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{
"abstract": "OBJECTIVE\nTo evaluate the transition from reference infliximab Remicade to biosimilar Remsima in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA).\n\n\nMETHODS\nPatients were informed through a letter about the transition to a biosimilar and were subsequently contacted for possible additional questions and whether they agreed upon the transition. Once agreed, Remsima was administered at the same dosage and interval as previous treatment with Remicade. Data on the transition were analyzed in January 2018. The primary outcome was the percentage of patients continuing treatment with Remsima and secondary outcome was the change in disease activity measured with the Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR). In addition, the reasons for discontinuation with infliximab or restarting Remicade were recorded.\n\n\nRESULTS\nIn total 47 patients were approached, 45 patients switched from Remicade to Remsima, two patients disagreed upon transition and continued Remicade. At the end of the follow-up period of 2 years, 39 patients (87%) continued with Remsima, three patients (7%) restarted Remicade due to inefficacy according to the patient (this was not objectified by the rheumatologist) 2 (4%) patients switched to another biological due to lack of effect and in one patient (2%) infliximab was stopped because of lung malignancy. Furthermore, the DAS28-ESR remained comparable before and after the switch, with a mean (SD) of 2.34 (±1.02) and 2.31 (±1.11) respectively.\n\n\nCONCLUSIONS\nIn our population, 87% of patients continued Remsima during the follow-up period of approximately 2 years. Three patients restarted Remicade, while retaining stable DAS28-ESR.",
"affiliations": "Amsterdam Rheumatology and Immunology Center, Reade, Rheumatology, Amsterdam, The Netherlands.;Amsterdam Rheumatology and Immunology Center, Reade, Rheumatology, Amsterdam, The Netherlands.;Amsterdam Rheumatology and Immunology Center, Reade, Rheumatology, Amsterdam, The Netherlands.;Amsterdam Rheumatology and Immunology Center, Reade, Rheumatology, Amsterdam, The Netherlands.;Amsterdam Rheumatology and Immunology Center, Reade, Rheumatology, Amsterdam, The Netherlands.;Amsterdam Rheumatology and Immunology Center, Reade, Rheumatology, Amsterdam, The Netherlands.;Amsterdam Rheumatology and Immunology Center, Reade, Rheumatology, Amsterdam, The Netherlands.;Amsterdam Rheumatology and Immunology Center, Reade, Rheumatology, Amsterdam, The Netherlands.",
"authors": "Layegh|Zohra|Z|https://orcid.org/0000-0002-8245-9725;Ruwaard|Jill|J|;Hebing|Renske C F|RCF|;L' Ami|Merel J|MJ|;van der Weele|Wilfred|W|;Nurmohamed|Mike T|MT|;Krieckaert|Charlotte|C|;Wolbink|Gertjan|G|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D059451:Biosimilar Pharmaceuticals; C000591237:CT-P13; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1111/1756-185X.13512",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-1841",
"issue": "22(5)",
"journal": "International journal of rheumatic diseases",
"keywords": "biosimilar; infliximab; transition",
"medline_ta": "Int J Rheum Dis",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D015535:Arthritis, Psoriatic; D001172:Arthritis, Rheumatoid; D059451:Biosimilar Pharmaceuticals; D057915:Drug Substitution; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101474930",
"other_id": null,
"pages": "869-873",
"pmc": null,
"pmid": "30767391",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacious transition from reference infliximab to biosimilar infliximab in clinical practice.",
"title_normalized": "efficacious transition from reference infliximab to biosimilar infliximab in clinical practice"
} | [
{
"companynumb": "NL-JNJFOC-20190539857",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Anti-N-methyl-D-aspartate receptor encephalitis is an autoimmune disorder characterized by behavioral changes, dyskinesia, and autonomic instability.\n\n\n\nWe describe a 14-year-old girl who initially presented with acute behavioral changes and seizures and who over a 2-week period developed high fever, tachycardia, and elevated blood pressures.\n\n\n\nBecause she received multiple medications including anticonvulsants and a neuroleptic, our patient was initially diagnosed with neuroleptic malignant syndrome, a disorder characterized by autonomic dysfunction, hyperthermia, muscle rigidity, and mental status changes usually caused by the use of a neuroleptic agent. Further investigation, however, revealed the presence of N-methyl-D-aspartate receptor antibodies and an ovarian teratoma. Symptoms resolved after teratoma resection and intravenous immunoglobulin therapy.\n\n\n\nWe propose that anti-N-methyl-D-aspartate receptor encephalitis can cause a paraneoplastic syndrome mimicking neuroleptic malignant syndrome.",
"affiliations": "Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, Missouri.;Department of Pediatric Neurology, Granger Medical Clinic, Riverton, Utah.;Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, Missouri. Electronic address: Making@slu.edu.",
"authors": "Rozier|Margaret|M|;Morita|Denise|D|;King|Marta|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.pediatrneurol.2016.03.023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-8994",
"issue": "63()",
"journal": "Pediatric neurology",
"keywords": "anti-NMDA receptor encephalitis; neuroleptic malignant syndrome; ovarian teratoma; paraneoplastic syndrome",
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D000293:Adolescent; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D009459:Neuroleptic Malignant Syndrome",
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "71-72",
"pmc": null,
"pmid": "27590992",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Potential Mimic of Neuroleptic Malignant Syndrome.",
"title_normalized": "anti n methyl d aspartate receptor encephalitis a potential mimic of neuroleptic malignant syndrome"
} | [
{
"companynumb": "US-ALVOGEN-2016-ALVOGEN-086381",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "1",... |
{
"abstract": "OBJECTIVE\nTo report two cases of Serratia marcescens endophthalmitis related to presumed aliquot drug contamination, and to determine the incidence of acute endophthalmitis after intravitreal injection of bevacizumab.\n\n\nMETHODS\nA retrospective chart review of 2020 consecutive intravitreal bevacizumab injection (IVBI) cases at the three affiliated hospitals of Seoul National University (A, B, and C) was carried out between 12 October 2006, and 31 January 2008. Bevacizumab was retrieved multiple times from a single original vial as needed and then discarded on the same day at hospital A and C, or prepared as a single dose aliquot vial at a compounding pharmacy in the hospital B.\n\n\nRESULTS\nThe incidence of endophthalmitis after IVBI was 2/2020 (0.099%). Two patients receiving IVBI on the same day, but by different surgeons in different sites in hospital B, developed acute endophthalmitis. S. marcescens was isolated from the vitreous sample of the two patients. Molecular typing with pulsed field gel electrophoresis showed that the organisms were of the same strain, which suggested that the drug was contaminated at the pharmacy.\n\n\nCONCLUSIONS\nEndophthalmitis is a rare complication after IVBI and can be caused by contaminated aliquot drug. Serratia is one of the causative organisms of acute endophthalmitis, which can have devastating consequences, despite the treatment. A compounding pharmacy in a hospital might not be able to guarantee that aliquoted drug is free of contamination for the IVBI.",
"affiliations": "Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea.",
"authors": "Lee|S H|SH|;Woo|S J|SJ|;Park|K H|KH|;Kim|J H|JH|;Song|J H|JH|;Park|K U|KU|;Heo|J W|JW|;Yu|H G|HG|;Yu|Y S|YS|;Chung|H|H|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab",
"country": "England",
"delete": false,
"doi": "10.1038/eye.2009.86",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0950-222X",
"issue": "24(2)",
"journal": "Eye (London, England)",
"keywords": null,
"medline_ta": "Eye (Lond)",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D004340:Drug Contamination; D009877:Endophthalmitis; D006801:Humans; D015994:Incidence; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D056910:Republic of Korea; D012189:Retrospective Studies; D016868:Serratia Infections; D012706:Serratia marcescens",
"nlm_unique_id": "8703986",
"other_id": null,
"pages": "226-32",
"pmc": null,
"pmid": "19407833",
"pubdate": "2010-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Serratia marcescens endophthalmitis associated with intravitreal injections of bevacizumab.",
"title_normalized": "serratia marcescens endophthalmitis associated with intravitreal injections of bevacizumab"
} | [
{
"companynumb": "KR-ROCHE-696957",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"drug... |
{
"abstract": "Heart failure, a common condition affecting older patients, is associated with increased hospitalization and mortality rates among geriatric patients. We describe the case of an 86-year-old woman with moderate renal failure, who presented pulmonary edema and severe myocardial dysfunction due to hypocalcemia. Renal failure, but also the combination of additional factors, may have contributed to hypocalcemia, including vitamin D deficiency, loop diuretics and glucocorticoid therapy - which alone can give rise to sodium retention and calciuresis, and worsens hypocalcemia. Although in animal experiments hypocalcemia has been shown to lead to cardiac decompensation, heart failure from hypocalcemia is quite rare in clinical practice. Calcium plays a key role in cardiac muscle contraction and metabolism. It is recommended that physicians check serum calcium levels in the elderly, as hypocalcemia is a reversible cause of heart failure.",
"affiliations": "Department of Internal Medicine, University of Messina, Messina, Italy. catalanoantonino@libero.it",
"authors": "Catalano|Antonino|A|;Basile|Giorgio|G|;Lasco|Antonino|A|",
"chemical_list": "D002118:Calcium",
"country": "Germany",
"delete": false,
"doi": "10.1007/BF03325272",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1594-0667",
"issue": "24(4)",
"journal": "Aging clinical and experimental research",
"keywords": null,
"medline_ta": "Aging Clin Exp Res",
"mesh_terms": "D000369:Aged, 80 and over; D002118:Calcium; D005260:Female; D006333:Heart Failure; D006801:Humans; D006996:Hypocalcemia",
"nlm_unique_id": "101132995",
"other_id": null,
"pages": "400-3",
"pmc": null,
"pmid": "23238316",
"pubdate": "2012-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypocalcemia: a sometimes overlooked cause of heart failure in the elderly.",
"title_normalized": "hypocalcemia a sometimes overlooked cause of heart failure in the elderly"
} | [
{
"companynumb": "IT-RANBAXY-2013R1-66524",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "The neurodevelopmental risks of fetal exposure are uncertain for many antiseizure medications (ASMs).\nTo compare children at 2 years of age who were born to women with epilepsy (WWE) vs healthy women and assess the association of maximum ASM exposure in the third trimester and subsequent cognitive abilities among children of WWE.\nThe Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multicenter investigation of pregnancy outcomes that enrolled women from December 19, 2012, to January 13, 2016, at 20 US epilepsy centers. Children are followed up from birth to 6 years of age, with assessment at 2 years of age for this study. Of 1123 pregnant women assessed, 456 were enrolled; 426 did not meet criteria, and 241 chose not to participate. Data were analyzed from February 20 to December 4, 2020.\nLanguage domain score according to the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), which incorporates 5 domain scores (language, motor, cognitive, social-emotional, and general adaptive), and association between BSID-III language domain and ASM blood levels in the third trimester in children of WWE. Analyses were adjusted for multiple potential confounding factors, and measures of ASM exposure were assessed.\nThe BSID-III assessments were analyzed in 292 children of WWE (median age, 2.1 [range, 1.9-2.5] years; 155 female [53.1%] and 137 male [46.9%]) and 90 children of healthy women (median age, 2.1 [range, 2.0-2.4] years; 43 female [47.8%] and 47 male [52.2%]). No differences were found between groups on the primary outcome of language domain (-0.5; 95% CI, -4.1 to 3.2). None of the other 4 BSID-III domains differed between children of WWE vs healthy women. Most WWE were taking lamotrigine and/or levetiracetam. Exposure to ASMs in children of WWE showed no association with the language domain. However, secondary analyses revealed that higher maximum observed ASM levels in the third trimester were associated with lower BSID-III scores for the motor domain (-5.6; 95% CI, -10.7 to -0.5), and higher maximum ASM doses in the third trimester were associated with lower scores in the general adaptive domain (-1.4; 95% CI, -2.8 to -0.05).\nOutcomes of children at 2 years of age did not differ between children of WWE taking ASMs and children of healthy women.\nClinicalTrials.gov Identifier: NCT01730170.",
"affiliations": "Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, California.;Pediatric Neuropsychology International, Augusta, Georgia.;Department of Neurology, Emory University, Atlanta, Georgia.;Emmes Company, Rockville, Maryland.;Emmes Company, Rockville, Maryland.;Emmes Company, Rockville, Maryland.;Emmes Company, Rockville, Maryland.;Department of Neurology, University of Southern California, Los Angeles.;Department of Neurology, Northwestern University, Evanston, Illinois.;Department of Neurology, Emory University, Atlanta, Georgia.;Minnesota Epilepsy Group, St Paul, Minnesota.;Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio.;Northwell Health, Manhasset, New York.;Department of Neurology, Wake Forest University, Winston-Salem, North Carolina.;Department of Neurology, Columbia University, New York, New York.;Department of Neurology, New York University, New York.;Department of Neurology, University of Washington, Seattle.;Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.",
"authors": "Meador|Kimford J|KJ|;Cohen|Morris J|MJ|;Loring|David W|DW|;May|Ryan C|RC|;Brown|Carrie|C|;Robalino|Chelsea P|CP|;Matthews|Abigail G|AG|;Kalayjian|Laura A|LA|;Gerard|Elizabeth E|EE|;Gedzelman|Evan R|ER|;Penovich|Patricia E|PE|;Cavitt|Jennifer|J|;Hwang|Sean|S|;Sam|Maria|M|;Pack|Alison M|AM|;French|Jacqueline|J|;Tsai|Jeffrey J|JJ|;Pennell|Page B|PB|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1001/jamaneurol.2021.1583",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6149",
"issue": "78(8)",
"journal": "JAMA neurology",
"keywords": null,
"medline_ta": "JAMA Neurol",
"mesh_terms": null,
"nlm_unique_id": "101589536",
"other_id": null,
"pages": "927-936",
"pmc": null,
"pmid": "34096986",
"pubdate": "2021-08-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Two-Year-Old Cognitive Outcomes in Children of Pregnant Women With Epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study.",
"title_normalized": "two year old cognitive outcomes in children of pregnant women with epilepsy in the maternal outcomes and neurodevelopmental effects of antiepileptic drugs study"
} | [
{
"companynumb": "US-UCBSA-2021029900",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nBupropion is a drug uniquely used both to treat depression and as an aid to smoking cessation. We investigated previously reported associations between first-trimester exposure to bupropion and cardiac defects.\n\n\nMETHODS\nUsing data gathered since 2003 by the Slone Epidemiology Center's Case-control Birth Defects Study, we classified subjects with cardiac defects into subgroups. Exposure categories included first-trimester bupropion alone or in combination with other antidepressants, first-trimester antidepressants other than bupropion, and no exposure to any antidepressant at any time from 2 months prior to pregnancy through delivery. We calculated odds ratios and 95% confidence intervals, controlling for confounding using logistic regression.\n\n\nRESULTS\nThere were 8611 non-malformed infants and 7913 infants with cardiac defects. Eight cardiac subgroups had sufficient subjects (two or more exposed cases) for analysis. The adjusted odds ratio (aOR) for first-trimester bupropion use in relation to ventricular septal defect (VSD) was slightly elevated (1.6, 95% confidence interval 1.0-2.8); for exposure to bupropion alone, the aOR was 2.5 (95% confidence interval 1.3-5.0). Risks were not materially elevated for bupropion in relation to the other seven cardiac subgroups.\n\n\nCONCLUSIONS\nWe did not confirm previously reported associations for left-sided defects overall but had too few exposed cases to evaluate specific defects in this category. We did observe an elevated risk of VSD following first-trimester bupropion use, particularly when used without other antidepressants. This pattern for bupropion alone was observed in all our risk comparisons and was not explained by higher doses or gestational timing.",
"affiliations": "Slone Epidemiology Center at Boston University, Boston, MA, USA.",
"authors": "Louik|Carol|C|;Kerr|Stephen|S|;Mitchell|Allen A|AA|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion",
"country": "England",
"delete": false,
"doi": "10.1002/pds.3661",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-8569",
"issue": "23(10)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": "antidepressants; bupropion; cardiac malformations; pharmacoepidemiology",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000293:Adolescent; D000328:Adult; D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion; D016208:Databases, Factual; D005260:Female; D006330:Heart Defects, Congenital; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016015:Logistic Models; D018811:Maternal Exposure; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011297:Prenatal Exposure Delayed Effects; D012306:Risk; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "9208369",
"other_id": null,
"pages": "1066-75",
"pmc": null,
"pmid": "24920293",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "First-trimester exposure to bupropion and risk of cardiac malformations.",
"title_normalized": "first trimester exposure to bupropion and risk of cardiac malformations"
} | [
{
"companynumb": "US-BAUSCH-BL-2017-029673",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPROPION"
},
"drugadditional": "3",
... |
{
"abstract": "We have evaluated an 82 years old PD patient who has acutely developed VH secondary to acute visual loss that was associated with increased electroencephalographic activity in the gamma range over the parietal, occipital and frontal regions. In this respect, we have tested the therapeutic effect of occipital lobe oriented rTMS application and its electrophysiological correlates that led to significant improvement in the hallucinatory symptomatology of the patient after two weeks. We have revealed that the improved hallucinatory symptoms after rTMS application resolved completely after switching from the pramipexole treatment to L-Dopa indicating that there could be a combined therapeutic effect of L-Dopa and rTMS. Furthermore, Quantitative-Electroencephalography analysis has shown that the therapeutic effects of rTMS and L-Dopa were seen with the improvement of impaired gamma power spectrum. Although the main limitation of this report is that this a single case study and that these findings need to be replicated in a larger sample, e.g., as part of a controlled trial, our present findings help us to enlighten the unknown pathophysiological overlapping between the visual hallucinations in PD and Charles Bonnet Syndrome. Finally, our study revealed increased gamma coherence and power spectrum which is seen with visual hallucinations and improved after the application of 1 Hz rTMS on the occipital lobe. These findings together suggest that rTMS could be used as a therapeutic tool for parkinsonian complex VH and probably due affecting gamma coherence and power spectrum.",
"affiliations": "Istanbul Medipol University, Faculty of Medicine, Department of Neurology, Istanbul, Turkey.;Istanbul Medipol University, Faculty of Medicine, Department of Neurology, Istanbul, Turkey.;Istanbul Medipol University, Faculty of Medicine, Department of Biophysics, Istanbul, Turkey.;Istanbul Medipol University, Vocational School, Program of Electroneurophysiology, Istanbul, Turkey.;Alanya Alaaddin Keykubat University, Faculty of Medicine, Department of Neurology, Antalya, Turkey. Electronic address: burak.yulug@alanya.edu.tr.",
"authors": "Hanoğlu|Taha|T|;Hanoğlu|Lütfü|L|;Güntekin|Bahar|B|;Aktürk|Tuba|T|;Yulug|Burak|B|",
"chemical_list": "D000978:Antiparkinson Agents; D007980:Levodopa; D000077487:Pramipexole",
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2019.08.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "69()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Charles Bonnet Syndrome; Coherence; Gamma activity; Parkinson’s disease; Power spectrum; Q-EEG; Visual hallucination; rTMS",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000369:Aged, 80 and over; D000978:Antiparkinson Agents; D004569:Electroencephalography; D006212:Hallucinations; D006801:Humans; D007980:Levodopa; D008297:Male; D010300:Parkinson Disease; D000077487:Pramipexole; D050781:Transcranial Magnetic Stimulation",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "281-284",
"pmc": null,
"pmid": "31477464",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The therapeutic role of repetitive transcranial magnetic stimulation (rTMS) in parkinsonian visual hallucinations: Electrophysiological correlates.",
"title_normalized": "the therapeutic role of repetitive transcranial magnetic stimulation rtms in parkinsonian visual hallucinations electrophysiological correlates"
} | [
{
"companynumb": "TR-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-101193",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE DIHYDROCHLORIDE"
... |
{
"abstract": "Erdheim-Chester disease (ECD) is a rare histiocytic disorder, characterized by the xanthomatous infiltration of tissues by CD68-positive and CD1a-/CD100-negative foamy histiocytes. In childhood, ECD is exceptionally rare, and only a dozen cases have been published so far. The cooccurence of Langerhans cell histiocytosis (LCH) and ECD is even rarer. Here, we report a 2-year-old boy, the youngest patient in the literature so far, who was diagnosed with concomitant BRAF mutation-positive LCH and ECD. In his case, conventional LCH treatment proved to be ineffective, but he is the youngest patient who was successfully treated with the BRAF inhibitor vemurafenib.",
"affiliations": "Second Department of Pediatrics.;Second Department of Pediatrics.;First Department of Pathology and Experimental Cancer Research, Semmelweis University.;Pediatric Hematology and Stem Cell Transplantation Unit, United St István and St László Hospital, Budapest, Hungary.;Second Department of Pediatrics.;Second Department of Pediatrics.;Second Department of Pediatrics.",
"authors": "Váradi|Zsófia|Z|;Bánusz|Rita|R|;Csomor|Judit|J|;Kállay|Krisztián|K|;Varga|Edit|E|;Kertész|Gabriella|G|;Csóka|Monika|M|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S121615",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S121615ott-10-521Case ReportEffective BRAF inhibitor vemurafenib therapy in a 2-year-old patient with sequentially diagnosed Langerhans cell histiocytosis and Erdheim–Chester disease Váradi Zsófia 1Bánusz Rita 1Csomor Judit 2Kállay Krisztián 3Varga Edit 1Kertész Gabriella 1Csóka Monika 11 Second Department of Pediatrics2 First Department of Pathology and Experimental Cancer Research, Semmelweis University3 Pediatric Hematology and Stem Cell Transplantation Unit, United St István and St László Hospital, Budapest, HungaryCorrespondence: Monika Csóka, Second Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, Budapest 1094, Hungary, Tel +36 20 825 9245, Email dr.csoka.monika@gmail.com2017 24 1 2017 10 521 526 © 2017 Váradi et al. This work is published and licensed by Dove Medical Press Limited2017The 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.Erdheim–Chester disease (ECD) is a rare histiocytic disorder, characterized by the xanthomatous infiltration of tissues by CD68-positive and CD1a-/CD100-negative foamy histiocytes. In childhood, ECD is exceptionally rare, and only a dozen cases have been published so far. The cooccurence of Langerhans cell histiocytosis (LCH) and ECD is even rarer. Here, we report a 2-year-old boy, the youngest patient in the literature so far, who was diagnosed with concomitant BRAF mutation-positive LCH and ECD. In his case, conventional LCH treatment proved to be ineffective, but he is the youngest patient who was successfully treated with the BRAF inhibitor vemurafenib.\n\nKeywords\nvemurafenibtreatmentErdheim–Chester diseaseLangerhans cell histiocytosispediatric histiocytic disorders\n==== Body\nIntroduction\nECD is a rare non-Langerhans histiocytic disorder, which typically causes bone lesions, but virtually any organ can be involved, and the presentation symptoms may be also varied, ranging from asymptomatic to multisystem, life-threatening forms. Although, according to the WHO classification, ECD is a neoplasm deriving from CD68-positive and CD1a- and S100-negative histiocytes, the exact pathogenesis has not been fully clarified yet, whether it has a malignant nature or an inflammatory nature.1 In recent years, a growing number of studies that have investigated the underlying mechanisms of ECD have identified an activating point mutation of BRAF V600E in >50% of ECD patients. This has given a basis for encouraging targeted therapies. The BRAF inhibitor vemurafenib has demonstrated activity in small cohorts of adults treated with multisystem and refractory ECD.2,3 Data about the usage and efficacy of vemurafenib in pediatric ECD are lacking. We report an excellent therapy response to vemurafenib in a 2-year-old ECD patient, who is the youngest patient in the literature so far.\n\nCase report\nA 20-month-old boy was presented with visible soft masses on the left temporal and right parietal bone after a ~1-year-long history of “seborrheic dermatitis” of the scalp, “diaper rash”, and recurrent episodes of upper airway infections and otitis media. MRI revealed a 5×5×2.5 cm size frontal destructive mass on the right, a 6×3×2 cm size frontotemporoparietal mass, and a 1×1×1 cm size frontal mass on the left side, and all of them caused bone lesions (Figure 1A and B). Based on the patient history, physical findings, and imaging studies, LCH came up as a possible diagnosis with skin and multifocal bone involvement, which was confirmed histologically: the biopsy specimen from one of the skull masses was histologically composed of CD1a- and S100-positive mononuclear cells with coffee bean-shaped nuclei, eosinophil granulocytes, and multinucleated giant cells (Figure 2A and B). Morphology and immunophenotype were typical for LCH. Furthermore, skeletal manifestations and solid organ involvement were excluded by bone scintigraphy and MRI. We started his chemotherapy based on LCH-III protocol’s appropriate arm, according to the risk of the disease. Thanks to the effectivity of the therapy, rapid regression of the skull masses was detectable in the beginning (Figure 1C and D), but in the fourth month of chemotherapy, hepatosplenomegaly, hypalbuminemia, serious pancytopenia occurred, the activity of the left frontal bone lesion came back (Figure 1E and F), and the skin symptoms flared up. Bone marrow biopsy was negative at that time. Thereafter, he required dose reduction of cytostatic drugs, his transfusion need was extreme, and he required platelet support almost daily and blood transfusion regularly as well. He required albumin products for severe hypalbuminemia, desferoxamine treatment for secondary hemosiderosis, hospital care almost continuously for frequent septic episodes, and durable heparin therapy for deep vein thrombosis. Due to the serious symptoms, we were forced to stop cytotoxic therapy and started corticosteroid maintenance therapy with indomethacin supplementation for a short period, which was stopped because of its platelet aggregation inhibitory effect and simultaneous gravis thrombocytopenia. Eight months after the initial diagnosis, splenectomy was performed due to symptoms of hypersplenia, and histology confirmed splenic fibrosis represented by multiple fibrohistiocytic nodules composed of foamy macrophages loaded with hemosiderin accompanied by maturing extramedullary hematopoiesis. Bone marrow biopsy at the same time revealed highly similar pathological findings: excessive (~75%) engagement of marrow by CD68-positive and CD1a- and S100-negative macrophages inducing mild fibrosis. These macrophages had water clear wide cytoplasm and rounded nuclei (Figure 3A and B). A significant number of Langerhans cells were not detected in these bone marrow and spleen samples. On plain radiograph of the painful knees, symmetric osteosclerosis could be seen (Figure 4A). Interestingly, low signal intensities could be seen in all visualized bones (not only in the long bones) on every MRI sequence (Figure 5). These findings raised the diagnosis of non-Langerhans cell ECD with extensive bone marrow and spleen involvement. BRAF V600E mutation positivity was confirmed by pyrosequencing in the initial LCH skull lesion and in the recent ECD bone marrow biopsy specimen as well. According to the diagnosis and the literature, we started IFN-alpha therapy, and then, in default of clinical improvement and after obtaining the result of BRAF V600E mutation positivity of his disease, we stopped IFN-alpha administration and started BRAF inhibitor vemurafenib therapy (according to the license by National Institute of Pharmacy and Nutrition; license number: OGYI/40060-1/2014). As there are no data about the pediatric dosage of vemurafenib, we calculated it by correlating the child’s body surface with the adults’ 2 m2 body surface and the associated adult dose (240 mg BID for 0.73 m2 body surface). Within a few days, we observed a rapid and impressive improvement in the general state; after 4 days of vemurafenib treatment, his thrombocyte count started to increase, and he did not require transfusions any more. The control bone marrow histological examination after 3 months of BRAF inhibitor therapy showed 60% residual disease, which decreased to 15% in the 11th month. In the 16th month of vemurafenib therapy we could detect complete remission in the bone marrow, which was also verified by BRAF mutation analysis. Our findings reveal that the histological disappearance of the disease from the bone marrow can last for several months; however, the radiological improvement takes a couple of weeks/month (Figure 4B), and the positive clinical response is the first indicator of the effective treatment. This improvement could be seen in a couple of days after starting the vemurafenib therapy.\n\nNow the patient is 4 years old, and he is in the 18th month of vemurafenib therapy given in the same dose from the beginning. His general status is excellent, no hepatosplenomegaly is found, blood count and routine laboratory parameters are normal, and his ECD is in complete remission. The detected side effects of vemurafenib are the lack of eyebrows, very dry, rough skin all over the body, and hypertension.\n\nAs there is no experience with the long-term use of vemurafenib in the literature and it can cause serious side effects, regarding the young age and the high-risk disease of our patient, the National Pediatric Stem Cell Transplantation Committee decided to treat him with allogenic stem cell transplantation; hence, the search for an appropriate donor is in progress. Parents’ consent has been obtained for the publication of this case report and its accompanying images.\n\nDiscussion\nECD is a rare histiocytic disorder, and since its first description in 1930, ~500 cases have been reported in the literature,4 and there are only a few publications about pediatric ECD patients.5–10 The pathogenesis is still incompletely understood, and there are an increasing number of contradictory results supporting a theory of either a reactive origin or a malignant origin. Recent discovery of the high prevalence of BRAF V600E oncogenic mutation in ECD and LCH but not in other histiocytic disorders suggests that both proliferations could derive from a common origin.11–13 In addition to the recognized oncogenic activity of BRAF V600E mutation, it has also been associated with OIS, a recently identified important mechanism against tumor proliferation. As a crucial part of this antitumor activity, BRAFV600E-mutated cells produce a wide range of cytokines and chemokines, and this local inflammatory reaction may prevent the transformation of the mutated cells to cancer. This hypothesis raises the possible rule of OIS in ECD as well.14,15 Although ECD can be distinguished from LCH by morphological and immunohistochemical evaluation, based on the same clonal mutations and similar clinical manifestations, the latest updated WHO classification includes them in the same “L” (Langerhans) group. Furthermore, studies suggest that the occurrence of both diseases in the same patient is not rare, and in 12%–20% of patients, they really present as LCH-ECD overlap syndrome.12,16,17 Hervier et al17 identified 23 patients with mixed histiocytosis, and both diseases (LCH and LCD) were diagnosed simultaneously in 11 patients (48%). Diagnosis of LCH preceded ECD – similarly to our case – in all remaining patients (52%). To our best knowledge, only one pediatric double diagnosis has been published so far: in 2015, Kim et al published a case of a 3-year-old boy with intracranial simultaneous LCH and ECD.18 In these mixed histiocytosis cases, both LCH and ECD bear the same BRAF V600E mutation. These data suggest the theory of the common clonal origin of these disorders.\n\nAs ECD is extremely rare in children, evidence regarding treatment is limited to case reports. Successful treatments with corticosteroid monotherapy, IFN-alpha, or anakinra have been published on a case-to-case basis.5,7–10 Since the prognosis of ECD has been reported as poor, search for new therapeutic approaches is essential. More than 50% prevalence of BRAF mutation in ECD patients gives a possible therapeutic target. Clinical experiences with the BRAF inhibitor vemurafenib in ECD are rapidly increasing, both in prospective clinical trials and in “off-label” administration.12 Initial case reports have demonstrated significant activity of vemurafenib in adult ECD patients: three different publications reported at least partial response following vemurafenib therapy, which involved ~30 ECD patients in all with multisystemic, refractory diseases.3,19,20 In the case of our patient, corticosteroid and IFN-alpha therapies proved to be ineffective, and hence we were forced to change to another therapy option. BRAF mutation positivity of his ECD gave us a potential therapeutic option, which proved to be very effective. Nevertheless, indefinite treatment with BRAF inhibition is potentially unsafe, given the risk of accelerating premalignant RAS-mediated neoplastic lesions, although to date no treatment course has been defined for vemurafenib in ECD.12 Attempting vemurafenib treatment cession and watch-and-wait attitude were not a real possibility in his case facing with his very high-risk disease. Since 2001, some case reports about autologous stem cell transplantation as a therapy in ECD have been published in the literature;21,22 in our case, due to extensive bone marrow infiltration, allogenic transplantation had to be preferred instead of autologous.\n\nExtensive bone marrow involvement in ECD is also not common, but the exact frequency is unknown because of the rarity of the disease, although case reports have been published in 2016 about bone marrow involvement in two adult ECD patients.23,24\n\nRecent publication reports the youngest ECD patient in the literature, and this is the first one about the successful application of the BRAF inhibitor vemurafenib in pediatric ECD. The case is also a rarity because of the consecutive presence of BRAF-positive LCH and ECD. Furthermore, according to our encouraging results with this boy, we suggest to think of vemurafenib as a possible, off-label therapy in pediatric ECD.\n\nAcknowledgments\nThis article was not supported by any financial or other relationships.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nAbbreviations\nECDErdheim Chester disease\n\nIFN-alphainterferon-alpha\n\nLCHLangerhans cell histiocytosis\n\nMRImagnetic resonance imaging\n\nOISoncogene-induced senescence\n\nFigure 1 The role of head MRI in the evaluation of therapy response.\n\nNotes: (A) T2W image shows left temporal bone involvement of LCH (white arrow). (B) This lesion shows inhomogenous diffusion restriction (black arrow) on the diffusion-weighted image. (C and D) Normal appearance of the left temporal area after the initial chemotherapy on T2W and diffusion-weighted images. (E and F) Signal abnormality in the left temporal area on the T2W (white arrow) and diffusion-weighted (black arrow) images.\n\nAbbreviations: LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging.\n\nFigure 2 Skull lesion in LCH.\n\nNotes: (A) Hematoxylin–eosin stain. Majority of the cells have coffee bean-shaped nuclei with open chromatin pattern and nuclear membrane grooves. (B) Strongly positive CD1a immune reaction, which is specific for LCH.\n\nAbbreviation: LCH, Langerhans cell histiocytosis.\n\nFigure 3 Massive bone marrow infiltration with ECD (original magnification).\n\nNotes: (A) Hematoxylin–eosin stain. The marrow spaces are extensively engaged by foamy macrophages. (B) S100 immune reaction. The immune phenotype of macrophages is consistent with the phenotype of the conventional tissue histiocytes (CD68 positive, S100 negative). S100 is a highly sensitive but a nonspecific marker of Langerhans cells, therefore a good marker for screening Langerhans cells, or exclude Langerhans cell origin of a tumorous proliferation.\n\nAbbreviation: ECD, Erdheim–Chester disease.\n\nFigure 4 Plain radiograph of the knees (A) before and (B) after vemurafenib treatment.\n\nNotes: (A) Bilateral, symmetric, irregular sclerotic changes in the metaphysis of the bones. (B) Normal bone structure with a radiolucent band and small cystic lesions next to the epiphyseal plates.\n\nFigure 5 Coronal T2W image of the spine shows very low signal intensity of the bone marrow that is specific for ECD.\n\nAbbreviation: ECD, Erdheim–Chester disease.\n==== Refs\nReferences\n1 Cives M Simone V Rizzo FM Erdheim–Chester disease: a systematic review Crit Rev Oncol Hematol 2015 95 1 1 11 25744785 \n2 Haroche J Charlotte F Arnaud L High prevalence of BRAF V600E mutations in Erdheim–Chester disease but not in other non-Langerhans cell histiocytoses Blood 2012 120 13 2700 2703 22879539 \n3 Haroche J Cohen-Aubart F Emile JF Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAF(V600E)-mutated Erdheim–Chester disease J Clin Oncol 2015 33 5 411 418 25422482 \n4 Campochiaro C Tomelleri A Cavalli G Berti A Dagna L Erdheim–Chester disease Eur J Intern Med 2015 26 4 223 229 25865950 \n5 Tran TA Fabre M Pariente D Erdheim–Chester disease in childhood: a challenging diagnosis and treatment J Pediatr Hematol Oncol 2009 31 10 782 786 19755920 \n6 Globerman H Burstein S Girardina PJ Winchester P Frankel S A xanthogranulomatous histiocytosis in a child presenting with short stature Am J Pediatr Hematol Oncol 1991 13 1 42 46 1903027 \n7 Song SY Lee SW Ryu KH Sung SH Erdheim–Chester disease with multisystem involvement in a 4-year-old Pediatr Radiol 2012 42 5 632 635 21879308 \n8 Sohn MH Kim MW Kang YH Jeong HJ Tc-99m MDP bone and Ga-67 citrate scintigraphy of Erdheim–Chester disease in a child Clin Nucl Med 2006 31 2 90 92 16424695 \n9 Joo CU Go YS Kim IH Kim CS Lee SY Erdheim–Chester disease in a child with MR imaging showing regression of marrow changes Skeletal Radiol 2005 34 5 299 302 15480644 \n10 Tran TA Pariente D Lecron JC Delwail A Taoufik Y Meinzer U Treatment of pediatric Erdheim–Chester disease with interleukin-1-targeting drugs Arthritis Rheum 2011 63 12 4031 4032 21898344 \n11 Badalian-Very G Vergilio JA Degar BA Recurrent BRAF mutations in Langerhans cell histiocytosis Blood 2010 116 11 1919 1923 20519626 \n12 Diamond EL Dagna L Hyman DM Consensus guidelines for the diagnosis and clinical management of Erdheim–Chester disease Blood 2014 124 4 483 492 24850756 \n13 Hervier B Haroche J Arnaud L Association of both Langerhans cell histiocytosis and Erdheim–Chester disease linked to the BRAFV600E mutation Blood 2014 124 7 1119 1126 24894769 \n14 Cangi MG Biavasco R Cavalli G BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim–Chester disease Ann Rheum Dis 2015 74 8 1596 1602 24671772 \n15 Cavalli G Biavasco R Borgiani B Dagna L Oncogene-induced senescence as a new mechanism of disease: the paradigm of Erdheim–Chester disease Front Immunol 2014 5 281 24982657 \n16 Emile JF Abla O Fraitag S Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages Blood 2016 127 22 2672 2681 26966089 \n17 Hervier B Haroche J Arnaud L French Histiocytoses Study Group Association of both Langerhans cell histiocytosis and Erdheim–Chester disease linked to the BRAFV600E mutation Blood 2014 124 7 1119 1126 24894769 \n18 Kim S Lee M Shin HJ Lee J Suh YL Coexistence of intracranial Langerhans cell histiocytosis and Erdheim-Chester disease in a pediatric patient: a case report Childs Nerv Syst 2016 32 5 893 896 26466952 \n19 Haroche J Cohen-Aubart F Emile JF Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim–Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation Blood 2013 121 9 1495 1500 23258922 \n20 Hyman DM Puzanov I Subbiah V Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations N Engl J Med 2015 373 8 726 736 26287849 \n21 Gaspar N Boudou P Haroche J High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation for adult histiocytic disorders with central nervous system involvement Haematologica 2006 91 8 1121 1125 16885054 \n22 Boissel N Wechsler B Leblond V Treatment of refractory Erdheim–Chester disease with double autologous hematopoietic stem-cell transplantation Ann Intern Med 2001 135 9 844 845 11694122 \n23 Abdellateef EE Abdelhai AR Gawish HH Abdulmonaem GA Abdelbary EH Ahmed AI The first reported case of Erdheim–Chester disease in Egypt with bilateral exophthalmos, loss of vision, and multi-organ involvement in a young woman Am J Case Rep 2016 17 360 370 27237445 \n24 Lim J Kim KH Suh KJ A unique case of Erdheim–Chester disease with axial skeleton, lymph node, and bone marrow involvement Cancer Res Treat 2016 48 1 415 421 25715762\n\n",
