 2-s2.0-85059277943\n19 Jayakumaran J. Patel S. D. Gangrade B. K. Narasimhulu D. M. Pandian S. R. Silva C. Robotic-assisted laparoscopy in reproductive surgery: a contemporary review Journal of Robotic Surgery 2017 11 2 97 109 10.1007/s11701-017-0682-4 2-s2.0-85012306095 28194637\n20 Mamilla D. Araque K. Brofferio A. Postoperative management in patients with pheochromocytoma and paraganglioma Cancers (Basel) 2019 11 10.3390/cancers11070936 2-s2.0-85068716524\n\n",
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"title": "Pheochromocytoma Presenting as Testicular Pain: An Unusual Case Report.",
"title_normalized": "pheochromocytoma presenting as testicular pain an unusual case report"
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"abstract": "Consensus guidelines on the management of methotrexate-induced nephrotoxicity using glucarpidase (Voraxaze) may be relatively unfamiliar to the nephrology community.\nA 61-year-old man with intravascular large B-cell lymphoma was admitted for cycle #1 of high-dose methotrexate (HDMTX) following 2 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. On admission, he was clinically euvolemic and had a creatinine clearance of 98 mL/min. He received standard HDMTX toxicity prophylaxis with volume expansion, urinary alkalinization, and leucovorin rescue.\nDespite prophylactic efforts, he developed a severe acute kidney injury, creatinine 63 to 226 µmol/L (2.56 mg/dL), following HDMTX, impaired methotrexate clearance, and neurotoxicity manifested by status epilepticus.\nHe was given glucarpidase to convert extracellular methotrexate into its inactive metabolites, glutamate and DAMPA (4-deoxy-4-amino-N 10-methylpteroic acid) at 52 hours post-HDMTX. Cross-reactivity between commercial methotrexate immunoassays with DAMPA led to falsely elevated methotrexate concentrations for much longer than expected based on the current guideline (5 days instead of <48 hours). This required ongoing monitoring of methotrexate concentration by mass spectrometry.\nThe patient remained nonoliguric and did not develop acute indications for dialysis. Serum creatinine peaked at 608 µmol/L (6.88 mg/dL) 6 days after HDMTX. He ultimately had a full renal and neurologic recovery.\nGlucarpidase is an effective option for nonrenal elimination of methotrexate-induced nephrotoxicity. Timing of methotrexate concentration monitoring to assess for toxicity, how to access the drug, and the need for ongoing monitoring by mass spectrometry beyond the guideline recommendation are highlighted for centers where HDMTX therapy may be used.",
"affiliations": "Nephrology, St. Michael's Hospital, University of Toronto, Ontario, Canada.;Department of Laboratory Medicine & Pathobiology, St. Michael's Hospital, University of Toronto, Ontario, Canada.;Department of Laboratory Medicine & Pathobiology, The Hospital for Sick Children, University of Toronto, Ontario, Canada.;Medical Oncology, St. Michael's Hospital, University of Toronto, Ontario, Canada.;Medical Oncology, St. Michael's Hospital, University of Toronto, Ontario, Canada.;Department of Pharmacy, St. Michael's Hospital, University of Toronto, Ontario, Canada.;Nephrology, St. Michael's Hospital, University of Toronto, Ontario, Canada.;Nephrology, St. Michael's Hospital, University of Toronto, Ontario, Canada.",
"authors": "Young|Ann|A|https://orcid.org/0000-0001-6562-8139;Beriault|Daniel|D|;Jung|Benjamin|B|;Nikonova|Anna|A|;Abosh|Dory|D|;Lee|Samantha|S|;Zaltzman|Jeff|J|;Perl|Jeffrey|J|",
"chemical_list": null,
"country": "England",
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"doi": "10.1177/2054358119895078",