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"journal": "OncoTargets and therapy",
"keywords": "Erdheim–Chester disease; Langerhans cell histiocytosis; pediatric histiocytic disorders; treatment; vemurafenib",
"medline_ta": "Onco Targets Ther",
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"pubdate": "2017",
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"references": "21898344;25865950;26466952;20519626;24850756;26966089;24982657;24671772;25744785;22879539;1903027;24894769;15480644;16424695;21879308;26287849;19755920;25422482;11694122;23258922;16885054;27237445;25715762",
"title": "Effective BRAF inhibitor vemurafenib therapy in a 2-year-old patient with sequentially diagnosed Langerhans cell histiocytosis and Erdheim-Chester disease.",
"title_normalized": "effective braf inhibitor vemurafenib therapy in a 2 year old patient with sequentially diagnosed langerhans cell histiocytosis and erdheim chester disease"
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"abstract": "Osteonecrosis of the jaw has been consistently reported in the literature associated to the high-dose intravenous bisphosphonate therapy. However, osteonecrosis can also occur in patients who have other risk factors.\nAn unusual case of ONJ in a patient being treated with esomeprazole is reported.\nThe probable association between proton pump inhibitor intake and osteonecrosis of the jaw should alert clinicians. Collaborations between medical and dental doctor and an early diagnosis might prevent or reduce the morbidity resulting from advanced destructive lesions of the jaw bone.\nOsteonecrosis of the jaw (ONJ) can occur in patients treated with bisphosphonates and corticosteroids and is associated with oral surgical procedures involving bone.Antacid drugs commonly used to treat gastro-oesophageal reflux could affect bone metabolism although no cases of ONJ in patients using proton pump inhibitors have been reported.Medical and dental practitioners should collaborate to prevent ONJ, identify previously unreported drug interactions, and treat patients in a more comprehensive manner.",
"affiliations": "Tuscan Stomatologic Institute, Versilia General Hospital, Lido di Camaiore, Italy.;Tuscan Stomatologic Institute, Versilia General Hospital, Lido di Camaiore, Italy.;Tuscan Stomatologic Institute, Versilia General Hospital, Lido di Camaiore, Italy.;Tuscan Stomatologic Institute, Versilia General Hospital, Lido di Camaiore, Italy.;Tuscan Stomatologic Institute, Versilia General Hospital, Lido di Camaiore, Italy.",
"authors": "Marconcini|Simone|S|;Giammarinaro|Enrica|E|;Cosola|Saverio|S|;Genovesi|Anna Maria|AM|;Covani|Ugo|U|",
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"fulltext": "\n==== Front\nEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2019_0012791279-1-9519-1-10-20191011ArticlesMandibular Osteonecrosis Associated with Antacid Therapy (Esomeprazole) Marconcini Simone Giammarinaro Enrica Cosola Saverio Genovesi Anna Maria Covani Ugo Tuscan Stomatologic Institute, Versilia General Hospital, Lido di Camaiore, Italy2019 14 10 2019 6 10 00127919 9 2019 23 9 2019 © EFIM 20192019This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseIntroduction\nOsteonecrosis of the jaw has been consistently reported in the literature associated to the high-dose intravenous bisphosphonate therapy. However, osteonecrosis can also occur in patients who have other risk factors.\n\nCase description\nAn unusual case of ONJ in a patient being treated with esomeprazole is reported.\n\nDiscussion\nThe probable association between proton pump inhibitor intake and osteonecrosis of the jaw should alert clinicians. Collaborations between medical and dental doctor and an early diagnosis might prevent or reduce the morbidity resulting from advanced destructive lesions of the jaw bone.\n\nLEARNING POINTS\nOsteonecrosis of the jaw (ONJ) can occur in patients treated with bisphosphonates and corticosteroids and is associated with oral surgical procedures involving bone.\n\nAntacid drugs commonly used to treat gastro-oesophageal reflux could affect bone metabolism although no cases of ONJ in patients using proton pump inhibitors have been reported.\n\nMedical and dental practitioners should collaborate to prevent ONJ, identify previously unreported drug interactions, and treat patients in a more comprehensive manner.\n\nMandibular osteonecrosisantacid therapyesomeprazoleosteonecrosis of the jawproton pump inhibitors\n==== Body\nINTRODUCTION\nOsteonecrosis of the jaw (ONJ) has been consistently reported in the literature since the 19th century[1]. It is an uncommon clinical entity with several causes, including head and neck irradiation, chemotherapy, trauma and periodontal disease[2]. Over the last 10 years, an increasing number of case reports have suggested that high-dose intravenous bisphosphonates may be associated with ONJ[3]. Patients typically presented with pain, impaired healing of extraction sockets, or exposed bone. Nearly all patients (86%) had undergone dental procedures and most were receiving long-term chemotherapy and short-term intermittent corticosteroid treatment[3]. However, ONJ can also occur in patients who are not treated with bisphosphonates and in patients without the traditional risk factors[4]. The authors report an unusual case of ONJ in a patient being treated with esomeprazole.\n\nCASE DESCRIPTION\nA 72-year-old man was referred to the Istituto Stomatologico Toscano (Lido di Camaiore, Italy) in September 2017. The patient had a complete removable prosthesis in the lower jaw and a partial removable prosthesis in the upper jaw. He complained of a chronic painful swelling in the left mandibular area. His medical history revealed intake of docetaxel and the steroid prednisone over a 3-year period following a diagnosis of prostate cancer. Extra-oral examination did not reveal any facial asymmetry. However, on intra-oral examination, an ulcerated area in the left lower jaw was noted after the prosthesis was removed (Fig. 1). The ulcer was exposing necrotic bone at the level of the alveolar crest. The lesion measured approximately 2 cm (mesiodistal) by 1 cm (buccal-lingual). Radiographic evaluation showed radiolucency in the corresponding area (Fig. 2). A provisional diagnosis of ONJ was made. After discussion with the patient, surgical debridement of the pathological lesion was performed under local anaesthesia (2% mepivacaine), with scraping instruments and a bone cutting forceps (Fig. 3). The mouth of the patient was rinsed for 1,5 minute with ozonized water (Aquolab EB2C Srl), for decontamination purposes, prior to the surgery and amoxicillin (500 mg three times a day for 7 days) and metronidazole (500 mg three times a day for 7 days) were prescribed to start the therapy before surgery. However, 3 months after surgery, the lesion had not healed and the patient was complaining of a moderate ache at the site of intervention.\n\nIt was decided to reconsider the possible side-effects and interactions of the drugs currently used by the patient. Further enquiry revealed that the patient was a long-term user of an over-the-counter proton pump inhibitor (PPI; Nexium, AstraZeneca, Basiglio, Milan, Italy) for the symptomatic treatment of gastro-oesophageal reflux. PPIs interfere with bone metabolism, as acknowledged by the FDA. It was therefore decided to immediately stop the antacid drug and to excise the necrotic bone, with scraping of the affected area in order to reach healthy bleeding bone (Fig. 4). The necrotic area was treated with local ozone therapy (Ozone DTA, Sweden & Martina S.p.A.) 2 days before surgery, and then once a day for the first week after surgery, followed by once a week for the next 2 months. Histological analysis of the excised bone confirmed the diagnosis of ONJ. A second cycle of antibiotic therapy was prescribed (amoxicillin 500 mg four times a day for 5 days) with chlorhexidine gluconate 0.2% for mouth rinsing. The patient’s symptoms resolved and the soft tissues had healed completely after 2 months (Fig. 5). The patient returned for follow-up visits at 6 months and 12 months with no adverse events recorded.\n\nDISCUSSION\nPPIs are commonly prescribed worldwide[5] and frequently used to treat gastro-intestinal disorders such as acid reflux and ulcers. They suppress the functions of the proton pump (H1/K1 ATPase), thus inhibiting gastric acidity[6]. Adverse effects, such as increased risk of infections, interaction with other drugs, dementia and reduced mineral absorption have been reported[7,8]. Reports have also shown that PPIs can impair bone metabolism: (a) the suppression of gastric acidity results in a reduction in intestinal calcium uptake and (b) PPIs down-regulate osteoclastic activity by inhibiting their surface proton pumps[9].\n\nOur patient presented with jaw osteonecrosis which resolved after suspension of antacid therapy with esomeprazole (Nexium). A recent cohort study, which included over 60,000 alendronate users in Denmark, investigated the presence of potential risk factors for ONJ requiring surgical treatment[10]. The authors suggested that ONJ risk appeared to be higher in patients with concomitant risk factors other than bisphosphonate treatment: a history of rheumatoid disease and the use of PPIs were independently associated with surgically treated ONJ. The esomeprazole Nexium is one of the most commonly used PPIs and it is often taken together with non-steroidal anti-inflammatory drugs (NSAIDs). Furthermore, NSAIDs are frequently prescribed for pain control after oral surgery, and their usage is also related to bone health[11]. In brief, adult patients who have a positive history of bisphosphonate use, cancer and oral surgery might be more likely to use PPIs and NSAIDs, and, therefore, be more prone to ONJ.\n\nRecent cohort studies on dental implant outcomes have suggested that PPI intake is associated with an increased risk of implant failure [12]. This association persisted after adjustment for multiple confounding factors[13]. Furthermore, study participants in implant programs had not included patients treated with bisphosphonates, since this was one of the exclusion criteria[14].\n\nLong-term use of PPIs is associated with reduced serum levels of calcium and vitamin B12, impaired collagen deposition in the extracellular matrix, and reduced bone strength. Recent evidence has also supported a gene modulating effect by PPIs towards lower expression of bone formation markers.\n\nThe observation of an association between PPI intake and ONJ should alert practitioners[15]. An early diagnosis might prevent or reduce the morbidity resulting from advanced destructive lesions of the jaw bone. Furthermore, osteoclast-selective PPIs may be an interesting anti-resorptive agent for future study.\n\nConflicts of Interests: The Authors declare that there are no competing interest\n\nFigure 1 Clinical view of exposed necrotic bone at the first examination\n\nFigure 2 Panoramic radiography of the patient’s jaw at the first examination\n\nFigure 3 Intra-operative photograph (first surgical procedure)\n\nFigure 4 Intra-operative photograph (second surgical procedure)\n\nFigure 5 Healed tissues 2 months after the second surgical procedure and the suspension of proton pump inhibitor therapy\n==== Refs\nREFERENCES\n1 Kumar SK Meru M Sedghizadeh PP Osteonecrosis of the jaws secondary to bisphosphonate therapy: a case series J Contemp Dent Pract 2008 9 63 69 18176650 \n2 Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws J Oral Maxillofac Surg 2007 65 369 376 17307580 \n3 Reilly MM Moore S Osteonecrosis of the jaw Oncology (Williston Park) 2008 22 39 41 18431898 \n4 Junquera L Gallego L Nonexposed bisphosphonate-related osteonecrosis of the jaws: another clinical variant? J Oral Maxillofac Surg 2008 66 1516 1517 18571043 \n5 Ali T Roberts DN Tierney WM Long-term safety concerns with proton pump inhibitors Am J Med 2009 10 896 903 \n6 Stedman C Barclay M Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors Aliment Pharmacol Ther 2000 14 963 978 10930890 \n7 Wright MJ Proctor DD Insogna KL Kerstetter JE Proton pump-inhibiting drugs, calcium homeostasis, and bone health Nutr Rev 2008 66 103 108 18254877 \n8 Eusebi LH Rabitti S Artesiani ML Proton pump inhibitors: risks of long-term use J Gastroenterol Hepatol 2017 32 1295 1302 28092694 \n9 O’Connell MB Madden DM Murray AM Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial Am J Med 2005 118 778 781 15989913 \n10 Eiken A Prieto-Alhambra D Eastell R Surgically treated osteonecrosis and osteomyelitis of the jaw and oral cavity in patients highly adherent to alendronate treatment: a nationwide user-only cohort study including over 60,000 alendronate users Osteoporos Int 2017 28 2921 2928 28664276 \n11 Zaidi M Modularity of osteoclast behaviour and “mode-specific” inhibition of osteoclast function Biosci Rep 1990 10 547 556 2085670 \n12 Wu X Al-Abedalla K Abi-Nader S Proton pump inhibitors and the risk of osseointegrated dental implant failure: a cohort study Clin Implant Dent Relat Res 2017 19 222 232 27766743 \n13 Nicolatou-Galitis O Kouri M Papadopoulou E MASCC Bone Study Group Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review Support Care Cancer 2019 27 2 383 394 30353228 \n14 Chrcanovic BR Kisch J Albrektsson T Intake of proton pump inhibitors is associated with an increased risk of dental implant failure Int J Oral Maxillofac Implants 2017 32 1097 1102 28632255 \n15 Ruiz AC Carrascosa MF Concha ST Gil AH Rivero JG Interstitial lung disease in a patient treated with denosumab Eur J Case Rep Intern Med 2019 6 7 001131 31410352\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2284-2594",
"issue": "6(10)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Mandibular osteonecrosis; antacid therapy; esomeprazole; osteonecrosis of the jaw; proton pump inhibitors",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001279",
"pmc": null,
"pmid": "31742205",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "27766743;18431898;28092694;30353228;28632255;18571043;2085670;31410352;19786155;17307580;15989913;10930890;28664276;18176650;18254877",
"title": "Mandibular Osteonecrosis Associated with Antacid Therapy (Esomeprazole).",
"title_normalized": "mandibular osteonecrosis associated with antacid therapy esomeprazole"
} | [
{
"companynumb": "IT-SA-2020SA026587",
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"activesubstancename": "PREDNISONE"
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"abstract": "There is some evidence that long-term phenytoin (PHT) use may occasionally give rise to irreversible cerebellar atrophy, but it is unclear whether such changes can occur after acute PHT intoxication. We describe a 38-year-old patient with accidental acute PHT overdose who developed severe cerebellar atrophy. This case provides evidence that acute PHT intoxication can, on rare occasions, result in irreversible cerebellar degeneration.",
"affiliations": "Department of Neuroepidemiology, Bombay Hospital, India.",
"authors": "Kuruvilla|T|T|;Bharucha|N E|NE|",
"chemical_list": "D010672:Phenytoin",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1528-1157.1997.tb01742.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "38(4)",
"journal": "Epilepsia",
"keywords": null,
"medline_ta": "Epilepsia",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D001284:Atrophy; D002526:Cerebellar Diseases; D002531:Cerebellum; D062787:Drug Overdose; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010672:Phenytoin",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "500-2",
"pmc": null,
"pmid": "9118858",
"pubdate": "1997-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cerebellar atrophy after acute phenytoin intoxication.",
"title_normalized": "cerebellar atrophy after acute phenytoin intoxication"
} | [
{
"companynumb": "IN-PFIZER INC-2015228841",
"fulfillexpeditecriteria": "1",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
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... |
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"abstract": "A 75-year-old woman presented with edema of the left leg in December 2012. On examination, there was a palpable 5-cm tumor in the left lower abdomen, and PET/CT showed lymphadenopathy of the tracheal, para-aortic, left iliac and inguinal regions with increased FDG uptake. We performed histopathological examination of the iliac lymph node and diagnosed diffuse large B-cell lymphoma (DLBCL), stage IIIA. The patient received 8 courses of R-CHOP chemotherapy and achieved a complete response. In April 2014, she noticed seven new painful erythematous vesicles <1 cm in size on the skin of the left lower abdominal region. Herpes zoster was suspected and valacyclovir was administered. However, this medication had no effect, and the vesicles enlarged and became nodular. Histopathological examination of one of the skin lesions revealed the infiltration of DLBCL and the diagnosis of zosteriform cutaneous recurrence of DLBCL was thus made. Skin lesions mimicking herpes zoster have been reported in certain types of hematological malignancies, and histopathological diagnosis should be performed in such cases.",
"affiliations": "Department of Hematology, Tokushima Prefectural Central Hospital.",
"authors": "Sumitani|Ryohei|R|;Mori|Keiko|K|;Sekimoto|Etsuko|E|;Shibata|Hironobu|H|;Noda|Toshinori|T|;Shikiji|Takanori|T|;Yamashita|Kyou|K|;Shigekiyo|Toshio|T|;Ozaki|Shuji|S|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000998:Antiviral Agents; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D014633:Valine; D000077483:Valacyclovir; D011241:Prednisone; D000212:Acyclovir",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.57.602",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "57(5)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000212:Acyclovir; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D000998:Antiviral Agents; D003520:Cyclophosphamide; D003937:Diagnosis, Differential; D004317:Doxorubicin; D005260:Female; D006562:Herpes Zoster; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D011241:Prednisone; D012008:Recurrence; D000069283:Rituximab; D012878:Skin Neoplasms; D016896:Treatment Outcome; D000077483:Valacyclovir; D014633:Valine; D014750:Vincristine",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "602-7",
"pmc": null,
"pmid": "27263785",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Diffuse large B-cell lymphoma recurring with zosteriform cutaneous lesions.",
"title_normalized": "diffuse large b cell lymphoma recurring with zosteriform cutaneous lesions"
} | [
{
"companynumb": "JP-JNJFOC-20170104238",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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"activesubstancename": "PREDNISOLONE"
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... |
{
"abstract": "Data from the Oxford Monitoring System for Attempted Suicide (2004-2011) were used to study hospital presentations for self-harm in which Suicidal Intent Scale (SIS) scores were obtained (N = 4,840). Regression of medians was used to control for the confounding effect of age and gender. Higher estimated median SIS scores were associated with increasing age, male gender, self-poisoning versus self-injury, multiple methods of self-harm versus self-injury alone, use of gas (mainly carbon monoxide), dangerous methods of self-injury (including hanging, gunshot), and use of alcohol as part of the act. For self-poisoning patients, there was a correlation between the number of tablets taken and the total SIS score. Compared with self-poisoning with paracetamol and paracetamol-containing compounds, self-poisoning with antipsychotics was associated with a lower median SIS score while antidepressants had the same estimated median as paracetamol. Use of alcohol within 6 hours of self-harm was associated with lower SIS scores. In conclusion, certain methods of self-harm, particularly dangerous methods of self-injury and self-poisoning with gas, were associated with high intent and should alert clinicians to potential higher risk of suicide. However, apart from use of gas, suicidal intent cannot be inferred from type of drugs used for self-poisoning.",
"affiliations": "Academic Centre, St Andrew's, Cliftonville, Northampton, UK.;Centre for Suicide Research, Department of Psychiatry, University of Oxford, Oxford, UK.;Centre for Statistics in Medicine, NDORMS, University of Oxford, Oxford, UK.;Centre for Suicide Research, Department of Psychiatry, University of Oxford, Oxford, UK.",
"authors": "Haw|Camilla|C|;Casey|Deborah|D|;Holmes|Jane|J|;Hawton|Keith|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/sltb.12168",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-0234",
"issue": "45(6)",
"journal": "Suicide & life-threatening behavior",
"keywords": null,
"medline_ta": "Suicide Life Threat Behav",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D003617:Dangerous Behavior; D005260:Female; D006760:Hospitalization; D006769:Hospitals, General; D006801:Humans; D033182:Intention; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D018570:Risk Assessment; D012307:Risk Factors; D016728:Self-Injurious Behavior; D059020:Suicidal Ideation; D013406:Suicide, Attempted; D006113:United Kingdom",
"nlm_unique_id": "7608054",
"other_id": null,
"pages": "732-46",
"pmc": null,
"pmid": "25916308",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Suicidal Intent and Method of Self-Harm: A Large-scale Study of Self-Harm Patients Presenting to a General Hospital.",
"title_normalized": "suicidal intent and method of self harm a large scale study of self harm patients presenting to a general hospital"
} | [
{
"companynumb": "GB-JNJFOC-20160116746",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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"activesubstance": {
"activesubstancename": "UNSPECIFIED INGREDIENT"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nThe association of human immunodeficiency virus (HIV) infection with Burkitt lymphoma is related to the presence of Epstein Barr virus infection and the impact of the HIV antigen on the expansion of B-polyclonal cells. In Southeast Europe, the association is rare, and recognizing this is important in the therapeutic decision to increase patient survival rate. The association of HIV with Burkitt lymphoma and tuberculosis is even more rarely described in the literature.\nWe present the case of a 40-year-old patient who presented with a 3-week history of fever (max. 38.7 °C), painful axillary swelling on the right side, lumbar pain, gait disorders, headache, and night sweats. Clinical manifestations included marked weight loss (about 30 kg in the last 2 months before his admission).\n\n\nMETHODS\nA LyCD4 count of 38/μL and a HIV1 viral load of 384,000/mm3, classified the patient into a C3 stage. A biopsy of the right axillary lymph node was performed for suspected ganglionic tuberculosis due to immunodeficiency. Histopathological examination confirmed the diagnosis of Burkitt lymphoma. Cultures on Löwenstein-Jensen medium from sputum harvested at first admission were positive for Mycobacterium tuberculosis.\n\n\nMETHODS\nHighly active antiretroviral therapy, chemotherapeutic agents for Burkitt lymphoma, anti-tuberculous drug therapy, neurosurgical intervention of spinal cord decompression, and antibiotic therapy of the associated bacterial infection.\n\n\nRESULTS\nBurkitt lymphoma disseminated rapidly, with central nervous system, spinal cord, osteomuscular, adrenal, and spleen involvement. The evolution under treatment was unfavorable, with patient death occurring 6 months after diagnosis.\n\n\nCONCLUSIONS\nThe association of HIV infection with Burkitt lymphoma and tuberculosis is rare in the highly active antiretroviral therapy (HAART) era, posing prompt and multidisciplinary therapeutic management issues. Similar cases of HIV-TB and Burkitt lymphoma association have been described, but none of the other cases showed the involvement of the central nervous system or of the bilateral adrenal glands.",
"affiliations": "Faculty of Medicine Sibiu, Academic Emergency Hospital Sibiu, Romania - Infectious Diseases Clinic.;Faculty of Medicine, \"FOISOR\" Clinical Hospital of Orthopedics, Traumatology and Osteoarticular TB Bucharest, Lucian Blaga University of Sibiu.;Department of Pathology.;Department of Radiology and Medical Imaging, Academic Emergency Hospital Sibiu, Sibiu, Romania.",
"authors": "Birlutiu|Victoria|V|;Birlutiu|Rares-Mircea|RM|0000-0001-7400-2904;Zaharie|Ioan Sorin|IS|;Sandu|Mariana|M|",
"chemical_list": "D000970:Antineoplastic Agents; D000995:Antitubercular Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000023853",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD \n\n33350777\nMD-D-19-09936\n10.1097/MD.0000000000023853\n23853\n4900\nResearch Article\nClinical Case Report\nBurkitt lymphoma associated with human immunodeficiency virus infection and pulmonary tuberculosis\nA case reportBirlutiu Victoria MD, PhDa Birlutiu Rares-Mircea resident doctor, PhD studentb∗ Zaharie Ioan Sorin MDc Sandu Mariana MD, PhDd Saranathan. Maya a Faculty of Medicine Sibiu, Academic Emergency Hospital Sibiu, Romania - Infectious Diseases Clinic\nb Faculty of Medicine, “FOISOR” Clinical Hospital of Orthopedics, Traumatology and Osteoarticular TB Bucharest, Lucian Blaga University of Sibiu\nc Department of Pathology\nd Department of Radiology and Medical Imaging, Academic Emergency Hospital Sibiu, Sibiu, Romania.\n∗ Correspondence: Rares-Mircea Birlutiu, Str. Lucian Blaga, Nr. 2A, Sibiu, 550169, Romania (e-mail: raresmircea@gmail.com).\n24 12 2020 \n24 12 2020 \n99 52 e2385315 12 2019 11 6 2020 28 10 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction:\nThe association of human immunodeficiency virus (HIV) infection with Burkitt lymphoma is related to the presence of Epstein Barr virus infection and the impact of the HIV antigen on the expansion of B-polyclonal cells. In Southeast Europe, the association is rare, and recognizing this is important in the therapeutic decision to increase patient survival rate. The association of HIV with Burkitt lymphoma and tuberculosis is even more rarely described in the literature.\n\nPatient concerns:\nWe present the case of a 40-year-old patient who presented with a 3-week history of fever (max. 38.7 °C), painful axillary swelling on the right side, lumbar pain, gait disorders, headache, and night sweats. Clinical manifestations included marked weight loss (about 30 kg in the last 2 months before his admission).\n\nDiagnosis:\nA LyCD4 count of 38/μL and a HIV1 viral load of 384,000/mm3, classified the patient into a C3 stage. A biopsy of the right axillary lymph node was performed for suspected ganglionic tuberculosis due to immunodeficiency. Histopathological examination confirmed the diagnosis of Burkitt lymphoma. Cultures on Löwenstein-Jensen medium from sputum harvested at first admission were positive for Mycobacterium tuberculosis.\n\nInterventions:\nHighly active antiretroviral therapy, chemotherapeutic agents for Burkitt lymphoma, anti-tuberculous drug therapy, neurosurgical intervention of spinal cord decompression, and antibiotic therapy of the associated bacterial infection.\n\nOutcome:\nBurkitt lymphoma disseminated rapidly, with central nervous system, spinal cord, osteomuscular, adrenal, and spleen involvement. The evolution under treatment was unfavorable, with patient death occurring 6 months after diagnosis.\n\nConclusions:\nThe association of HIV infection with Burkitt lymphoma and tuberculosis is rare in the highly active antiretroviral therapy (HAART) era, posing prompt and multidisciplinary therapeutic management issues. Similar cases of HIV-TB and Burkitt lymphoma association have been described, but none of the other cases showed the involvement of the central nervous system or of the bilateral adrenal glands.\n\nKeywords\nBurkitt lymphomadose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximabhighly active antiretroviral therapyhuman immunodeficiency virus infectionpulmonary tuberculosisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThe association of human immunodeficiency virus (HIV) infection with Burkitt lymphoma (BL) is 261 times higher than that in the general population and is linked to the presence of Epstein Barr virus infection and the impact of the HIV antigen on the expansion of B-polyclonal cells. In some areas, the incidence of BL in HIV patients is 23 per 100,000 persons (like in southern Louisiana), compared with the Southeast Europe where the association is rare.[1] Recognizing this association is important for the therapeutic decision to increase patient survival rate. Concomitant administration of highly active antiretroviral therapy (HAART) with Burkitt lymphoma chemotherapy, dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R), is associated with good efficacy and tolerance, thus improving the prognosis of the disease. We present the case of a 40-year-old patient with HIV infection associated with disseminated Burkitt lymphoma, with central nervous system, spinal cord, osteomuscular, adrenal, and spleen involvement and pleuropulmonary tuberculosis, a case that posed particular treatment problems.\n\n2 Case report\nWe present the case of a male Caucasian patient, aged 40 years, who presented with a 3 weeks history of chills, and fever (max. 38.7 °C), painful axillary swelling on the right side, lumbar pain, gait disorders, headache, and night sweats. Clinical manifestations occurred in the context of a marked weight loss (about 30 kg in the last 2 months before his admission).\n\nHe was examined by a general practitioner, and then by a neurologist who recommended laboratory tests (results that revealed a biological inflammatory syndrome) and lumbar spine magnetic resonance imaging (MRI) to be performed. The lumbar spine MRI findings were as follows: an extradural intracanal mass lesion posterior to the L4 and L5 vertebrae possibly suggesting a hematic focal mass. Adjacent to the L4 spinous process, a paravertebral area with fluid densities suggesting an abscess or muscular contusion. Small edema like focal area anterior and inferior to T10 vertebra angle suggesting spondylodiscitis.\n\nAfter neurosurgical assessment, the patient was admitted to the Infectious Diseases Clinic for further investigations due to suspicion of spondylodiscitis, persistence of the fever of unknown origin and the biologic inflammatory syndrome of unknown origin. At the time of admission, on physical examination, the following were noted: altered general condition, normal weight (body mass index [BMI] of 22.69 kg/m2), pallor, right axillary conglomerate of about 4 cm of lymph node masses, right mobile painless supraclavicular lymphadenopathy with a diameter of 1.5 cm, lower extremity myalgia, irritative cough, basal diminished vesicular sounds, interscapular bronchial rales, heart rate (HR) of 96 beats per minute (bpm), blood pressure (BP) of 120/80 mmHg, 2 cm hepatomegaly, walking abnormalities, and diminished tendon reflexes.\n\nThe main laboratory examinations that were performed are presented in Table 1.\n\nTable 1 Evolution of the main laboratory examinations during hospitalization.\n\nParameter\tValues\tReference value\t\n\t02.05.2018\t11.05.2018\t02.07.2018\t13.07.2018\t17.07.2018\t19.07.2018\t\t\nHemoglobin\t11.3/dL\t10.1 g/dL\t10.5 g/dL\t9.9 g/dL\t9.4 g/dL\t8.4 g/dL\t12–15 g/dL\t\nHematocrit\t33.0%\t29.9%\t30.7%\t27.9%\t26.4%\t24.1%\t37–47%\t\nWBC\t7.060 × 103/μL\t4.320 × 103/μL\t2.640 × 103/μL\t0.19 × 103/μL\t0.20 × 103/μL\t7.72 × 103/μL\t4–10 × 103/μL\t\nDifferential blood count:\t\n Neutrophils\t54.3%\t48.6%\t40.2%\t26.2%\t25%\t86.8%\t30–75%\t\n Lymphocytes\t22.5%\t27.5\t34.8\t57.9%\t50%\t2.7%\t25–35%\t\n Monocytes\t19.4%\t22.5%\t24.2%\t5.3%\t10%\t10.1%\t2–10%\t\n Eosinophils\t3.8%\t1.4%\t0.4%\t5.3%\t5%\t0.3%\t1–4%\t\n Basophils\t0.0%\t0.0%\t0.4%\t5.3%\t10%\t0.1%\t0–1%\t\nThrombocytes\t228 × 103/μL\t218 × 103/μL\t206 × 103/μL\t80 × 103/μL\t64 × 103/μL\t247 × 103/μL\t150–400 × 103/μL\t\nProthrombin time, s\t12.6 s\t12.1 s\t13 s\t\t\t\t9.9–12.3 s\t\nINR\t1.11\t1.06\t1\t\t\t\t0.86–1.1\t\nHemoculture\tNegative\t\t\t\t\t\t\t\nFibrinogen\t488.8 mg/dL\t572.9 mg/dL\t\t397.5 mg/dL\t\t\t170–420 mg/dL\t\nC-reactive protein\t54.22\t81.68\t\t61.47\t\t\t<6 mg/dL\t\nESR\t100\t75\t\t26\t\t\t0–20 mm/h\t\nAST\t33 U/L\t\t\t24 U/L\t\t\t5–34 U/L\t\nALT\t31 U/L\t\t\t44 U/L\t\t\t<55 U/L\t\nHepatitis B surface antigen\tNegative\t\t\t\t\t\t\t\nHepatitis C antibodies\t\t\t\t\t\t\t\t\n\tNegative\t\t\t\t\t\t\t\nHIV antibodies\tPositive\t\t\t\t\t\t\t\nA native thoraco-abdominal multiple detector computed tomography (MDCT) scan with contiguous sections was performed which revealed right axillary lymphadenopathy with a diameter of 46.5/27.5 mm, left axillary infracentrimetric lymphadenopathies, right adrenal gland tumor of 35/29 mm, and mediastinal infracentimetric lymphadenopathies.\n\nA LyCD4 count of 38/μL and a HIV1 viral load of 384,000 copies/mL confirmed the HIV infection, and also classified the patient in a C3 stage according to the CDC.\n\nA biopsy of the right axillary lymph node was performed for the suspicion of ganglionic tuberculosis due to immunodeficiency. Histopathological examination confirmed Burkitt lymphoma diagnosis.\n\nImmunohistochemical staining of the lymph node revealed the following: few CD3+ and CD5+ reactive T lymphocytes; diffuse atypical positive lymphoid population for CD10 and CD20. On CD23 and CD30 staining, no positive lymphocytes were found in the atypical lymphoid population. BCL2 expression was negative on BCL2 immunohistochemical staining. In addition CyclinD1 and DBA44 staining were negative, with a Ki67 score of 90% (CD10+, CD20+, BCL2–, CycinD1–, Ki 67–90%, CD23–, CD30–) (Fig. 1).\n\nFigure 1 Histopathological aspect. Hematoxylin and eosin-stained sections of lymph node. Magnification ×100. Deletion of the follicular structure, diffuse proliferation with medium-sized atypical lymphoid cells, with large nuclei and prominent nucleoli, with numerous mitoses nuclei and with the presence of macrophage areas with intracytoplasmic detritus (“starry sky” appearance). Areas of necrosis of the “ghostly” aspect of the atypical cells.\n\nFor the same suspicion of ganglionic tuberculosis due to immunodeficiency, sputum was harvested for cultures on Löwenstein-Jensen medium. An acid-fast bacillus (AFB) stain for Mycobacteria on a sample of sputum was also performed. The stain was applied on a direct and concentrated smear. The result was a negative AFB smear.\n\nAntiretroviral therapy with Raltegravir, Emtricitabine, and Tenofovir Disoproxil Fumarate was initiated. The recommendation was also made to initiate the Burkitt lymphoma treatment. Unfortunately, the patient seeking a second opinion postponed the beginning of the treatment.\n\nThe patient returned after a month to the emergency department with right facial paralysis, paraplegia, and loss of the sphincter reflex for micturition and defecation.\n\nA computed tomography (CT) scan reassessment of the patient was performed, and revealed intracranial and intraorbital lesions with dural extension, invasion of the cranial bone structures, bilateral adrenal nodes (6 cm in diameter on the right side, and 4 cm on the left side), hepatosplenomegaly, bilateral pleural effusion, and multiple vertebral, sacral, and femoral lesions (complete description is available as supplementary material).\n\nCranial and lumbar magnetic resonance imaging (MRI) was also performed and the findings were the following: multiple disseminated restrictive tumor masses in the scalp, with transosseous dissemination and dural intersection; bilateral restrictive, massive paravertebral muscle masses, larger on the right side, with intrartechal invasion from L2 to S2 and complete stenosis of the spinal canal at the L3 to L5 level. The presence of a prevertebral and para-aortic lymph node metastasis of approximately 3 cm was also confirmed (Figs. 2–4).\n\nFigure 2 CT scan sections. CT = computed tomography.\n\nFigure 3 MRI sequence. MRI = magnetic resonance imaging.\n\nFigure 4 MRI sequences. MRI = magnetic resonance imaging.\n\nThe patient was referred to the Department of Neurosurgery, where a L3–L4 and L4–L5 laminectomy was performed. Subsequently, he was referred to the Department of Hematology for the therapeutic management decision regarding Burkitt lymphoma. Biopsies from the excised tumors were taken, and histopathological examination confirmed Burkitt lymphoma. The microscopic appearance corroborated with the immunohistochemical aspect of positive lymphoid population for CD10, CD20, and KI67 and a negative expression of BCL2 indicates a Burkitt lymphoma, allowing its differentiation with diffuse large B-cell lymphoma and non-classifiable B-cell lymphoma with intermediate aspects between diffuse large B-cell lymphoma and Burkitt lymphoma.\n\nBone marrow examination revealed an infiltration by peroxidase-negative blasts cells of 6% to 36%.\n\nDA-EPOCH-R therapy was initiated (rituximab 700mg-etoposide 96 mg day 1–4, sindovine 0.77 mg/d day 1–4, endoxan 1450 mg/d day 5, and doxorubicin 20 mg day 3–4) associated with filgrastim 48 MU SC on day 5, preceded by cyclophosphamide 200 mg, 2× 1 vial/d and prednisone 60 mg/m2/d for 5 days. The initiation of radiotherapy was delayed due to the medullary aplasia that occurred after the treatment, and it was initiated after the correction of the blood count.\n\nDuring the hospitalization period in the Department of Hematology, an episode of diarrhea occurred, which was confirmed to be related to a Clostridium difficile infection. C difficile infection was diagnosed according to the guidelines published by the European Society of Clinical Microbiology and Infectious Diseases using 2 highly sensitive tests: GDH EIA (glutamate dehydrogenase enzyme immunoassay) and toxin A/B EIA, both tests were positive. The episode of CDI has been managed with oral vancomycin 4× 125 mg per day for 14 days (Figs. 5–8).\n\nFigure 5 Histopathological aspect. Hematoxylin and eosin-stained sections of bone marrow. Magnification ×100. Partially preserved architecture with approximately 50% infiltration with medium-sized atypical lymphoid cells with large nuclei and prominent nucleoli, with extensive tumor necrosis. In less infiltrated areas, myeloid–erythroid ratio: within normal range. Hyperplastic erythroid population with less erythroblastic islets. Easily hyperplasic granulocytic population with slightly multiple precursors with lower maturation. Easily multiplied megakaryocytes in all maturation phases. Plasmocytes within normal limits.\n\nFigure 6 Histopathological aspect. Immunohistochemically staining of the bone marrow for CD10 and CD20. Magnification ×100. Positive in the lymphoid atypical population, except in the areas of tumor necrosis.\n\nFigure 7 Histopathological aspect. Immunohistochemical staining of the bone marrow for BCL2 with negative expression. Magnification ×100.\n\nFigure 8 Histopathological aspect. Ki67 positive (80%) in the atypical viable lymphocyte population. Magnification ×100.\n\nCultures on Löwenstein-Jensen medium from sputum harvested at first admission were positive for Mycobacterium tuberculosis, after 6 weeks of incubation.\n\nHighly active antiretroviral therapy and Burkitt lymphoma chemotherapeutic agents were combined with anti-tuberculosis drug therapy (with rifabutin, pyrazinamide, ethambutol, and isoniazid). The evolution was unfavorable with the patient's death occurring 6 months after diagnosis.\n\n3 Discussions\nBurkitt lymphoma is the most aggressive form of non-Hodgkin lymphoma with B lymphocytes,[2] with endemic or sporadic evolution, or being associated with immunodeficiency syndromes: HIV infection, congenital immunodeficiency syndromes or in allografted patients.[3,4] It is characterized by a particularly high rate of proliferation (approximately 100%),[5] with cells doubling time of 24 hours and cytogenetic specific changes of the c-MYC proto-oncogene. Cases associated with HIV infection represent 30% to 40% of non-Hodgkin lymphoma associated with HIV infection. Disseminated forms of BL with central nervous system involvement represent 20% to 30% of cases. In the history of HIV therapy, the association of HIV infection with non-Hodgkin lymphoma was 60 to 200 times higher than that in the general population.[6]\n\nThere have been cases of BL with lymph node, hepatic, and pancreatic localization,[7] sometimes with an obstructive jaundice evolution.[8–10] Also there have been cases of BL with cardiac involvement, concurrently with extradural lumbosacral lesions[11] or ethmoidal sinuses and cerebral (temporal) impairment.[12] Central nervous system involvement in HIV-infected patients is appropriate for differential diagnosis, especially in cases with focal neurologic deficits, with opportunistic infections such as cerebral toxoplasmosis.[13] Disseminated BL with lymph nodes, central nervous system, and bilateral adrenal gland involvement associated with tuberculosis in an HIV-infected patient has yet not been described by other authors. The evolution of our case is extremely reserved, having as unfavorable prognostic factors, the CD4+ cell count below 100 cells/μL, age over 35 years, and an advanced stage of the disease (BL stage IV).[14,15]\n\nSimilar cases of HIV-TB and Burkitt lymphoma association have been described, cases with dissemination at an oropharyngeal, mediastinum, or pleural level,[16] and none of these cases presented with involvement of the central nervous system or of the bilateral adrenal glands.\n\nHAART therapy associated with DA-EPOCH ± Rituximab (administered according to CD4+ lymphocyte counts) appears to be associated with the best survival rate like CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine).[17]\n\nThe present case describes an association of HIV infection with disseminated LB and pulmonary tuberculosis initially with the absence of imaging changes. Regarding the HIV-infected patient who is in the last stage of HIV infection (AIDS), the risk of reactivation of a latent TB infection increases by approximately 20-folds,[18] and each third death is attributed to TB.[19] According to the Joint United Nations Programme on HIV/AIDS, in 2016, worldwide, 1.2 million new cases of TB associated with HIV infection were recorded. According to the data published by the European Centre for Disease Prevention and Control, 58.994 cases were recorded in Europe in 2016, of which 13.617 cases in Romania,[20] of which 9.222 cases with pulmonary localization, 10.5% being multidrug-resistant, and 5.6% pandrug-resistant TB forms,[21] motivating the clinician's prudence in the investigation of TB in HIV-infected patients. Imaging changes may be absent in coinfected HIV/TB patients or may be atypical,[21] so the decision to investigate patients for TB by smear, culture, Xpert MTB/RIF assay, or molecular diagnosis is absolutely necessary for countries where TB infection is endemic/epidemic.\n\nThe presence of mediastinal adenopathy may be the only imaging change in pulmonary TB in HIV-infected patients with CD4+ cell counts below 200 cells/μL.[22,23] It is estimated that 60% to 68.8% of TB cases in patients in the last stage of HIV infection are associated with mediastinal/hilar adenopathy.[24,25]\n\nIn our case, the aspect of the CT scan of the thorax and a negative AFB smear seemed to be sufficient to rule out a possible HIV-TB coinfection, but the dynamic imaging changes correlated with positive cultures on Löwenstein-Jensen medium confirmed the diagnosis. Susceptibility testing of the M tuberculosis isolated strain demonstrated conservation of sensitivity to treatment and allowed the use of first-line therapy drugs (rifabutin, pyrazinamide, ethambutol, and isoniazid). TB treatment was initiated after the first month of HAART and Burkitt lymphoma chemotherapy, without developing immune reconstitution inflammatory syndrome. The patient partially recovered neurologically and was able to move his legs but only in a supine position. At 3 months after the initiation of HAART therapy the CD4+ cell count was 178 cells/μL. Unfortunately at 6 months the patient's death was attributed to Burkitt lymphoma.\n\n4 Conclusions\nBurkitt lymphoma is a rare form of non-Hodgkin lymphoma associated with HIV infection, which classifies the patient in the AIDS stage. The rapid progression to dissemination or amelioration of the patient's condition depends on the promptness of initiating the HAART-associated with cytostatic therapy.\n\nAuthor contributions\nConceptualization: Victoria Birlutiu.\n\nData curation: Victoria Birlutiu, Ioan Sorin Zaharie, Mariana Sandu.\n\nFormal analysis: Victoria Birlutiu, Rares Mircea Birlutiu, Ioan Sorin Zaharie, Mariana Sandu.\n\nInvestigation: Victoria Birlutiu, Rares Mircea Birlutiu, Ioan Sorin Zaharie, Mariana Sandu.\n\nProject administration: Victoria Birlutiu.\n\nResources: Victoria Birlutiu.\n\nValidation: Victoria Birlutiu, Rares Mircea Birlutiu.\n\nVisualization: Victoria Birlutiu, Rares Mircea Birlutiu.\n\nWriting – original draft: Victoria Birlutiu, Rares Mircea Birlutiu.\n\nWriting – review & editing: Victoria Birlutiu, Rares Mircea Birlutiu.\n\nSupplementary Material\nSupplemental Digital Content\n Abbreviations: BL = Burkitt lymphoma, CT = computed tomography, DA-EPOCH-R = dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab, HAART = highly active antiretroviral therapy, HIV = human immunodeficiency virus, MRI = magnetic resonance imaging, TB = tuberculosis.\n\nHow to cite this article: Birlutiu V, Birlutiu RM, Zaharie IS, Sandu M. Burkitt lymphoma associated with human immunodeficiency virus infection and pulmonary tuberculosis: A case report. Medicine. 2020;99:52(e23853).\n\nInformed consent: Written informed consent was obtained from the patient's parents for publication of this case report and any accompanying images. The study was accepted by the Ethics Committee of the hospital and they encouraged publishing the article. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nThe authors have no conflicts of interest to disclose.\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\n\nSupplemental digital content is available for this article.\n\nALT = alanine aminotransferase; AST = aspartate aminotransferase; ESR = erythrocyte sedimentation rate; HIV = human immunodeficiency virus.\n==== Refs\nReferences\n[1] Johnson DH Reske TM Twase H \nHIV-associated Burkitt lymphoma: case report and literature review\n. Blood \n2013 ;122 :5072 .\n[2] Levine A \nChallenges in the management of Burkitt's lymphoma\n. Clin Lymphoma \n2002 ;3 : suppl : S19 –25\n.12521385 \n[3] Gong JZ Stenzel TT Bennett ER \nBurkitt lymphoma arising in organ transplant recipients: a clinicopathologic study of five cases\n. Am J Surg Pathol \n2003 ;27 :818 –27\n.12766587 \n[4] Xicoy B Ribera JM Esteve J \nPost-transplant Burkitt's leukemia or lymphoma. Study of five cases treated with specific intensive therapy (PETHEMA ALL-3/97 trial)\n. Leuk Lymphoma \n2003 ;44 :1541 –3\n.14565657 \n[5] Chan JK \nThe new World Health Organization classification of lymphomas: the past, the present, and the future\n. Hematol Oncol \n2001 ;19 :129 –50\n.11754390 \n[6] Thirlwell C Sarker D Stebbing J \nAcquired immunodeficiency syndrome-related lymphoma in the era of highly active antiretroviral therapy\n. Clin Lymphoma \n2003 ;4 :86 –92\n.14556679 \n[7] Rwegerera GM Rivera YP Zhou F \nDisseminated Burkitt's lymphoma with a pancreatic mass in a HIV positive woman diagnosed by axillary lymph node biops\n. J Clin Diagn Res \n2017 ;11 :OD14 –6\n.\n[8] Chaudhari D Khan S Saleem A \nObstructive jaundice as an initial manifestation of non-Hodgkin lymphoma: treatment dilemma and high mortality\n. Case Rep Med \n2013 ;2013 :259642 .23818904 \n[9] Odemis B Parlak E Basar O \nBiliary tract obstruction secondary to malignant lymphoma: experience at a referral center\n. Dig Dis Sci \n2007 ;52 :2323 –32\n.17406815 \n[10] Ravindra KV Stringer MD Prasad KR \nNon-Hodgkin lymphoma presenting with obstructive jaundice\n. Br J Surg \n2003 ;90 :845 –9\n.12854111 \n[11] Basavaraj A Shinde A Kulkarni R \nHIV associated Burkitt's lymphoma\n. J Assoc Physicians India \n2014 ;62 :723 –7\n.25856946 \n[12] Stroup JS Bransteitter BA Stephens JR \nBurkitt lymphoma in an adult HIV-positive patient\n. Infect Dis Clin Pract \n2007 ;15 :116 –8\n.\n[13] Kersten MJ Van Oers RH \nManagement of AIDS-related non-Hodgkin's lymphomas\n. Drugs \n2001 ;61 :1301 –15\n.11511024 \n[14] Straus D \nPrognostic factors in the treatment of human immunodeficiency virus-associated non-Hodgkin's lymphoma\n. Recent Results Cancer Res \n2002 ;159 :143 –8\n.11785838 \n[15] Gabarre J Raphael M Lepage E \nHuman immunodeficiency virus-related lymphoma: relation between clinical features and histology subtypes\n. Am J Med \n2001 ;111 :704 –11\n.11747850 \n[16] Lehmann C Wyen C Hoffmann C \nSuccessful administration of aggressive chemotherapy concomitant to tuberculostatic and highly active antiretroviral therapy in a patient with AIDS-related Burkitt's lymphoma\n. HIV Med \n2005 ;6 :51 –3\n.15670254 \n[17] Johnson DH Reske TM Twase H \nHIV-associated Burkitt Lymphoma: case report and literature review\n. Blood \n2013 ;122 :5072 .\n[18] Getahun H Gunneberg C Granich R \nHIV infection-associated tuberculosis: the epidemiology and the response\n. Clin Infect Dis \n2010 ;50 : suppl : S201 –7\n.20397949 \n[19] UNAIDS-Global AIDS Monitoring; 2018. Available at: www.unaids.org/en/resources/fact-sheet .\n[20] European Centre for Disease Prevention and Control/WHO Regional Office for Europe. Tuberculosis surveillance and monitoring in Europe 2018 – 2016 data Stockholm: ECDC; 2018 .\n[21] Nachiappan AC Rahbar K Shi X \nPulmonary tuberculosis: role of radiology in diagnosis and management\n. Radiographics \n2017 ;37 :52 –72\n.28076011 \n[22] Badie BM Mostaan M Izadi M \nComparing radiological features of pulmonary tuberculosis with and without HIV infection\n. J AIDS Clin Res \n2012 ;3 :188 .\n[23] Castañer E Gallardo X Mata JM \nRadiologic approach to the diagnosis of infectious pulmonary diseases in patients infected with the human immunodeficiency virus\n. Eur J Radiol \n2004 ;51 :114 –29\n.15246517 \n[24] Almeida LAde Barba MF Moreira FA \nComputed tomography findings of pulmonary tuberculosis in adult AIDS patients\n. Radiologia Brasileira \n2011 ;44 :13 –9\n.\n[25] Aaron L Saadoun D Calatroni I \nTuberculosis in HIV-infected patients: a comprehensive review\n. Clin Microbiol Infect \n2004 ;10 :388 –98\n.15113314\n\n",
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"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D023241:Antiretroviral Therapy, Highly Active; D000995:Antitubercular Agents; D001921:Brain; D002051:Burkitt Lymphoma; D018791:CD4 Lymphocyte Count; D000075902:Clinical Deterioration; D019299:Decompression, Surgical; D017809:Fatal Outcome; D015658:HIV Infections; D006801:Humans; D008297:Male; D019635:Neurosurgical Procedures; D013116:Spinal Cord; D014397:Tuberculosis, Pulmonary; D019562:Viral Load",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Burkitt lymphoma associated with human immunodeficiency virus infection and pulmonary tuberculosis: A case report.",
"title_normalized": "burkitt lymphoma associated with human immunodeficiency virus infection and pulmonary tuberculosis a case report"
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"abstract": "Neoadjuvant chemotherapy with docetaxel, oxaliplatin, fluorouracil, and leucovorin (FLOT regimen) has shown promising results in terms of pathological response and survival rate in patients with locally advanced resectable gastric cancer (LAGC). However, tegafur gimeracil oteracil potassium capsule (S-1) plus oxaliplatin (SOX regimen) is the preferred chemotherapy regimen in Eastern countries. Here, we conduct an open label, two-arm, phase II randomized interventional clinical trial (Dragon III; ClinicalTrials.gov: NCT03636893) to evaluate the safety and efficacy of both regimens. Patients with LAGC are randomly assigned to receive either 4 cycles of the neoadjuvant FLOT regimen (40 patients) or 3 cycles of the SOX regimen (34 patients) before gastrectomy. The primary endpoint is the comparison of complete (TRG1a) or subtotal (TRG1b) tumor regression grading in the primary tumor. There are no significant differences in adverse effects or postoperative morbidity and mortality between the two groups. No significant differences in the proportion of tumor regression grading between the FLOT group and the SOX group are found. Complete or subtotal TRG is 20.0% in the FLOT group versus 32.4% in the SOX group. Therefore, our study does not find statistically significant differences between neoadjuvant FLOT and SOX regimens for the primary outcomes reported here in locally advanced gastric cancer.",
"affiliations": "Department of General Surgery, Gastrointestinal Surgery Unit, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai, China. rjsurgeon@hotmail.com.;Department of Pathology Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Pathology Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Medical Oncology Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Medical Oncology Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of General Surgery, Gastrointestinal Surgery Unit, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai, China.;Department of General Surgery, Gastrointestinal Surgery Unit, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai, China.;Department of General Surgery, Gastrointestinal Surgery Unit, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai, China.;Department of General Surgery, Gastrointestinal Surgery Unit, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai, China.;Department of General Surgery, Gastrointestinal Surgery Unit, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai, China. lc10897@rjh.com.cn.;Department of General Surgery, Gastrointestinal Surgery Unit, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai, China.;Department of General Surgery, Gastrointestinal Surgery Unit, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai, China.;Department of General Surgery, Gastrointestinal Surgery Unit, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai, China. zzg@rjh.com.cn.",
"authors": "Sah|Birendra Kumar|BK|0000-0002-7415-960X;Zhang|Benyan|B|;Zhang|Huan|H|;Li|Jian|J|;Yuan|Fei|F|;Ma|Tao|T|;Shi|Min|M|;Xu|Wei|W|;Zhu|Zhenglun|Z|;Liu|Wentao|W|;Yan|Chao|C|;Li|Chen|C|0000-0002-7157-5202;Liu|Bingya|B|0000-0002-4406-3762;Yan|Min|M|;Zhu|Zhenggang|Z|0000-0003-4769-5463",
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"fulltext": "\n==== Front\nNat Commun\nNat Commun\nNature Communications\n2041-1723 Nature Publishing Group UK London \n\n19965\n10.1038/s41467-020-19965-6\nArticle\nNeoadjuvant FLOT versus SOX phase II randomized clinical trial for patients with locally advanced gastric cancer\nhttp://orcid.org/0000-0002-7415-960XSah Birendra Kumar rjsurgeon@hotmail.com 1 Zhang Benyan 2 Zhang Huan 3 Li Jian 4 Yuan Fei 2 Ma Tao 5 Shi Min 5 Xu Wei 1 Zhu Zhenglun 1 Liu Wentao 1 Yan Chao 1 http://orcid.org/0000-0002-7157-5202Li Chen lc10897@rjh.com.cn 1 http://orcid.org/0000-0002-4406-3762Liu Bingya 1 Yan Min 1 http://orcid.org/0000-0003-4769-5463Zhu Zhenggang zzg@rjh.com.cn 1 1 grid.16821.3c0000 0004 0368 8293Department of General Surgery, Gastrointestinal Surgery Unit, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai, China \n2 grid.16821.3c0000 0004 0368 8293Department of Pathology Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China \n3 grid.16821.3c0000 0004 0368 8293Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China \n4 grid.16821.3c0000 0004 0368 8293Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China \n5 grid.16821.3c0000 0004 0368 8293Department of Medical Oncology Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China \n30 11 2020 \n30 11 2020 \n2020 \n11 609314 7 2020 8 11 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Neoadjuvant chemotherapy with docetaxel, oxaliplatin, fluorouracil, and leucovorin (FLOT regimen) has shown promising results in terms of pathological response and survival rate in patients with locally advanced resectable gastric cancer (LAGC). However, tegafur gimeracil oteracil potassium capsule (S-1) plus oxaliplatin (SOX regimen) is the preferred chemotherapy regimen in Eastern countries. Here, we conduct an open label, two-arm, phase II randomized interventional clinical trial (Dragon III; ClinicalTrials.gov: NCT03636893) to evaluate the safety and efficacy of both regimens. Patients with LAGC are randomly assigned to receive either 4 cycles of the neoadjuvant FLOT regimen (40 patients) or 3 cycles of the SOX regimen (34 patients) before gastrectomy. The primary endpoint is the comparison of complete (TRG1a) or subtotal (TRG1b) tumor regression grading in the primary tumor. There are no significant differences in adverse effects or postoperative morbidity and mortality between the two groups. No significant differences in the proportion of tumor regression grading between the FLOT group and the SOX group are found. Complete or subtotal TRG is 20.0% in the FLOT group versus 32.4% in the SOX group. Therefore, our study does not find statistically significant differences between neoadjuvant FLOT and SOX regimens for the primary outcomes reported here in locally advanced gastric cancer.\n\nNeoadjuvant FLOT regimen has shown promising results for the treatment of locally advanced gastric cancer, however SOX regimen remains the preferred chemotherapy in Eastern countries. Here the authors report that the two therapies result in similar outcomes, measured as clinical downstaging and pathological response, in a phase II randomized clinical trial.\n\nSubject terms\nGastric cancerRandomized controlled trialsissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nFor locally advanced gastric cancer (LAGC), there has been a positive trend in neoadjuvant chemotherapy after the milestone publication of the MAGIC trial in 2006, and results from this trial were recently even supported by those from clinical trials from Asian countries1–5. Furthermore, recent studies have shown that neoadjuvant chemotherapy is well tolerated and does not influence postoperative morbidity or mortality in gastric cancer patients6. A large-scale German study clearly showed the superiority of neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin (the FLOT regimen) over epirubicin, cisplatin, and fluorouracil or capecitabine (the ECF or ECX regimens, respectively) in terms of pathological response and overall survival7,8. Docetaxel-based triplet chemotherapy, the FLOT regimen, is not a common chemotherapy in China; however, there have been published studies that show that the modified or standard FLOT regimen is safe and effective in Chinese patients9,10. Taxane-based triplet chemotherapy was considered more toxic in the past; therefore, doublet chemotherapy with the oral tegafur–gimeracil–oteracil potassium capsule (S-1) is the mainstream adjuvant chemotherapy in Asian countries, and a few studies have suggested S-1 plus platinum-based chemotherapy as neoadjuvant chemotherapy for locally advanced gastric cancer, especially with bulky lymph nodes11–13.\n\nIn recent years, several studies have been carried out in East Asian countries on the efficacy of perioperative chemotherapy for patients with LAGC. Among them, the preliminary results of two large-scale RCT trials (RESOLVE, RESONANCE) in China suggested that the neoadjuvant SOX regimen is beneficial in terms of R0 resectability, TRG, ypTNM, and pCR. Patients in the neoadjuvant chemotherapy group achieved a longer 3-year DFS than the control group14,15. To our knowledge, there is no previous study on neoadjuvant chemotherapy for LAGC that compared the efficacy between the SOX and FLOT regimens. For patients undergoing neoadjuvant chemotherapy, the pathological response rate or tumor regression grading is considered one of the major factors that influence overall survival16,17. We conducted this study to evaluate the safety and efficacy of both regimens. The main purpose of this study was to explore that whether there is a difference of pathological response after neoadjuvant chemotherapy with doublet SOX and triplet FLOT regimen.\n\nIn this work, we compare the rate of postoperative tumor regression between the neoadjuvant chemotherapy FLOT and SOX groups. Our study does not find statistically significant differences between neoadjuvant FLOT and SOX regimens for the primary outcomes reported here in locally advanced gastric cancer.\n\nResults\nTrial design and enrollment\nAltogether, 74 patients (40 patients in the FLOT group and 34 patients in the SOX group) were enrolled between August 2018 and March 2020. Nine patients in the FLOT group and ten patients in the SOX group dropped out for different reasons (Fig. 1). Finally, 55 patients completed the planned chemotherapy and underwent surgical resection. All cases were analyzed, no data were excluded. All 74 randomly assigned cases were considered the intention-to-treat (ITT) population, and 55 patients who had completed all planned chemotherapies and underwent surgery were considered the per-protocol (PP) population. The trial was ended after the surgical treatment of 55th patient. This was determined without any assessment of outcomes. We decided to end the trial at this point, to have a preliminary result, and discuss whether to go for phase III trial.Fig. 1 CONSORT diagram.\nFLOT docetaxel, oxaliplatin, fluorouracil, and leucovorin, SOX tegafur–gimeracil oteracil potassium capsule (S-1) plus oxaliplatin.\n\n\n\nReasons for patients dropout\nThere was one death registered in SOX arm. The main cause of death was the grade IV hematological adverse event, followed by multiple organs failure and pulmonary infection. In the FLOT arm, one patient had acute cerebral infarction after the first chemo cycle. The patient did not continue further chemotherapy and surgical treatment. In the SOX arm, one patient was diagnosed for deep venous thrombosis. The DVT was diagnosed during evaluation for surgical treatment, i.e., 3 weeks after the completion of all three chemotherapy cycles. The patient refused to undergo surgical treatment.\n\nThere were also three cases of protocol violation in SOX arm. Two of them requested for other chemotherapies after allocation in SOX arm. One case was laparoscopically diagnosed to have peritoneal metastases after allocation, and thus did not receive neoadjuvant chemotherapy.\n\nClinical characteristics\nThere was no significant difference in any clinical parameters between the FLOT and SOX groups, including age, sex, or BMI (Table 1, P > 0.05). There was no significant difference in terms of the location of the tumor or the type of resection. Thirty-two percent of patients in the FLOT group and 33.4% of patients in the SOX group had tumors in the proximal site of the stomach. All patients underwent D2 lymphadenectomy, 58.1% of patients in the FLOT group and 62.5% in the SOX group underwent total gastrectomy. One patient in each group underwent pancreatoduodenectomy due to local invasion.Table 1 Demographic data.\n\nParameter\tFLOT\tSOX\t\nSex\t\n Male\t29 (72.5)\t21 (61.8)\t\n Female\t11 (27.5)\t13 (38.2)\t\nAge (years)\t\n Median\t67\t61\t\n Range\t27–76\t34–80\t\nBody mass index\t\n Median\t23.41\t23.18\t\n Range\t15.69–29.48\t17.31–27.82\t\nTumor (pre-NAC CT)\t\n T4A\t23 (57.5)\t21 (61.8)\t\n T4B\t17 (42.5)\t13 (38.2)\t\nLymph node (pre-NAC CT)\t\n N0\t1 (2.5)\t3 (8.8)\t\n N1\t4 (10.0)\t6 (17.6)\t\n N2\t31 (77.5)\t17 (50.0)\t\n N3\t4 (10.0)\t8 (23.5)\t\nTNM stage (pre-NAC CT)\t\n IIB\t1 (2.5)\t3 (8.8)\t\n III\t22 (55.0)\t18 (52.9)\t\n IVA\t17 (42.5)\t13 (38.2)\t\nAnalysis of intention-to-treat (ITT) population.\n\n\n\nAdverse effects\nAll the 55 patients in per-protocol population completed the planned chemotherapy with full dose of respective chemotherapy regime (as described in “Methods”). All patients completed three cycles of neoadjuvant chemotherapy in the SOX group and four cycles of chemotherapy in the FLOT group before surgery. There was no significant difference in chemotherapy-related hematological or nonhematological adverse effects between the two groups (Table 2, P > 0.05). Most of the hematological or nonhematological adverse events were below grade 3. Nine and five events of hematological grade 3–4 adverse events were observed in the FLOT and SOX groups, respectively (Table 2). Adverse events for patients who were dropped out are described in Supplementary Table 1.Table 2 Adverse effects.\n\nParameter\tFLOT\tSOX\t\nWBC decreased\t\n Grade 0, 1, 2\t30 (96.8)\t24 (100.0)\t\n Grade 3, 4\t1 (3.2)\t0\t\nNeutrophil count decreased\t\n Grade 0, 1, 2\t29 (93.5)\t22 (91.7)\t\n Grade 3, 4\t2 (6.5)\t2 (8.3)\t\nFebrile neutropenia\t\n Grade 0, 1, 2\t31 (100.0)\t23 (95.8)\t\n Grade 3, 4\t0\t1 (4.2)\t\nAnemia\t\n Grade 0, 1, 2\t27 (87.1)\t22 (91.7)\t\n Grade 3, 4\t4 (12.9)\t2 (8.3)\t\nPlatelet count decreased\t\n Grade 0, 1, 2\t30 (96.8)\t24 (100.0)\t\n Grade 3, 4\t1 (3.2)\t0\t\nAminotrasferase increased\t\n Grade 0, 1, 2\t30 (96.8)\t24 (100.0)\t\n Grade 3, 4\t1 (3.2)\t0\t\nNausea\t\n Grade 0, 1, 2\t30 (96.8)\t24 (100.0)\t\n Grade 3, 4\t1 (3.2)\t0\t\nVomiting\t\n Grade 0, 1, 2\t30 (96.8)\t24 (100.0)\t\n Grade 3, 4\t1 (3.2)\t0\t\nDiarrhea\t\n Grade 0, 1, 2\t31 (100.0)\t24 (100.0)\t\n Grade 3, 4\t0\t0\t\nPeripheral neuropathy\t\n Grade 0, 1, 2\t31 (100.0)\t24 (100.0)\t\n Grade 3, 4\t0\t0\t\nFatigue\t\n Grade 0, 1, 2\t31 (100.0)\t24 (100.0)\t\n Grade 3, 4\t0\t0\t\nAnorexia\t\n Grade 0, 1, 2\t30 (96.8)\t24 (100.0)\t\n Grade 3, 4\t1 (3.2)\t0\t\nOral mucositis\t\n Grade 0, 1, 2\t31 (100.0)\t24 (100.0)\t\n Grade 3, 4\t0\t0\t\nAnalysis of per-protocol population except otherwise indicated.\n\n\n\nRadiological response\nThere was no significant difference in the pretreatment cTNM stage between the FLOT group and the SOX group (Table 1). A total of 41.9% versus 37.5% of cases were diagnosed as stage IVa in the FLOT and SOX groups, respectively. There was no significant difference concerning the radiological response rate between the two groups (Table 3). In the ITT population, the disease control rate (PR + SD) was comparable between the FLOT group (75.0%) and the SOX group (67.6%), and the overall response rate (ORR) was 55.0% in the FLOT group versus 41.2% in the SOX group (Table 3, P > 0.05).Table 3 Post neoadjuvant chemotherapy (NAC) CT evaluation.\n\nParameter\tFLOT\tSOX\tP value\t\nTumor (post-NAC CT)\t\n T1\t1 (3.2)\t1 (4.2)\t0.412\t\n T2\t9 (29.0)\t10 (41.7)\t\t\n T3\t13 (41.9)\t5 (20.8)\t\t\n T4A\t8 (25.8)\t8 (33.3)\t\t\nLymph node (post-NAC CT)\t\n N0\t4 (12.9)\t7 (29.2)\t0.214\t\n N1\t12 (38.7)\t9 (37.5)\t\t\n N2\t15 (48.4)\t7 (29.2)\t\t\n N3\t0\t1 (4.2)\t\t\nTNM stage (post-NAC CT)\t\n I\t3 (9.7)\t5 (20.8)\t0.435\t\n IIA\t7 (22.6)\t6 (25.0)\t\t\n IIB\t1 (3.2)\t2 (8.3)\t\t\n III\t20 (64.5)\t11 (45.8)\t\t\nResponse rate\t\n PR\t22 (71.0)\t14 (58.3)\t0.691\t\n SD\t8 (25.8)\t9 (37.5)\t\t\n PD\t1 (3.2)\t1 (4.2)\t\t\nOverall response rate (ITT population)\t22 (55.0)\t14 (41.2)\t0.254\t\nDisease control rate (ITT population)\t30 (75.0)\t23 (67.6)\t0.606\t\nAnalysis of per-protocol population except otherwise indicated (the Fisher’s exact test).\n\n\n\nPathological response\nAmong the PP population, there was no significant difference in any pathological parameters (Table 4, P > 0.05). Patients in both groups had favorable margin-free resection: 87.1% in the FLOT group and 100.0% in the SOX group. Lauren’s classification showed that 58.1% of tumors in the FLOT group and 54.2% of tumors in the SOX group were intestinal types. The proportion of T4a tumors and N2 lymph nodes was relatively higher in the FLOT group than in the SOX group, and a greater proportion of postoperative stage III tumors (ypTNM) was observed in the FLOT group than in the SOX group (54.8% versus 45.8%), but there was no significant difference between the two groups.Table 4 Clinicopathological results of two groups.\n\nParameter\tFLOT\tSOX\tP value\t\nTumor site\t\n Proximal\t7 (22.6)\t7 (29.2)\t0.622\t\n Proximal body\t3 (9.7)\t1 (4.2)\t\n Body\t7 (22.6)\t3 (12.5)\t\n Distal body\t6 (19.4)\t5 (20.8)\t\n Distal\t8 (25.8)\t6 (25.0)\t\n Total\t0\t2 (8.3)\t\nType of gastrectomy\t\n Partial\t13 (41.9)\t9 (37.5)\t0.787\t\n Total\t18 (58.1)\t15 (62.5)\t\nLauren’s classification\t\n Intestinal\t18 (58.1)\t13 (54.2)\t0.389\t\n Diffuse\t7 (22.6)\t6 (25.0)\t\n Mixed\t3 (9.7)\t5 (20.8)\t\n Unclassifiable\t3 (9.7)\t0\t\nExtent of resection\t\n R0\t27 (87.1)\t24 (100.0)\t0.123\t\n R1\t4 (12.9)\t0\t\nNerve invasion\t\n Negative\t16 (51.6)\t14 (58.3)\t0.785\t\n Positive\t15 (48.4)\t10 (41.7)\t\nVessels invasion\t\n Negative\t25 (80.6)\t17 (70.8)\t0.525\t\n Positive\t6 (19.4)\t7 (29.2)\t\nTumor\t\n Unclassifiable\t1 (3.2)\t0\t0.916\t\n T1A\t1 (3.2)\t1 (4.2)\t\n T1B\t1 (3.2)\t1 (4.2)\t\n T2\t2 (6.5)\t3 (12.5)\t\n T3\t19 (61.3)\t16 (66.7)\t\n T4A\t6 (19.4)\t2 (8.3)\t\n T4B\t1 (3.2)\t1 (4.2)\t\nLymph node\t\n N0\t10 (32.3)\t9 (37.5)\t0.692\t\n N1\t4 (12.9)\t3 (12.5)\t\n N2\t10 (32.3)\t5 (20.8)\t\n N3A\t6 (19.4)\t4 (16.7)\t\n N3B\t1 (3.2)\t3 (12.5)\t\nHarvested lymph nodes\t\n Median (no.)\t34\t36\t0.599\t\nYpTNM\t\n I\t3 (9.7)\t3 (12.5)\t0.736\t\n II\t11 (35.5)\t10 (41.7)\t\n III\t17 (54.8)\t11 (45.8)\t\nAnalysis of per-protocol population except otherwise indicated (the Fisher’s exact test).\n\n\n\nPrimary outcomes\nThe overall pathological response (TRG grade 1a + 1b + 2) rate was 67.7% in the FLOT group versus 75% in the SOX group (Table 5, P > 0.05). In the ITT population, the complete or subtotal TRG was 20% in the FLOT group and 32.4% in the SOX group, but there was no significant difference between the two groups (P > 0.05).Table 5 Difference of histopathological tumor regression in intention-to-treat (ITT) population.\n\nTRG\tFLOT\t95% CI\tSOX\t95% CI\tP value\t\nComplete or subtotal\t8 (20.0)\t10.0–39.9\t11 (32.4)\t17.9–58.4\t0.289\t\n1A\t1 (2.5)\t0.3–17.7\t0\tNA\t1.000\t\n1B\t7 (17.5)\t8.3–36.7\t11 (32.4)\t17.9–58.4\t0.178\t\n2\t13 (32.5)\t18.8–55.9\t7 (20.6)\t9.8–43.1\t0.300\t\n3\t10 (25.0)\t13.4–46.4\t6 (17.6)\t7.9–39.2\t0.574\t\nThe Fisher’s exact test.\n\n\n\nPostoperative morbidity\nThere was no significant difference in the postoperative stay at the hospital between the FLOT group and the SOX group, and the median length of stay was 9 days in both groups. There was no significant difference in overall postoperative morbidity between the two groups (Table 6, P > 0.05). Two (6.5%) anastomotic leakages were observed in the FLOT group and 1 (4.2%) in the SOX group. One patient underwent reoperation for intra-abdominal hemorrhage in the SOX group. There were no deaths due to postoperative complications in either group.Table 6 Postoperative complications per-protocol (PP) population.\n\nComplication\tFLOT\tSOX\tP value\t\nClavien Dindo grading\t\t\t\t\t\nGrade I\t\t0\t1\t\t\nGrade II\t\t7\t3\t\t\nGrade III\tGrade IIIa\t2\t1\t\t\nGrade IIIb\t0\t1\t\t\nGrade IV\tGrade IVa\t0\t2\t\t\nGrade IVb\t0\t0\t\t\nGrade V\t\t0\t0\t\t\nOverall complications\t\t9 (29.0)\t8 (33.3)\t0.775\t\nAbdominal complication\t\t7 (22.6)\t5 (20.8)\t0.100\t\nIntra-abdominal hemorrhage\t\t0\t1 (4.2)\t0.436\t\nSuperficial wound dehiscence\t\t0\t1 (4.2)\t0.436\t\nPulmonary infection\t\t2 (6.5)\t1 (4.2)\t1.000\t\nAbdominal infection\t\t4 (12.9)\t2 (8.3)\t0.686\t\nAnastomotic leakage\t\t2 (6.5)\t1 (4.2)\t1.000\t\nPancreatic fistula\t\t0\t1 (4.2)\t0.436\t\nImpaired renal function\t\t1 (3.2)\t0\t1.000\t\nCardiac/respiratory failure\t\t0\t1 (4.2)\t0.436\t\nReadmission\t\t1 (3.2)\t1 (4.2)\t1.000\t\nReoperation\t\t0\t1 (4.2)\t0.436\t\nDeath\t\t0\t0\tNA\t\nAnalysis of PP population except otherwise indicated (the Fisher’s exact test).\n\n\n\nDiscussion\nInitial reports on the FLOT4 trial showed that 37% of patients in the FLOT group versus 23% in the ECF/ECX group achieved complete or subtotal tumor regression after neoadjuvant chemotherapy7. Further results on survival revealed that the patients in the FLOT group had an overall survival of 50 months versus 35 months in patients in the ECF/ECX group8. Recent small-scale studies from China also suggested that the FLOT regimen was safe and feasible in Chinese patients9,10. A propensity-score-matched retrospective study from China also suggested that patients with neoadjuvant FLOT had improved overall survival compared with patients who underwent surgery first18. The results of these studies suggested that the FLOT regimen was beneficial to locally advanced gastric cancer in terms of pathological regression and survival. However, the combination of fluorouracil and platinum chemoagents, e.g., SOX or XELOX regimens, is commonly used as neoadjuvant chemotherapy in East Asia, including Japan11–13. Preliminary results of two large-scale RCTs from China (RESOLVE and RESONANCE) further concluded that the SOX regimen is beneficial for LAGC14,15. As a result, some controversy remains regarding whether the FLOT regimen is similarly beneficial in East Asian patients. Whether there are any differences between the triplet and the doublet chemoagents in terms of adverse effects and survival benefit has not been studied. In our study, we investigated neoadjuvant FLOT and SOX regimens for patients with LAGC in an attempt to compare the adverse effects and postoperative pathological response between the two groups. Although the sample size is not large enough, to our knowledge, there was no head-to-head comparative study of the FLOT and SOX regimens as neoadjuvant chemotherapy for LAGC. The higher proportion of complete or subtotal TRG in the SOX group than in the FLOT group does not indicate the superiority of the SOX regimen over the FLOT regimen because there was no significant difference in terms of statistical calculations. However, at the very least, the results of this study urge the need for further large-scale multicenter randomized trials. Our results may provide some insights for further trials.\n\nThere was no difference in the FLOT and SOX groups in terms of adverse effects and postoperative morbidity. Thus, this study further validated the results of our previous study that neoadjuvant chemotherapy with the FLOT regimen is safe in Chinese patients10. We observed a very low rate of leucopenia and neutropenia in both groups. This was significantly lower than that was reported in the original FLOT trial. As per protocol, the use of GCSF was restricted to treatment only, thus preventive GCSF was not used. However, on post hoc analysis, we found GCSF was used more frequently in the FLOT group (94.9%) than in the SOX group (43.3%). The GCSF was prescribed to any patient who had WBC or Neutrophil count lower than the normal range, regardless of severity. Probably this might be the main cause of the significantly lower occurrence of grades 3–4 neutropenia in this cohort. Besides all the patients received preventive Leucogen tablets and Batilol Tablets orally, starting right after chemotherapy. Both medications are indicated for stimulating granulocytes. Therefore notably lower rate of leucopenia and neutropenia of this cohort should be interpreted considering the above factors.\n\nIn this study, the demographic data show that patients in both groups were well balanced by randomized assignment. The univariate analysis of all data suggested that TRG was associated with sex, nerve invasion, vessel invasion, and postoperative pathological stage. However, there was no difference in any of these factors between the two groups (Table 4). These data suggest that these known factors, which might have a role in a pathological response, did not influence the results of this study.\n\nThere was a conflicting result for the radiological response rate with that of pathological results, which showed that a greater proportion of ORR was seen in the FLOT group than in the SOX group, although there was no statistically significant difference. Therefore, we further analyzed the data according to the stratification of pretreatment clinical staging and postoperative pathological TNM staging. The proportion of complete or subtotal TRG was higher in the SOX group, but there was no significant difference compared to the FLOT group (Table 7).Table 7 Complete or subtotal tumor regression.\n\nStage type\tStage\tFLOT\tSOX\tP value\t\ncTNM\tIIB\t1/1 (100.0)\t1/3 (33.3)\tNS\t\nIII\t5/17 (29.0)\t6/12 (50.0)\tNS\t\n\tIVA\t2/13 (15.4)\t4/9 (44.4)\tNS\t\nypTNM\tI\t3/3 (100.0)\t3/3 (100.0)\tNS\t\nII\t5/11 (45.5)\t6/10 (60.0)\tNS\t\nIII\t0/17\t2/11 (18.2)\tNS\t\ncTNM pretreatment clinical TNM stage, ypTNM postoperative pathological TNM stage.\n\nAnalysis of per-protocol population except otherwise indicated (the Fisher’s exact test).\n\n\n\nApproximately 37% of patients achieved complete or subtotal TRG in the FLOT4 trial7, but only 20% of patients achieved complete or subtotal TRG in the FLOT group of our study. Even if we did not compare the result with the SOX group, this result shows that the proportion of complete or subtotal TRG was less than the result of the FLOT4 trial. We hypothesize that the heterogeneity was caused by racial biological differences, and perhaps the FLOT regimen was not as effective in Chinese patients as it was reported to be in German patients. However, concrete data are needed to support this hypothesis. In contrast, the proportion of complete or subtotal TRG in the SOX group was 32.4%, which was comparable to the result of FLOT chemotherapy in the FLOT4 trial7.\n\nWe did not calculate the sample number because there was no good-quality research on tumor regression grading in the SOX regimen, and we had only the results of the FLOT4 trial. Most likely, this was the most important limitation of this study. The number of participants was empirically estimated to obtain preliminary results, and initially, 60 patients were expected to be enrolled for the analysis, but there were a substantial number of patients who dropped out of the trial. Because the primary endpoint of our study was to compare the pathological regression, the cut-off time for data analysis was set at the completion of the surgery of the 55th patient. This cut-off time was set after discussion among investigators and statisticians, without knowing the pathological results. Nonetheless, we must interpret the result of this study cautiously as the study is exploratory and therefore with no sample size calculation the power to show a difference between the arms is not demonstrated strongly. Another concern is that the primary endpoint of TRG may not translate into OS benefit therefore cannot be considered both regimens are equivalent in survival. The results of DFS and OS for this cohort are still awaited, which will provide further insight into these findings. Of course, further multicenter RCT studies are necessary to elaborate the differences between the FLOT regimen and the SOX regimen as neoadjuvant chemotherapy for patients with LAGC in terms of overall survival.\n\nOur study did not find statistically significant difference between neoadjuvant FLOT and SOX regimens for locally advanced gastric cancer patients in terms of clinical downstaging and pathological response. There was no significant difference in adverse effects and postoperative morbidity between the two groups. The results for disease-free survival and overall survival are still awaited. A large-scale phase III multicenter randomized controlled trial is necessary for the validation of this result.\n\nMethods\nThis was an investigator-initiated, phase II, open-label, randomized controlled trial. The first patient was enrolled on August 22, 2018, and the last patient was enrolled on November 14, 2019. Data of all patients were collected between August 2018 and March 2020 at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, a large volume dedicated center for gastric cancer in Shanghai, China. An English translation of the main sections (including study design, inclusion/exclusion criteria, and pre-specified outcomes) of the original study protocol is available as Supplementary Note 1 within the Supplementary Information file. This trial is registered at ClinicalTrials.gov with trial number: NCT03636893 (Dragon III: Neoadjuvant Chemotherapy (FLOT Versus SOX) for Gastric Cancer).\n\nInclusion criteria\nInclusion criteria were set as patients with any sex, age between 18 and 80 years old, a non-obstructive tumor of the stomach or esophagogastric junction, histologically confirmed adenocarcinoma with clinical-stage within cTNM: cT3 to cT4b, lymph node N1–N3 and without distant metastases (M0). Other inclusion criteria were adequate hematological function, liver function, renal function, heart function, and pulmonary function. Performance status was required to have below 2 according to Eastern Cooperative Oncology Group (ECOG). Written informed consent from the patient was mandatory for enrollment.\n\nExclusion criteria\nPatients were excluded if they were confirmed or highly suspicious for distant metastases, retroperitoneal lymph node metastases, locally invaded irresectable tumors, recurrent gastric cancer, secondary malignant disease, had prior chemo- or radiotherapy, or participated in another clinical trial. Patients were also excluded if they had acute infectious diseases, uncontrolled systemic disease or comorbidities, known contraindications, or hypersensitivity to chemotherapeutic agents.\n\nReasons for dropout\nAfter enrollment in the study, the patients were dropped out if they did not comply with the study protocol or withdrew the consent for any reason. Patients were also dropped out if they were unable to complete planned treatment for any reason, refused to undergo surgery at the same hospital.\n\nEthics\nThe study was performed according to the Declaration of Helsinki and Good Clinical Practice Guidelines as defined by the International Conference on Harmonization. The institutional review board of Ruijin Hospital approved the study protocol, and patients gave written informed consent for the planned treatment. The study was conducted and analyzed by Unit III of the Department of Gastrointestinal Surgery at Ruijin Hospital. This study was monitored by the Clinical Research Center of Ruijin Hospital (the official body responsible for guiding and monitoring all types of research in the hospital), and a timely meeting was performed to check the implementation of protocol guidelines.\n\nPretreatment assessment\nAll patients completed all the routine tests, including, but not limited to, the following:Complete blood count, liver and renal function test, clotting analysis, serum tumor biomarkers.\n\nElectrocardiography, echocardiography, plain chest radiography.\n\nUpper gastrointestinal endoscopy and biopsy for pathological diagnosis.\n\nEnhanced computed tomography of the chest, abdomen, and pelvis. CT examination included arterial, venous, and portal phases. CT images consisted of transverse, sagittal, and coronary sections.\n\nFor suspicious distant metastases, supraclavicular lymph nodes or retroperitoneal lymph nodes on CT, we performed ultrasound tests or magnetic resonance imaging (MRI) as appropriate.\n\nPatients underwent bone scintigraphy or positron emission tomography (PET) for suspicious lesions on CT examination.\n\nFinally, the diagnosis of peritoneal metastases was made by exploratory laparoscopy.\n\nFor clinical staging of the disease, we followed the eighth edition of the tumor–node–metastasis (TNM) classification, issued by the International Union against Cancer (UICC).\n\n\n\nRecruitment\nAny gastric cancer patient who was admitted at the center, and met the criteria for inclusion was considered for recruitment, thus we confirm that there was no selection bias during recruitment. Patients were screened by the trained clinicians at the designated center and the principal investigators were responsible for the evaluation of pretreatment assessment and deciding for enrollment.\n\nRandomization and blinding\nWe applied the simple randomization without blocks and stratification of any factors. The randomization was performed using a predetermined code. The random allocation sequence was generated by the statistician at the Clinical Research Center (Central body to overlook all clinical trials). The randomized code was generated by the Random Number Generators of the SPSS statistical software. And the active number generator was initialized by a reproducible fixed value. A randomized sequence was created for 1:1 allocation of 100 cases, 50 cases in each group. The random numbers were placed in sealed envelopes, and a serial number was assigned to each envelope according to the sequence of allocation of the randomized number. Each envelope was opened sequentially, according to the admission sequence of subjects.