"fulltext": "\n==== Front\nCan J Kidney Health DisCan J Kidney Health DisCJKspcjkCanadian Journal of Kidney Health and Disease2054-3581SAGE Publications Sage CA: Los Angeles, CA 10.1177/205435811989507810.1177_2054358119895078Educational Case ReportDAMPAned Methotrexate: A Case Report and Review of the Management of Acute Methotrexate Toxicity https://orcid.org/0000-0001-6562-8139Young Ann 1Beriault Daniel 2Jung Benjamin 3Nikonova Anna 4Abosh Dory 4Lee Samantha 5Zaltzman Jeff 1Perl Jeffrey 11 Nephrology, St. Michael’s Hospital, University of Toronto, Ontario, Canada2 Department of Laboratory Medicine & Pathobiology, St. Michael’s Hospital, University of Toronto, Ontario, Canada3 Department of Laboratory Medicine & Pathobiology, The Hospital for Sick Children, University of Toronto, Ontario, Canada4 Medical Oncology, St. Michael’s Hospital, University of Toronto, Ontario, Canada5 Department of Pharmacy, St. Michael’s Hospital, University of Toronto, Ontario, CanadaAnn Young, Nephrology, St. Michael’s Hospital, University of Toronto, 30 Bond Street, 3 Shuter, Room 060, Toronto, Ontario, Canada M5B 1W8. Email: ann.young@mail.utoronto.ca21 12 2019 2019 6 20543581198950785 9 2019 6 11 2019 © The Author(s) 20192019Canadian Society of Nephrology, unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Rationale:\nConsensus guidelines on the management of methotrexate-induced nephrotoxicity using glucarpidase (Voraxaze) may be relatively unfamiliar to the nephrology community.\n\nPresenting concerns of the patient:\nA 61-year-old man with intravascular large B-cell lymphoma was admitted for cycle #1 of high-dose methotrexate (HDMTX) following 2 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. On admission, he was clinically euvolemic and had a creatinine clearance of 98 mL/min. He received standard HDMTX toxicity prophylaxis with volume expansion, urinary alkalinization, and leucovorin rescue.\n\nDiagnoses:\nDespite prophylactic efforts, he developed a severe acute kidney injury, creatinine 63 to 226 µmol/L (2.56 mg/dL), following HDMTX, impaired methotrexate clearance, and neurotoxicity manifested by status epilepticus.\n\nInterventions:\nHe was given glucarpidase to convert extracellular methotrexate into its inactive metabolites, glutamate and DAMPA (4-deoxy-4-amino-N10-methylpteroic acid) at 52 hours post-HDMTX. Cross-reactivity between commercial methotrexate immunoassays with DAMPA led to falsely elevated methotrexate concentrations for much longer than expected based on the current guideline (5 days instead of <48 hours). This required ongoing monitoring of methotrexate concentration by mass spectrometry.\n\nOutcomes:\nThe patient remained nonoliguric and did not develop acute indications for dialysis. Serum creatinine peaked at 608 µmol/L (6.88 mg/dL) 6 days after HDMTX. He ultimately had a full renal and neurologic recovery.\n\nLessons learned:\nGlucarpidase is an effective option for nonrenal elimination of methotrexate-induced nephrotoxicity. Timing of methotrexate concentration monitoring to assess for toxicity, how to access the drug, and the need for ongoing monitoring by mass spectrometry beyond the guideline recommendation are highlighted for centers where HDMTX therapy may be used.\n\nAbrégé\nJustification:\nLes lignes directrices consensuelles sur la prise en charge de la néphrotoxicité induite par le méthotrexate par l’administration de glucarpidase (VoraxazeMD) sont possiblement mal connues en néphrologie.\n\nPrésentation du cas:\nNous présentons le cas d’un patient de 61 ans atteint d’un lymphome intravasculaire à grandes cellules B qui avait été admis pour un cycle de traitement à dose élevée de méthotrexate (HDMTX) après deux cycles de chimiothérapie par R-CHOP. À l’admission, le patient était cliniquement euvolémique et présentait une clairance de la créatinine à 98 mL/min. Le patient a reçu la prophylaxie standard pour une toxicité à HDMTX avec expansion volumique, alcalinisation urinaire et sauvetage par leucovorine.\n\nDiagnostic:\nMalgré les mesures prophylactiques, l’état du patient a évolué vers une grave insuffisance rénale aigüe (créatinine initiale de 63 à 226 µmol/L [2,56 mg/dL]) après le traitement au HDMTX, de même qu’une altération de la clairance du méthotrexate et une neurotoxicité manifestée par un status epilepticus.\n\nInterventions:\nLe patient a reçu du glucarpidase pour convertir le méthotrexate extracellulaire en ses métabolites inactifs, le glutamate et le DAMPA (acide 4-déoxy-4-amino-N10-méthylptéroïque) 52 heures après le traitement au HDMTX. La réactivité croisée entre les immunoessais commerciaux au méthotrexate et le DAMPA a entraîné des concentrations faussement élevées de méthotrexate pour beaucoup plus longtemps que prévu selon la recommandation actuelle (5 jours plutôt que < 48 heures). Cette situation a nécessité une surveillance continue de la concentration du méthotrexate par spectrométrie de masse.\n\nRésultats:\nLe patient est demeuré non oligurique et n’a pas nécessité de dialyse. Le taux de créatinine sérique a culminé à 608 µmol/L (6,88 mg/dL) six jours après l’administration de HDMTX. Les fonctions rénale et neurologique du patient se sont finalement rétablies complètement.\n\nLeçons tirées:\nLa glucarpidase est une option efficace pour éliminer de façon non rénale la néphrotoxicité induite par le méthotrexate. Le moment de mesurer la concentration de méthotrexate pour évaluer la toxicité, la façon d’accéder au médicament et la nécessité d’une surveillance continue par spectrométrie de masse au-delà de la recommandation actuelle sont clarifiés pour les centres où un traitement par HDMTX pourrait être administré.\n\nlymphomamethotrexatetoxicityglucarpidaseDAMPAcover-dateJanuary-December 2019typesetterts1\n==== Body\nWhat was known before\nGlucarpidase can be used for nonrenal elimination of methotrexate in the setting of nephrotoxicity. Its use is supported by recent guidelines published in the oncology literature.\n\nWhat this adds\nCross-reactivity of commercial methotrexate immunoassays with DAMPA (4-deoxy-4-amino-N10-methylpteroic acid) led to falsely elevated methotrexate concentrations for much longer than expected (4-5 days). Thus, ongoing monitoring of methotrexate concentrations by mass spectrometry beyond the guideline recommendation is suggested.\n\nIntroduction\nHigh-dose methotrexate (HDMTX; ≥500 mg/m2) is used as part of chemotherapy regimens for various adult and childhood cancers.1 By interfering with folate metabolism, methotrexate (MTX) impairs thymidine and DNA synthesis in rapidly dividing malignant cells, leading to cell death. Polyglutamation increases the size and charge of MTX, enhancing its antiproliferative effects through intracellular accumulation and decreased efflux.2 Methotrexate is primarily excreted by the kidneys (80%-90%).3 Methotrexate can cause afferent arteriolar vasoconstriction, precipitate in tubules, and cause direct tubular injury. Acute kidney injury (AKI) has been reported in 2% to 12% of patients receiving HDMTX.4 In cases of severe renal dysfunction, glucarpidase (Voraxaze) can be used for nonrenal elimination by converting extracellular MTX into its inactive metabolites.5\n\nPresenting Concerns\nA 61-year-old man was admitted for cycle #1 of HDMTX. Three months ago, he was diagnosed with intravascular large B-cell lymphoma (ILCL). He initially presented with seizures and the diagnosis was confirmed via right temporal lobe biopsy. His seizures were controlled with levetiracetam. Prior to admission, he received 2 of 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy with no adverse effects. Other medical history was noncontributory.\n\nClinical Findings\nOn admission, he was euvolemic with an unremarkable physical examination. His creatinine was 63 µmol/L (0.71 mg/dL) and his creatinine clearance was 98 mL/min. Serum alanine aminotransferase was normal (38 U/L). Per protocol, he underwent volume expansion and urinary alkalinization with intravenous (IV) sodium bicarbonate 0.15 mEq/mL at 160 mL/h. Urine pH was assessed every 12 hours and maintained at ≥7.0, with urine output ≥ 100 mL/h. After 12 hours of pretreatment, he received 6500 mg (=3500 mg/m2) of IV MTX over 4 hours, which was well tolerated.\n\nFollowing HDMTX, he developed an AKI with a creatinine of 226 µmol/L (2.56 mg/dL) and a methotrexate concentration ([MTX]) of 175 µmol/L by immunoassay (>35× the toxic threshold) at 18 hours. High-dose leucovorin (folinic acid) was immediately started at 1860 mg (=1000 mg/m2) IV over 30 minutes every 3 hours to allow the formation of reduced intracellular folate in the presence of MTX. Variability in polyglutamation between tumor cells and nonmalignant cells allows leucovorin to selectively rescue nonmalignant cells from the effects of HDMTX while maintaining tumor cell cytotoxicity.2\nTable 1 summarizes the patient’s clinical course.