\n\nA blinded statistician was responsible for randomized assignment of interventions, either the FLOT or the SOX group. The assignment was made by telephone contact or text messages after the patient met the inclusion criteria and signed the informed consent form. The patient and care givers were not masked after allocation of intervention. Outcome assessment for the primary endpoint was performed by strictly blinded pathologists. Other data for post hoc analysis were also collected by blinded clinicians.\n\nNeoadjuvant chemotherapy\nPatients were transferred to the Department of Medical Oncology for chemotherapy, a standard protocol for chemotherapy was circulated, and timely inspection was performed by the investigators and members of the Clinical Research Center to evaluate the implementation of the protocol. Antiemetic drugs with dexamethasone were routinely administered intravenously before chemotherapy. Other supportive drugs, including granulocyte colony-stimulating factor (GCSF), were given for treatment purposes only. Preventive use of GCSF was not allowed. Surgical intervention was allowed for an emergency, e.g., acute upper gastrointestinal bleeding or perforation.\n\nPatients in the FLOT group received four cycles of standard FLOT chemotherapy7, and the patients in the SOX group received three cycles of S-1 plus oxaliplatin before curative gastrectomy.\n\nA cycle of FLOT chemotherapy consists of the following:\n\nDay 1: Intravenous 5-fluorouracil (5-FU) 2600 mg/m² via peripherally inserted central catheter (PICC) continued for 24 h\n\nIntravenous leucovorin 200 mg/m2\n\nIntravenous oxaliplatin 85 mg/m2\n\nIntravenous docetaxel 50 mg/m2\n\nThe next chemotherapy cycle was repeated on the 15th day.\n\nThe cycle of SOX chemotherapy consisted of the following:\n\nDay 1: Intravenous oxaliplatin 130 mg/m²\n\nDay 1–14: Oral tegafur–gimeracil oteracil potassium capsule (S-1) 80 mg/m² twice/day.\n\nThe next chemotherapy was repeated on the 22nd day.\n\nEvaluation of adverse effects\nAdverse effects were recorded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE 4.0). Drug dose or timing was adjusted for patients with grade three and above adverse effects. Patients with progressive disease were allowed to have alterations in their treatment. Patients were allowed to withdraw from the study for any reason.\n\nTumor restaging\nRadiologists followed the guidelines of Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) for comparison of radiological response to neoadjuvant chemotherapy19. Two specialized radiologists independently evaluated the response rate, and the final result was obtained after reviewing both results.\n\nSurgery\nPatients underwent surgical resection between 2 and 4 weeks after the completion of neoadjuvant chemotherapy. Exploratory laparoscopy was routinely performed to rule out peritoneal or distant metastases. Only specialist surgeons for gastric cancer were allowed to perform the surgery, and all surgeons were fully aware of the study protocol. Partial or total gastrectomy with D2 lymphadenectomy was performed according to Japanese gastric cancer treatment guidelines19,20. Patients with adjacent involved organs underwent combined resection along with gastrectomy. Combined resection was allowed only if R0 resection could be achieved. Distal gastrectomy with Billroth I gastroduodenostomy or Billroth II gastrojejunostomy with Braun anastomosis or Uncut Roux-en-Y gastrojejunostomy or Roux-en-Y gastrojejunostomy was performed for the tumors located at the antrum or lower part of the stomach body. Total gastrectomy with Roux-en-Y esophagojejunostomy was performed for the proximal or large tumors at the body of the stomach. The extent of the surgery was documented to state whether the procedure was curative or noncurative according to the definition stated in Japanese gastric cancer treatment guidelines20.\n\nPathological assessment\nPathologists were blinded to the allocation types of neoadjuvant chemotherapies. After formalin fixation and paraffin embedding, pathologists performed an immunohistochemical examination of all resected specimens. The routine examination included the tumor type; the depth of tumor invasion; the involved lymph nodes; the resection margins; and the invasion of nerves, lymphatics, or blood vessels. Resection or R status was nominated for curative resection (R0) or noncurative resection (R1 and R2). Pathological examinations also included the following: the measurement of the macroscopically identifiable residual tumor and/or scarring indicating the site of the previous tumor bed. Two specialized pathologists followed the Becker criteria for tumor regression grading (TRG)16. Any conflicting results were settled after re-examination and discussion among both pathologists and investigators.\n\nTumor regression grade (TRG) and Becker criteria\nTumor regression grade according to Becker criteria included “Grade 1a” (Complete tumor regression i.e., 0% residual tumor per tumor bed), “Grade 1b” (Subtotal tumor regression i.e., <10% residual tumor per tumor bed) “Grade 2” (Partial tumor regression i.e., 10–50% residual tumor per tumor bed), “Grade 3” (Minimal or no tumor regression i.e., >50% residual tumor per tumor bed).\n\nPrimary outcomes\nTotal percentage of patients with pathologically complete tumor regression (TRG1a) and subtotal tumor regression (TRG1b) in the primary tumor; blinded pathologists assessed the TRG after having specimen of the last enrolled patient.\n\nSecondary outcomes\nOverall survival (OS) and disease-free survival (DFS) were set as the secondary endpoints, which will be assessed after five years from the surgery of the last enrolled patient. OS and DFS were defined as the time from randomization to death from any cause and the time from randomization to relapse of disease, respectively.\n\nSample size and power calculation\nThis was an exploratory study. Sample was not estimated according to statistical power calculation; the sample size was estimated empirically. The data analysis cut-off time was set at the completion of surgery for the 55th patient, who met the criteria for per-protocol (PP) analysis.\n\nStatistics and reproducibility\nThe primary endpoint was analyzed in the ITT population, defined as all the patients who were randomly assigned to a treatment. Postoperative morbidity and mortality were analyzed in the PP population, which is the number of patients who had surgery after the completion of all planned neoadjuvant chemotherapy. Comparisons of other factors except primary endpoint were post hoc analyses. The statistical analysis was performed with Statistical Package for Social Science (SPSS) version 22.0 for Windows (SPSS, Inc., Chicago, IL). Kolmogorov–Smirnov Test was used to test the normality of the data. The continuous data are described as the median and range. Categorical data are expressed as frequencies and percentage. The Fisher’s exact test was used to compare the differences in rate between the two groups. Univariate analysis for the association of TRG with clinicopathological factors was performed with Fisher’s exact test. An exploratory analysis with Fisher’s exact test was done to compare the differences in rate of TRG according to pretreatment clinical staging and postoperative pathological TNM staging. All P values presented are two-sided, and a P value < 0.05 was considered statistically significant. All the described results were tested for replication by two independent statisticians. Each statistician checked the results twice, thus altogether the results were successfully replicated for four times.\n\nReporting summary\nFurther information on research design is available in the Nature Research Reporting Summary linked to this article.\n\nSupplementary information\nSupplementary Information\n\n Reporting summary\n\n Peer review information\nNature Communications thanks the anonymous reviewer (s) for their contribution to the peer review of this work.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThese authors contributed equally: Birendra Kumar Sah, Benyan Zhang.\n\nSupplementary information\nSupplementary information is available for this paper at 10.1038/s41467-020-19965-6.\n\nAcknowledgements\nThe authors thank the department of pathology, department of oncology, department of radiology, Ruijin Hospital for their kind cooperation, and all the support. Special thanks to the Center for clinical research, Ruijin Hospital, for their support. The overall costs of publication will be funded by grants from the National Natural Science Foundation of China (No. 91529302 (BY Liu), No. 81772509 (Liu BY), and No. 81871904 (Zhu ZG).\n\nAuthor contributions\nB.K.S. designed the study, collected the patient data, and drafted the paper. C.L. and Z.G.Z. participated in the design of the study and edited the final paper. H.Z. reviewed the radiological results; B.Z. and F.Y. independently reviewed the pathological results (TRG). J.L. participated in the design of the study and checked all the statistical calculations. T.M., M.S., and W.X. collected the patient data for adverse effects. Z.L.Z., W.L., C.Y., B.L., and M.Y. assisted in collection of the data and edited the final paper. All authors read and approved the paper for publication.\n\nData availability\nAll the original clinical data can be made available on reasonable request from the corresponding author (Birendra Kumar Sah) at any time in a de-identified manner. A translated copy of the main sections of the original study protocol is available in the Supplementary Information file. The remaining data are available within the Article, Supplementary Information, or available from the authors upon request.\n\nCompeting interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Cunningham D Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer N. Engl. J. Med 2006 355 11 20 10.1056/NEJMoa055531 16822992 \n2. Li W Qin J Sun YH Liu TS Neoadjuvant chemotherapy for advanced gastric cancer: a meta-analysis World J. Gastroenterol. 2010 16 5621 5628 10.3748/wjg.v16.i44.5621 21105197 \n3. Ronellenfitsch, U. et al. Perioperative chemo (radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach, gastroesophageal junction, and lower esophagus. Cochrane Database Syst Rev. CD008107 (2013).\n4. Zhao JH Which is better for gastric cancer patients, perioperative or adjuvant chemotherapy: a meta-analysis BMC Cancer 2016 16 631 10.1186/s12885-016-2667-5 27519527 \n5. Eto K Prophylactic effect of neoadjuvant chemotherapy in gastric cancer patients with postoperative complications Gastric Cancer 2018 21 703 709 10.1007/s10120-017-0781-y 29188456 \n6. Katayama H An integrated analysis of two phase II trials (JCOG0001 and JCOG0405) of preoperative chemotherapy followed by D3 gastrectomy for gastric cancer with extensive lymph node metastasis Gastric Cancer 2019 22 1301 1307 10.1007/s10120-019-00981-5 31264058 \n7. Al-Batran SE Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial Lancet Oncol. 2016 17 1697 1708 10.1016/S1470-2045(16)30531-9 27776843 \n8. Al-Batran SE Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial Lancet 2019 393 1948 1957 10.1016/S0140-6736(18)32557-1 30982686 \n9. Zhou C Dose-finding study of modified FLOT (mFLOT) regimen as first-line treatment in Chinese patients with metastatic adenocarcinoma of stomach Cancer Chemother. Pharm. 2020 85 113 119 10.1007/s00280-019-03982-4 \n10. Sah, B. K. et al. Dragon III—Phase 1: feasibility and safety of neoadjuvant chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) for locally-advanced gastric cancer patients in China. Preprint at: https://www.medrxiv.org/content/10.1101/2020.05.22.20110668v7 (2020).\n11. Kim GM A randomized phase II trial of S-1-oxaliplatin versus capecitabine-oxaliplatin in advanced gastric cancer Eur. J. Cancer 2012 48 518 526 10.1016/j.ejca.2011.12.017 22243774 \n12. Yamada Y Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naive patients with advanced gastric cancer Ann. Oncol. 2015 26 141 148 10.1093/annonc/mdu472 25316259 \n13. Satake H Phase I study of neoadjuvant chemotherapy with S-1 and oxaliplatin for locally advanced gastric cancer (Neo G-SOX PI) ESMO Open 2017 2 e000130 10.1136/esmoopen-2016-000130 28761726 \n14. Ji, J. et al. Perioperative chemotherapy of oxaliplatin combined with S-1 (SOX) versus postoperative chemotherapy of SOX or oxaliplatin with capecitabine (XELOX) in locally advanced gastric adenocarcinoma with D2 gastrectomy: a randomized phase III trial (RESOLVE trial). Ann. Oncol. 30 Supplement 5 (2019).\n15. Wang X Early results of the randomized, multicenter, controlled evaluation of S-1 and oxaliplatin as neoadjuvant chemotherapy for Chinese advanced gastric cancer patients (RESONANCE Trial) J. Clin. Oncol. 2020 8 280 10.1200/JCO.2020.38.4_suppl.280 \n16. Becker K Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy Cancer 2003 98 1521 1530 10.1002/cncr.11660 14508841 \n17. Tomasello G Tumor regression grade and survival after neoadjuvant treatment in gastro-esophageal cancer: a meta-analysis of 17 published studies Eur. J. Surg. Oncol. 2017 43 1607 1616 10.1016/j.ejso.2017.03.001 28347525 \n18. Wang K Docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT) as preoperative and postoperative chemotherapy compared with surgery followed by chemotherapy for patients with locally advanced gastric cancer: a propensity score-based analysis Cancer Manag. Res. 2019 11 3009 3020 10.2147/CMAR.S200883 31114348 \n19. Eisenhauer EA New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur. J. Cancer 2009 45 228 247 10.1016/j.ejca.2008.10.026 19097774 \n20. Japanese Gastric Cancer A. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer20, 1–19 (2017).\n\n",
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"title": "Neoadjuvant FLOT versus SOX phase II randomized clinical trial for patients with locally advanced gastric cancer.",
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"abstract": "OBJECTIVE\nTo compare the risk of developing uveitis in patients initiating anti-tumor necrosis factor (anti-TNF) agents (adalimumab, etanercept, and infliximab) for ankylosing spondylitis (AS).\n\n\nMETHODS\nAnti-TNF-naive patients with a diagnosis of AS and without a history of uveitis (N = 2115) who subsequently initiated anti-TNF therapy for AS were identified in a large claims database (2005 to 2011). A multivariate Cox proportional-hazards model was used to compare the risk of uveitis in patients who received etanercept or infliximab vs adalimumab.\n\n\nRESULTS\nThe median number of days to the first occurrence of uveitis after initiation of anti-TNF was 191. Among the three anti-TNF groups, the median time to event of uveitis was longest in patients taking adalimumab (243 days), followed by etanercept (182 days) and infliximab (144 days). The incidence rate for uveitis over 1 year was lowest for patients who received adalimumab (2.4%, N = 717), highest for patients who received etanercept (4.5%, N = 1087), and intermediate for patients who received infliximab (3.2%, N = 311). The risk of uveitis was 1.9 times higher in patients receiving etanercept compared with those taking adalimumab (hazard ratio [HR]: 1.91, 95% confidence interval [CI]: 1.1 to 3.31). For patients taking infliximab, the risk of uveitis was not statistically significantly different (HR: 1.35, 95% CI: 0.62 to 2.95) compared to adalimumab.\n\n\nCONCLUSIONS\nThe results indicated that initial adalimumab therapy is associated with a significantly lower risk of developing uveitis compared to initial etanercept therapy in patients diagnosed with AS and no prior history of uveitis; however, the risk was not different between adalimumab and infliximab. Limitations to consider when interpreting this conclusion include that disease-level clinical data, such as disease duration, were not available for inclusion in the model and that risk of uveitis beyond 1 year was not evaluated.",
"affiliations": "University of Franche-Comté and CHU de Besançon, Department of Rheumatology , Besançon , France.",
"authors": "Wendling|Daniel|D|;Joshi|Avani|A|;Reilly|Patrick|P|;Jalundhwala|Yash J|YJ|;Mittal|Manish|M|;Bao|Yanjun|Y|",
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"title": "Comparing the risk of developing uveitis in patients initiating anti-tumor necrosis factor therapy for ankylosing spondylitis: an analysis of a large US claims database.",
"title_normalized": "comparing the risk of developing uveitis in patients initiating anti tumor necrosis factor therapy for ankylosing spondylitis an analysis of a large us claims database"
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"abstract": "Herpes simplex virus is the most common cause of severe and potentially fatal sporadic encephalitis worldwide. Recurrence of neurologic symptoms after resolution of the initial episode of HSV encephalitis and despite adequate treatment with intravenous acyclovir is well recognized albeit rare. Most of these recurrences had no evidence of replicating virus and are immune in nature with only a minority of these recurrences representing true virologic relapses. Immunocompromised patients are predominantly at greater risk for virologic relapse of HSV encephalitis with potentially severe and at times fatal consequences. We describe a patient with small cell lung cancer and brain metastasis who underwent chemotherapy, treatment with dexamethasone and whole brain radiotherapy who subsequently suffered two episodes of HSV encephalitis three months and seven months after completion of radiotherapy and while on dexamethasone treatment.",
"affiliations": "Department of Medicine, Infectious Diseases Unit, Sultan Qaboos University Hospital, Oman.;Department of Medicine, Infectious Diseases Unit, Sultan Qaboos University Hospital, Oman.;Department of Radiology and Molecular Imaging, Sultan Qaboos University Hospital, Oman.;Department of Medicine, Infectious Diseases Unit, Sultan Qaboos University Hospital, Oman.;Department of Microbiology andImmunology, Sultan Qaboos University Hospital, Oman.;Department of Medicine, Neurology Unit, Sultan Qaboos University Hospital, Oman.;Department of Medicine, Oncology Unit, Sultan Qaboos University Hospital, Oman.",
"authors": "Balkhair|A|A|;Al Wahaibi|A|A|;Raniga|S|S|;Al Amin|M|M|;Ba Alawi|F|F|;El-Tigani|M|M|;Kumar|S|S|",
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"doi": "10.1016/j.idcr.2019.e00626",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(19)30225-210.1016/j.idcr.2019.e00626e00626ArticleRelapse of herpes simplex encephalitis in a patient with metastatic small cell lung cancer following scalp sparing whole brain radiotherapy Balkhair A. balkhair2020@gmail.coma⁎Al Wahaibi A. aRaniga S. bAl Amin M. aBa Alawi F. cEl-Tigani M. dKumar S. ea Department of Medicine, Infectious Diseases Unit, Sultan Qaboos University Hospital, Omanb Department of Radiology and Molecular Imaging, Sultan Qaboos University Hospital, Omanc Department of Microbiology andImmunology, Sultan Qaboos University Hospital, Omand Department of Medicine, Neurology Unit, Sultan Qaboos University Hospital, Omane Department of Medicine, Oncology Unit, Sultan Qaboos University Hospital, Oman⁎ Corresponding author. balkhair2020@gmail.com20 8 2019 2019 20 8 2019 18 e0062624 7 2019 16 8 2019 17 8 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Late virologic relapse of Herpes simplex virus encephalitis [HSE] is a scarcely reported clinical entity.\n\n• We report a case of HSE with late virologic relapse in a patient with metastatic small cell lung cancer.\n\n• Possible association between cranial radiotherapy and dexamethasone with subsequent risk of HSE and relapse is exemplified.\n\n• We propose antiviral prophylaxis for at-risk immunocompromised patients receiving dexamethasone or whole brain radiotherapy.\n\n• We emphasised the seriousness of virologic relapse of HSE in immunocompromised patients.\n\n\n\nHerpes simplex virus is the most common cause of severe and potentially fatal sporadic encephalitis worldwide. Recurrence of neurologic symptoms after resolution of the initial episode of HSV encephalitis and despite adequate treatment with intravenous acyclovir is well recognized albeit rare. Most of these recurrences had no evidence of replicating virus and are immune in nature with only a minority of these recurrences representing true virologic relapses. Immunocompromised patients are predominantly at greater risk for virologic relapse of HSV encephalitis with potentially severe and at times fatal consequences. We describe a patient with small cell lung cancer and brain metastasis who underwent chemotherapy, treatment with dexamethasone and whole brain radiotherapy who subsequently suffered two episodes of HSV encephalitis three months and seven months after completion of radiotherapy and while on dexamethasone treatment.\n\nKeywords\nHerpes simplex encephalitisSmall cell lung cancerWhole brain radiotherapyRelapseOman\n==== Body\nIntroduction\nHerpes simplex virus (HSV) is the most common cause of severe and potentially fatal sporadic encephalitis worldwide [1] with an incidence of approximately 2–4 cases per million per year [2]. The typical presentation of Herpes simplex encephalitis (HSE) consists of decreased consciousness (90%), fever (80%), and focal neurologic deficits (70%) [3]. Clinical presentation, brain MRI and CSF analysis are the foundations of diagnosis of HSE including relapses [3].\n\nPrior to the availability of acyclovir, mortality from HSE was unacceptably high (70%) [4]. Currently, 30-day mortality from HSE ranges between 5% and 10% whereas 20% of survivors suffer a severe neurologic sequel [4]. The pathology of HSE is a necrotizing, hemorrhagic, inflammatory encephalitis in the mesiotemporal, inferofrontal, and insular cortices, with grey matter being affected more than white matter [5]. Early diagnosis and treatment of HSE including relapses is critical to favorable clinical outcome [6] with current guidelines recommending treatment of HSE with intravenous acyclovir at a dose of 10–12 mg/kg given every 8 h for 2–3 weeks [7]. The role of corticosteroids on the neurological outcomes in patients with HSE is unknown. A randomized trial comparing acyclovir plus placebo vs acyclovir plus dexamethasone was ended due to insufficient enrollment [8].\n\nAs larger numbers of patients survived HSE, it became apparent that 10%–25% of survivors experience relapse or recurrence of neurologic symptoms despite adequate treatment with intravenous acyclovir [9]. Interestingly, most of these “relapsed” cases had no evidence of replicating virus neither in brain tissue nor viral DNA in CSF, suggesting an immune-mediated mechanism accounting for the recurrences of neurologic symptoms [10]. It is now believed that antibody against the N-methyl-D-aspartate receptor (NMDAR) is key factor in the pathogenesis of neurologic symptoms following recovery from the initial episode of HSE resulting in an autoimmune neurologic relapse [11] suggesting that only a minority (<5%) of adequately treated adult patients with HSE experience a “true” virologic relapse [12] making it a rare clinical entity.\n\nIt is believed that virologic relapse in HSE is a consequence of reactivation of a latent HSV in the trigeminal or olfactory root ganglia whereas first HSE episodes follow viral ascent from oral sites via the trigeminal or olfactory nerves in HSV-1 and from genital sites via sacral nerve roots in HSV-2 [5]. It has been observed that reactivation of latent HSV infection leading to virologic relapse of HSE may follow immunosuppression [13], chemoradiation [14], and deep brain stimulation among others [15].\n\nClinical or neuroradiological relapse in patients with previous HSE intuitively necessitates distinguishing between virologic relapse (reflected by a positive PCR for HSV in CSF) and an immune-mediated condition (such as anti-NMDA receptor encephalitis) since therapeutic approaches to these two conditions largely differ with antiviral therapy for the former and immunotherapy for the latter [16]. The use of PCR for the detection of HSV DNA in CSF is considered the gold standard for the diagnosis of HSE. It is “however” not known whether the sensitivity of PCR in detecting HSE relapses is equivalent to its sensitivity in primary HSE [17].\n\nWe describe a patient with small cell lung cancer and brain metastasis who underwent chemotherapy, treatment with dexamethasone and whole brain radiotherapy who subsequently suffered two episodes of HSE three months and seven months after completion of radiotherapy and while on dexamethasone treatment.\n\nCase presentation\nA 72-year-old man presented with a three-day history of fever, somnolence and new-onset seizure. Sixteen months prior to current presentation, he was diagnosed with metastatic small cell lung cancer for which he received chemotherapy [cisplatin and etoposide] and chest radiotherapy. A year later, he was found to have a solitary metastatic brain lesion for which he underwent scalp sparing palliative whole brain radiotherapy (30 Gy given in 10 fractions over 2 weeks) which he completed three months prior to this presentation. He was continued on dexamethasone at a dose of 4 mg daily.\n\nPhysical examination revealed a sick looking, obtunded man with positive signs of meningeal irritation. Glasgow coma scale was 13/15. Pupils were reactive, equal and of normal size. Prévost sign (deviation of the eyes away from the hemiparesis in acute cortical hemiparetic stroke) was positive with right-sided gaze. Paratonia of all four limbs was demonstrated with signs of left hemiparesis. He was febrile (38.40C), normotensive but tachycardic (116/min) and tachypneic (21/min). Oxygen saturation was 98% (room air). No skin rash. Rest of examination was normal. His condition rapidly worsened with increasing seizures and he became unresponsive requiring urgent endotracheal intubation and mechanical ventilation. He was transferred to the intensive care unit with a presumptive diagnosis of right hemispheric stroke (complicating metastatic brain lesion) and meningoencephalitis and the following antimicrobials were empirically given: ceftriaxone 2 g iv q12 h, ampicillin 2 g iv q4h, and acyclovir 12 mg/kg iv q8h. Additionally, intravenous levetiracetam (1000 mg q12 h) was administered.\n\nInitial laboratory investigations were normal except for mild thrombocytopenia [131,000/μL] and lymphopenia [500 /μL]. Brain MRI was performed (Fig. 1).Fig. 1 (A–F): Brain MRI images at first presentation with HSV encephalitis.\n\nA: FLAIR coronal image demonstrating gyral oedema and hyperintensity predominantly involving the right insular cortex and the right medial temporal lobe. Fig. 1B: Diffusion weighted axial image showing a linear area of hyperintensity involving the right insular cortex suggestive of diffusion restriction. Fig. 1C: Susceptibility weighted axial image revealing presence of petechial haemorrhage in the right insular cortex. Fig. 1D: Post gadolinium T1W coronal image demonstrating mild patchy gyral enhancement in the insular cortex. Fig. 1E and F: A rounded rim enhancing lesion with marked perilesional vasogenic oedema is shown at the right centrum semiovale keeping with the known brain metastasis from small cell lung cancer.\n\nFig. 1\n\nCerebrospinal fluid (CSF) examination showed clear fluid with 16 cells/μL (100% lymphocytes). CSF protein and glucose were 77 mg/dL and 67 mg/dL (blood glucose: 144 mg/dL) respectively. Herpes simplex virus (HSV) DNA was detected by PCR analysis of CSF. Subsequently, CSF culture showed no growth.\n\nA diagnosis of HSV meningoencephalitis and left-sided stroke complicating brain metastasis with secondary seizures was made. The patient was continued on intravenous acyclovir (12 mg/kg q8h) for three weeks during which dexamethasone continued at 4 mg/day. He made slow recovery with improving consciousness and cognition in addition to resolution of seizures. He was discharged home tracheostomized and with major functional disability resulting from residual left-sided hemiparesis. He was continued on levetiracetam (1500 mg po q12 h) and dexamethasone (2 mg po q12 h) at time of discharge. A repeat CSF analysis was not done prior to discharge.\n\nFour months later, he presented again with a-two-day history of fever, worsening level of consciousness, and seizures. Physical examination revealed a tracheostomized, encephalopathic man with Glasgow coma scale of 10/15. Pupils were reactive, equal and of normal size. Signs of previous left hemiparesis were again demonstrated. He was febrile (39.00C), normotensive but bradycardic (61/min) and tachypneic (19/min). Oxygen saturation was 92% (room air). There was no rash and the rest of examination was normal. Initial laboratory investigations were normal except for a hemoglobin of 6.4 g/dL, platelet count of 145,000 /μL, and absolute lymphocyte count of 900 /μL. MRI brain (Fig. 2) and EEG (Fig. 3) are depicted below.Fig. 2 (A and B): Brain MRI images at time of relapse of HSV encephalitis.\n\nA: Diffusion weighted axial image revealing new cortical signal abnormality with diffusion restriction involving the right inferior temporal gyrus and both hippocampi. Fig. 2B: FLAIR axial image demonstrating worsening of the right temporal lobe hyperintensity compared to the previous MRI.\n\nFig. 2Fig. 3 (A and B): Electroencephalographic (EEG) at presentation with relapse of HSV encephalitis.\n\nA: EEG recording demonstrating frequent left posterior temporal periodic lateralized epileptiform discharges (PLEDS) characteristic of HSV encephalitis. Fig. 3B: EEG recording showing PLEDS arising from left temporal and right frontal, temporal, and parietal lobes.\n\nFig. 3\n\nA repeat CSF examination showed clear fluid with 5 cells/μL (100% lymphocytes). CSF protein was 106 mg/dL and CSF glucose was 80 mg/dL (blood glucose: 200 mg/dL). Herpes Simplex Virus (HSV) DNA was again detected by PCR analysis of CSF. Autoimmune encephalitis including anti-NMDA receptor antibodies and paraneoplastic screen panels in CSF were both negative.\n\nA diagnosis of relapse of herpes simplex encephalitis was made and the patient was treated with intravenous acyclovir (12 mg/kg q8h) for three weeks. Despite treatment, the patient neurological condition worsened and remained in coma until his death four weeks after admission.\n\nDiscussion\nVirologic relapse in HSE remains a rare clinical entity [12] and is infrequently reported. Furthermore, late relapse of HSE, defined as recurrence more than three months after the first initial encephalitic episode, is rarer [18]. We believe this case represents late virologic relapse of HSV culminating in second episode of HSE four months after primary HSE. Our proposition is supported by near complete resolution of the neurological symptoms associated with the first presentation on antiviral therapy, four months of symptom-free period, and second positive HSV PCR coinciding with recurrence of compatible clinical, radiological and electroencephalographic correlates. Like this patient, all documented cases of HSE, albeit primary infection, following brain radiotherapy were notable for absent or minimal CSF cell count [19]. In this case, CSF cell count was 16 cells/μL and 5 cells/μL in first and relapse presentation respectively.\n\nThere are several plausible explanations, although poorly understood, for virologic relapse of HSE some of which apply to this patient. Several anecdotal reports suggest an association between suboptimal dosing and relatively shorter duration of acyclovir therapy with relapse of HSE [20]. This is unlikely explanation in this case where intravenous acyclovir was administered at adequate dosing (12 mg/kg q8hr) and duration (three weeks). Immunocompetent patients with HSV encephalitis will typically have a negative CSF HSV PCR after 14 days of acyclovir treatment [18]. It is known that immunocompromised patients may fail to completely suppress or fully eradicate HSV from CSF hence they are presumed to be at greater risk for relapse of HSE [21]. Evidence of “virologic cure” after completion of treatment of the first presentation is lacking in this case. Hence possible contribution of this to clinical relapse in this case cannot be ascertained.\n\nIncidence of primary HSE in cancer patients treated with prior whole brain radiotherapy is reportedly significantly higher in comparison to the general population with reported incidence of 1:250 and 2–4:1 million respectively [2] and the association between brain radiotherapy and HSE is well documented even though limited to approximately thirty reports [22]. Contrarywise, the association of whole brain radiotherapy with virologic relapse of HSE is largely unknown. In this patient settings, palliative scalp sparing whole brain radiotherapy was administered for metastatic brain lesion following which (3 months later) he presented with first episode of HSE. We believe that exposure to brain radiotherapy contributed to this patient vulnerability for primary HSE in agreement with published literature. Moreover, we propose that whole brain radiotherapy predisposed this patient to virologic relapse of HSE four months after the first episode.\n\nDexamethasone might pose a risk for relapse of HSE as suggested by a systematic review [23]. This patient was prescribed dexamethasone for relief of symptoms related to brain metastasis. He was on 4 mg daily concomitant with brain radiotherapy and up until the first presentation and 8 mg daily between the first and the second presentations with HSE. Dexamethasone, we believe, was a likely culprit for predisposing this patient to primary and recurrent HSE. It is therefore evident that this patient had several potential predispositions to relapse of HSE including underlying cancer, chemotherapy, whole brain radiotherapy and dexamethasone.\n\nTo our knowledge, there are no studies evaluating the potential role of antiviral prophylaxis for the prevention of relapse of HSE. Until this is done, we suggest that patients at risk for HSE relapse [like this patient] warranted consideration for oral suppressive antiviral therapy. Recently, a placebo-controlled study showed that oral valacyclovir (2 g q8h) given for three months post HSE did not improve neurologic outcome [24]. This study unfortunately did not evaluate the impact on virologic relapse.\n\nWe believe that virologic relapse of HSE may be underestimated and misdiagnosed. Given the potential serious consequences of relapse of HSE, at-risk immunocompromised patients receiving dexamethasone or whole brain radiotherapy may be considered for prophylactic antiviral therapy during and for an extended period following completion of treatment. Recurrence of symptoms or new neurological deficits should raise concern for HSV viral relapse.\n\nPatient consent\nPatient consent was not required for this publication.\n\nFunding\nNone.\n\nDeclaration of Competing Interest\nThe authors declare that they have no conflict of interest.\n\nAcknowledgment\nWe acknowledge that:\n\nThis work is original and has not been published previously.\n\nThe manuscript is not under consideration for publication elsewhere.\n\nThe submission is approved by all authors.\n\nFirst/corresponding author was responsible for the writing and revising the manuscript, second author contributed to the first draft of the manuscript, and all authors contributed to the clinical care of the patient and to the revision of several drafts before submission.\n==== Refs\nReferences\n1 Weinstein G.M. Small J.E. Herpes simplex encephalitis Small J.E. Noujaim D.L. Ginat D.T. Kelly H.R. Schaefer P.W. Neuroradiology: spectrum and evolution of disease 2019 Saunders 50 55 \n2 Graber J.J. Rosenblum M.K. DeAngelis L.M. Herpes simplex encephalitis in patients with cancer J Neurooncol 105 2 2011 415 421 21637964 \n3 Chakraborty S. Donner M. Colan D. Fatal herpes encephalitis in a patient with small cell lung cancer following prophylactic cranial radiation – a case report with review of literature Anticancer Res 33 8 2013 3263 3268 23898089 \n4 Jouan Y. Grammatico-Guillon L. Espitalier F. Cazals X. François P. Guillon A. Long-term outcome of severe herpes simplex encephalitis: a population-based observational study Crit Care 19 1 2015 345 26387515 \n5 Allen J. Aksamit Jr Acute viral encephalitis Goldman L. Schafer A. Cecil R. Goldman’s cecil medicine twenty fourth ed. 2012 Elsevier/Saunders Philadelphia, PA 422 424 \n6 Poissy J.I. Wolff M. Dewilde A. Factors associated with delay to acyclovir administration in 184 patients with herpes simplex virus encephalitis Clin Microbiol Infect 15 6 2009 560 564 19392906 \n7 Tunkel A.R. Glaser C.A. Bloch K.C. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America Clin Infect Dis 47 3 2008 303 327 18582201 \n8 Martinez-Torres F. Menon S. Pritsch M. Protocol of German trial of acyclovir and corticosteroids in herpes simplex virus encephalitis (GACHE): a multicentre, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial BMC Neurol 8 2008 40 18959773 \n9 Bale J.F. Pasquier R.D. Relapse in herpes simplex virus encephalitis: it’s not just about the virus Neurology 85 20 2015 1730 1731 26491087 \n10 Rabinstein A.A. Herpes virus encephalitis in adults: current knowledge and old myths Neurol Clin 35 4 2017 695 705 28962808 \n11 Venkatesan A. Immune-mediated encephalitis for the infectious disease specialist Curr Opin Infect Dis 32 3 2019 251 258 31021956 \n12 Whitley R.J. Gnann J.W. Viral encephalitis: familiar infections and emerging pathogens Lancet 359 9305 2002 507 513 11853816 \n13 Silvano G.I. Lazzari G. Resta F. Buccoliero G. Pezzella G. Pisconti S. A herpes simplex virus-1 fatal encephalitis following chemoradiotherapy, steroids, and prophylactic cranial irradiation in a small cell lung cancer patient Lung Cancer 57 2 2007 243 246 17368625 \n14 Okada M. Miyake K. Shinomiya A. Kawai N. Tamiya T. Relapse of herpes encephalitis induced by temozolomide-based chemoradiation in a patient with malignant glioma J Neurosurg 118 2 2013 258 263 23101441 \n15 Hamdi H. Robin E. Stahl J.P. Anterior thalamic stimulation induced relapsing encephalitis Stereotact Funct Neurosurg 97 2 2019 132 136 31055582 \n16 Armangue T. Moris G. Cantarín-Extremera V. Autoimmune post–herpes simplex encephalitis of adults and teenagers Neurology 85 20 2015 1736 1743 26491084 \n17 Rigamonti A. Lauria G. Mantero V. Salmaggi A. A case of late herpes simplex encephalitis relapse J Clin Virol 58 1 2013 269 270 23757375 \n18 Tyler K.L. Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret’s Herpes 11 2 2004 57A 64A \n19 Jakob N.J. Lenhard T. Schnitzler P. Herpes simplex virus encephalitis despite normal cell count in cerebrospinal fluid Crit Care Med 40 4 2012 1304 1308 22067626 \n20 Valencia I. Miles D.K. Melvin J. Relapse of herpes encephalitis after acyclovir therapy: report of two new cases and review of the literature Neuropediatrics 35 6 2004 371 376 15627947 \n21 Tan I.L. McArthur J.C. Venkatesan A. Nath A. Atypical manifestations and poor outcome of herpes simplex encephalitis in the immunocompromised Neurology 79 21 2012 2125 2132 23136265 \n22 Sermer D.J. Woodley J.L. Thomas C.A. Hedlund J.A. Herpes simplex encephalitis as a complication of whole-brain radiotherapy: a case report and review of the literature Case Rep Oncol 7 3 2014 774 779 25722668 \n23 Ramos-Estebanez C. Lizarraga K.J. Merenda A. A systematic review on the role of adjunctive corticosteroids in herpes simplex virus encephalitis: is timing critical for safety and efficacy? Antivir Ther 19 2 2014 133 139 24009096 \n24 Gnann J.W. Sköldenberg B. Hart J. Herpes simplex encephalitis: lack of clinical benefit of long-term valacyclovir therapy Clin Infect Dis 61 5 2015 683 691 25956891\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "18()",
"journal": "IDCases",
"keywords": "Herpes simplex encephalitis; Oman; Relapse; Small cell lung cancer; Whole brain radiotherapy",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e00626",
"pmc": null,
"pmid": "31528539",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "15319091;19392906;23757375;26491084;21637964;26387515;15627947;18959773;24009096;26491087;25722668;25956891;22067626;17368625;23136265;31055582;23898089;18582201;28962808;11853816;31021956;23101441",
"title": "Relapse of herpes simplex encephalitis in a patient with metastatic small cell lung cancer following scalp sparing whole brain radiotherapy.",
"title_normalized": "relapse of herpes simplex encephalitis in a patient with metastatic small cell lung cancer following scalp sparing whole brain radiotherapy"
} | [
{
"companynumb": "OM-FERA PHARMACEUTICALS, LLC-2019PRG00228",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditi... |
{
"abstract": "Plasma metanephrines have become the biochemical test of choice for suspected phaeochromocytomas and paragangliomas in many institutions. We encountered two separate cases of significantly elevated plasma metanephrines in patients taking midodrine, a sympathomimetic drug used in the treatment of severe postural hypotension, in the absence of a diagnosis of phaeochromocytomas and paragangliomas. Upon stopping midodrine treatment, plasma metanephrine concentrations returned to normal in both patients. To explore the hypothesis that midodrine or its metabolite desglymidodrine might interfere with the metanephrines assay, we tested the interaction of midodrine with metanephrine assays from two different centres. High-performance liquid chromatography tandem mass spectrometry on plasma samples and on methanolic extract of midodrine demonstrated co-elution of the metabolite desglymidodrine with metanephrine. We conclude that patients taking midodrine may have falsely elevated plasma metanephrine as a result of analytical interference, and clinicians need to be aware of this problem.",
"affiliations": "1 Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.;1 Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.;2 Department of Clinical Biochemistry, John Radcliffe Hospital, Oxford, UK.;3 Blood Sciences, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK.;3 Blood Sciences, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK.;3 Blood Sciences, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK.;4 Department of Specialist Chemical Pathology, LabPlus, Auckland City Hospital, Auckland, New Zealand.;4 Department of Specialist Chemical Pathology, LabPlus, Auckland City Hospital, Auckland, New Zealand.;4 Department of Specialist Chemical Pathology, LabPlus, Auckland City Hospital, Auckland, New Zealand.;4 Department of Specialist Chemical Pathology, LabPlus, Auckland City Hospital, Auckland, New Zealand.;4 Department of Specialist Chemical Pathology, LabPlus, Auckland City Hospital, Auckland, New Zealand.;1 Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.",
"authors": "Emms|Holly|H|http://orcid.org/0000-0001-5616-3608;Farah|George|G|;Shine|Brian|B|;Boot|Chris|C|;Toole|Barry|B|;McFadden|Martin|M|;Lam|Leo|L|http://orcid.org/0000-0003-1405-9890;Ou|Zong-Quan|ZQ|;Woollard|Gerald|G|;Madhavaram|Hima|H|;Kyle|Campbell|C|;Grossman|Ashley B|AB|",
"chemical_list": "D058646:Adrenergic alpha-1 Receptor Agonists; D013566:Sympathomimetics; D008676:Metanephrine; D008879:Midodrine",
"country": "England",
"delete": false,
"doi": "10.1177/0004563218755817",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-5632",
"issue": "55(4)",
"journal": "Annals of clinical biochemistry",
"keywords": "Midodrine; interference; liquid chromatography tandem mass spectroscopy; normetanephrine; paraganglioma; phaeochromocytoma; plasma metanephrines",
"medline_ta": "Ann Clin Biochem",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D058646:Adrenergic alpha-1 Receptor Agonists; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008676:Metanephrine; D008879:Midodrine; D010235:Paraganglioma; D010673:Pheochromocytoma; D013566:Sympathomimetics; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "0324055",
"other_id": null,
"pages": "509-515",
"pmc": null,
"pmid": "29357678",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Falsely elevated plasma metanephrine in patients taking midodrine.",
"title_normalized": "falsely elevated plasma metanephrine in patients taking midodrine"
} | [
{
"companynumb": "GB-SHIRE-GB201814547",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SODIUM"
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{
"abstract": "Thrombocytopenia with absent radii (TAR) syndrome is a rare genetic condition causing absent radial bones and thrombocytopenia. Management is generally supportive although there may be a role for platelet-stimulating agents such as romiplostim. In this case, we highlight the obstacles in managing end-stage heart failure in a patient with TAR syndrome.",
"affiliations": "Department of Internal Medicine, University of Hawai'i System, Honolulu, Hawaii, USA jeankim@hawaii.edu.;Department of Internal Medicine, University of Hawai'i System, Honolulu, Hawaii, USA.;Queen's Heart Institute, Queen's Medical Center, Honolulu, Hawaii, USA.;Department of Cardiovascular Disease, Kuakini Medical Center, Honolulu, Hawaii, USA.",
"authors": "Kim|Jean|J|;Kewcharoen|Jakrin|J|;Lum|Corey J|CJ|;Azuma|Steven S|SS|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243127",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "cardiovascular system; haematology (incl blood transfusion); heart failure",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000080984:Congenital Bone Marrow Failure Syndromes; D006333:Heart Failure; D006801:Humans; D011884:Radius; D013921:Thrombocytopenia; D038062:Upper Extremity Deformities, Congenital",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34257121",
"pubdate": "2021-07-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Uncommon obstacle: management of end-stage heart failure in thrombocytopenia with absent radii (TAR) syndrome.",
"title_normalized": "uncommon obstacle management of end stage heart failure in thrombocytopenia with absent radii tar syndrome"
} | [
{
"companynumb": "US-TEVA-2022-US-2023655",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nHypersensitivity to triazoles is a rare occurrence and cross-reactivity between agents is unknown. We present a successful voriconazole challenge in a patient allergic to fluconazole and itraconazole.\n\n\nMETHODS\nA 41-year-old immunocompetent male with coccidioidomycosis developed fever, eosinophilia and maculopapular rash from fluconazole. Switching to itraconazole resulted in worsening of the rash and skin sloughing over 25% of his body. He was given an oral-graded challenge of voriconazole which he tolerated without incident.\n\n\nCONCLUSIONS\nThis is the first report of a lack of cross-reactivity between itraconazole and voriconazole.",
"affiliations": "Western University of Health Sciences, Pomona, CA, USA.;Department of Pharmacy, Kern Medical, Bakersfield, CA, USA.;Department of Medicine, Kern Medical, Bakersfield, CA, USA.;Department of Medicine, Kern Medical, Bakersfield, CA, USA.",
"authors": "Benjamin Lash|D|D|;Jolliff|J|J|http://orcid.org/0000-0001-7598-5965;Munoz|A|A|;Heidari|A|A|",
"chemical_list": "D000935:Antifungal Agents; D017964:Itraconazole; D015725:Fluconazole; D065819:Voriconazole",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12417",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "41(5)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "allergy; fluconazole; itraconazole; voriconazole",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D003429:Cross Reactions; D004342:Drug Hypersensitivity; D015725:Fluconazole; D006801:Humans; D017964:Itraconazole; D008297:Male; D065819:Voriconazole",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "566-7",
"pmc": null,
"pmid": "27430151",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cross-reactivity between voriconazole, fluconazole and itraconazole.",
"title_normalized": "cross reactivity between voriconazole fluconazole and itraconazole"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-16-01830",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
"... |
{
"abstract": "Real-world tolerability and effectiveness of nebivolol as first add-on therapy were compared with hydrochlorothiazide, metoprolol, and amlodipine. Medical records of hypertensive adults initiating nebivolol, hydrochlorothiazide, metoprolol, or amlodipine as first add-on therapy between December 16, 2010 and July 21, 2011 were retrospectively abstracted (N = 1600; 400/treatment). Outcomes included medication-related side-effect rates and blood pressure (BP) reduction and control. Compared with nebivolol, metoprolol and amlodipine had significantly higher side-effect rates (incidence rate ratio [95% CI]: 1.82 [1.14-2.92] and 2.67 [1.69-4.21]), respectively); the hydrochlorothiazide-nebivolol rate ratio was not significant (1.61 [0.95-2.71]). All treatments reduced BP at 2 months. Metoprolol, amlodipine, and hydrochlorothiazide were associated with significantly lower odds of achieving 2-month BP control than nebivolol (odds ratios [95% CI]: 0.34 [0.23-0.51], 0.51 [0.35-0.75] and 0.66 [0.44-0.99], respectively). In a real-world setting, nebivolol as first add-on therapy was associated with fewer side effects than metoprolol or amlodipine and with a higher BP control rate than hydrochlorothiazide, metoprolol, or amlodipine.",
"affiliations": "Analysis Group, Boston, MA, USA.;Analysis Group, Los Angeles, CA, USA.;Analysis Group, Boston, MA, USA.;Analysis Group, Boston, MA, USA.;Allergan plc, Madison, NJ, USA.;Allergan plc, Madison, NJ, USA.",
"authors": "Ayyagari|Rajeev|R|0000-0003-0870-2309;Xie|Jipan|J|;Cheng|David|D|;Wu|Eric Q|EQ|;Huang|Xing-Yue|XY|;Chen|Stephanie|S|",
"chemical_list": "D000959:Antihypertensive Agents; D000068577:Nebivolol; D006852:Hydrochlorothiazide; D017311:Amlodipine; D008790:Metoprolol",
"country": "United States",
"delete": false,
"doi": "10.1111/jch.13312",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-6175",
"issue": "20(6)",
"journal": "Journal of clinical hypertension (Greenwich, Conn.)",
"keywords": "beta blockers; combination therapy; hypertension; side effects",
"medline_ta": "J Clin Hypertens (Greenwich)",
"mesh_terms": "D000328:Adult; D000368:Aged; D017311:Amlodipine; D000959:Antihypertensive Agents; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide; D006973:Hypertension; D008297:Male; D008790:Metoprolol; D008875:Middle Aged; D000068577:Nebivolol; D011897:Random Allocation; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "100888554",
"other_id": null,
"pages": "1058-1066",
"pmc": null,
"pmid": "29902367",
"pubdate": "2018-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12888152;24352797;18303936;19404314;22352883;19815121;15207957;16257341;8179848;20050100;20571428;23551727;29902367;18480115;21366845;19454737;21536983;18192850;15207952;14656957;22947356;14615107;18020542",
"title": "A retrospective study evaluating the tolerability and effectiveness of adjunctive antihypertensive drugs in patients with inadequate response to initial treatment.",
"title_normalized": "a retrospective study evaluating the tolerability and effectiveness of adjunctive antihypertensive drugs in patients with inadequate response to initial treatment"
} | [
{
"companynumb": "US-VALIDUS PHARMACEUTICALS LLC-US-2018VAL000899",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOPROLOL TARTRATE"
},
... |
{
"abstract": "We evaluated the efficacy and safety of neoadjuvant chemotherapy using modified OPTIMOX1 plus bevacizumab for advanced rectal cancer.\n\n\nMETHODS\nNine cases with highly advanced rectal cancer for which curative surgery was potentially difficult were enrolled(clinical T4 in 7 cases, lateral node metastasis in 3 cases, M1 in 2 cases).\n\n\nRESULTS\nThe number of courses of modified OPTIMOX1(mFOLFOX6 and sLV5FU2, alternating administration)plus bevacizumab ranged from 1 to 21(median: 10). Surgical procedures consisted of internal sphincter resection(ISR)in 4 patients, ultra-low anterior resection(ULAR)in 2 patients, pelvic exenteration(TPE)in 2 patients, and Hartmann's procedure in 1 patient. Liver resection was conducted in 2 patients. RM1 was confirmed in 2 patients, but curative surgery was performed in the other patients. Histological efficacy of grade x/1a/1b/2were seen in the above 1/4/2/2 cases, respectively. Neurotoxicity associated with oxaliplatin was mild; no grade 3 neurotoxicity was noted. Recurrence has been confirmed in 5 patients at the median follow-up period of 650 days.\n\n\nCONCLUSIONS\nIt was suggested that modified OPTIMOX1 plus bevacizumab is effective and safe to administer as a neoadjuvant chemotherapy for curative resection or anus-preserving surgery in patients with highly advanced rectal cancer.",
"affiliations": "Dept. of Surgery, Teikyo University, Japan.",
"authors": "Hirano|Atsushi|A|;Koda|Keiji|K|;Suzuki|Masato|M|;Yamazaki|Masato|M|;Tezuka|Tohru|T|;Kosugi|Chihiro|C|;Imai|Kenichiro|K|;Nakagawa|Ryosuke|R|;Adachi|Kenichiro|K|;Shiragami|Risa|R|;Yasuda|Hideki|H|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "39(7)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009944:Organoplatinum Compounds; D011379:Prognosis; D012004:Rectal Neoplasms; D012008:Recurrence",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1087-91",
"pmc": null,
"pmid": "22790044",
"pubdate": "2012-07",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Evaluation of modified OPTIMOX1 plus bevacizumab as the neoadjuvant therapy for highly advanced rectal cancers.",
"title_normalized": "evaluation of modified optimox1 plus bevacizumab as the neoadjuvant therapy for highly advanced rectal cancers"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2016RR-117808",
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"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
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"dr... |
{
"abstract": "Post-transplant lymphoproliferative disorder (PTLD) usually develops with systemic symptoms, such as fever, generalized lymphadenopathy, and elevation in the lactate dehydrogenase level. Here, we present the case of a 65-year-old female patient with PTLD localized to the colon; the patient only had mild diarrhea without systemic symptoms. She had myelodysplastic syndrome and was treated with cord blood transplantation (CBT). She had a past medical history of sigmoid colon cancer treated with colonosectomy and adjuvant chemotherapy. After CBT, she achieved complete remission and was discharged after 60 days. Further, 79 days after CBT, she presented with abdominal pain. Computed tomography scan revealed adhesive ileus. The abdominal pain was resolved in 1 day with conservative treatment, however, mild diarrhea persisted. Therefore, we performed colonoscopy and found multiple ulcerative lesions in the upper colon. A pathological examination revealed PTLD. Furthermore, elevation of EBV-DNA in the blood was also confirmed. There was no detectable lesion on positron emission tomography-computed tomography (PET-CT) outside the colon; thus, we diagnosed PTLD localized into the colon that was successfully treated with rituximab. Our present experience suggests that it might be important to perform endoscopy and monitoring of EBV-DNA for early detection of PTLD, especially localized in the gastrointestinal tract.",
"affiliations": "Department of Hematology/Oncology, University of Yamanashi.;Department of Hematology/Oncology, University of Yamanashi.;Department of Hematology/Oncology, University of Yamanashi.;Department of Hematology/Oncology, University of Yamanashi.;Department of Hematology/Oncology, University of Yamanashi.;Department of Hematology/Oncology, University of Yamanashi.;Department of Hematology/Oncology, University of Yamanashi.",
"authors": "Suzuki|Megumi|M|;Kawashima|Ichiro|I|;Suzuki|Jun|J|;Kumagai|Takuma|T|;Koshiishi|Megumi|M|;Nakajima|Kei|K|;Kirito|Keita|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.62.170",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "62(3)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "EBV-DNA; Gastrointestinal tract; Hematopoietic stem cell transplantation; Post-transplant lymphoproliferative disorder",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D003106:Colon; D036101:Cord Blood Stem Cell Transplantation; D003967:Diarrhea; D055088:Early Detection of Cancer; D020031:Epstein-Barr Virus Infections; D005260:Female; D006801:Humans; D008232:Lymphoproliferative Disorders; D000072078:Positron Emission Tomography Computed Tomography",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "170-175",
"pmc": null,
"pmid": "33828009",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Post-transplant lymphoproliferative disorder localized to the colon presented with mild diarrhea after cord blood transplantation.",
"title_normalized": "post transplant lymphoproliferative disorder localized to the colon presented with mild diarrhea after cord blood transplantation"
} | [
{
"companynumb": "JP-SA-2021SA216537",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Immune checkpoint inhibitors (ICIs) have revolutionized oncology, but are associated with immune-related adverse events. Clinically, pneumonitis is a well-recognized complication, but its histopathologic features are poorly understood. Institutional archives were searched for patients having ICI therapy and subsequent lung tissue sampling. After excluding infectious cases, 9 patients (5 women, median: 59 y) were identified with clinically suspected ICI-related pneumonitis. Clinical history, imaging, and pathology slides were reviewed. Patients received pembrolizumab (6 cases), nivolumab (1), ipilimumab followed by pembrolizumab (1), or pembrolizumab followed by nivolumab (1); the latter experienced pneumonitis with both agents. Treatment duration ranged from 1 to 33 cycles (median: 8). Three patients received concurrent chemotherapy and 1 received radiation; the remainder received ICI monotherapy. Symptoms were nonspecific; 2 patients were asymptomatic. Thoracic imaging showed bilateral ground glass or nodular opacities in all cases, often with pleural effusion. Histologically, organizing pneumonia was seen in 7 patients, all with subclinical or mild disease, admixed with vague non-necrotizing airspace granulomas in 3 cases; all 6 patients with follow-up did well. One patient had acute fibrinous pneumonitis and 1 had diffuse alveolar damage; both died. All 9 cases showed foamy macrophages and pneumocyte vacuolization; 6 had rare eosinophils. ICI-related pneumonitis presents as bilateral ground-glass opacities or nodules, and usually manifests as organizing pneumonia histopathologically, often with vague non-necrotizing airspace granulomas. Foamy macrophages and pneumocyte vacuolization are characteristic and rare eosinophils are often seen. Less commonly, acute fibrinous pneumonitis or diffuse alveolar damage can occur, which may be fatal.",
"affiliations": "Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ.;Division of Pulmonary and Critical Care Medicine.;Departments of Radiology.;Departments of Radiology.;Division of Pulmonary and Critical Care Medicine.;Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.",
"authors": "Larsen|Brandon T|BT|;Chae|June M|JM|;Dixit|Anuj S|AS|;Hartman|Thomas E|TE|;Peikert|Tobias|T|;Roden|Anja C|AC|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological",
"country": "United States",
"delete": false,
"doi": "10.1097/PAS.0000000000001298",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-5185",
"issue": "43(10)",
"journal": "The American journal of surgical pathology",
"keywords": null,
"medline_ta": "Am J Surg Pathol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D004334:Drug Administration Schedule; D004804:Eosinophils; D005260:Female; D005487:Foam Cells; D006801:Humans; D008168:Lung; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009369:Neoplasms; D011014:Pneumonia; D011379:Prognosis; D013997:Time Factors; D014617:Vacuoles",
"nlm_unique_id": "7707904",
"other_id": null,
"pages": "1331-1340",
"pmc": null,
"pmid": "31162288",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical and Histopathologic Features of Immune Checkpoint Inhibitor-related Pneumonitis.",
"title_normalized": "clinical and histopathologic features of immune checkpoint inhibitor related pneumonitis"
} | [
{
"companynumb": "US-009507513-2004USA004834",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nAspirin hypersensitivity is not a rare condition among patients with acute coronary syndrome. However, despite the publication of several successful desensitization protocols, the procedure is not as widespread as expected. We present a cohort of patients with acute coronary syndrome undergoing aspirin desensitization to evaluate its short- and long-term efficacy and safety and to reinforce data from previous studies.\n\n\nMETHODS\nOf 1306 patients admitted to our Coronary Care Unit between February 2011 and February 2013, 24 (1.8%) had a history of aspirin hypersensitivity. All 24 patients underwent an eight-dose aspirin desensitization protocol (0.1, 0.3, 1, 3, 10, 25, 50 and 100 mg of aspirin given by mouth every 15 minutes) after premedication with antihistamines and corticosteroids or antileucotrienes. Previously prescribed β blockers and angiotensin-converting enzyme inhibitors were not discontinued. All patients were desensitized within 72 hours of admission. Those requiring urgent catheterization (five patients with ST segment elevation myocardial infarction) were desensitized within 12 hours of catheterization and the remainder before catheterization.\n\n\nRESULTS\nAll patients were successfully desensitized and only one presented with an urticarial reaction. The five patients with ST segment elevation myocardial infarction were treated with abciximab until desensitization was complete. All but one patient underwent catheterization and 20 underwent percutaneous coronary intervention, most (66%) with the implantation of a bare metal stent. At follow-up (a minimum of 6-24 months), only two patients had discontinued aspirin, both due to gastrointestinal bleeding, and no hypersensitivy reaction had occurred.\n\n\nCONCLUSIONS\nAspirin desensitization is effective and safe in unstable patients with acute coronary syndrome in both the short and long term.",
"affiliations": "Cardiology Department, Hospital General Universitario de Albacete, Albacete, Spain.;Cardiology Department, Hospital General Universitario de Albacete, Albacete, Spain.;Cardiology Department, Hospital General Universitario de Albacete, Albacete, Spain.;Cardiology Department, Hospital General Universitario de Albacete, Albacete, Spain.;Cardiology Department, Hospital General Universitario de Albacete, Albacete, Spain.;Cardiology Department, Hospital General Universitario de Albacete, Albacete, Spain.;Cardiology Department, Hospital General Universitario de Albacete, Albacete, Spain.;Cardiology Department, Hospital General Universitario de Albacete, Albacete, Spain.;Cardiology Department, Hospital General Universitario de Albacete, Albacete, Spain.;Cardiology Department, Hospital General Universitario de Albacete, Albacete, Spain.;Cardiology Department, Hospital General Universitario de Albacete, Albacete, Spain.;Cardiology Department, Hospital General Universitario de Albacete, Albacete, Spain.;Cardiology Department, Hospital General Universitario de Albacete, Albacete, Spain.",
"authors": "Córdoba-Soriano|Juan Gabriel|JG|;Corbí-Pascual|Miguel|M|;López-Neyra|Isabel|I|;Navarro-Cuartero|Javier|J|;Hidalgo-Olivares|Víctor|V|;Barrionuevo-Sánchez|Maria Isabel|MI|;Prieto-Mateos|Daniel|D|;Gutiérrez-Díez|Antonio|A|;Gallardo-López|Arsenio|A|;Fuentes-Manso|Raquel|R|;Gómez-Pérez|Alberto|A|;Lafuente-Gormaz|Carlos|C|;Jiménez-Mazuecos|Jesús|J|",
"chemical_list": "D001241:Aspirin",
"country": "England",
"delete": false,
"doi": "10.1177/2048872615618509",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2048-8726",
"issue": "5(7)",
"journal": "European heart journal. Acute cardiovascular care",
"keywords": "Aspirin allergy; acute coronary syndrome; aspirin desensitization; coronary stenting; ischaemic heart disease",
"medline_ta": "Eur Heart J Acute Cardiovasc Care",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000368:Aged; D000369:Aged, 80 and over; D001241:Aspirin; D006328:Cardiac Catheterization; D003888:Desensitization, Immunologic; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D011446:Prospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101591369",
"other_id": null,
"pages": "41-50",
"pmc": null,
"pmid": "26589727",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Early aspirin desensitization in unstable patients with acute coronary syndrome: Short and long-term efficacy and safety.",
"title_normalized": "early aspirin desensitization in unstable patients with acute coronary syndrome short and long term efficacy and safety"
} | [
{
"companynumb": "ES-INGENUS PHARMACEUTICALS NJ, LLC-ING201702-000046",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ASPIRIN\\CARISOPRODOL"
},
... |
{
"abstract": "Neuroleptic malignant syndrome (NMS) is a dangerous adverse response to antipsychotic drugs. It is characterized by the four major clinical symptoms of hyperthermia, severe muscle rigidity, autonomic dysfunction, and altered mental state. Serum creatine kinase (CK) elevation occurs in over 90% of NMS cases. In the present study, the detailed temporal changes in serum CK and degree of muscle rigidity, and the relationship between CK concentration and degree of muscle rigidity over the time course from fever onset, were evaluated in 24 affected patients. The results showed that serum CK peaked on day 2 after onset of fever and returned to within normal limits at day 12. Mild muscle rigidity was observed before the onset of fever in 17 of 24 cases (71%). Muscle rigidity was gradually exacerbated and worsened until day 4 after onset of fever. These findings confirm physicians' empirical understanding of serum CK concentrations and muscle rigidity in NMS based on data accumulated from numerous patients with the syndrome, and they indicate that serum CK may contribute to the early detection of NMS.",
"affiliations": "Department of Psychiatry, Jichi Medical University, Tochigi, Japan.",
"authors": "Nisijima|Koichi|K|;Shioda|Katutoshi|K|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/NDT.S45084",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1176-6328",
"issue": "9()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "creatine kinase; muscle rigidity; neuroleptic malignant syndrome",
"medline_ta": "Neuropsychiatr Dis Treat",
"mesh_terms": null,
"nlm_unique_id": "101240304",
"other_id": null,
"pages": "853-9",
"pmc": null,
"pmid": "23818785",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": "19724770;23271911;1689186;3809245;19702493;8093494;11525080;2886491;2567121;7906709;2886157;2863986;10954878;7473299;17645916;14143329;15996751;17558126;7897404",
"title": "Temporal changes in serum creatine kinase concentration and degree of muscle rigidity in 24 patients with neuroleptic malignant syndrome.",
"title_normalized": "temporal changes in serum creatine kinase concentration and degree of muscle rigidity in 24 patients with neuroleptic malignant syndrome"
} | [
{
"companynumb": "JP-MYLANLABS-2015M1002291",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMANTADINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAcute disseminated encephalomyelitis is generally preceded by an infection, and it is usually self-limiting and non-recurrent. However, when there are multiple attacks of acute disseminated encephalomyelitis followed by optic neuritis, it is defined as acute disseminated encephalomyelitis-optic neuritis. To the best of our knowledge, there are no previous reports of acute disseminated encephalomyelitis and optic neuritis preceded by autoinflammation, triggered by periodic fever syndrome. We report on a case of acute disseminated encephalomyelitis with optic neuritis and periodic fever syndrome in a 12-year-old Ecuadorian Hispanic boy with several relapses over the past 10 years, always preceded by autoinflammatory manifestations and without evidence of infectious processes. Whole exome sequencing was performed, and although the results were not conclusive, we found variants in genes associated with both autoinflammatory (NLRP12) and neurological (POLR3A) phenotypes that could be related to the disease pathogenesis having a polygenic rather than monogenic trait.\n\n\nCONCLUSIONS\nWe propose that an autoinflammatory basis should be pursued in patients diagnosed as having acute disseminated encephalomyelitis and no record of infections. Also, we show that our patient had a good response after 1 year of treatment with low doses of intravenous immunoglobulin and colchicine.",
"affiliations": "Massachusetts General Hospital, 55 Fruit St, Boston, MA, 02114, USA. pledesma@mgh.harvard.edu.;Universidad San Francisco de Quito, Escuela de Medicina, Diego de Robles, Cumbaya, 170901, Quito, Ecuador.;Hospital de los Valles, Av. Interoceanica km 12.5 y Av. Florencia, Quito, Ecuador.;Hospital de los Valles, Av. Interoceanica km 12.5 y Av. Florencia, Quito, Ecuador.;Universidad San Francisco de Quito, Escuela de Medicina, Diego de Robles, Cumbaya, 170901, Quito, Ecuador. lpedroza@usfq.edu.ec.",
"authors": "Ledesma|Pablo A|PA|;Guerra|Juan Carlos|JC|;Burbano|Manuel|M|;Procel|Patricio|P|;Pedroza|Luis Alberto|LA|",
"chemical_list": "D006074:Gout Suppressants; D016756:Immunoglobulins, Intravenous; D003078:Colchicine",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-019-2305-3",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 230510.1186/s13256-019-2305-3Case ReportWhole exome sequencing in a child with acute disseminated encephalomyelitis, optic neuritis, and periodic fever syndrome: a case report Ledesma Pablo A. pledesma@mgh.harvard.edu 123Guerra Juan Carlos juancarlosguerra100@gmail.com 34Burbano Manuel m_burbanososa@hotmail.com 4Procel Patricio patricioprocel@gmail.com 4Pedroza Luis Alberto lpedroza@usfq.edu.ec 351 0000 0004 0386 9924grid.32224.35Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 USA 2 000000041936754Xgrid.38142.3cHarvard Medical School, 25 Shattuck St, Boston, MA 02115 USA 3 0000 0000 9008 4711grid.412251.1Universidad San Francisco de Quito, Escuela de Medicina, Diego de Robles, Cumbaya, 170901 Quito, Ecuador 4 Hospital de los Valles, Av. Interoceanica km 12.5 y Av. Florencia, Quito, Ecuador 5 0000 0001 2160 926Xgrid.39382.33Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030 USA 14 12 2019 14 12 2019 2019 13 36814 11 2018 28 10 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAcute disseminated encephalomyelitis is generally preceded by an infection, and it is usually self-limiting and non-recurrent. However, when there are multiple attacks of acute disseminated encephalomyelitis followed by optic neuritis, it is defined as acute disseminated encephalomyelitis-optic neuritis. To the best of our knowledge, there are no previous reports of acute disseminated encephalomyelitis and optic neuritis preceded by autoinflammation, triggered by periodic fever syndrome.\n\nCase summary\nWe report on a case of acute disseminated encephalomyelitis with optic neuritis and periodic fever syndrome in a 12-year-old Ecuadorian Hispanic boy with several relapses over the past 10 years, always preceded by autoinflammatory manifestations and without evidence of infectious processes. Whole exome sequencing was performed, and although the results were not conclusive, we found variants in genes associated with both autoinflammatory (NLRP12) and neurological (POLR3A) phenotypes that could be related to the disease pathogenesis having a polygenic rather than monogenic trait.\n\nConclusion\nWe propose that an autoinflammatory basis should be pursued in patients diagnosed as having acute disseminated encephalomyelitis and no record of infections. Also, we show that our patient had a good response after 1 year of treatment with low doses of intravenous immunoglobulin and colchicine.\n\nKeywords\nCase reportWhole exome sequencingAcute disseminated encephalomyelitisADEMADEM-ONOptic neuritisNLRP12Periodic fever syndromeFamilial cold autoinflammatory syndromeFCAS2issue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nMultiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) are autoinflammatory demyelinating diseases of the central nervous system (CNS). One of the main differences between these two entities is the chronicity and progressive neurological disability in MS, while ADEM is self-limiting, non-recurrent, and rarely produces neurological disabilities [1]. However, when there are multiple ADEM attacks followed by optic neuritis (ON), it is defined as ADEM-ON [2]. It is widely known that the clinical presentation of ADEM is an inflammatory process, and it is preceded by vaccination or infections. However, some cases are secondary to a fever of unknown origin [3, 4], which raises the question if a periodic fever syndromes (PFS) could be the recurrent trigger of the CNS inflammatory process in ADEM-ON as has been previously reported in MS [5]. NLRP12-associated autoinflammatory disorder (NLRP12AD) is a type 2 familial cold autoinflammatory syndrome (FCAS2), and part of the PFS [6–9]. It is an immune-mediated disease characterized by the presence of recurrent fever (of unknown origin) and other autoinflammatory features such as mouth ulcers and headaches [10]. Here, we describe a patient diagnosed as having ADEM-ON who also presented with familial cold autoinflammatory syndrome (FCAS) for whom we used whole exome sequencing (WES) to dissect possible variants in a non-HLA set of genes that could explain the patient’s clinical features (immunological and neurological).\n\nCase presentation\nOur patient is a 12-year-old Ecuadorian Hispanic boy from unrelated Hispanic parents; he presented to the pediatric department of the “Hospital de los Valles” with mouth ulcers, bilateral vision loss, headache, fever, lethargy, ataxia, dizziness, and left-sided hemiparesis. A clinical examination did not reveal any identifiable cause of fever. His familial history was unremarkable except for his maternal grandfather, who had type II diabetes mellitus. Our patient’s past medical history revealed a 10-year history of several episodes of pharyngitis, mouth ulcers, headaches, dizziness, fevers of unknown origin, and tonsillitis. These symptoms commonly preceded the appearance of neurological symptoms such as delayed speech, hypotonia, vision loss, ataxia, lethargy, and left hemiparesis. This pattern had been consistent and often required hospitalization for the treatment of neurological manifestations. The treatment consisted of corticoid therapy, which offered rapid improvement. Moreover, he has significant endocrine features, including small stature, delayed bone age, obesity, small hands, and hypogonadotropic hypogonadism. Although Prader–Willi syndrome was suspected, genetic analysis ruled this out. Ophthalmological imaging studies at his first hospitalization 10 years ago were consistent with a demyelinating and axonal lesion of the left optic tract, which is compatible with ON. In addition, C-reactive protein (CRP), an inflammatory index, was elevated at every hospitalization. The following laboratory studies, which were carried out on several occasions, had results within the normal range: complete blood count (CBC); serum chemistry; urine and blood culture; strep test; throat swab; serology for cytomegalovirus, (CMV), Epstein-Barr virus (EBV), herpes simplex viruses (HSV), rubella, and toxoplasmosis; immunologic screening for antinuclear antibodies, rheumatologic factor, immunoglobulin A (IgA) and immunoglobulin M (IgM) antiphospholipids; thyroid hormones; cortisol; and insulin. He also underwent the following examinations: chest and abdominal X-rays which were normal; pathergy test which was negative; brain magnetic resonance imaging (MRI) studies including fluid-attenuated inversion recovery (FLAIR) T2 sequences which showed multiple hyperintense lesions throughout the years (Fig. 1); spinal cord MRI studies that did not disclose any lesion; and cerebrospinal fluid analyses which were consistently normal with negative oligoclonal bands. MS was ruled out because he did not meet the McDonald diagnostic criteria for this disease. In addition, anti-myelin-associated glycoprotein (MAG), anti-aquaporin 4 (AQP4), and anti-myelin basic protein (MBP) were ordered but failed to disclose the diagnosis. Anti-myelin oligodendrocyte glycoprotein (MOG) was ordered, and the titer was 1:80 (considered negative); however, he was in treatment with intravenous immunoglobulin (IVIG) at the time of the anti-MOG evaluation. Given the unusual phenotype, we decided to perform a WES via a commercial service offered by the Baylor Miraca Genetics Laboratories. A list of variants potentially associated with the neurologic and immune features of our patient are listed in Table 1. A WES was not performed on his parents due to financial reasons. Even though the results were not conclusive, we found variants in genes associated with both autoinflammatory (NLRP12) and neurological (POLR3A) phenotypes that could be related to the disease pathogenesis being a polygenic rather than monogenic trait.\nFig. 1 Fluid-attenuated inversion recovery T2 sequences showing multiple hyperintense lesions through the years. a 2008: Multiple injuries, mainly subcortical in temporal and occipitotemporal gyrus, and in the white matter of the corona radiata and semioval center. Lesions are enhanced after contrast. b 2010: Frontal subcortical injuries. Periatrial and parahippocampal lesions. There is a persistence of white matter lesions, and there are new infratentorial lesions. c 2011: Persistence of the periatrial lesions and left midbrain lesion. d 2013: Persistence of periatrial lesions and two small and new lesions in the basal ganglia infratentorial lesions. e 2014: New appearance of lesions in the cortex. Frontal and right superior temporal subcortical lesions. Right periatrial lesion has increased in size, reaching the cortex, parietal and occipital gyrus and corona radiata. f 2015: Persistence of periatrial lesions. There are smaller lesions in the white matter of the middle and lower right temporal gyrus and the semioval center. g 2017: After 7 months with intravenous immunoglobulin treatment – same lesions as the last magnetic resonance imaging in 2015. No new changes\n\n\nTable 1 Whole exome sequencing (WES) variants potentially associated with the neurologic and immunologic features of the patient\n\n\tGene name\tIsoform and nucleotide change (cDNA)\tAmino acid change\tdbSNP reference\tSIFT/PolyPhen\tDisease/Phenotype associated\t\nNeurologic related diseases\tTRIM65\tNM_173547\n\nc.1A>G\n\n\tp.M1H\tNovel variant\tDamaging/Probably damaging\tProbably associated to white matter hyperintensity\n\nPMID:25586835\n\n\t\nPOLR3A\tNM_007055\n\nc.2934G>C\n\n\tp.E978D\tNovel variant\tDamaging/Benign\tLeukodystrophy, Hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism (MIM:607694)\t\nTSC2\tNM_000548\n\nc.2445G>T\n\n\tp.M815I\tNovel variant\tTolerated/Possibly damaging\tTuberous sclerosis (MIM:613254)\t\nGLI2\tNM_005270\n\nc.67G>T\n\n\tp.A23S\tNovel variant\tTolerated/Benign\tHoloprosencephaly 9 (MIM:610829); Culler-Jones syndrome (MIM:615849)\t\nLAMA1\tNM_005559\n\nc.7724C>T\n\n\tT2575M\trs76482057\tDamaging/Benign\tPoretti-Boltshauser syndrome (MIM:615960)\t\nLAMA1\tNM_005559\n\nc.2808+5G>A\n\n\tSplicing\trs201030108\tNA/NA\tPoretti-Boltshauser syndrome (MIM:615960)\t\nNDUFA10\tNM_004544\n\nc.1036G>A\n\n\tp.E346K\tNovel variant\tDamaging/Benign\tLeigh syndrome (MIM:256000)\t\nImmunologic related diseases\tNLRP12\tNM_144687\n\nc.910C>T\n\n\tp.H304Y\trs141245482\tDamaging/Probably damaging\tFamilial cold autoinflammatory syndrome (MIM:611762)\t\nCSF3R\tNM_000760\n\nc.2360A>G\n\n\tp.Y787C\trs150281231\tTolerated/Benign\tNeutrophilia, Hereditary (MIM:162830)\t\nSIAE\tNM_170601\n\nc.688C>T\n\n\tp.R230W\trs200862001\tDamaging/Probably damaging\tAutoimmune disease (MIM:613551)\t\nMCM4\tNM_005914\n\nc.2063A>G\n\n\tp.K688R\tNovel variant\tTolerated/Benign\tNatural killer cell and glucocorticoid deficiency with DNA repair defect (MIM:609981)\t\ncDNA complementary deoxyribonucleic acid, dbSNP Single Nucleotide Polymorphism Database, MIM Mendelian Inheritance in Man, NA not available, PolyPhen Polymorphism Phenotyping, SIFT Sorting Intolerant From Tolerant\n\n\n\nA final diagnosis of ADEM-ON and NLRP12AD was established. For the past year, our patient has remained on a monthly therapy with IVIG 500 mg/kg and orally administered colchicine (0.5 mg daily). With this treatment, he has remained free of new autoinflammatory and neurological episodes and has not required corticoids. An MRI study performed 7 months after the start of IVIG and colchicine showed an absence of new lesions.\n\nDiscussion\nADEM is considered an autoinflammatory demyelinating disease of the CNS and is often secondary to infections [1]. However, some cases have been associated with recurrent inflammation and absence of known infections [3, 4], raising the question if autoinflammation could trigger CNS demyelination as has been previously reported in MS [5]. It could be expected to be of genetic origin – probably with a monogenic basis – based on the common origin of both diseases (that is, autoinflammation and ADEM-ON) and the early onset of manifestations. Although none of the variants can be considered to be the sole cause of the disease, we hypothesize that the presence of polymorphisms in NLRP12 and SIAE (Table 1) trigger systemic autoinflammation, and such inflammation could influence the demyelination process in an unknown fashion. NLRP12AD, part of the cryopyrin-associated periodic syndromes (CAPS), has been associated with several autoinflammatory conditions that are similar to the immunological features of our patient [9–12]. However, to the best of our knowledge, there are no cases of NLRP12AD and inflammatory diseases in the CNS of humans. Interestingly, the role of NLRP12 in inflammasome activation in the brain of murine models, including a model of experimental autoimmune encephalomyelitis, has been recently described [13–15]. In addition, SIAE has also been associated with susceptibility to autoimmune diseases [16]. However, this association has been questioned [17]. Although we failed to find a candidate gene or a genetic link with the neurological manifestations, the variant in POLR3A is important because bi-allelic mutations on this gene are associated with hypomyelinating leukodystrophy 7 (HLD7) [18]. Interestingly, our patient presents hypogonadotropic hypogonadism, which is one of the hallmarks of HLD7; however, the other clinical features and the MRI pattern are barely compatible with HLD7. Although only one of the POLR3A alleles is mutated, a new association between heterozygous mutations in POLR3A and susceptibility to varicella-zoster virus (VZV) infection (including encephalitis) was described recently. However, our patient did not show any evidence of VZV infection. Furthermore, these cases presented incomplete penetrance in healthy carriers [19]. Thus, we cannot rule out a possible influence of the POLR3A in the clinical features presented by our patient. High doses of IVIG are broadly used for the treatment of autoimmune diseases of different etiologies, including ADEM [20]. However, the use of low doses of IVIG in ADEM-ON has not been extensively documented. Recently, a cohort of patients with multiphasic disseminated encephalomyelitis (MDEM), of whom some received monthly IVIG treatment, was described [21]. These patients showed improved clinical manifestations, similar to our case. Our patient has had recurrent autoinflammatory symptoms leading to neurologic episodes every 6 months on average. Since the treatment with low-dose IVIG and colchicine was started, he has not presented any autoinflammatory or neurologic symptoms. It is known that IVIG at high doses works as an immunosuppressant to treat several autoimmune diseases. This effect is probably mediated by scavenging of complement and blockade or modulation of Fc receptors. At low doses, it is used as a prophylactic treatment in patients with immunodeficiencies in part by neutralizing the antigens. This could be a possibility in this patient because it could be neutralizing the virus or antigens. Therefore, this treatment prevents potential infections that usually trigger the autoinflammation and neurological manifestations, as is broadly known in ADEM or MDEM [1]. In any of these two scenarios, the IVIG and colchicine are preventing the inflammation that precedes the neurological manifestations. Typically, FCAS is treated with interleukin-1 (IL-1) inhibitors such as anakinra, rilonacept, or canakinumab [22, 23]. However, given the difficulty of finding these drugs in Ecuador and our patient’s economic inability to acquire them, colchicine was prescribed. This medication has a widespread effect on autoinflammatory disorders and has been widely accepted as a treatment in other PFS, such as in familial Mediterranean fever (FMF) [22]. Apart from some minor gastrointestinal side effects, the medication has been well tolerated by our patient, and he has not presented any autoinflammatory or neurological symptoms.