\n\nTable 1. Patient’s Timeline.\n\nDay\tEvent\tHours post-HDMTX\tSerum creatinine (µmol/L)\tMethotrexate concentration\t\nDay -41\tDiagnosed with DLBCL with cerebral vessel involvement\t\t\t\t\nDay -33\tR-CHOP, cycle #1\t\t\t\t\nDay -12\tR-CHOP, cycle #2\t\t\t\t\nDay 0\tHDMTX, cycle #1\t0 (=1400h)\t63 (at baseline)\t\t\nAKI identified\nHigh-dose leucovorin started at 1000 mg/m2 IV every 3 hours (10× standard dose)\t18\t226\t175 µmol/L (>35× the toxic threshold)\t\nDay 1\tProgressive AKI\t41\t374\t31 µmol/L (persistently toxic concentration)\t\nNeurotoxicity (status epilepticus), patient transferred to ICU\t42\t\t\t\n\nGlucarpidase procured and administered, 50 units/kg IV over 5 minutes\n\t\n52\n\t\n434\n\t\t\nDay 2\tDiscrepancy between methotrexate concentration by immunoassay and LC-MS/MS\t60\t479\tImmunoassay: 7.26 µmol/L\nLC-MS/MS: <0.05 µmol/L\t\nDay 6\tPeak serum creatinine reached; patient remained nonoliguric with no acute indications for dialysis\t\t608\tImmunoassay: 1.60 µmol/L\t\nDay 31\tPatient transferred to ward\t\t88\t\t\nDay 38\tR-CHOP, cycle #3\t\t63\t\t\nDay 44\tPatient discharged to rehab\t\t60\t\t\nNote. To convert serum creatinine from µmol/L to mg/dL, multiply by 0.0113. HDMTX = high-dose methotrexate; DLBCL = diffuse large B-cell lymphoma; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; AKI = acute kidney injury; IV = intravenous; ICU = intensive care unit; LC-MS/MS = liquid chromatography-tandem mass spectrometry.\n\nDiagnostic Focus and Assessment\nDespite undergoing volume expansion, urinary alkalinization, and leucovorin rescue, the patient had progressive AKI from MTX-induced nephrotoxicity with a further increase in creatinine to 374 µmol/L (4.23 mg/dL). Notably, he had no traditional risk factors for MTX toxicity, such as body mass index ≥ 25 kg/m2, urine pH < 7.0, IV fluid intake < 3 L/m2/24 h, diarrhea, or baseline renal or hepatic dysfunction.6 Previous case reports identified a potential interaction between MTX and levetiracetam resulting in delayed MTX elimination, but a retrospective review of 81 patients receiving 280 cycles of HDMTX did not support this interaction.7 Whether he was genetically susceptible to having altered pharmacodynamics of MTX handling was unknown; no testing was done to evaluate this. With severe renal dysfunction, MTX clearance was impaired as evidenced by persistently elevated [MTX] (31.00 µmol/L at 41 hours by immunoassay). This led to neurotoxicity manifested by electroencephalogram (EEG)-confirmed status epilepticus from a right temporal focus. There have been 3 other cases of status epilepticus in adults receiving HDMTX.8-10 The patient had a diagnostic brain biopsy, which likely increased his risk for neurological complications. He also developed a transaminitis 1 week after HDMTX, peaking at 12 times the upper limit of normal after 3 weeks.\n\nTherapeutic Focus and Assessment\nGiven his severe AKI and clinical sequelae following HDMTX, a decision was made to administer glucarpidase (Voraxaze), the carboxypeptidase G2 enzyme that converts extracellular MTX into its inactive metabolites, glutamate and DAMPA (4-deoxy-4-amino-N10-methylpteroic acid), which are eliminated by the liver. Glucarpidase decreases plasma [MTX] by 98% within 15 minutes if given within 48 to 60 hours of HDMTX.4 An alternative would have been high-flux hemodialysis (HFHD). Methotrexate has a low molecular weight (454 daltons), but its dialyzability is limited by high protein binding (50%) and high volume of distribution. Serum MTX clearance using HFHD is between 1.00 and 2.04 mL/min/kg11 and has a half-life during HFHD of 2.3 to 3.4 hours,12 with a mean reduction in [MTX] between 42% and 94% over 4 to 12 hours.13 Prolonged treatment is often required because hemodialysis clears MTX from the intravascular compartment and a rebound of free MTX may be seen when dialysis is stopped. Continuous venovenous hemodiafiltration with maximum effluent rates has also been effective.14\n\nPer the 2017 consensus guidelines on the use of glucarpidase in the setting of rising creatinine, expert opinion recommends its use in patients