\n\nConclusions\nTo the best of our knowledge, this is the first case of NLRP12-associated autoinflammatory disease with neurological manifestations. We suggest that patients with ADEM-ON should be evaluated for autoinflammation (including variants in NLRP12) in the absence of documented infections.\n\nAbbreviations\nADEMAcute disseminated encephalomyelitis\n\nADEM-ONMultiple acute disseminated encephalomyelitis attacks followed by optic neuritis\n\nAQP4Aquaporin 4\n\nCAPSCryopyrin-associated periodic syndromes\n\nCBCComplete blood count\n\nCMVCytomegalovirus\n\nCNSCentral nervous system\n\nCRPC-reactive protein\n\nEBVEpstein–Barr virus\n\nFCASFamilial cold autoinflammatory syndrome\n\nFCAS2Type 2 familial cold autoinflammatory syndrome\n\nFLAIRFluid-attenuated inversion recovery\n\nFMFFamilial Mediterranean fever\n\nHLD7Hypomyelinating leukodystrophy 7\n\nHSVHerpes simplex viruses\n\nIgAImmunoglobulin A\n\nIgMImmunoglobulin M\n\nIL-1Interleukin-1\n\nIVIGIntravenous immunoglobulin\n\nMAGMyelin-associated glycoprotein\n\nMBPMyelin basic protein\n\nMDEMMultiphasic disseminated encephalomyelitis\n\nMOGMyelin oligodendrocyte glycoprotein\n\nMSMultiple sclerosis\n\nNLRP12ADNLRP12-associated autoinflammatory disorder\n\nONOptic neuritis\n\nPFSPeriodic fever syndromes\n\nVZVVaricella-zoster virus\n\nWESWhole exome sequencing\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors thank Marcela Bovera for assistance in the clinical data collection and Dr Kevin Rostasy for the anti-MOG evaluation.\n\nAuthors’ contributions\nConception and design of the work: PAL and LAP. Clinical data collection: PAL, JCG, MB, and PP. Imaging data collection and analysis: PAL, JCG, and LAP. Genomic data analysis: LAP. Laboratory data collection and analysis: PAL and LAP. Drafting the article: PAL and LAP. Critical revision of the article: PAL, JCG, MB, PP, and LAP. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: PAL, JCG, MB, PP, and LAP. All authors read and approved the final manuscript.\n\nAuthors’ information\nPAL: Postdoctoral Research Fellow, Massachusetts General Hospital and Harvard Medical School. Previously: Instructor at Universidad San Francisco de Quito Medical School.\n\nLAP: Professor of Immunology and Genetics, Universidad San Francisco de Quito. Adjunct Associate Professor of Pediatrics at Baylor College of Medicine.\n\nJCG: Professor of Radiology, Universidad San Francisco de Quito. Head of Radiology, Hospital de los Valles (Quito, Ecuador).\n\nMB: Pediatric Endocrinologist, Hospital de los Valles (Quito, Ecuador).\n\nPP: Pediatric Neurologist, Hospital de los Valles (Quito, Ecuador).\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThis study was carried out in accordance with the recommendations of the Institutional Review Board from the Universidad San Francisco de Quito with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Institutional Review Board from the Universidad San Francisco de Quito, with the protocol number: 2015-061 T.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s legal guardians for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Esposito S Di Pietro GM Madini B A spectrum of inflammation and demyelination in acute disseminated encephalomyelitis (ADEM) of children Autoimmun Rev 2015 14 923 929 10.1016/j.autrev.2015.06.002 26079482 \n2. Pohl D Alper G Van Haren K Acute disseminated encephalomyelitis, Updates on an Inflammatory CNS syndrome Neurology 2016 87 38 45 10.1016/B978-0-323-53088-0.00018-X \n3. Ching BH Mohamed AR Khoo TB Multiphasic disseminated encephalomyelitis followed by optic neuritis in a child with gluten sensitivity Mult Scler 2015 21 1209 1211 10.1177/1352458515593404 26199345 \n4. Costanzo MD Camarca ME Colella MG Acute disseminated encephalomyelitis presenting as fever of unknown origin: case report BMC Pediatr 2011 11 103 10.1186/1471-2431-11-103 22074226 \n5. Schuh E Lohse P Ertl-Wagner B Expanding spectrum of neurologic manifestations in patients with NLRP3 low-penetrance mutations Neurol Neuroimmunol Neuroinflamm 2015 2 e109 10.1212/NXI.0000000000000109 26020059 \n6. Jéru I Duquesnoy P Fernandes-Alnemri T Mutations in NALP12 cause hereditary periodic fever syndromes Proc Natl Acad Sci 2008 105 5 1614 1619 10.1073/pnas.0708616105 18230725 \n7. Volpe G Mauro A Mellos A NLRP12-associated autoinflammatory disorder: case report Pediatr Rheumatol 2014 12 Suppl 1 P262 10.1186/1546-0096-12-S1-P262 \n8. Borghini S Tassi S Chiesa S Clinical Presentation and Pathogenesis of Cold-Induced Autoinflammatory Disease in a Family With Recurrence of an NLRP12 Mutation Arthritis Rheum 2011 63 3 830 839 10.1002/art.30170 21360512 \n9. Xia X Dai C Zhu X Liao Q Identification of a Novel NLRP12 Nonsense Mutation (Trp408X) in the Extremely Rare Disease FCAS by Exome Sequencing PLoS One 2016 11 6 e0156981 10.1371/journal.pone.0156981 27314497 \n10. Caso Francesco Rigante Donato Vitale Antonio Lucherini Orso Maria Costa Luisa Atteno Mariangela Compagnone Adele Caso Paolo Frediani Bruno Galeazzi Mauro Punzi Leonardo Cantarini Luca Monogenic Autoinflammatory Syndromes: State of the Art on Genetic, Clinical, and Therapeutic Issues International Journal of Rheumatology 2013 2013 1 15 10.1155/2013/513782 \n11. De Pieri C Vuch J De Martino E Genetic profiling of autoinflammatory disorders in patients with periodic fever: a prospective study Pediatr Rheumatol Online J 2015 13 11 10.1186/s12969-015-0006-z 25866490 \n12. Shen M Tang L Shi X Zeng X Yao Q NLRP12 autoinflammatory disease: a Chinese case series and literature review Clin Rheumatol 2017 36 1661 1667 10.1007/s10067-016-3410-y 27633793 \n13. Nagyőszi P Nyúl-Tóth Á Fazakas C Wilhelm I Kozma M Molnár J Haskó J Krizbai IA Regulation of NOD-like receptors and inflammasome activation in cerebral endothelial cells J Neurochem 2015 135 551 564 10.1111/jnc 26083549 \n14. Chang Sulie Huang Wenfei Mao Xin Sarkar Sabroni NLRP12 Inflammasome Expression in the Rat Brain in Response to LPS during Morphine Tolerance Brain Sciences 2017 7 12 14 10.3390/brainsci7020014 \n15. Gharagozloo M Mahvelati TM Imbeault E Gris P Zerif E Bobbala D Ilangumaran S Amrani A Gris D The nod-like receptor, Nlrp12, plays an anti-inflammatory role in experimental autoimmune encephalomyelitis J Neuroinflammation 2015 12 198 10.1186/s12974-015-0414-5 26521018 \n16. Surolia I Pirnie SP Chellappa V Taylor KN Cariappa A Moya J Liu H Bell DW Driscoll DR Diederichs S Haider K Netravali I Le S Elia R Dow E Lee A Freudenberg J De Jager PL Chretien Y Varki A MacDonald ME Gillis T Behrens TW Bloch D Collier D Korzenik J Podolsky DK Hafler D Murali M Sands B Stone JH Gregersen PK Pillai S Functionally defective germline variants of sialic acid acetylesterase in autoimmunity Nature 2010 466 243 247 10.1038/nature09115 20555325 \n17. Hunt KA Smyth DJ Balschun T Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry Nat Genet 2011 44 3 5 10.1038/ng.1037 22200769 \n18. Wolf NI Vanderver A van Spaendonk RM Schiffmann R Brais B Bugiani M Sistermans E Catsman-Berrevoets C Kros JM Pinto PS Pohl D Tirupathi S Strømme P de Grauw T Fribourg S Demos M Pizzino A Naidu S Guerrero K van der Knaap MS Bernard G 4H Research Group Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations Neurology 2014 83 1898 1905 10.1212/WNL.0000000000001002 25339210 \n19. Ogunjimi B Zhang SY Sørensen KB Skipper KA Carter-Timofte M Kerner G Luecke S Prabakaran T Cai Y Meester J Bartholomeus E Bolar NA Vandeweyer G Claes C Sillis Y Lorenzo L Fiorenza RA Boucherit S Dielman C Heynderickx S Elias G Kurotova A Auwera AV Verstraete L Lagae L Verhelst H Jansen A Ramet J Suls A Smits E Ceulemans B Van Laer L Plat Wilson G Kreth J Picard C Von Bernuth H Fluss J Chabrier S Abel L Mortier G Fribourg S Mikkelsen JG Casanova JL Paludan SR Mogensen TH Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections J Clin Invest 2017 127 3543 3556 10.1172/JCI92280 28783042 \n20. Gadian J Kirk E Holliday K Lim M Absoud M Systematic review of immunoglobulin use in pediatric neurological and neurodevelopmental disorders Dev Med Child Neurol 2017 59 136 144 10.1111/dmcn.13349 27900773 \n21. Baumann M Hennes EM Schanda K Karenfort M Kornek B Seidl R Diepold K Lauffer H Marquardt I Strautmanis J Syrbe S Vieker S Höftberger R Reindl M Rostásy K Children with multiphasic disseminated encephalomyelitis and antibodies to the myelin oligodendrocyte glycoprotein (MOG): Extending the spectrum of MOG antibody positive diseases Mult Scler 2016 22 1821 1829 10.1177/1352458516631038 26869530 \n22. Hoffman HM Therapy of autoinflammatory syndromes J Allergy Clin Immunol 2009 124 6 1129 1138 10.1016/j.jaci.2009.11.001 20004774 \n23. Haar N Lachmann H Özen S Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review Ann Rheum Dis 2013 72 5 678 685 10.1136/annrheumdis-2011-201268 22753383\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "13(1)",
"journal": "Journal of medical case reports",
"keywords": "ADEM; ADEM-ON; Acute disseminated encephalomyelitis; Case report; FCAS2; Familial cold autoinflammatory syndrome; NLRP12; Optic neuritis; Periodic fever syndrome; Whole exome sequencing",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000284:Administration, Oral; D002648:Child; D003078:Colchicine; D004673:Encephalomyelitis, Acute Disseminated; D005334:Fever; D006074:Gout Suppressants; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D009902:Optic Neuritis; D012008:Recurrence; D016896:Treatment Outcome; D000073359:Whole Exome Sequencing",
"nlm_unique_id": "101293382",
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"pmid": "31836009",
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"title": "Whole exome sequencing in a child with acute disseminated encephalomyelitis, optic neuritis, and periodic fever syndrome: a case report.",
"title_normalized": "whole exome sequencing in a child with acute disseminated encephalomyelitis optic neuritis and periodic fever syndrome a case report"
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"abstract": "Most atypical fractures associated with the long-term treatment with bisphosphonates (BP) commonly develop in the femoral shaft or subtrochanteric region. We report a rare case of bilateral atypical ulnar fractures in an 86-year-old woman with osteoporosis who finished the treatment with teriparatide for 2 years after long-term treatment with BP. She slid down from an approximately 30-cm-tall seat and slightly contused her left elbow. Plain radiography revealed that both ulnae had a noncomminuted short oblique fracture with cortical thickening and sclerosis at the fracture site. Based on the clinical and radiological findings, she was diagnosed with bilateral atypical ulnar fractures. The fracture of the left ulna was completely displaced and treated surgically. On the other hand, since the right ulna was an incomplete fracture, it was treated conservatively. During surgery, drilling with Kirschner wire and curettage were performed in the osteosclerotic lesion, and an autologous cancellous bone graft was inserted from the ipsilateral olecranon. Bone union was achieved in both fractures at 1 year after surgery. There have been no reports regarding the development of atypical ulnar fractures occurring after the long-term treatment with BP and 2-year use of teriparatide, and the treatment strategies of such fractures have not been established. If teriparatide cannot be used after occurring atypical fractures, the use of low-intensity pulsed ultrasound (LIPUS) and subsequent treatment for osteoporosis are recommended for the bone union. In addition, the treatment of the osteosclerotic lesion and rigid internal fixation are required in surgery.",
"affiliations": "Department of Orthopaedic Surgery, Municipal Tsuruga Hospital, 1-6-60, Mishimamachi, Tsuruga-shi, Fukui, 914-8502, Japan. you.you.mounin@gmail.com.;Department of Orthopaedic Surgery, Municipal Tsuruga Hospital, 1-6-60, Mishimamachi, Tsuruga-shi, Fukui, 914-8502, Japan.;Department of Orthopaedic Surgery, Municipal Tsuruga Hospital, 1-6-60, Mishimamachi, Tsuruga-shi, Fukui, 914-8502, Japan.;Department of Orthopaedic Surgery, Municipal Tsuruga Hospital, 1-6-60, Mishimamachi, Tsuruga-shi, Fukui, 914-8502, Japan.;Department of Orthopaedic Surgery, Municipal Tsuruga Hospital, 1-6-60, Mishimamachi, Tsuruga-shi, Fukui, 914-8502, Japan.",
"authors": "Asano|Y|Y|https://orcid.org/0000-0002-8777-6076;Tajiri|K|K|;Yagishita|S|S|;Nakanishi|H|H|;Ishii|T|T|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D019379:Teriparatide",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-020-05618-3",
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"issn_linking": "0937-941X",
"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": "Atypical ulnar fracture; Bisphosphonate; Osteoporosis; Teriparatide",
"medline_ta": "Osteoporos Int",
"mesh_terms": "D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D006801:Humans; D019379:Teriparatide; D014458:Ulna Fractures",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "2473-2476",
"pmc": null,
"pmid": "32910217",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral atypical ulnar fractures occurring after long-term treatment with bisphosphonate for 7 years and with teriparatide for 2 years: a case report.",
"title_normalized": "bilateral atypical ulnar fractures occurring after long term treatment with bisphosphonate for 7 years and with teriparatide for 2 years a case report"
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"companynumb": "JP-ALVOGEN-2020-ALVOGEN-114742",
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"abstract": "A 68-year-old female patient with a past medical history of atrial fibrillation on anticoagulation regimen with Apixaban and Clopidogrel presented for her scheduled Watchman device implantation. The device was indicated as patient was high risk for falling. Successful implantation of the left atrial appendage device was carried out, and the patient was sent to the floor. One hour after the procedure, the patient started having left-sided diplopia along with severe eye pain. An immediate CT scan of the head showed left superior orbital mass, concerning for hematoma. Urgent left canthotomy with cantholysis was conducted bedside. However, despite early interventions, the patient's vision was lost.",
"affiliations": "Internal Medicine Division, White River Health System, Batesville, AR 72501, USA.;Electrophysiology Division, White River Health System, Batesville, AR 72501, USA.",
"authors": "Sawalha|Khalid|K|0000-0002-1234-9133;Nair|Devi|D|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/clinpract11020046",
"fulltext": "\n==== Front\nClin Pract\nClin Pract\nclinpract\nClinics and Practice\n2039-7275\n2039-7283\nMDPI\n\n10.3390/clinpract11020046\nclinpract-11-00046\nCase Report\nDoubly Blinded: An Uncommon Cause of Acute Visual Loss Due to Orbital Compartment Syndrome\nhttps://orcid.org/0000-0002-1234-9133\nSawalha Khalid 1*\nNair Devi 2\n1 Internal Medicine Division, White River Health System, Batesville, AR 72501, USA\n2 Electrophysiology Division, White River Health System, Batesville, AR 72501, USA; DGNair1@yahoo.com\n* Correspondence: Ksawalha@aol.com; Tel.: +1-984-364-1158\n24 5 2021\n6 2021\n11 2 327331\n14 4 2021\n18 5 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nA 68-year-old female patient with a past medical history of atrial fibrillation on anticoagulation regimen with Apixaban and Clopidogrel presented for her scheduled Watchman device implantation. The device was indicated as patient was high risk for falling. Successful implantation of the left atrial appendage device was carried out, and the patient was sent to the floor. One hour after the procedure, the patient started having left-sided diplopia along with severe eye pain. An immediate CT scan of the head showed left superior orbital mass, concerning for hematoma. Urgent left canthotomy with cantholysis was conducted bedside. However, despite early interventions, the patient’s vision was lost.\n\nretrobulbar hematoma\norbital compartment syndrome\n==== Body\n1. Introduction\n\nRetrobulbar hemorrhage (RBH) is a very rare complication with an incidence reported to be lower than 1% of cases related to blunt facial trauma [1]. It is a rapidly progressing, sight-threatening emergency that results in an accumulation of blood in the retrobulbar space. This blood accumulation acts as a compartment syndrome in which increased intra-ocular pressure (IOP) may result in damage to intra-orbital structures such as the optic nerve. This, in turn, can result in irreversible damage if not managed quickly [2]. Early recognition of symptoms and clinical signs is the mainstay of management. However, despite the urgent interventions, complications might be permanent, unfortunately.\n\n2. Case Presentation\n\nA 68-year-old white female patient with a past medical history of atrial fibrillation, hypertension and anxiety presented for her scheduled Watchman device implantation. Her risk of bleeding secondary to falling was high given her multiple recent falls at home. Four days prior to her procedure, she recalled having a left-sided headache for which she did not seek medical attention as she related it to being stressed about the procedure. Her anticoagulation regimen included Apixaban and Clopidogrel, of which both were held five days prior to the procedure. The patient underwent successful placement of the left atrial appendage device with no immediate complications. During the procedure she received 10,000 units of Heparin and with an activated clotting time of 312 s (150–600 s). One hour after the procedure, she started complaining of nausea and left-sided diplopia along with left eye swelling and severe pain. Physical examination revealed left eye edema, peri-orbital ecchymosis, proptosis, and loss of pupillary response. Left ophthalmic examination revealed corneal edema and cupping of the optic disc. Left ocular movement was limited to all direction. The right eye was normal. An immediate CT scan of the head revealed left periorbital soft tissue swelling with a left superior orbital hyperdense mass, concerning for hematoma, measuring 3.7 × 2.9 × 1.5 cm (Figure 1 and Figure 2). Urgent left canthotomy with cantholysis was conducted bedside, in which both intra-ocular pressure and pain were significantly reduced from 52 mm hg to 24 mm hg (10–21 mm hg). Later, despite early interventions, the patient’s left vision was lost completely.\n\n3. Discussion\n\nSpontaneous retrobulbar hemorrhage is a rare sight-threatening phenomenon that is most commonly associated with orbital trauma, repair of orbital floor fractures, ocular surgery, endoscopic sinus surgery, retrobulbar injections, and other head and neck procedures, including blepharoplasty, where bleeding may occur in proximity to the globe. Rarely, it occurs in susceptible individuals after general anesthesia as a result of coughing, straining, vomiting, or extremely elevated blood pressure, particularly in the presence of anticoagulants such as Aspirin and Coumadin. Incidence varies among surgical procedures, occurring in 0.04 percent of blepharoplasties [3], 0.43 percent of endoscopic sinus surgeries [4], and in up to 3.2 percent of orbital floor fractures [5].\n\nOnset of symptoms typically occurs within three hours of surgery and the vast majority within 24 h; however, onset may occur as many as nine days after surgery [6,7]. Clinicians should have a high index of suspicion for this complication after head and neck procedures, especially after orbital floor repair [8,9,10,11,12].\n\nThe clinical presentation may be dramatic in appearance, and the diagnosis is made based on clinical signs and symptoms. Proptosis with severe stabbing pain, vision loss, and a sensation of pressure are common. Patients may also experience nausea and vomiting, diplopia, and visual flashes [13]. External examination of the eye may reveal eyelid hematoma or ecchymosis, subconjunctival hemorrhage, proptosis, or ophthalmoplegia. If the optic nerve is compromised, pupillary light reflexes will be abnormal, with a relative afferent pupillary defect. Brain imaging is necessary to assess orbital structures as well as presence of pathological lesions. CT or MRI can confirm the diagnosis and exclude other potential causes [6]. Due to the emergent nature of retrobulbar hemorrhage in cases associated with trauma, CT is preferred because it shows the bony anatomy in a timely manner. In cases where vascular anomalies are suspected, MRI is the choice. Emergency ophthalmology consultation is indicated if the diagnosis is suspected.\n\nRBH occurs in a confined orbital space that is surrounded by a bony wall; this results in a rapid elevation of intra-orbital pressure. This pressure is transmitted to the eye and optic nerve causing ischemia through orbital compartment syndrome (OCS). OCS is a true ophthalmologic emergency that requires immediate decompression with a lateral canthotomy and inferior cantholysis, and may be performed at the bedside with local anesthesia. Emergency surgical decompression should not be delayed for imaging or administration of topical or systemic medications aimed at lowering intraocular pressure. Evacuation of the hematoma may be performed subsequent to decompression. Prognosis for vision is dependent on the time from the onset of symptoms to decompression, with poor outcomes reported in symptom-to-treatment intervals as short as four hours. Retrobulbar hematoma is responsible for almost half of all cases of visual loss associated with repair of orbital floor fractures [5].\n\nPrevention includes primarily surgical hemostasis, avoidance of excessive coughing and straining with emergence, and retching in the recovery room [8,9,10,11,12]. In our case, despite early recognition of symptoms and prompt surgical intervention within the reported literature time frame, the patient still endured loss of vision. Therefore, patients with a potential risk and a high suspicion of orbital compartment syndrome, such as those on blood thinners or undergoing procedures in which they will receive anticoagulants, should be systematically monitored for signs and symptoms, and assessed closely.\n\n4. Conclusions\n\nThis case sheds light on the urgent nature of orbital compartment syndrome and the importance of early recognition and intervention. Teaching, training, and early surgical decompression is reported to be the only solution to save the blind eye, but despite this, it may remain blind.\n\nAuthor Contributions\n\nK.S.: Writing and gathering the data for the manuscript. D.N.: Reviewing the manuscript. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nOur institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent Statement\n\nVerbal Informed consent was obtained directly from the patient prior to writing this manuscript.\n\nData Availability Statement\n\nData available upon request.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Axial view of Brain CT scan showing left periorbital soft tissue swelling with hyper dense mass. This appears to be located above the superior rectus muscle (Arrow).\n\nFigure 2 Sagittal view of Brain CT scan showing left soft tissue swelling with hyper dense mass in the left superior orbit measuring 3.7 × 2.9 × 1.5 cm (Arrow).\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Fattahi T. Brewer K. Retana A. Ogledzki M. Incidence of retrobulbar hemorrhage in the emergency department J. Oral Maxillofac. Surg. 2014 72 2500 2502 10.1016/j.joms.2014.06.457 25249171\n2. Lima V. Burt B. Leibovitch I. Prabhakaran V. Goldberg R.A. Selva-Nayagam D. Orbital compartment syndrome: The ophthalmic surgical emergency Surv. Ophthalmol. 2009 54 441 449 10.1016/j.survophthal.2009.04.005 19539832\n3. DeMere M. Wood T. Austin W. Eye complications with blepharoplasty or other eyelid surgery. A national survey Plast. Reconstr. Surg. 1974 53 634 637 10.1097/00006534-197406000-00003 4857299\n4. Stankiewicz J.A. Chow J.M. Two faces of orbital hematoma in intranasal (endoscopic) sinus surgery Otolaryngol. Head Neck Surg. 1999 120 841 847 10.1016/S0194-5998(99)70324-4 10352437\n5. Gosau M. Schöneich M. Draenert F.G. Ettl T. Driemel O. Reichert T.E. Retrospective analysis of orbital floor fractures--complications, outcome, and review of literature Clin. Oral Investig. 2011 15 305 313 10.1007/s00784-010-0385-y 20165966\n6. Hass A.N. Penne R.B. Stefanyszyn M.A. Flanagan J.C. Incidence of postblepharoplasty orbital hemorrhage and associated visual loss Ophthalmic Plast. Reconstr. Surg. 2004 20 426 432 10.1097/01.IOP.0000143711.48389.C5 15599241\n7. Teng C.C. Reddy S. Wong J.J. Lisman R.D. Retrobulbar hemorrhage nine days after cosmetic blepharoplasty resulting in permanent visual loss Ophthalmic Plast. Reconstr. Surg. 2006 22 388 389 10.1097/01.iop.0000235500.88819.c8 16985426\n8. Lee L.A. Roth S. Posner K.L. Cheney F.W. Caplan R.A. Newman N.J. Domino K.B. The American Society of Anesthesiologists Postoperative Visual Loss Registry: Analysis of 93 spine surgery cases with postoperative visual loss Anesthesiology 2006 105 652 659 10.1097/00000542-200610000-00007 17006060\n9. Rettinger G. Christ P. Meythaler F.H. Erblindung durch Zentralarterienverschluss nach Septumkorrektur [Blindness caused by central artery occlusion following nasal septum correction] HNO 1990 38 105 109 2341295\n10. Whiteman D.W. Rosen D.A. Pinkerton R.M. Retinal and choroidal microvascular embolism after intranasal corticosteroid injection Am. J. Ophthalmol. 1980 89 851 853 10.1016/0002-9394(80)90178-6 7386564\n11. Fu A.D. McDonald H.R. Eliott D. Fuller D.G. Halperin L.S. Ramsay R.C. Johnson R.N. Ai E. Complications of general anesthesia using nitrous oxide in eyes with preexisting gas bubbles Retina 2002 22 569 574 10.1097/00006982-200210000-00006 12441721\n12. Silvanus M.T. Moldzio P. Bornfeld N. Peters J. Visual loss following intraocular gas injection Dtsch. Arztebl Int. 2008 105 108 112 19633760\n13. Deveer M. Cullu N. Beydilli H. Sozen H. Yeniceri O. Parlak S. Spontaneous retrobulbar haematoma Case Rep. Radiol. 2015 2015 796834 10.1155/2015/796834 26090258\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2039-7275",
"issue": "11(2)",
"journal": "Clinics and practice",
"keywords": "orbital compartment syndrome; retrobulbar hematoma",
"medline_ta": "Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "101563282",
"other_id": null,
"pages": "327-331",
"pmc": null,
"pmid": "34073719",
"pubdate": "2021-05-24",
"publication_types": "D002363:Case Reports",
"references": "16985426;2341295;19539832;10352437;25249171;12441721;17006060;26090258;20165966;15599241;7386564;19633760;4857299",
"title": "Doubly Blinded: An Uncommon Cause of Acute Visual Loss Due to Orbital Compartment Syndrome.",
"title_normalized": "doubly blinded an uncommon cause of acute visual loss due to orbital compartment syndrome"
} | [
{
"companynumb": "US-SA-2021SA205808",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "HEPARIN SODIUM"
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... |
{
"abstract": "Multiple sclerosis (MS) is a chronic, disabling, immune-mediated, demyelinating and degenerative disease of the central nervous system. Approved disease-modifying therapies may be incompletely effective in some patients with highly active relapsing disease and high risk of disability. The use of immunoablative or myeloablative therapy followed by autologous hematopoietic cell transplantation (AHCT) has been investigated in retrospective studies, clinical trials, and meta-analyses/systematic reviews as an approach to address this unmet clinical need. On behalf of the American Society for Blood and Bone Marrow Transplantation (ASBMT), a panel of experts in AHCT and MS convened to review available evidence and make recommendations on MS as an indication for AHCT. A review of recent literature identified 8 retrospective studies, 8 clinical trials, and 3 meta-analyses/systematic reviews. In aggregate, these studies indicate that AHCT is an efficacious and safe treatment for active relapsing forms of MS to prevent clinical relapse, magnetic resonance imaging-detectable lesion activity, and worsening disability and to reverse disability without unexpected adverse events. Based on the available evidence, the ASBMT recommends that treatment-refractory relapsing MS with high risk of future disability be considered a \"standard of care, clinical evidence available\" indication for AHCT. Collaboration of neurologists with expertise in treating MS and transplantation physicians with experience performing AHCT for autoimmune disease is crucial for ensuring appropriate patient selection and optimizing transplantation procedures to improve patient outcomes. Transplantation centers in the United States and Canada are strongly encouraged to report baseline and outcomes data on patients receiving AHCT for multiple sclerosis to the Center for International Blood and Marrow Transplant Research.",
"affiliations": "Mellen Center for MS Treatment and Research, Cleveland Clinic, Cleveland, Ohio. Electronic address: cohenj@ccf.org.;Mellen Center for MS Treatment and Research, Cleveland Clinic, Cleveland, Ohio.;Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.;Multiple Sclerosis Center, Swedish Neuroscience Institute, Seattle, Washington.;Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.;Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado.;University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.;Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.;Division of Blood and Marrow Transplantation, Stanford University, Stanford, California.;Blood and Marrow Transplant Program, Cleveland Clinic, Cleveland, Ohio.;Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.;Blood and Marrow Transplant Program, Colorado Blood Cancer Institute, Denver, Colorado.;Department of Hematology and Oncology, Medical College of Wisconsin and Center for International Blood and Marrow Transplant Research, Milwaukee, Wisconsin.;Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina.;Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, Tennessee.;Blood and Marrow Transplant Program, University of Calgary, Calgary, Alberta, Canada.;Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.",
"authors": "Cohen|Jeffrey A|JA|;Baldassari|Laura E|LE|;Atkins|Harold L|HL|;Bowen|James D|JD|;Bredeson|Christopher|C|;Carpenter|Paul A|PA|;Corboy|John R|JR|;Freedman|Mark S|MS|;Griffith|Linda M|LM|;Lowsky|Robert|R|;Majhail|Navneet S|NS|;Muraro|Paolo A|PA|;Nash|Richard A|RA|;Pasquini|Marcelo C|MC|;Sarantopoulos|Stefanie|S|;Savani|Bipin N|BN|;Storek|Jan|J|;Sullivan|Keith M|KM|;Georges|George E|GE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2019.02.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "25(5)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Autologous hematopoietic cell transplantation; Coverage; Indication; Multiple sclerosis; Stem cells",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D002170:Canada; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D009103:Multiple Sclerosis; D010348:Patient Care Team; D016879:Salvage Therapy; D012955:Societies, Medical; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "845-854",
"pmc": null,
"pmid": "30794930",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article; D017065:Practice Guideline; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Autologous Hematopoietic Cell Transplantation for Treatment-Refractory Relapsing Multiple Sclerosis: Position Statement from the American Society for Blood and Marrow Transplantation.",
"title_normalized": "autologous hematopoietic cell transplantation for treatment refractory relapsing multiple sclerosis position statement from the american society for blood and marrow transplantation"
} | [
{
"companynumb": "US-OTSUKA-2019_027666",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe aim of this study is to provide information about lithium effectiveness and safety in the treatment of old patients with mood disorders.\n\n\nMETHODS\nThe study is naturalistic in nature and design and considers all patients aged ≥75 years attending our center in the past 10 years. We obtained patients' socio-demographic and clinical characteristics, the worst Global Assessment of Functioning score assigned in the course of treatment, the Clinical Global Impression (CGI) score at the beginning of treatment, the CGI-Improvement (CGI-I) highest score achieved in the follow-up, and drop-out rates. We compared patients treated with lithium, in some cases associated with other psychotropic medications, and patients treated with psychotropic medications other than lithium. Furthermore, we analyzed lithium side effects and causes of lithium withdrawal.\n\n\nRESULTS\nIn the considered period, 25 lithium-treated patients achieved higher CGI-I scores after treatment in comparison with 138 patients not receiving lithium. Drop-out rates were similar in the two groups. Mean dose of lithium was 390 ± 178.5 mg/day. Among lithium treated patients, neither hypothyroidism nor renal failure were significant problems. Thyroxine treatment was prescribed to 8 (32%) lithium-treated patients. Lithium was withdrawn in 6 (24%) patients, respectively for ineffectiveness, heart disease (unrelated to lithium), erratic and unpredictable metabolism of lithium, poor compliance (two cases), and mitigation of the disease.\n\n\nCONCLUSIONS\nLithium remains irreplaceable and maintains a high effectiveness in the treatment of elderly patients. Low doses and frequent monitoring are recommended.",
"affiliations": null,
"authors": "Raja|Michele|M|;Raja|Silvia|S|",
"chemical_list": "D018020:Lithium Compounds",
"country": "Italy",
"delete": false,
"doi": "10.1708/1600.17456",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0035-6484",
"issue": "49(4)",
"journal": "Rivista di psichiatria",
"keywords": null,
"medline_ta": "Riv Psichiatr",
"mesh_terms": "D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D018020:Lithium Compounds; D008297:Male; D019964:Mood Disorders",
"nlm_unique_id": "0425672",
"other_id": null,
"pages": "180-2",
"pmc": null,
"pmid": "25174694",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lithium treatment in elderly patients affected by mood disorders.",
"title_normalized": "lithium treatment in elderly patients affected by mood disorders"
} | [
{
"companynumb": "IT-ROXANE LABORATORIES, INC.-2015-RO-01882RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LITHIUM CARBONATE"
},
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{
"abstract": "BACKGROUND\nTreatment of IgA nephropathy (IgAN) in Japan has recently changed, from oral prednisolone (oPSL) to tonsillectomy plus steroid pulse (TSP) therapy. However, a few studies have compared their efficacy and safety.\n\n\nMETHODS\nIgAN patients diagnosed in our institution between 1991 and 2013, treated with TSP or oPSL, aged ≥16 years, with ≥1 g/day proteinuria, and estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m2, and no other renal disease were selected. Baseline clinical and histological findings, clinical outcomes, and adverse events were compared. Clinical remission (CR) was defined as <0.3 g/day proteinuria and <5 urinary red blood cells per high-powered field.\n\n\nRESULTS\nSixty-six patients were identified; after propensity score adjustment, 26 patients were selected in each group. CR rates were significantly higher at 12 (30.8 % vs. 3.9 %), 36 (47.3 % vs. 7.9 %), and 72 (57.8 % vs. 20.1 %) months (p < 0.01), and the renal survival rate, defined as the development of a 25 % reduction from baseline eGFR, was significantly higher at 12 (96.2 % vs. 69.2 %), 36 (96.2 % vs. 61.5 %), and 72 (96.2 % vs. 41.0 %) months in the TSP than the oPSL group (p < 0.001). Multivariate analysis showed that TSP was the only independent factor associated with CR (hazard ratio, 3.58; 95 % confidence interval, 1.32-10.91, p = 0.01). The number of patients with adverse events was significant lower in TSP group than in oPSL group (11.5 % vs. 34.6 %, p = 0.04).\n\n\nCONCLUSIONS\nCR rates are higher; protection of renal function and prevention from adverse events were superior with TSP than with oPSL in patients with IgAN and moderate-to-severe proteinuria.",
"affiliations": "Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.;Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan. takamori@kc.twmu.ac.jp.;Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.;Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.;Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.",
"authors": "Hoshino|Yoshie|Y|;Moriyama|Takahito|T|;Uchida|Keiko|K|;Tsuchiya|Ken|K|;Nitta|Kosaku|K|",
"chemical_list": "D005938:Glucocorticoids; D011239:Prednisolone; D008775:Methylprednisolone",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10157-016-1324-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1342-1751",
"issue": "21(4)",
"journal": "Clinical and experimental nephrology",
"keywords": "IgA nephropathy; Proteinuria; Remission induction; Steroid; Tonsillectomy",
"medline_ta": "Clin Exp Nephrol",
"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001706:Biopsy; D016009:Chi-Square Distribution; D003131:Combined Modality Therapy; D005260:Female; D005919:Glomerular Filtration Rate; D005922:Glomerulonephritis, IGA; D005938:Glucocorticoids; D006801:Humans; D007564:Japan; D053208:Kaplan-Meier Estimate; D007668:Kidney; D008297:Male; D008775:Methylprednisolone; D015999:Multivariate Analysis; D011239:Prednisolone; D057216:Propensity Score; D016016:Proportional Hazards Models; D011507:Proteinuria; D020551:Pulse Therapy, Drug; D012074:Remission Induction; D012189:Retrospective Studies; D013997:Time Factors; D014068:Tonsillectomy; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9709923",
"other_id": null,
"pages": "617-623",
"pmc": null,
"pmid": "27549901",
"pubdate": "2017-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "19339088;9047155;19398868;6406547;24081865;17337885;11576876;22833253;21081691;10093981;14694168;12759582;23913115;15768796;15156529;26123429;23519367;23744063;3628707;8684533;22684645;19449181;24658533;12213946",
"title": "Comparison of oral steroids with tonsillectomy plus steroid pulse therapy in patients with IgA nephropathy.",
"title_normalized": "comparison of oral steroids with tonsillectomy plus steroid pulse therapy in patients with iga nephropathy"
} | [
{
"companynumb": "JP-PFIZER INC-2017389130",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
{
"abstract": "Benign hepatic lesions may occur after chemotherapy treatment and may mimic metastases at imaging. We describe focal nodular hyperplasia (FNH) lesions diagnosed at MRI that occurred de novo after treatment with oxaliplatin.\n\n\n\nThis is a multiinstitutional case series. We report 14 adult patients with cancer (eight men and six women) with a history of treatment with oxaliplatin and development of new hepatic lesions diagnosed as FNH at pathologic analysis or MRI or both. Imaging and pathology features of the included lesions, the interval since chemotherapy, and the temporal evolution were reviewed.\n\n\n\nThe mean interval between the completion of oxaliplatin treatment and the identification of new hepatic FNH at imaging was 47.6 months. In seven of 14 (50%) patients, the index lesion was diagnosed at pathologic analysis (biopsy or resection) as FNH. In the remaining seven cases, the diagnosis was based on highly accurate MRI features (e.g., hyper- or isointensity of the lesion on hepatobiliary phase images). Lesion growth or occurrence of new lesions was present in 75% of patients at imaging follow-up.\n\n\n\nFNH lesions can occur de novo after treatment with oxaliplatin. Recognizing the typical MRI appearance of these lesions may avoid unnecessary biopsy or surgery and reduce patients' anxiety.",
"affiliations": "1 Department of Radiology, University of Pittsburgh, UPMC Presbyterian, Ste 201, East Wing, 200 Lothrop St, Pittsburgh, PA 15213.;2 Section of Radiological Sciences, Department of Biopathology and Medical Biotechnologies, University of Palermo, Palermo, Italy.;3 Radiology Department, Beaujon Hospital, University Hospitals Paris Nord Val de Seine, Assistance Publique-Hôpitaux de Paris, Clichy, France.;4 Department of Radiology, Spedali Civili di Brescia, Brescia, Italy.;5 Department of Radiology, Seoul National University Hospital, Seoul, Korea.;7 ASP di Agrigento, Ospedali Civili Riuniti di Sciacca, Sciacca, Italy.;8 Laboratoire d'Imagerie Biomédicale, Hôpital Pitié-Salpêtrière, UPMC Univ Paris 06, CNRS, INSERM, AP-HP, Sorbonne Universités, Paris, France.;9 Service d'Imagerie, Groupe Hospitalier Diaconesses Croix Saint Simon, Paris, France.;10 Service de Radiologie, Hôpital de la Croix-Rousse, Lyon, France.;3 Radiology Department, Beaujon Hospital, University Hospitals Paris Nord Val de Seine, Assistance Publique-Hôpitaux de Paris, Clichy, France.;3 Radiology Department, Beaujon Hospital, University Hospitals Paris Nord Val de Seine, Assistance Publique-Hôpitaux de Paris, Clichy, France.",
"authors": "Furlan|Alessandro|A|;Brancatelli|Giuseppe|G|;Dioguardi Burgio|Marco|M|;Grazioli|Luigi|L|;Lee|Jeong Min|JM|;Murmura|Elena|E|;Lucidarme|Olivier|O|;Strauss|Christiane|C|;Rode|Agnes|A|;Ronot|Maxime|M|;Vilgrain|Valerie|V|",
"chemical_list": "D000970:Antineoplastic Agents; D003287:Contrast Media; D000077150:Oxaliplatin",
"country": "United States",
"delete": false,
"doi": "10.2214/AJR.17.18867",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-803X",
"issue": "210(4)",
"journal": "AJR. American journal of roentgenology",
"keywords": "MRI; focal nodular hyperplasia; gadoxetate disodium; oxaliplatin",
"medline_ta": "AJR Am J Roentgenol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D003287:Contrast Media; D005260:Female; D020518:Focal Nodular Hyperplasia; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D000077150:Oxaliplatin",
"nlm_unique_id": "7708173",
"other_id": null,
"pages": "775-779",
"pmc": null,
"pmid": "29323545",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Focal Nodular Hyperplasia After Treatment With Oxaliplatin: A Multiinstitutional Series of Cases Diagnosed at MRI.",
"title_normalized": "focal nodular hyperplasia after treatment with oxaliplatin a multiinstitutional series of cases diagnosed at mri"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2018US-173027",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"dru... |
{
"abstract": "Fentanyl overdoses are increasing and few data guide emergency department (ED) management. We evaluate the safety of an ED protocol for patients with presumed fentanyl overdose.\n\n\n\nAt an urban ED, we used administrative data and explicit chart review to identify and describe consecutive patients with uncomplicated presumed fentanyl overdose (no concurrent acute medical issues) from September to December 2016. We linked regional ED and provincial vital statistics databases to ascertain admissions, revisits, and mortality. Primary outcome was a composite of admission and death within 24 hours. Other outcomes included treatment with additional ED naloxone, development of a new medical issue while in the ED, and length of stay. A prespecified subgroup analysis assessed low-risk patients with normal triage vital signs.\n\n\n\nThere were 1,009 uncomplicated presumed fentanyl overdose, mainly by injection. Median age was 34 years, 85% were men, and 82% received out-of-hospital naloxone. One patient was hospitalized and one discharged patient died within 24 hours (combined outcome 0.2%; 95% confidence interval [CI] 0.04% to 0.8%). Sixteen patients received additional ED naloxone (1.6%; 95% CI 1.0% to 2.6%), none developed a new medical issue (0%; 95% CI 0% to 0.5%), and median length of stay was 173 minutes (interquartile range 101 to 267). For 752 low-risk patients, no patients were admitted or developed a new issue, and one died postdischarge; 3 (0.4%; 95% CI 0.01% to 1.3%) received ED naloxone.\n\n\n\nIn our cohort of ED patients with uncomplicated presumed fentanyl overdose-typically after injection-deterioration, admission, mortality, and postdischarge complications appear low; the majority can be discharged after brief observation. Patients with normal triage vital signs are unlikely to require ED naloxone.",
"affiliations": "Department of Emergency Medicine, St Paul's Hospital and the University of British Columbia, Vancouver, Canada. Electronic address: frank.scheuermeyer@gmail.com.;Department of Emergency Medicine, St Paul's Hospital and the University of British Columbia, Vancouver, Canada.;Department of Emergency Medicine, St Paul's Hospital and the University of British Columbia, Vancouver, Canada.;Department of Emergency Medicine, St Paul's Hospital and the University of British Columbia, Vancouver, Canada.;Department of Emergency Medicine, St Paul's Hospital and the University of British Columbia, Vancouver, Canada.;Department of Emergency Medicine, St Paul's Hospital and the University of British Columbia, Vancouver, Canada.;British Columbia Center for Disease Control, Vancouver, Canada.;Department of Emergency Medicine, St Paul's Hospital and the University of British Columbia, Vancouver, Canada.;Department of Emergency Medicine, St Paul's Hospital and the University of British Columbia, Vancouver, Canada.;Department of Emergency Medicine, St Paul's Hospital and the University of British Columbia, Vancouver, Canada.;Department of Emergency Medicine, St Paul's Hospital and the University of British Columbia, Vancouver, Canada.;Department of Emergency Medicine, Rockyview Hospital and the University of Calgary, Calgary, Canada.",
"authors": "Scheuermeyer|Frank X|FX|;DeWitt|Christopher|C|;Christenson|Jim|J|;Grunau|Brian|B|;Kestler|Andrew|A|;Grafstein|Eric|E|;Buxton|Jane|J|;Barbic|David|D|;Milanovic|Stefan|S|;Torkjari|Reza|R|;Sahota|Indy|I|;Innes|Grant|G|",
"chemical_list": "D009270:Naloxone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.annemergmed.2018.01.054",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0644",
"issue": "72(1)",
"journal": "Annals of emergency medicine",
"keywords": null,
"medline_ta": "Ann Emerg Med",
"mesh_terms": "D000328:Adult; D002170:Canada; D062787:Drug Overdose; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D007902:Length of Stay; D008297:Male; D009026:Mortality; D009270:Naloxone; D017410:Practice Guidelines as Topic; D019233:Retreatment; D012189:Retrospective Studies; D019037:Urban Health Services",
"nlm_unique_id": "8002646",
"other_id": null,
"pages": "1-8.e1",
"pmc": null,
"pmid": "29530654",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety of a Brief Emergency Department Observation Protocol for Patients With Presumed Fentanyl Overdose.",
"title_normalized": "safety of a brief emergency department observation protocol for patients with presumed fentanyl overdose"
} | [
{
"companynumb": "CA-TEVA-2018-CA-943593",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "3",
"d... |
{
"abstract": "Posttransplant lymphoproliferative disorder is a serious complication of solid-organ transplant. Extranodal involvement is common; however, isolated involvement of the central nervous system is extremely rare and represents a particularly difficult therapeutic challenge with no current consensus on optimal treatment. Here, we describe a 70-year-old woman who developed Epstein-Barr virus-related primary central nervous system lymphoma 19 months after kidney transplant. Immunosuppression was reduced, and the patient was started on high-dose methotrexate, which was complicated by acute kidney injury and discontinued. She then received a rituximab and temozolomide chemotherapeutic regimen and achieved complete clinical response. Seventeen months after diagnosis, she is alive and has not developed any other posttransplant lymphoproliferative disorder. We review the current literature and discuss treatment options for patients with primary central nervous system posttransplant lymphoproliferative disorder following kidney transplant.",
"affiliations": "From the School of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.",
"authors": "Abbassi|Mashya|M|;Riley|Roger|R|;Malkin|Mark|M|;Tang|Yang|Y|;Rajendran|Bipin|B|;Yazbeck|Victor|V|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069283:Rituximab; D000077204:Temozolomide",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2016.0171",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "17(1)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D016543:Central Nervous System Neoplasms; D038524:Diffusion Magnetic Resonance Imaging; D020031:Epstein-Barr Virus Infections; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008223:Lymphoma; D000069283:Rituximab; D000077204:Temozolomide; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "111-114",
"pmc": null,
"pmid": "28447926",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Treatment of Primary Central Nervous System Posttransplant Lymphoproliferative Disorder in an Adult Kidney Transplant Recipient: A Case Report.",
"title_normalized": "treatment of primary central nervous system posttransplant lymphoproliferative disorder in an adult kidney transplant recipient a case report"
} | [
{
"companynumb": "US-PFIZER INC-2019229645",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAge is an unfavorable prognostic factor in glioblastoma multiforme (GBM). To assess the possibility and the advantage of radiotherapy (RT) plus concomitant/sequential temozolomide (TMZ) in patients over 65 years with GBM, we analyzed 4 prospective trials in terms of compliance and outcomes.\n\n\nMETHODS\nElderly patients with histologically proven GBM, included in 4 prospective phase II studies with a Karnofsky Performance Status (KPS) >70 and a Charlson Comorbidity Index (CCI) <3, were selected for these analyses. Patients were treated by 3D-conformal RT (60 Gy), fractionated stereotactic conformal-RT (69.4 Gy), or intensity-modulated RT with simultaneous integrated boost (63 Gy). Concomitant (standard modality, first and last week, or from the Monday to Friday) and adjuvant chemotherapy with TMZ was administered. To stratify patients, recursive partitioning analysis was used. Safety and tolerability were measured by the National Cancer Institute Common Criteria. Progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier method.\n\n\nRESULTS\nFrom 2001 to 2011, 201 patients were enrolled in 4 trials and 111 elderly patients were recruited for this analysis. Compliance was 96.4%: 4/111 patients discontinued treatment, prevalently for disease progression. During radiochemotherapy, acute toxicity was mild. At a median follow-up of 64 months (range, 9 to 122 mo), median PFS and OS were 10 and 13 months, respectively. Extent of surgery (P=0.009) and radiation dose (P=0.01) significantly improved survival.\n\n\nCONCLUSIONS\nRadiochemotherapy is effective and well tolerated by elderly patients when KPS >70 and CCI <3; therefore these criterions should be considered to enroll elderly patients in combined prospective study.",
"affiliations": "*Department of Radiation Oncology, IRCCS/CROB, Rionero in Vulture (PZ) Departments of †Radiation Oncology ‡Neurosurgery, Catholic University of Sacred Heart, Rome, Italy.",
"authors": "Fiorentino|Alba|A|;Balducci|Mario|M|;De Bonis|Pasquale|P|;Chiesa|Silvia|S|;De Filippo|Laura|L|;Mangiola|Annunziato|A|;De Rose|Fiorenza|F|;Autorino|Rosa|R|;Rinaldi|Carla|C|;Fersino|Sergio|S|;Diletto|Barbara|B|;Matteucci|Paolo|P|;Ciurlia|Elisa|E|;Fusco|Vincenzo|V|;Anile|Carmelo|C|;Valentini|Vincenzo|V|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide",
"country": "United States",
"delete": false,
"doi": "10.1097/COC.0b013e3182868ea2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "38(1)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating; D001932:Brain Neoplasms; D059248:Chemoradiotherapy; D059186:Chemoradiotherapy, Adjuvant; D003606:Dacarbazine; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma; D006801:Humans; D053208:Kaplan-Meier Estimate; D017567:Karnofsky Performance Status; D008297:Male; D018579:Patient Selection; D020266:Radiotherapy, Conformal; D012189:Retrospective Studies; D000077204:Temozolomide; D016896:Treatment Outcome",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "23-7",
"pmc": null,
"pmid": "23388566",
"pubdate": "2015-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Can elderly patients with newly diagnosed glioblastoma be enrolled in radiochemotherapy trials?",
"title_normalized": "can elderly patients with newly diagnosed glioblastoma be enrolled in radiochemotherapy trials"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-106942",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"dr... |
{
"abstract": "Melioidosis is rare in the United States and endemic to Southeast Asia and Australia. Treatment includes an initial intensive phase of intravenous ceftazidime or meropenem monotherapy depending on severity. The following report describes a case of persistent bacteremia with ceftazidime failure and prolonged meropenem therapy on a ceftazidime-susceptible strain of Burkholderia pseudomallei.",
"affiliations": "HSHS St. Elizabeth's Hospital, O'Fallon, IL 62269, USA. sumbul.meraj@gmail.com.;HSHS St. Elizabeth's Hospital, O'Fallon, IL 62269, USA. brandy.rodenberg@hshs.org.;HSHS St. Elizabeth's Hospital, O'Fallon, IL 62269, USA. stephanie.thannum@hshs.org.;HSHS St. Elizabeth's Hospital, O'Fallon, IL 62269, USA. jared.sheley@hshs.org.;HSHS St. Elizabeth's Hospital, O'Fallon, IL 62269, USA. jena.foreman@hshs.org.",
"authors": "Meraj|Sumbul|S|;Rodenberg|Brandy|B|;Thannum|Stephanie|S|;Sheley|Jared|J|;Foreman|Jena|J|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/tropicalmed4010020",
"fulltext": "\n==== Front\nTrop Med Infect DisTrop Med Infect DistropicalmedTropical Medicine and Infectious Disease2414-6366MDPI 10.3390/tropicalmed4010020tropicalmed-04-00020Case ReportPersistent Burkholderia pseudomallei Bacteremia in A Filipino Immigrant to the United States: A Case Report Meraj Sumbul 1*Rodenberg Brandy 1*Thannum Stephanie 1Sheley Jared 12Foreman Jena 11 HSHS St. Elizabeth’s Hospital, O’Fallon, IL 62269, USA; stephanie.thannum@hshs.org (S.T.); jared.sheley@hshs.org (J.S.); jena.foreman@hshs.org (J.F.)2 School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL 62025, USA* Correspondence: sumbul.meraj@gmail.com (S.M.); brandy.rodenberg@hshs.org (B.R.); Tel.: +1-618-484-6292 (S.M.); +1-618-972-1449 (B.R.)28 1 2019 3 2019 4 1 2031 12 2018 26 1 2019 © 2019 by the authors.2019Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Melioidosis is rare in the United States and endemic to Southeast Asia and Australia. Treatment includes an initial intensive phase of intravenous ceftazidime or meropenem monotherapy depending on severity. The following report describes a case of persistent bacteremia with ceftazidime failure and prolonged meropenem therapy on a ceftazidime-susceptible strain of Burkholderia pseudomallei.\n\nBurkholderia pseudomalleimelioidosisceftazidimeresistancepersistent bacteremia\n==== Body\n1. Introduction\nBurkholderia pseudomallei is a Gram-negative, aerobic bacillus found naturally in the water and soil of many countries in Southeast Asia, the Pacific Islands, and northern Australia [1]. Transmission of this bacterium occurs through inoculation, ingestion, or inhalation. Historically, in the 19th and 20th centuries, this bacterium had been used as a bioterrorism weapon due to its translocation in water leading to infection during monsoon season in areas where it is endemic [2,3]. Infection with B. pseudomallei, commonly known as melioidosis, presents as pneumonia in nearly 50% of patients, but may also cause bone, skin/soft tissue, or central nervous system infections. In many cases, the infection progresses to bacteremia that can rapidly become fatal [1,3]. Risk factors for melioidosis include travel to, or residence in, endemic areas, immunosuppression, smoking, chronic lung disease, diabetes mellitus, chronic liver disease, and renal insufficiency [4]. Melioidosis may present as an acute, chronic, or latent infection, and inappropriate treatment or shortened duration of therapy may lead to relapse or re-infection [4]. Relapse rates vary based on patient-specific risk factors, but have ranged from 5%–10%, and the mortality rates following B. pseudomallei infection are as high as 34.8%, despite appropriate ceftazidime or meropenem intensive therapy [5]. Although rare in the United States (US), the number of reported cases to the Centers for Disease Control and Prevention continues to grow, with most patients reporting recent travel outside of the US. Due to this rarity of melioidosis in the US, there are no established US treatment guidelines and available treatment information consists of international studies and guidelines. \n\nCurrent treatment recommendations in Australia include an intensive phase of intravenous (IV) antibiotics followed by a prolonged oral eradication phase, which minimizes the risk of relapse [6,7]. These recommendations include a minimum of 10–14 days of IV ceftazidime or meropenem followed by a three- to six-month eradication phase using oral sulfamethoxazole/trimethoprim, doxycycline, or amoxicillin/clavulanate depending on the source of infection and other patient-specific factors [8].\n\nSeveral studies have established ceftazidime monotherapy as the first-line intensive therapy agent. An open randomized trial compared 120 mg/kg/day ceftazidime to conventional therapy, which consisted of the combination of chloramphenicol, doxycycline, and sulfamethoxazole/trimethoprim, and found that ceftazidime reduced mortality from 74% to 37%, comparatively [9]. Ceftazidime monotherapy has also been compared to ceftazidime plus sulfamethoxazole/trimethoprim and was found to have similar rates of both mortality and recurrences [10]. Observational studies have shown that meropenem therapy may be clinically preferable over ceftazidime due to the concerns of potential resistance through penicillin binding protein 3 gene deletions in B. pseudomallei, lack of growth of resistant strains on agar plates, and early relapse of bacteremia associated with ceftazidime [11]. Meropenem is currently preferred over ceftazidime in cases of neuromelioidosis, persistent bacteremia, and critically ill patients [12,13]. Currently there is no strong evidence comparing carbapenems and ceftazidime, but there is a randomized, blinded trial comparing ceftazidime to meropenem underway in Thailand [14].\n\nPersistent bacteremia with B. pseudomallei correlates to increased risk of death from melioidosis. Therefore, blood cultures should be performed weekly. Repeating cultures from other sites have shown no benefit for prognostic value [15]. Furthermore, when growing B. pseudomallei, it is recommended to utilize Ashdown agar in preference to blood agar when available due to potential organism misidentification as Pseudomonas or Burkholderia spp., which could delay appropriate treatment [15].\n\n2. Patient Case\nThe patient’s written informed consent and Southern Illinois University Edwardsville IRB approval were obtained for this case report. A supplemental table (Table A1) has been provided in Appendix A, which outlines antibiotic therapy and culture reports throughout the patient’s hospital admission. \n\nOur patient is an 81-year-old, 53 kg, 160 cm tall female from the Philippines who presented to our emergency department in southwestern Illinois with shortness of breath. Her past medical history is significant for asthma, hypertension, dyslipidemia, cerebral aneurysm, and arthritis. She reported moving to the US in 1979 and had recently returned from a one-month long visit to Quezon City, an urban area in the Philippines, five days prior to admission. Risk factors for melioidosis in this patient included: Travel to an endemic country and asthma (controlled at baseline). The patient had no sick contacts during or after her visit to the Philippines. There were no adverse weather events and the patient had no exposure to rural or agricultural areas during her stay.\n\nThe patient expressed having increased shortness of breath while ambulating or performing any exertional activities, along with decreased appetite, left-sided chest pain, weakness, fever, cough, and wheezing. Computed tomography (CT) of the chest demonstrated left upper lobe pneumonia, small bilateral pleural effusions, and bibasilar atelectasis. Chest x-ray showed patchy left basilar opacity suggestive of an infiltrate. Blood cultures and a respiratory culture were obtained in the emergency department prior to initiation of ceftriaxone and azithromycin for empiric treatment of suspected community-acquired pneumonia. On admission, her white blood cell (WBC) count was 12,900 cells/µL, temperature was 38.6 °C, and the patient was admitted with an initial diagnosis of pneumonia with acute respiratory distress. \n\nOn day three of admission, WBC count continued to trend up to 20,900 cells/µL while on ceftriaxone and azithromycin. The blood cultures drawn on day one of admission reported growth of Burkholderia species in one out of two bottles, and the respiratory culture resulted with no growth as the final result. Based on a creatinine clearance of 48 mL/min, ceftazidime 2 grams IV was initiated at a decreased dosing frequency of every 12 h, instead of every eight h, on day four of admission. \n\nWhile on ceftazidime, the blood cultures drawn on day four reported the same growth of Burkholderia species. The patient’s WBC count continued to increase, peaking at 33,300 cells/µL, before trending down to 16,200 cells/µL by day eight of admission (day five of ceftazidime therapy). \n\nOn day nine of admission, the patient’s WBC count increased to 18,600 from 16,200 cells/µL, and CT with contrast of the chest was performed and demonstrated progressive complete consolidation of the superior lingular segment of the left upper lobe and new internal cavitation, which was concerning for necrotizing pneumonia. A two-dimensional (2D) echocardiogram did not demonstrate any vegetation at this time. Given the worsening CT findings coupled with persistent bacteremia, therapy was changed to meropenem 1 g IV every eight h.\n\nOn day 13 of admission, the regional laboratory reported the results of the culture drawn on day one of admission. Identification and susceptibility were the following: B. pseudomallei, susceptible to chloramphenicol, ceftazidime, meropenem, and sulfamethoxazole/trimethoprim. The Centers for Disease Control and Prevention were notified of the results from the regional public health laboratory. A CT of the abdomen and pelvis was performed and did not demonstrate any fluid collection or abscesses. Later that same day, temperature increased to 37.2 °C. Due to identification and susceptibility testing, and decrease in patient’s creatinine clearance, repeat blood cultures were obtained and the dose of meropenem was increased to 2 grams every 12 h, and sulfamethoxazole/trimethoprim (320 mg trimethoprim component) twice daily was added to the therapy regimen. Incidentally, the blood cultures drawn on day 13 were drawn before starting sulfamethoxazole/trimethoprim and returned no growth after a total of 10 days of IV therapy (five days of ceftazidime and five days of meropenem). \n\nMeropenem was continued for four days after the first negative blood culture was drawn (on day 13 of admission) for a total of 14 days IV intensive therapy. The patient was discharged home on oral sulfamethoxazole/trimethoprim (320 mg trimethoprim component) twice daily for a planned duration of three months. \n\nTwo weeks after hospital discharge, the patient was readmitted due to hyponatremia, hyperkalemia, and acute kidney injury. The sulfamethoxazole/trimethoprim dose was decreased during that admission. The previous dose was resumed on discharge as the admitting diagnoses resolved. Blood cultures repeated during this hospitalization were negative. \n\nOne month after the initial hospitalization, the patient was seen in clinic and remained free of symptoms of infection. No fevers or decrease in oxygen saturation was documented.\n\nOne month into treatment with sulfamethoxazole/trimethoprim, the patient developed acute kidney injury with a serum creatinine of 1.30 mg/dL (baseline of 0.64 mg/dL). Due to this adverse effect, therapy was switched to oral doxycycline 100 mg twice daily to complete the remaining course of maintenance therapy. Completion of the antibiotic regimen was confirmed through follow up with the patient in an outpatient infectious diseases clinic. \n\n3. Discussion\nSince this patient was not critically ill on hospital admission and had a pulmonary source of infection, ceftazidime therapy was not initiated until blood cultures returned positive for Burkholderia spp. Treatment was broadened to meropenem due to lack of clearance of bacteremia after approximately a week of ceftazidime therapy, in the setting of worsening of pneumonia with cavitation on CT. Sulfamethoxazole/trimethoprim was added in addition to meropenem due to a mild fever and one positive blood culture while on meropenem. We later found out that the blood cultures that were drawn immediately before starting sulfamethoxazole/trimethoprim were negative. Thus, microbiological cure was achieved after prolonged persistence of bacteremia on meropenem monotherapy.\n\nBoth ceftazidime and meropenem dosing were adjusted based on the patient’s renal function, though guidelines make no recommendation regarding renal dose adjustment for either of these medications in the treatment of B. pseudomallei bacteremia. The recommended dosing interval for both drugs is every eight h. According to drug compendia, the recommended frequency is every 12 h, when considering this patient’s creatinine clearance, due to drug elimination being slowed in renal impairment. With the dose adjustment, the patient did receive lower than studied doses of ceftazidime and meropenem [9,16].\n\nThe treatment of persistent bacteremia caused by B. pseudomallei after failed ceftazidime therapy is not well-studied or mentioned in the international treatment recommendations. While meropenem and ceftazidime have similar mortality rates according to observational studies, meropenem is typically reserved for septic shock and those patients deemed critically ill [12]. One study demonstrated emerging resistance to ceftazidime therapy not evident on susceptibility reports due to the poor growth of the bacteria on typical laboratory culture medium (ex. agar plates) [11]. Our facility’s microbiology laboratory used blood agar and chocolate agar as culture media for this isolate, which typically yields identification of Burkholderia spp. or Pseudomonas spp. After the specimen was identified as Burkholderia spp., by our laboratory, the specimens were sent to a regional public health lab for identification and susceptibility testing. The culture media used by that laboratory was not disclosed to the authors, though Ashdown agar is recommended for culture media. [14] The susceptibility report that we were sent by a regional public health laboratory confirmed susceptibility to ceftazidime; however, the patient remained bacteremic after six days of ceftazidime, prompting the change to meropenem. Given the delay in identification of B. pseudomallei, and the lack of proper culture media for testing, meropenem therapy could have been initiated more expeditiously had the resources been in place to identify this organism earlier in the patient’s hospital stay. \n\nThe risk of mortality from infection with B. pseudomallei is increased with persistent bacteremia; therefore, it is prudent to complete blood cultures once weekly. [15] In our case, blood cultures were drawn far more frequently than weekly, as the authors were not immediately aware that the pathogen was B. pseudomallei. Had identification occurred earlier in the patient’s stay, the ordering of excessive blood cultures could have been avoided, which would have also decreased risk of exposure to laboratory personnel.\n\nBased on our treatment, we are not able to determine whether or not sulfamethoxazole/trimethoprim should be used in combination with meropenem after ceftazidime failure. However, this case does support the use of meropenem monotherapy for the microbiological cure of persistent B. pseudomallei bacteremia in cases of clinical ceftazidime failure, despite ceftazidime susceptibility being shown in vitro. Further studies will be necessary to determine efficacy of meropenem vs. ceftazidime monotherapy in achieving microbiological cure in persistent bacteremia with B. pseudomallei. Furthermore, given the patient’s travel history and the rarity of melioidosis in the United States, it would have been beneficial to have had appropriate identification and susceptibility testing earlier in the patient’s hospitalization so that therapy could have been optimized sooner.\n\n4. Conclusions\nThis is the first case report published on persistent bacteremia with B. pseudomallei in the United States. Despite in vitro testing confirming susceptibility for ceftazidime against B. pseudomallei, we report a case where a patient had persistent bacteremia with ceftazidime monotherapy, with persistent positive blood cultures on initial meropenem therapy. Prospective clinical trials are needed to determine the efficacy of ceftazidime compared to meropenem for microbiological cure.\n\nAuthor Contributions\nInvestigation, data collection, S.M.; writing—original draft preparation, B.R.; writing—review and editing, S.T., J.S., and J.F. \n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest. \n\nAppendix A\ntropicalmed-04-00020-t0A1_Table A1Table A1 Antibiotic therapy and culture results throughout admission.\n\nDay of Admission 1\tCulture Results\tAntibiotic Therapy\t\nDay 1 \n(blood culture #1 collected)\t--\t--\t\nDay 2\t--\tCeftriaxone/Azithromycin\t\nDay 3\t#1 B. pseudomallei (1 out of 2) 2\tCeftriaxone/Azithromycin\t\nDay 4 \n(blood culture #2 collected)\t--\tCeftazidime 2 grams Q12H\t\nDay 5\t--\tCeftazidime 2 grams Q12H\t\nDay 6 \n(blood culture #3 collected)\t#2 B. pseudomallei (2 out of 2) 2\tCeftazidime 2 grams Q12H\t\nDay 7\t--\tCeftazidime 2 grams Q12H\t\nDay 8\t#3 B. pseudomallei (2 out of 2) 2\tCeftazidime 2 grams Q12H\t\nDay 9\t--\tCeftazidime 2 grams Q12H/Meropenem 1 gram Q8H\t\nDay 10\n(blood culture #4 collected)\t--\tMeropenem 1 gram Q8H\t\nDay 11\t--\tMeropenem 1 gram Q8H\t\nDay 12\t#4 B. pseudomallei (2 out of 2) 2\tMeropenem 1 gram Q8H\t\nDay 13\n(blood culture #5 collected)\t-\tMeropenem 2 grams Q12H/Sulfamethoxazole/Trimethoprim DS\t\nDay 14\tNo growth Day 1\tMeropenem 2 grams Q12H/Sulfamethoxazole/Trimethoprim DS\t\nDay 15\tNo growth Day 2\tMeropenem 2 grams Q12H Sulfamethoxazole/Trimethoprim DS\t\nDay 16\tNo growth Day 3\tMeropenem 2 grams Q12H/Sulfamethoxazole/Trimethoprim DS\t\nDay 17\tNo growth Day 4\tMeropenem 2 grams Q12H/Sulfamethoxazole/Trimethoprim DS\t\nDay 18\tNo growth Day 5\tSulfamethoxazole/Trimethoprim DS\t\n1 Intensive IV antibiotic therapy does not include days of ineffective antibiotic treatment for B. pseudomallei (days 1–3). DS—double strength; 800 mg sulfamethoxazole/160 mg trimethoprim); Q—every, H—hours (Q12H—every 12 h). 2 Identification and susceptibility testing for these cultures did not result until day 13 of hospital admission.\n==== Refs\nReferences\n1. Melioidosis Centers for Disease Control and Prevention Available online: https://www.cdc.gov/melioidosis/index.html (accessed on 1 December 2018) \n2. Lipsitz R. Garges S. Aurigemma R. Baccam P. Blaney D.D. Cheng A.C. Currie B.J. Dance D. Gee J.E. Larsen J. Workshop on treatment of and postexposure prophylaxis for Burkholderia pseudomallei and, B. mallei Infection Emerg. Infect. Dis. 2012 18 e2 10.3201/eid1812.120638 23171644 \n3. Currie B.J. Melioidosis: Evolving concepts in epidemiology, pathogenesis, and treatment Semin. Respir. Crit. Care Med. 2015 36 111 125 10.1055/s-0034-1398389 25643275 \n4. Zueter A. Yean C.Y. Abumarzouq M. Rahman Z.A. Deris Z.Z. Harun A. The epidemiology and clinical spectrum of melioidosis in a teaching hospital in a North-Eastern state of Malaysia: A fifteen-year review BMC Infect. Dis. 2016 16 333 10.1186/s12879-016-1583-2 27423906 \n5. Simpson A.J. Suputtamongkol Y. Smith M.D. Angus B.J. Rajanuwong A. Wuthiekanun V. Howe P.A. Walsh A.L. Chaowagul W. White N.J. Comparison of imipenem and ceftazidime as therapy for severe melioidosis Clin. Infect. Dis. 1999 29 381 387 10.1086/520219 10476746 \n6. Barman P. Sidhwa H. Shirkhande P.A. Melioidosis: A Case Report J. Glob. Infect. Dis. 2011 3 183 186 10.4103/0974-777X.81697 21731307 \n7. Pitman M.C. Luck T. Marshall C.S. Anstey N.M. Ward L. Currie B.J. Intravenous Therapy Duration and Outcomes in Melioidosis: A New Treatment Paradigm PLoS Negl. Trop. Dis. 2015 9 e0003586 10.1371/journal.pntd.0003586 25811783 \n8. Cheng J.W. Hayden M.K. Singh K. Heimler I. Gee J.E. Proia L. Sha B.E. Burkholderia pseudomallei Infection in US Traveler Returning from Mexico, 2014 Emerg. Infect. Dis. 2015 21 1884 1885 10.3201/eid2110.150815 26401597 \n9. White N.J. Dance D.A.B. Chaowagul W. Wattanagoon Y. Wuthiekanun V. Pitakwatchara N. Halving of mortality of severe melioidosis by ceftazidime Lancet 1989 2 697 701 10.1016/S0140-6736(89)90768-X 2570956 \n10. Chierakul W. Anunnatsiri S. Chaowagul W. Peacock S.J. Chetchotisakd P. Day N.P. Addition of Trimethoprim-Sulfamethoxazole to Ceftazidime during Parenteral Treatment of Melioidosis Is Not Associated with a Long-Term Outcome Benefit Clin. Infect. Dis. 2007 15 521 523 10.1086/520010 17638209 \n11. Chantratita N. Rholl D.A. Sim B. Wuthiekanun V. Limmathurotsakul D. Amornchai P. Thanwisai A. Chua H.H. Ooi W.F. Holden M.T. Antimicrobial resistance to ceftazidime involving loss of penicillin-binding protein 3 in, B. pseudomallei Proc. Natl. Acad. Sci. USA 2011 1 17165 17170 10.1073/pnas.1111020108 21969582 \n12. Cheng A.C. Fisher D.A. Anstey N.M. Stephens D.P. Jacups S.P. Currie B.J. Outcomes of Patients with Melioidosis Treated with Meropenem Antimicrob. Agents Chemother. 2004 48 1763 1765 10.1128/AAC.48.5.1763-1765.2004 15105132 \n13. Dance D. Treatment and prophylaxis of melioidosis Int. J. Antimicrob. Agents 2014 43 310 318 10.1016/j.ijantimicag.2014.01.005 24613038 \n14. Clinicaltrials.gov A Randomized Double Blinded Comparison of Ceftazidime and Meropenem in Severe Melioidosis (ATOM) NCT00579956 Available online: https://clinicaltrials.gov/ct2/show/NCT00579956?cond=melioidosis&rank=3. (accessed on 16 January 2019) \n15. Limmathurotsakul D. Wuthiekanun V. Wongsuvan G. Pangmee S. Amornchai P. Teparrakkul P. Repeat blood culture positive for, B. pseudomallei indicates an increased risk of death from melioidosis Am. J. Trop. Med. Hyg. 2011 84 858 861 10.4269/ajtmh.2011.10-0618 21633019 \n16. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc. Available online: https://www.wolterskluwercdi.com/clinical-drug-information/ (accessed on 18 January 2019)\n\n",
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"title": "Persistent Burkholderia pseudomallei Bacteremia in A Filipino Immigrant to the United States: A Case Report.",
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"abstract": "After failure of anthracycline- and platinum-based therapy, no effective therapies exist for management of metastatic triple-negative breast cancer (TNBC). We report a case of metastatic TNBC harboring MCL1 amplification, as identified by comprehensive genomic profiling in the course of clinical care. MCL1 is an antiapoptotic gene in the BCL2 family, and MCL1 amplification is common in TNBC (at least 20%). A personalized dose-reduced regimen centered on a combination of sorafenib and vorinostat was implemented, based on preclinical evidence demonstrating treatment synergy in the setting of MCL1 amplification. Although hospice care was being considered before treatment initiation, the personalized regimen yielded 6 additional months of life for this patient. Further rigorous studies are needed to confirm that this regimen or derivatives thereof can benefit the MCL1-amplified subset of TNBC patients.",
"affiliations": "Foundation Medicine Inc., Cambridge, Mass., USA.;Arlington Cancer Center, Arlington, Tex., USA.;Foundation Medicine Inc., Cambridge, Mass., USA.;Foundation Medicine Inc., Cambridge, Mass., USA.;Foundation Medicine Inc., Cambridge, Mass., USA.;Foundation Medicine Inc., Cambridge, Mass., USA; Albany Medical College, Albany, N.Y., USA.;Arlington Cancer Center, Arlington, Tex., USA.",
"authors": "Ali|Siraj M|SM|;Watson|Jessica|J|;Wang|Kai|K|;Chung|Jon H|JH|;McMahon|Caitlin|C|;Ross|Jeffrey S|JS|;Dicke|Karel A|KA|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000443371cro-0009-0112Published online: February, 2016A Combination of Targeted Therapy with Chemotherapy Backbone Induces Response in a Treatment-Resistant Triple-Negative MCL1-Amplified Metastatic Breast Cancer Patient Ali Siraj M. aWatson Jessica bWang Kai aChung Jon H. aMcMahon Caitlin aRoss Jeffrey S. acDicke Karel A. b*aFoundation Medicine Inc., Cambridge, Mass., USAbArlington Cancer Center, Arlington, Tex., USAcAlbany Medical College, Albany, N.Y., USA*Karel A. Dicke, MD, PhD Arlington Cancer Center 906 West Randol Mill Rd Arlington, TX 76012 (USA) E-Mail precisionmedicinekd@gmail.comJan-Apr 2016 18 2 2016 18 2 2016 9 1 112 118 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.After failure of anthracycline- and platinum-based therapy, no effective therapies exist for management of metastatic triple-negative breast cancer (TNBC). We report a case of metastatic TNBC harboring MCL1 amplification, as identified by comprehensive genomic profiling in the course of clinical care. MCL1 is an antiapoptotic gene in the BCL2 family, and MCL1 amplification is common in TNBC (at least 20%). A personalized dose-reduced regimen centered on a combination of sorafenib and vorinostat was implemented, based on preclinical evidence demonstrating treatment synergy in the setting of MCL1 amplification. Although hospice care was being considered before treatment initiation, the personalized regimen yielded 6 additional months of life for this patient. Further rigorous studies are needed to confirm that this regimen or derivatives thereof can benefit the MCL1-amplified subset of TNBC patients.\n\nKey Words\nMCL1Triple-negative breast cancerBAP1EverolimusSorafenib\n==== Body\nCase Presentation\nA 51-year-old female was diagnosed in November 2008 with stage IIA, N0, M0, ER-/PR-, HER2-negative breast cancer with two lumpectomies. She received six rounds of cyclophosphamide and docetaxel from December 2008 to March 2009, followed by irradiation to the left breast in April/May 2009. She remained disease free for 2 years and then had a recurrence in the left breast in September 2011. The patient received two rounds of doxorubicin and paclitaxel, but she did not respond. In November 2011, she received carboplatin/nab-paclitaxel without response. In December 2011, a left total mastectomy was performed demonstrating a poorly differentiated breast adenocarcinoma measuring 7.1 cm in the greatest dimension located centrally in the specimen and with clear margins. The tumor was Nottingham grade 3, with lymphovascular invasion but no evidence of nipple and skin involvement. The left central node was identified and assessed as free of tumor, demarcating this as T3, N0, (clinical) M0 disease and as stage IIB, node-negative and triple-negative breast cancer (TNBC).\n\nOver the next 2 months, the patient received two rounds of gemcitabine and carboplatin with additional irradiation to the skin on the left side. Six months later, PET scan imaging revealed suspicious lesions in the right (contralateral) breast with suspicious foci also in the operative site on the left. A right mastectomy was performed in March 2012, and the patient received four cycles of eribulin. Two months later, biopsy of the left neck was performed revealing metastatic carcinoma. Subsequent PET scan then revealed lesions in the axial skeleton consistent with metastatic disease.\n\nHaving exhausted standard-of-care treatment, the patient was entered into three clinical trials serially utilizing NOTCH inhibitors, MEK inhibitors, and a trial utilizing a CDK4/6 dual inhibitor. After rapid failure of each investigational agent in the course of 1 year, a CT performed on April 17, 2013, showed greater than 50% liver involvement of tumor; other sites also involved were the lymph nodes, lung, and skeletal systems. On May 9, 2013, the patient came to the Arlington Cancer Center for a fourth clinical opinion. At that time, tumor involvement in the liver had increased to greater than 85% per CT scan, and because of rapid progression in the liver, life expectancy was estimated to be 1 month. Earlier that year a breast tissue specimen was submitted for comprehensive genomic profiling which was used by us to identify options for treatment as all standard-of-care and clinical trials had been exhausted (see Methods). On May 14, 2013, personalized treatment based on the genomic profile of the tumor was initiated.\n\nMethods\nWith patient permission, the left primary mastectomy specimen was submitted for comprehensive genomic profiling (FoundationOne), performed in a CLIA-certified, CAP-accredited, NYS-regulated laboratory (Foundation Medicine). DNA extracted from formalin-fixed paraffin-embedded tumor was analyzed by hybridization capture of 3,320 exons from 186 cancer-related genes and 37 introns of 14 genes commonly rearranged in cancer. At least 50 ng of DNA was isolated and sequenced to high, uniform coverage, as previously described [1]. All classes of genomic alterations (GA) consisting of base substitutions, short insertions, and deletions, focal gene amplifications, homozygous deletions, and select rearrangements were determined and reported for this case. Clinically relevant GA (CRGA) were defined as those which suggest benefit from targeted therapies, or mechanism-based clinical trials. Tumor response was measured by PET/CT and CT scans throughout the treatment.\n\nResults\nHybrid capture-based CGP demonstrated that the tumor harbored MCL1 amplification and base substitutions in BAP1 C649fs*6 (a truncating alteration) and a TP53 (a splice site mutation). On the basis of the genomic profiling results, the patient was treated with an intensive personalized multidrug regimen with targeted therapy including sorafenib (Nexavar) and vorinostat (Zolinza) to target MCL1 [2, 3, 4, 5, 6], everolimus (Afinitor), cetuximab (Erbitux) to specifically target the mTOR and EGFR pathways [7, 8], as well as the chemotherapeutic agent nab-paclitaxel (Abraxane), which was selected by biomarker testing (SPARC poly- and monoclonal antibodies [9]), and denosumab (Xjeva), a RANKL binder, was added for bone metastases [10, 11] (table 1). Eight courses (C) were administered with variable dosing of vorinostat, sorafenib, and nab-paclitaxel. Dosing for each agent was altered on the basis of toxicity during treatment as observed by the treating physician.\nC1 showed a major response in the liver, lung, and lymph nodes, but not in the skeletal system (fig. 1). Toxicity was noted, mainly weakness, GI toxicity consisting of nausea, vomiting, and diarrhea, and bone marrow toxicity consisting of anemia, thrombocytopenia and neutropenia (grade 3). Platelets were kept artificially above 70,000/m3 to avoid severe nose bleeding by sorafenib, and hemoglobin was kept above 8 g/100 ml to avoid fatigue due to anemia. Still there was significant total overall weakness, and the patient needed treatment respite of 4 weeks. After 4 weeks of rest, significant progression of disease was noted in the skeletal system, so denosumab was added to the previous regimen and then maintained throughout future courses. C2 was started and in order to decrease toxicity, we shortened the length of treatment from 6 weeks to 3 weeks. Response was shown in C2, but not as profound as after C1. The doses of vorinostat and sorafenib were increased in C3,4. A significant overall response was observed. However, side effects significantly increased including weakness, diarrhea, nausea, vomiting and bone marrow toxicities. In C5 vorinostat was held, and the other drugs including sorafenib were decreased by 25%. Disease progression was observed in this cycle. In C6 vorinostat was restarted at lower dose, and sorafenib and the other drugs were continued at the same level as C5, resulting in stabilization of disease, including osseous metastases. In C7 vorinostat and sorafenib were further increased, which resulted in overall decrease of disease. However, toxicity was significant and the treatment was interrupted for 1 month and the patient's disease further progressed. C8 was started with lower doses of sorafenib, vorinostat, and nab-paclitaxel. Due to weakness and GI toxicity, treatment was discontinued at patient's request, and the patient expired thereafter.