with 24-hour [MTX] > 50 µM, 36-hour [MTX] > 30 µM, 42-hour [MTX] > 10 µM, or 48-hour [MTX] > 5 µM.15 The patient’s [MTX] was within the recommended treatment range. As such, glucarpidase was procured and administered (50 units/kg IV bolus over 5 minutes) at 52 hours post-HDMTX. He required 4 vials (1000 units/vial) at a cost of CAD39 200. There were no contraindications per the drug monograph and no dose adjustments needed for renal dysfunction.5 A smaller dose may have also been effective.16 Leucovorin was held 2 hours before and after glucarpidase to prevent its metabolism to 5-formylpteroate and glutamate.15\n\nThe patient’s [MTX] reassessed 8 hours after glucarpidase remained elevated at 7.26 µmol/L by immunoassay but was <0.05 µmol/L by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Figure 1 shows his [MTX] using 3 different assays. Cross-reactivity with DAMPA ranges from 26% to 100% for common MTX immunoassays,17,18 leading to falsely elevated [MTX]. Consensus guidelines advise on monitoring [MTX] during the first 48 hours by a chromatographic method only, which is based on the pharmacokinetic literature suggesting that DAMPA’s half-life is 9 hours,5 after which monitoring by immunoassay is considered acceptable. Interestingly, his [MTX] by immunoassay remained falsely elevated for more than 4.5 days after glucarpidase, far longer than 48 hours. The patient had not yet developed any significant liver impairment that would have impacted DAMPA’s metabolism.\n\nFigure 1. Patient’s methotrexate concentrations.\n\nNote. To convert serum creatinine from µmol/L to mg/dL, multiply by 0.0113. MTX = methotrexate; LC-MS/MS = liquid chromatography-tandem mass spectrometry; HDMTX = high-dose methotrexate.\n\nFollow-up and Outcomes\nThe patient remained nonoliguric with urine output consistently ≥ 100 mL/h and did not develop acute indications for dialysis. Serum creatinine peaked at 608 µmol/L (6.88 mg/dL) 6 days after HDMTX, with full recovery to baseline by 31 days. His renal course was consistent with previous literature.19 Neurologically, his seizures were controlled with clobazam and lacosamide. His course was further complicated by febrile neutropenia and treated with broad-spectrum antibiotics. He was discharged to rehab 45 days after admission. The possibility of rechallenging him with intrathecal MTX was discussed; however, he declined further MTX and continued with R-CHOP chemotherapy.\n\nDiscussion\nThis report highlights a case of MTX-induced nephrotoxicity managed with glucarpidase that was refractory to standard prophylaxis. The 2017 consensus guidelines on the use of glucarpidase may be relatively unfamiliar to the nephrology community.15 This patient had a toxic [MTX] and severe AKI at 18 hours, but there are no recommendations on administering glucarpidase within 24 hours of receiving HDMTX. In retrospect, had [MTX] been reassessed at 24 hours, glucarpidase may have been administered earlier than 52 hours before he experienced further clinical toxicity.\n\nGlucarpidase is only approved in the United States but was accessible through Health Canada’s Special Access Program given the serious nature of this patient’s clinical course despite standard prophylaxis. Since 2017, there have been 19 orders across Canada, 172 orders in the United States, and 222 orders within the European Union, predominantly in France (S. Ward, BTG International Inc, personal communication, February 14, 2019). Glucarpidase is costly, but it is difficult to compare the costs to acute dialysis given the unknown duration of therapy needed. In Canada, the incremental cost of AKI requiring dialysis has been estimated at CAD18 291.20 Cost considerations of using glucarpidase would need to be weighed against the speed and effectiveness at which glucarpidase decreases plasma [MTX] and the inherent risks associated with hemodialysis.\n\nA novel finding from this case is the prolonged duration of falsely elevated [MTX] by immunoassay due to the cross-reactivity with DAMPA (4-5 days). Perhaps, the pharmacokinetic literature on DAMPA is not as robust as expected. In this case, elevated [MTX] by immunoassay beyond 48 hours after glucarpidase caused unnecessary confusion and consideration of the need for repeat glucarpidase or dialysis. Confirmation of undetectable [MTX] by LC-MS/MS supported ongoing expectant management. Future iterations of glucarpidase consensus guidelines should advise for monitoring by LC-MS/MS well beyond 48 hours. Notably, only 1 lab in Canada is equipped to analyze MTX by LC-MS/MS, which is relevant for Canadian physicians who may use this drug. In the future, an immunoassay designed to address this limitation may aid in clinical decision making.\n\nThe authors acknowledge The Hospital for Sick Children for the measurement of methotrexate by chemiluminescent immunoassay and LC-MS/MS.\n\nList of Abbreviations: AKI, acute kidney injury; CNS, central nervous system; DAMPA, 4-deoxy-4-amino-N10-methylpteroic acid; EEG, electroencephalogram; HDMTX, high-dose methotrexate; HFHD, high-flux hemodialysis; ILCL, intravascular large B-cell lymphoma; LC-MS/MS, liquid chromatography-tandem mass spectrometry; [MTX], methotrexate concentration; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.\n\nEthics Approval and Consent to Participate: Research Ethics Board approval was not required for this case report. The authors obtained written patient consent to disseminate this case.\n\nConsent for Publication: Consent for publication has been provided by all authors.\n\nAvailability of Data and Materials: The data and materials are not available for this study.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nORCID iD: Ann Young \nhttps://orcid.org/0000-0001-6562-8139\n==== Refs\nReferences\n1 \nTreon SP Chabner BA. \nConcepts in use of high-dose methotrexate therapy . Clin Chem . 1996 ;42 (8 \nPt 2):1322 -1329 .8697606 \n2 \nCohen IJ. \nDefining the appropriate dosage of folinic acid after high-dose methotrexate for childhood acute lymphatic leukemia that will prevent neurotoxicity without rescuing malignant cells in the central nervous system . J Pediatr Hematol Oncol . 2004 ;26 (3 ):156 -163 .15125607 \n3 \nWinograd B Lippens RJ Oosterbaan MJ Dirks MJ Vree TB van der Kleijn E. \nRenal excretion and pharmacokinetics of methotrexate and 7-hydroxy-methotrexate following a 24-h high dose infusion of methotrexate in children . Eur J Clin Pharmacol . 1986 ;30 (2 ):231 -238 .3709652 \n4 \nWidemann BC Balis FM Kim A , et al\nGlucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome . J Clin Oncol . 2010 ;28 (25 ):3979 -3986 .20679598 \n5 \nVoraxaze Dosing & Administration—Voraxaze . https://www.voraxaze.com/Dosing-Administration. Accessed February 11, 2019 .\n6 \nSchwartz S Borner K Muller K , et al\nGlucarpidase (carboxypeptidase g2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy . Oncologist . 2007 ;12 (11 ):1299 -1308 .18055849 \n7 \nReeves D DiDominick S Finn S Kim HJ Shake A. \nMethotrexate elimination when coadministered with levetiracetam . Ann Pharmacother . 2016 ;50 (12 ):1016 -1022 .27511814 \n8 \nNaing A Luong D Extermann M. \nMethotrexate-induced status epilepticus . Am J Hematol . 2005 ;80 (1 ):35 -37 .16138356 \n9 \nFinkelstein Y Zevin S Heyd J Bentur Y Zigelman Y Hersch M. \nEmergency treatment of life-threatening intrathecal methotrexate overdose . Neurotoxicology . 2004 ;25 (3 ):407 -410 .15019303 \n10 \nRao RD Swanson JW Dejesus RS Hunt CH Tefferi A. \nMethotrexate induced seizures associated with acute reversible magnetic resonance imaging (MRI) changes in a patient with acute lymphoblastic leukemia . Leuk Lymphoma . 2002 ;43 (6 ):1333 -1336 .12153004 \n11 \nWall SM Johansen MJ Molony DA DuBose TD JrJaffe N Madden T. \nEffective clearance of methotrexate using high-flux hemodialysis membranes . Am J Kidney Dis . 1996 ;28 (6 ):846 -854 .8957036 \n12 \nSaland JM Leavey PJ Bash RO Hansch E Arbus GS Quigley R. \nEffective removal of methotrexate by high-flux hemodialysis . Pediatr Nephrol . 2002 ;17 (10 ):825 -829 .12376811 \n13 \nWidemann BC Balis FM Kempf-Bielack B , et al\nHigh-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma . Cancer . 2004 ;100 (10 ):2222 -2232 .15139068 \n14 \nVilay AM Mueller BA Haines H Alten JA Askenazi DJ. \nTreatment of methotrexate intoxication with various modalities of continuous extracorporeal therapy and glucarpidase . Pharmacotherapy . 2010 ;30 (1 ):111 .20030480 \n15 \nRamsey LB Balis FM O’Brien MM , et al\nConsensus guideline for use of glucarpidase in patients with high-dose methotrexate induced acute kidney injury and delayed methotrexate clearance . Oncologist . 2018 ;23 (1 ):52 -61 .29079637 \n16 \nScott JR Zhou Y Cheng C , et al\nComparable efficacy with varying dosages of glucarpidase in pediatric oncology patients . Pediatr Blood Cancer . 2015 ;62 (9 ):1518 -1522 .25631103 \n17 \nAlbertioni F Rask C Eksborg S , et al\nEvaluation of clinical assays for measuring high-dose methotrexate in plasma . Clin Chem . 1996 ;42 (1 ):39 -44 .8565230 \n18 \nBouquie R Gregoire M Hernando H , et al\nEvaluation of a methotrexate chemiluminescent microparticle immunoassay: comparison to fluorescence polarization immunoassay and liquid chromatography-tandem mass spectrometry . Am J Clin Pathol . 2016 ;146 (1 ):119 -124 .27357291 \n19 \nWidemann BC Adamson PC. \nUnderstanding and managing methotrexate nephrotoxicity . Oncologist . 2006 ;11 (6 ):694 -703 .16794248 \n20 \nCollister D Pannu N Ye F , et al\nHealth care costs associated with AKI . Clin J Am Soc Nephrol . 2017 ;12 (11 ):1733 -1743 .29051143\n\n",
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"keywords": "DAMPA; glucarpidase; lymphoma; methotrexate; toxicity",
"medline_ta": "Can J Kidney Health Dis",
"mesh_terms": null,
"nlm_unique_id": "101640242",
"other_id": null,
"pages": "2054358119895078",
"pmc": null,
"pmid": "31903191",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "27511814;8697606;12376811;12153004;3709652;18055849;20679598;16138356;15019303;15139068;27357291;8957036;29079637;29051143;25631103;16794248;15125607;20030480;8565230",
"title": "DAMPAned Methotrexate: A Case Report and Review of the Management of Acute Methotrexate Toxicity.",
"title_normalized": "dampaned methotrexate a case report and review of the management of acute methotrexate toxicity"
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"abstract": "We present the case of a patient who presented to the Emergency Department (ED) 48 h after successful in vitro fertilization with abdominal pain, hypotension, and free fluid on an ED-focused abdominal sonogram for trauma study. This presentation is typical of Ovarian Hyperstimulation Syndrome (OHSS), a diagnosis that may be unfamiliar to many Emergency Physicians. With the increasing frequency of in vitro fertilization procedures, this disease process is becoming more common. Numerous complications can occur with OHSS, including third-space fluid accumulation, hemoconcentration, renal failure, and thromboembolic phenomena. Vigilance is required as these patients are at increased risk of ovarian torsion, ovarian rupture with internal hemorrhage, ectopic pregnancy, and infection. This case report provides an overview of clinical features and emergent management of OHSS.",
"affiliations": "Madigan Army Medical Center Emergency Department, Tacoma, Washington, USA.",
"authors": "Madill|Justin J|JJ|;Mullen|Neil B|NB|;Harrison|Benjamin P|BP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2007.11.074",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "35(3)",
"journal": "The Journal of emergency medicine",
"keywords": null,
"medline_ta": "J Emerg Med",
"mesh_terms": "D015746:Abdominal Pain; D000328:Adult; D005260:Female; D005307:Fertilization in Vitro; D006400:Hematocrit; D006801:Humans; D016471:Ovarian Hyperstimulation Syndrome; D010053:Ovary; D011247:Pregnancy; D014463:Ultrasonography",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "283-6",
"pmc": null,
"pmid": "18403169",
"pubdate": "2008-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ovarian hyperstimulation syndrome: a potentially fatal complication of early pregnancy.",
"title_normalized": "ovarian hyperstimulation syndrome a potentially fatal complication of early pregnancy"
} | [
{
"companynumb": "US-009507513-2009-191645-NL",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CHORIOGONADOTROPIN ALFA"
},
"drugadditional... |
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