\n\nDiscussion\nTNBC is an aggressive disease defined as breast carcinoma with negative slide-based assays for estrogen, progesterone receptor and HER2. Consistent with being a diagnosis of exclusion, TNBC is widely understood to encompass significant genomic heterogeneity [12]. Alterations in BRCA1/2 that create defects in homologous recombination define an important subset of TNBC with sensitivity to first-line platinum treatment and PARP inhibitors, but for the remaining majority of TNBC not harboring BRCA alterations, no particular benefit can be ascribed to such therapies [13].\n\nThe metastatic TNBC case reported here harbored amplification of MCL1, and a truncating mutation in BAP1, as well as a mutated TP53. MCL1, a member of the BCL2 antiapoptotic gene family is amplified in 20–54% of TNBC cases [14]. Amplification of MCL1 is thought to interfere with the physiologic induction of apoptosis, which is broadly consistent with a role in oncogenesis [15]. MCL1 amplification is one of three alterations observed in this tumor, potentially empirically consistent with this alteration being an oncogenic driver. Given the assumption of MCL1 amplification serving as an oncogenic driver, no molecularly targeted therapies specific to this alteration are known to exist at present, highlighting a large unmet medical need in this subset of MCL1-amplified TNBC patients with a poor prognosis.\n\nSorafenib is a promiscuous multikinase inhibitor that has defied ready characterization of its antineoplastic in vivo effect. Preclinical studies have demonstrated that sorafenib can induce cell death/apoptosis mediated by the downregulation of MCL1, but it remains to be definitively demonstrated whether this is the relevant effect of sorafenib [2, 3]. Interestingly, a synergy of co-administration of sorafenib and vorinostat, a histone deacetylase inhibitor has been observed, and this proapoptotic effect is also thought to be routed through MCL1 [4, 5, 6].\n\nFor this patient, the clinical benefit of the regimen was quite remarkable, and the ‘dropout’ of individual therapies does hint at the relevant importance of each component. However, it is impossible to define the most important components, and relevance of each therapy vis-à-vis the GA. Sorafenib has previously been investigated as a combination therapy in breast cancer, typically with a chemotherapy backbone, but differing conclusions as to clinical benefit have been reached, and definitive studies are ongoing [15, 16]. In such studies, even if biomarker stratification was performed, no genomic stratification was used as criteria for entry, so responders to sorafenib cannot be segregated on the basis of MCL1 amplifications or other alterations [17].\n\nNo anecdotal clinical reports or completed clinical trials are currently available to guide treatment for MCL1-amplified breast cancers. The personalized treatment regimen utilized here resulted in the patient experiencing 6 months of extended survival. The administration of sorafenib and vorinostat in the presence of the MCL1 amplification is essential to the success of this program. Given the high frequency of MCL1 amplification in TNBC, the current case study potentially suggests that other such patients might benefit from a similar treatment regimen.\n\nThe importance of vorinostat and sorafenib is supported by results of C5 when a decreased dose of sorafenib and deletion of vorinostat led to progression of disease, furthermore by results of C6 which stabilized disease when vorinostat was reintroduced. In C7 there was additional disease response when raising the dosage of the 2 drugs. In contrast to other cycles in which dropout of other agents, e.g., everolimus, were still effective in inducing disease response.\n\nIn conclusion, the efficacy of sorafenib and vorinostat in combination with a backbone of other nontargeted therapies in this MCL1-amplified TNBC is a provocative observation that warrants additional investigation, as at present, MCL1-amplified TNBC patients are unable to benefit from molecular targeted therapy in current practice paradigms.\n\nStatement of Ethics\nThe patient and her husband gave informed consent to Dr. Karel Dicke at the time of treatment protocol, after full disclosure of risks, side effects and potential benefit.\n\nDisclosure Statement\nS.M.A., C.M., J.H.C., and J.S.R. are employees of and have equity interest in Foundation Medicine, Inc. K.W. is a former employee of, current consultant to, and has equity interest in Foundation Medicine, Inc. J.W. and K.D. have nothing to declare.\n\nFig. 1 Left: PET scan 5/14/2013 before treatment shows hepatomegaly with intense hypermetabolic FDG accumulation (SUV up to 20) throughout the entire liver with very low areas of normal hepatic parenchyma. Right: PET scan 6/27/13 after C1 shows subsided hepatomegaly and decrease of liver metastases with a decrease in FDG activity (SUV between 4 and 6).\n\nTable 1 Treatment program\n\nTarget\t\tDrug\tDose range\t\nEnhance apoptosis by targeting MCL-1\t\n[4, 5, 6]\tHistone deacetylase inhibitor/MCL-1\tZolinza (vorinostat)\t200–600 mg/day\t\n[2, 3]\tMultiple receptor tyrosine kinases/MCL-1\tNexavar (sorafenib)\t200–800 mg/day\t\n\t\nInhibition of mitosis (i.e. killing)\t\n[9]\tAntimicrotubule agent/SPARC\tAbraxane (nab-paclitaxel)\t50–75 mg/m2 weekly\t\n\t\nSilencing the proliferation pathway\t\n[16]\tEGFR inhibitor\tErbitux (cetuximab)\t250 mg/kg weekly\t\n[17]\tmTOR inhibitor/rapamycin analogue\tAffinitor (everolimus)\t5 mg/day\t\n\t\nOsteoclast activity mediation\t\n[10, 11]\tRANKL binder\tXjeva (denosumab)\t120 mg every 4 weeks\n==== Refs\nReferences\n1 Frampton GM Fichtenholtz A Otto GA Wang K Downing SR He J Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing Nat Biotechnol 2013 31 1023 1031 24142049 \n2 Fecteau J-F, Bharati IS O'Hayre M Handel TM Kipps TJ Messmer D Sorafenib-induced apoptosis of chronic lymphocytic leukemia cells is associated with downregulation of RAF and myeloid cell leukemia sequence 1 (Mcl-1) Mol Med Camb Mass 2012 18 19 28 21979753 \n3 Abdulghani J Allen JE Dicker DT Liu YY Goldenberg D Smith CD Sorafenib sensitizes solid tumors to Apo2L/TRAIL and Apo2L/TRAIL receptor agonist antibodies by the Jak2-Stat3-Mcl1 axis PloS One 2013 8 e75414 \n4 Dasmahapatra G Yerram N Dai Y Dent P Grant S Synergistic interactions between vorinostat and sorafenib in chronic myelogenous leukemia cells involve Mcl-1 and p21CIP1 down-regulation Clin Cancer Res Off J Am Assoc Cancer Res 2007 13 4280 4290 \n5 Park MA Zhang G Martin AP Hamed H Mitchell C Hylemon PB Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation Cancer Biol Ther 2008 7 1648 1662 18787411 \n6 Park MA Mitchell C Zhang G Yacoub A Allegood J Häussinger D Vorinostat and sorafenib increase CD95 activation in gastrointestinal tumor cells through a Ca(2+)-de novo ceramide-PP2A-reactive oxygen species-dependent signaling pathway Cancer Res 2010 70 6313 6324 20631069 \n7 Pirker R Pereira JR von Pawel J EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study Lancet Oncol 2012 13 33 42 22056021 \n8 Baselga J Campone M Everolimus in postmenopausal hormone-receptor-positive advance breast cancer N Eng J Med 2012 366 520 529 \n9 Desai N Trieu V SPARC expression correlates with tumor response to albumin-bound paclitaxel in head and neck cancer patients Transl Oncol 2009 2 59 64 19412420 \n10 Roodman GD Mechanisms of bone metastasis N Engl J Med 2004 350 1655 1664 15084698 \n11 Mundy GR Metastasis to bone: causes, consequences and therapeutic opportunities Nat Rev Cancer 2002 2 584 593 12154351 \n12 Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours Nature 2012 490 61 70 23000897 \n13 Lord CJ Ashworth A Mechanisms of resistance to therapies targeting BRCA-mutant cancers Nat Med 2013 19 1381 1388 24202391 \n14 Balko JM Giltnane JM Wang K Schwarz LJ Young CD Cook RS Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets Cancer Discov 2014 4 232 245 24356096 \n15 Haschka MD Soratroi C Kirschnek S Häcker G Hilbe R Geley S The NOXA-MCL1-BIM axis defines lifespan on extended mitotic arrest Nat Commun 2015 6 6891 25922916 \n16 Gradishar WJ Kaklamani V Sahoo TP Lokanatha D Raina V Bondarde S A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer Eur J Cancer 2013 49 312 322 22954665 \n17 Baselga J Segalla JGM Roché H Del Giglio A Pinczowski H Ciruelos EM Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer J Clin Oncol Off J Am Soc Clin Oncol 2012 30 1484 1491\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "9(1)",
"journal": "Case reports in oncology",
"keywords": "BAP1; Everolimus; MCL1; Sorafenib; Triple-negative breast cancer",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "112-8",
"pmc": null,
"pmid": "27293397",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "24202391;12154351;22149876;22412143;18787411;15084698;17634558;24086526;21979753;24142049;19412420;25922916;23000897;20631069;22056021;22954665;24356096",
"title": "A Combination of Targeted Therapy with Chemotherapy Backbone Induces Response in a Treatment-Resistant Triple-Negative MCL1-Amplified Metastatic Breast Cancer Patient.",
"title_normalized": "a combination of targeted therapy with chemotherapy backbone induces response in a treatment resistant triple negative mcl1 amplified metastatic breast cancer patient"
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"abstract": "Malignant psoas syndrome (MPS) is a rare clinical condition caused by cancer invasion of the iliopsoas muscle and has very poor prognosis. We report a case involving a 58-year-old woman with bilateral MPS caused by advanced bladder cancer. Rapid progress of a severe crouching posture with multiple deep venous thromboses was an important symptom of this case. Although 4 cycles of chemotherapy were administered, the patient died 8 months following disease onset. Since, these noteworthy symptoms have never been previously reported, in this report, we present the characteristic physical findings using photographs and cancer-related events that occur in MPS.",
"affiliations": "Division of Urology, Department of Surgery, Faculty of Medical Sciences, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, Postal cord: 910-1193, Japan.;Division of Urology, Department of Surgery, Faculty of Medical Sciences, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, Postal cord: 910-1193, Japan.;Division of Urology, Department of Surgery, Faculty of Medical Sciences, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, Postal cord: 910-1193, Japan.;Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, Postal cord: 910-1193, Japan.;Division of Urology, Department of Surgery, Faculty of Medical Sciences, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, Postal cord: 910-1193, Japan.",
"authors": "Tsuchiyama|Katsuki|K|;Ito|Hideaki|H|;Seki|Masaya|M|;Inai|Kunihiro|K|;Yokoyama|Osamu|O|",
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"doi": "10.1016/j.eucr.2019.100958",
"fulltext": "\n==== Front\nUrol Case RepUrol Case RepUrology Case Reports2214-4420Elsevier S2214-4420(19)30225-610.1016/j.eucr.2019.100958100958OncologyAdvanced bladder cancer with malignant psoas syndrome: A case report with a focus on physical findings and complications Tsuchiyama Katsuki tttuti@u-fukui.ac.jpa∗Ito Hideaki uroito@u-fukui.ac.jpaSeki Masaya mseki@u-fukui.ac.jpaInai Kunihiro kinai@u-fukui.ac.jpbYokoyama Osamu oyoko@u-fukui.ac.jpaa Division of Urology, Department of Surgery, Faculty of Medical Sciences, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, Postal cord: 910-1193, Japanb Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, Postal cord: 910-1193, Japan∗ Corresponding author. tttuti@u-fukui.ac.jp02 7 2019 9 2019 02 7 2019 26 10095822 6 2019 1 7 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Malignant psoas syndrome (MPS) is a rare clinical condition caused by cancer invasion of the iliopsoas muscle and has very poor prognosis. We report a case involving a 58-year-old woman with bilateral MPS caused by advanced bladder cancer. Rapid progress of a severe crouching posture with multiple deep venous thromboses was an important symptom of this case. Although 4 cycles of chemotherapy were administered, the patient died 8 months following disease onset. Since, these noteworthy symptoms have never been previously reported, in this report, we present the characteristic physical findings using photographs and cancer-related events that occur in MPS.\n\nKeywords\nMalignant psoas syndromeBladder cancerAbbreviations\nMPS, malignant psoas syndrome\n==== Body\nIntroduction\nMalignant psoas syndrome (MPS) is a rare cancer-associated complication caused by tumor infiltration to the iliopsoas muscle.1 Painful fixed flexion of the hip joint and lumbosacral plexopathy are important signs of MPS. Many of the MPS-related case reports mention the importance of palliative treatment for refractory cancer pain.1, 2, 3 It has also been pointed out that the diagnosis of MPS may be delayed because many medical personnel are unaware of the syndrome and its characteristic symptoms.2 We report a case of bilateral MPS involving severe symptoms, with a focus on characteristic physical findings and cancer-related events caused by MPS.\n\nCase presentation\nA 58-year-old woman visited the orthopedic department of our hospital presenting with a one month-history of a gait disorder with right leg pain. Intense pain and fixed flexion of the right hip joint was noted. She was unable to stand and walk independently at the first visit. Computed tomography (CT) revealed a muscle-invasive bladder tumor (Fig. 1A) and extensive metastatic lesions invading the iliopsoas muscle (Fig. 1B); she was then referred to our department.Fig. 1 (A, B, C) Computed tomography at the first visit showing a thrombus in the inferior vena cava (red arrow); (D) Computed tomography after 4 cycles of chemotherapy. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 1\n\nCystoscopy showed large, solid, non-papillary tumors from the posterior wall to the right-sided wall of the bladder. Transurethral resection was performed for pathological diagnosis which revealed high-grade urothelial carcinoma. Systemic chemotherapy with gemcitabine and carboplatin was administered, due to her renal hypofunction caused by hydronephrosis. In addition, extensive deep venous thromboses (DVT) were observed below the inferior vena cava (Fig. 1C); therefore, anticoagulation therapy using warfarin was initiated.\n\nAfter 2 cycles of chemotherapy, the tumor size (diameter) reduced by 10%. However, after 2 additional cycles of chemotherapy, a marked increase in tumor size was observed (Fig. 1D); an increase in DVT was also noted. The contracture of the bilateral hip joint was exacerbated; therefore, the patient was unable to sit on the bed without assistance due to discomfort (Fig. 2A). Chemotherapy was discontinued due to cancer progression. She died 2 months after chemotherapy termination (8 months post-onset).Fig. 2 (A) Photograph of the patient at the end of chemotherapy. (B) Macroscopic view of excessive flexion of lower extremities just before postmortem investigation.\n\nFig. 2\n\nWe performed an autopsy to investigate the reasons for rapid cancer progression and flexion contractures of the hip joints (Fig. 2B). Fig. 3A shows the spread of a disseminated tumor in the retroperitoneal cavity. Macroscopically, the tumor consisted of numerous lymph nodes sized ≤1 cm; these lymph nodes fused with and replaced the psoas major muscle. Histopathologically, the tumor was a poorly differentiated urothelial carcinoma showing differentiation into squamous cell carcinoma and adenocarcinoma with signet ring cells (Fig. 3B and C).Fig. 3 (A) Horizontal section at the level of the kidneys showing multiple extraperitoneal lymph nodes (red arrowheads). (B) Microscopic examination of a hematoxylin–eosin-stained specimen showing an area of differentiation into squamous cell carcinoma and (C) an area of differentiation into adenocarcinoma. Ao: aorta; IVC: inferior vena cava.. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 3\n\nDiscussion\nThe major characteristics of MPS are i) lumbosacral plexopathy, ii) painful hip flexion, and iii) malignant involvement of the psoas major muscle. Since the first report of an MPS case by Stevens et al., in 1990, 40 cases, including ours, have been reported in the English literature.1 MPS has a very poor prognosis because it occurs in the advanced stages of cancer; many cases have reported a prognosis for survival of 0.5–36 months after MPS diagnosis. Refractory pain due to cancer invasion is often involved, and many reports have mentioned the importance of palliative treatment for cancer pain. However, few case reports have described the characteristic physical findings or psoas muscle invasion-related symptoms observed in patients with MPS.\n\nIn this report, Fig. 2A and B provide visual references demonstrated the characteristic physical posture observed in patients with MPS. Because the patient's bilateral hip joints were strongly flexed, she had to spend time in a crouching position. The autopsy revealed that metastatic lymph node cancer had spread not only to the iliopsoas muscle but also to the entire pelvis, with remnants of little muscle fibers. Such extensive spread of the disease was considered to be a reason for severe flexion and contraction of the bilateral hip joint.\n\nIn this case, the tumor put pressure on the inferior vena cava, causing an extensive DVT on the caudal side of the tumor. The risk of coagulopathy has been reported to increase in patients with advanced cancers. Patients may develop cerebral embolization, venous thrombosis or other symptoms resulting from cancer-related hypercoagulation, referred to as Trousseau's syndrome.4 In addition to cancer-associated thrombosis, direct compression of the inferior vena cava by the tumor in the iliopsoas muscle and long-term underlying conditions may increase thrombogenic risks in patients with MPS. Mizoguchi et al., reported that DVTs associated with colorectal cancer improved with use of anticoagulant therapy and tumor resection.5 However, providing treatments other than anticoagulation therapy to patients with MPS is difficult because of progressive disease. In this case, no improvement was observed in patients with DVT even after administering anticoagulation therapy. Therefore, the patient developed severe edema in both lower limbs, resulting in a further decrease in activities of daily living.\n\nConclusion\nWe presented the typical physiological findings and complications related to MPS. We suggest that attention be paid to not only cancer pain but also to other complications, such as DVTs, while treating patients with MPS. Furthermore, our findings show that these cancer-related events can occur in a short period.\n\nConflicts of interest\nNone.\n\nConsent\nWritten informed consent was obtained from the patient's family.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgements\nNone.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.eucr.2019.100958.\n==== Refs\nReferences\n1 Stevens M.J. Gonet Y.M. Malignant psoas syndrome: recognition of an oncologic entity Australas Radiol 34 1990 150 154 2241667 \n2 Takamatsu S. Murakami K. Takaya H. Malignant psoas syndrome associated with gynecological malignancy: three case reports and a review of the literature Mol Clin Oncol 9 2018 82 86 29977543 \n3 Ampil F.L. Lall C. Datta R. Palliative management of metastatic tumors involving the psoas muscle: case reports and review of the literature Am J Clin Oncol 24 2001 313 314 11404508 \n4 Trousseau A. Plegmasia alba dolens Clinique Medicale de l'Hotel-Dieu Paris 3 1865 654 712 \n5 Mizoguchi S. Sawai T. Hirota A. Trousseau's syndrome causing refractory deep venous thrombosis Intern Med 57 2018 623 626 29225244\n\n",
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"issn_linking": "2214-4420",
"issue": "26()",
"journal": "Urology case reports",
"keywords": "Bladder cancer; MPS, malignant psoas syndrome; Malignant psoas syndrome",
"medline_ta": "Urol Case Rep",
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"nlm_unique_id": "101626357",
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"pages": "100958",
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"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": "11404508;2241667;29225244;29977543",
"title": "Advanced bladder cancer with malignant psoas syndrome: A case report with a focus on physical findings and complications.",
"title_normalized": "advanced bladder cancer with malignant psoas syndrome a case report with a focus on physical findings and complications"
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"abstract": "BACKGROUND\nProsthetic joint infections remain a significant cause of morbidity and are frustrating for patients and physicians alike. Unusual causes of infection may be seen in selected circumstances and a high index of suspicion and a careful history are required to ensure an accurate and timely diagnosis can be made.\n\n\nMETHODS\nWe present a case of Mycobacterium bovis prosthetic joint infection secondary to intravesicular Bacillus Calmette-Guérin (BCG) treatment for prior bladder cancer definitively identified by spoligotyping. A favorable clinical outcome was observed following surgical intervention and a 12-month course of anti-mycobacterial therapy.\n\n\nCONCLUSIONS\nBCG therapy, a live attenuated strain of M. bovis, has become the mainstay of adjunctive therapy for bladder cancer and infectious complications, including those affecting the musculoskeletal system, may be seen years after initial therapy. An awareness of this complication and appropriate discussions with the institution's microbiology laboratory may allow for an accurate and timely identification.",
"affiliations": "University of California Davis Medical Center, Sacramento, CA, USA.;Department of Orthopedics, University of California Davis Medical Center, Sacramento, CA, USA.;Department of Medical Microbiology and Immunology, University of California - Davis, University of California Davis Medical Center, Sacramento, CA, USA. grthompson@ucdavis.edu.",
"authors": "Nguyen|Minh-Vu Hoang|MH|;Giordani|Mauro M|MM|;Thompson|George R|GR|http://orcid.org/0000-0001-8518-5750",
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"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 395110.1186/s12879-019-3951-1Case ReportThe double-edged sword - prosthetic joint infection following BCG treatment for bladder cancer: a case report Nguyen Minh-Vu Hoang mvunguyen@ucdavis.edu 1Giordani Mauro M. mauro.giordani@ucdmc.ucdavis.edu 2http://orcid.org/0000-0001-8518-5750Thompson George R. IIIgrthompson@ucdavis.edu 341 0000 0000 9752 8549grid.413079.8University of California Davis Medical Center, Sacramento, CA USA 2 0000 0000 9752 8549grid.413079.8Department of Orthopedics, University of California Davis Medical Center, Sacramento, CA USA 3 0000 0000 9752 8549grid.413079.8Department of Medical Microbiology and Immunology, University of California – Davis, University of California Davis Medical Center, Sacramento, CA USA 4 0000 0000 9752 8549grid.413079.8Department of Internal Medicine, Division of Infectious Diseases, University of California Davis Medical Center, Sacramento, CA 95817 USA 18 4 2019 18 4 2019 2019 19 3319 10 2018 3 4 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nProsthetic joint infections remain a significant cause of morbidity and are frustrating for patients and physicians alike. Unusual causes of infection may be seen in selected circumstances and a high index of suspicion and a careful history are required to ensure an accurate and timely diagnosis can be made.\n\nCase presentation\nWe present a case of Mycobacterium bovis prosthetic joint infection secondary to intravesicular Bacillus Calmette-Guérin (BCG) treatment for prior bladder cancer definitively identified by spoligotyping. A favorable clinical outcome was observed following surgical intervention and a 12-month course of anti-mycobacterial therapy.\n\nConclusions\nBCG therapy, a live attenuated strain of M. bovis, has become the mainstay of adjunctive therapy for bladder cancer and infectious complications, including those affecting the musculoskeletal system, may be seen years after initial therapy. An awareness of this complication and appropriate discussions with the institution’s microbiology laboratory may allow for an accurate and timely identification.\n\nKeywords\nProsthetic joint infectionBCGMycobacterium bovisissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nProsthetic joint infections remain a significant problem and affect 1–2% of all joint replacement surgeries [1]. The majority of these infections are caused by bacterial pathogens such as Staphylococcus aureus, gram-negative bacilli, or from mixed infections [2]. The diagnosis of less-common causes of infection requires a careful history and thoughtful discussions with the microbiology laboratory to ensure other potential etiologic agents can be sought and thereafter definitively identified.\n\nCase presentation\nA 90-year-old Hispanic male dairy farmer with a complex medical history notable for a left total hip arthroplasty (THA), bladder carcinoma in situ status-post intravesicular Bacillus Calmette-Guérin (BCG) (a live attenuated strain of Mycobacterium bovis) treatment, and chronic kidney disease who presented with subacute worsening pain of his left thigh. He had a THA placed thirty-one years previously. He had papillary bladder tumor status-post fulguration five years prior to admission with subsequent recurrence of bladder carcinoma in situ diagnosed a year later; he underwent six initial and six maintenance instillations of BCG treatment with remission of his bladder cancer.\n\nFour years after BCG therapy, the patient developed new-onset drainage from the left lateral thigh. This was followed by swelling of his entire left thigh with increasing purulent discharge and pain with movement. He subsequently experienced chills, rigors, and a fever of 101 °F the morning prior to admission. On presentation he was afebrile with normal vital signs. His exam was significant for an open wound on the lateral left thigh with purulent drainage and surrounding erythema. Pain was noted adduction of the left hip. Initial laboratory tests were notable for a white blood cell count of 10,200 cells/mm3, a C-reactive protein of 9.7 mg/dL, and sedimentation rate of 71 mm/hr. Radiograph of the left hip showed “extensive lucencies” around the left THA (Fig. 1).Fig. 1 Peri-prosthetic lucency consistent with long-standing infection\n\n\n\nThe patient underwent incision and drainage with an antibiotic spacer placed following admission. Wound, hip fluid, and abscess cultures obtained during irrigation and debridement were negative for bacterial pathogens, however given his history of prior BCG therapy the microbiology laboratory was asked to additionally perform mycobacterial cultures and these grew acid-fast bacilli (AFB) concerning for Mycobacterium tuberculosis complex. After a brief course of clindamycin, ceftriaxone, vancomycin, and metronidazole, he was started on isoniazid 300 mg PO daily, rifampin 600 mg PO daily, pyrazinamide 1500 mg daily, ethambutol 1200 mg daily, and Vitamin B6 50 mg PO daily. He was placed in temporary airborne isolation while he had three sputa assessed for active pulmonary tuberculosis, which were negative for Mycobacterium spp. Nucleic Acid Amplification Testing (Cepheid, Sunnyvale, California) detected Mtb complex in his hip fluid culture.\n\nSusceptibility testing for Mtb complex showed monoresistance to pyrazinamide, which was suggestive of M. bovis. As the patient had prior exposure to livestock and BCG therapy the isolate was further evaluated by spacer oligonucleotide typing (spoligotyping) and found by the California State Department of Health to be identical to that of the vaccine strain M. bovis BCG used previously in the treatment of his bladder cancer. The patient completed a 12 month course of rifampin, isoniazid and ethambutol without event and free of symptomatic, or radiographic recurrence.\n\nDiscussion and conclusions\nOur case illustrates an M. bovis prosthetic joint infection as a complication of intravesicular BCG therapy. M. bovis is a zoonotic mycobacteria related to Mtb known to cause tuberculosis in cattle, also known as bovine tuberculosis, and other animals. It is recently better known for its employment in modern medicine as the primary ingredient in the BCG vaccine that protects humans from Mtb infection and the intravesicular BCG therapy for bladder carcinoma. Despite our ability to harness this organism for potential therapeutic benefit, [3] it still retains its ability to cause human disease.\n\nM. bovis infects humans by either transmission from an infected animal or M. bovis-derived therapeutic intervention (BCG). Direct exposure to M. bovis-infected animals can lead to tuberculosis in humans; immunocompromised individuals are the most susceptible, notably those with human immunodeficiency virus co-infection [4]. Other risk factors pertinent to our case are Hispanic descent and other immunosuppressed states including chronic kidney disease [5]. Among those who are exposed to cattle a common route of transmission is ingestion of unpasteurized milk from an infected cow, but because of the advent of farming infection control and milk pasteurization, this has become less common [6]. Our patient was infected by his BCG therapy for his bladder carcinoma, which was confirmed by spoligotyping to differentiate from any potential M. bovis exposure he may have previously encountered as a dairy farmer.\n\nA wide range of BCG infections as complications from prior therapy for bladder carcinoma have been described [7–11]. Prosthetic joint infections are exceedingly rare, with few cases previously presented and none confirmed by spoligotyping/PCR as BCG [12–20]. The nine cases reviewed consist of middle-to-elderly age patients, eight of which were men, without specified ethnicity who had joint arthroplasties and bladder carcinoma needing instillations of BCG therapy. They generally present months to years after their last BCG instillation with worsening localized pain at the site of their arthroplasties and evidence of local bone lesions on radiograph [12, 14–20]. Only one case had a co-morbid immunosuppressive diagnosis (diabetes) [14], only one had systemic B-symptoms [18], and five had elevated serum measurements of acute phase reactants [13, 15–18]. All cases had microbiological confirmation of M. bovis and received appropriate anti-tuberculous treatment in addition to surgical source control. Our case is different than the prior cases as he is the first to have PCR confirmed BCG infection rather than probable infection with BCG (the presence of M. bovis in a patient with prior BCG).\n\nIdentifying an M. bovis infection is both clinically, radiographically, and microbiologically challenging because it is part of the Mtb complex with Mycobacterium tuberculosis, Mycobacterium africanum, and Mycobacterium microti [21]. Clinicians diagnose M. bovis in a similar approach to an Mtb infection. Radiographic findings can be non-specific and mimic malignancy, or other infectious causes necessitating a tissue diagnosis for confirmation [22]. initially with microscopy with AFB staining followed by culture and nucleic acid testing of pertinent specimens. Because M. bovis is innately resistant to pyrazinamide, it is often suggested based on monoresistance to pyrazinamide on susceptibility testing; more advanced molecular genetic testing is required for definitive diagnosis [23]. For this case, spoligotyping was employed to identify and confirm the etiology as BCG [24]. In addition to surgical source control needed for a prosthetic joint infection, treatment for BCG and other mycobacterial infections consists of rifampin, isoniazid, and ethambutol for 12 months [25, 26].\n\nIn summary, our case is an elderly man with confirmed BCG prosthetic joint infection from his prior intravesicular BCG therapy. Such complications are exceedingly rare and reinforce the need for a thorough history and a high index of suspicion to make an accurate diagnosis. Clinicians should suspect this infection in elderly or immunocompromised patients with an infected prosthesis and a history of intravesicular BCG therapy. If a mycobacterial culture grows Mtb complex with monoresistance to pyrazinamide, clinicians can consider spoligotyping to definitively diagnose BCG and trace the strain to its source.\n\nProsthetic joint infection from the BCG strain of M. bovis is a rare infectious complication of prior BCG therapy and requires a high-index of suspicion. A thorough history and working knowledge of unusual causes of prosthetic joint infection allowed for a rapid diagnosis and initiation of therapy.\n\nAbbreviations\nAFBAcid-fast bacilli\n\nBCGBacillus Calmette-Guérin\n\nPCRPolymerase chain reaction\n\nTHATotal hip arthroplasty\n\nAcknowledgements\nNone.\n\nFunding\nNone.\n\nAvailability of data and materials\nAll information used for the current report is available from the corresponding author.\n\nAuthors’ contributions\nMHN provided clinical care for the patient and wrote the manuscript, GRT and MMG provided clinical care for the patient and provided edits to the manuscript. All authors have read and approved the manuscript.\n\nEthics approval and consent to participate\nNot required.\n\nConsent for publication\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patient’s family. A copy of the consent form is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Osmon DR Berbari EF Berendt AR Lew D Zimmerli W Steckelberg JM Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America Clin Infect Dis 2013 56 e1 e25 10.1093/cid/cis803 23223583 \n2. Zimmerli W Trampuz A Ochsner PE Prosthetic-joint infections N Engl J Med 2004 351 1645 1654 10.1056/NEJMra040181 15483283 \n3. Lamm DL Efficacy and safety of bacille Calmette-Guerin immunotherapy in superficial bladder cancer Clin Infect Dis 2000 31 Suppl 3 S86 S90 10.1086/314064 11010830 \n4. LoBue PA Enarson DA Thoen CO Tuberculosis in humans and animals: an overview Int J Tuberc Lung Dis 2010 14 1075 1078 20819249 \n5. Gallivan M Shah N Flood J Epidemiology of human Mycobacterium bovis disease, California, USA, 2003-2011 Emerg Infect Dis 2015 21 435 443 10.3201/eid2103.141539 25693687 \n6. O'Reilly L.M. Daborn C.J. The epidemiology of Mycobacterium bovis infections in animals and man: A review Tubercle and Lung Disease 1995 76 1 46 10.1016/0962-8479(95)90591-X \n7. Steg A Adjiman S Debre B BCG therapy in superficial bladder tumours--complications and precautions Eur Urol 1992 21 Suppl 2 35 40 10.1159/000474920 \n8. Serretta V Although rare, severe complications following intravesical bacillus Calmette-Guerin treatment should not be overlooked Infect Dis (Lond) 2015 47 732 733 10.3109/23744235.2015.1055795 26169587 \n9. Gonzalez-Del Vecchio M Ruiz-Serrano MJ Gijon P Sanchez-Somolinos M de Egea V Garcia de Viedma D Differences between a probable and proven BCG infection following intravesical instillations: 16 years experience in a tertiary care hospital Diagn Microbiol Infect Dis 2016 85 338 343 10.1016/j.diagmicrobio.2016.04.006 27157988 \n10. Paterson DL Patel A Bacillus Calmette-Guerin (BCG) immunotherapy for bladder cancer: review of complications and their treatment Aust N Z J Surg 1998 68 340 344 10.1111/j.1445-2197.1998.tb04768.x 9631906 \n11. Gonzalez OY Musher DM Brar I Furgeson S Boktour MR Septimus EJ Spectrum of bacille Calmette-Guerin (BCG) infection after intravesical BCG immunotherapy Clin Infect Dis 2003 36 140 148 10.1086/344908 12522745 \n12. Chazerain P Desplaces N Mamoudy P Leonard P Ziza JM Prosthetic total knee infection with a bacillus Calmette Guerin (BCG) strain after BCG therapy for bladder cancer J Rheumatol 1993 20 2171 2172 \n13. Leach WJ Halpin DS Mycobacterium bovis infection of a total hip arthroplasty: a case report J Bone Joint Surg Br 1993 75 661 662 10.1302/0301-620X.75B4.8331128 8331128 \n14. Guerra CE Betts RF O'Keefe RJ Shilling JW Mycobacterium bovis osteomyelitis involving a hip arthroplasty after intravesicular bacille Calmette-Guerin for bladder cancer Clin Infect Dis 1998 27 639 640 10.1086/514714 9770167 \n15. Segal A Krauss ES Infected total hip arthroplasty after intravesical bacillus Calmette-Guerin therapy J Arthroplast 2007 22 759 762 10.1016/j.arth.2006.07.010 \n16. Reigstad O Siewers P A total hip replacement infected with mycobacterium bovis after intravesicular treatment with Bacille-Calmette-Guerin for bladder cancer J Bone Joint Surg Br. 2008 90 225 227 10.1302/0301-620X.90B2.20038 18256093 \n17. Srivastava A Ostrander J Martin S Walter N Mycobacterium bovis infection of total hip arthroplasty after intravesicular bacille Calmette-Guerin therapy Am J Orthop (Belle Mead NJ). 2011 40 E226 E228 22263218 \n18. Aitchison LP Jayanetti V Lindstrom ST Sekel R Myobacterium bovis peri-prosthetic hip infection with successful prosthesis retention following intravesical BCG therapy for bladder carcinoma Australas Med J 2015 8 307 314 10.4066/AMJ.2015.2475 26576201 \n19. Rispler DT Stirton JW Gilde AK Kane KR Mycobacterium bovid infection of total knee arthroplasty after bacille Calmette-Guerin therapy for bladder cancer Am J Orthop (Belle Mead NJ) 2015 44 E46 E48 25658082 \n20. Fouasson-Chailloux A Metayer B Menu P Khatchatourian L Glemarec J Dauty M Total hip arthroplasty infection due to Mycobacterium bovis, after BCG therapy Ann Phys Rehabil Med 2016 59s e112 10.1016/j.rehab.2016.07.250 \n21. Grange, John M, Yates, Malcolm D, Kantor, Isabel N. de and World Health Organization. Emerging and other Communicable Diseases, Surveillance and Control. Guidelines for speciation within the Mycobacterium tuberculosis complex / John M. Grange, Malcolm D. Yates and Isabel N. de Kantor, 2nd ed. Geneva : World Health Organization; 1996.\n22. Perez-Jacoiste Asin MA Fernandez-Ruiz M Lopez-Medrano F Lumbreras C Tejido A San Juan R Bacillus Calmette-Guerin (BCG) infection following intravesical BCG administration as adjunctive therapy for bladder cancer: incidence, risk factors, and outcome in a single-institution series and review of the literature Medicine 2014 93 236 254 10.1097/MD.0000000000000119 25398060 \n23. Hlavsa MC Moonan PK Cowan LS Navin TR Kammerer JS Morlock GP Human tuberculosis due to Mycobacterium bovis in the United States, 1995-2005 Clin Infect Dis 2008 47 168 175 10.1086/589240 18532886 \n24. Kamerbeek J Schouls L Kolk A van Agterveld M van Soolingen D Kuijper S Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology J Clin Microbiol 1997 35 907 914 9157152 \n25. Nahid P Dorman SE Alipanah N Barry PM Brozek JL Cattamanchi A Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America clinical practice guidelines: treatment of drug-susceptible tuberculosis Clin Infect Dis 2016 63 e147 e195 10.1093/cid/ciw376 27516382 \n26. LoBue PA Moser KS Treatment of Mycobacterium bovis infected tuberculosis patients: San Diego County, California, United States, 1994-2003 Int J Tuberc Lung Dis. 2005 9 333 338 15786900\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "19(1)",
"journal": "BMC infectious diseases",
"keywords": "BCG; Mycobacterium bovis; Prosthetic joint infection",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001170:Arthritis, Infectious; D001500:BCG Vaccine; D006615:Hip; D006801:Humans; D008297:Male; D009163:Mycobacterium bovis; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "331",
"pmc": null,
"pmid": "30999879",
"pubdate": "2019-04-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11010830;12522745;1396946;15483283;15786900;17689788;18256093;18532886;20819249;22263218;23223583;25398060;25658082;25693687;26169587;26576201;27157988;27516382;7579326;8014956;8331128;9157152;9631906;9770167",
"title": "The double-edged sword - prosthetic joint infection following BCG treatment for bladder cancer: a case report.",
"title_normalized": "the double edged sword prosthetic joint infection following bcg treatment for bladder cancer a case report"
} | [
{
"companynumb": "US-SA-2019SA119589",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
},
... |
{
"abstract": "Extraskeletal myxoid chondrosarcoma is a rare sarcoma with low sensitivity to cytotoxic chemotherapy. Retrospective evidence suggests that antiangiogenic drugs could be a treatment option. We aimed to investigate the activity of pazopanib, an antiangiogenic drug, in patients with advanced extraskeletal myxoid chondrosarcoma.\n\n\n\nIn this single-arm, open-label phase 2 trial, three parallel independent cohorts of different histotypes of advanced sarcomas were recruited (extraskeletal myxoid chondrosarcoma, typical solitary fibrous tumour, and malignant-dedifferentiated solitary fibrous tumour). In each cohort, patients received pazopanib. In this Article, we report the results of the cohort of patients with advanced extraskeletal myxoid chondrosarcoma. Separate reporting of the three cohorts was prespecified in the study protocol. In this cohort, adult patients (aged ≥18 years) with a diagnosis of NR4A3-translocated, metastatic, or unresectable extraskeletal myxoid chondrosarcoma, who had Response Evaluation Criteria in Solid Tumors (RECIST) progression in the previous 6 months, and had an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled at 11 study sites of the Spanish, Italian, and French sarcoma groups. Patients received oral pazopanib (800 mg/day) continuously, until disease progression, unacceptable toxicity, death, non-compliance, patient refusal, or investigator's decision. The primary endpoint was the proportion of patients achieving an objective response according to RECIST 1·1 in the modified intention-to-treat population (patients who provided consent and had a central molecularly confirmed diagnosis of extraskeletal myxoid chondrosarcoma). The safety analysis included all patients who received at least one dose of pazopanib. This study is registered with ClinicalTrials.gov, number NCT02066285.\n\n\n\nBetween June 24, 2014, and Jan 17, 2017, 26 patients entered the study and started pazopanib. Of these, 23 met the eligibility criteria for the modified intention-to-treat analysis. Median follow-up was 27 months (IQR 18-30). 22 patients (one patient died before the primary analysis) were evaluable for the primary endpoint: four (18% [95% CI 1-36]) had a RECIST objective response. No deaths or grade 4 adverse events occurred. The most frequent grade 3 adverse events were hypertension (nine [35%] of 26 patients), increased concentration of alanine aminotransferase (six [23%]), and increased aspartate aminotransferase (five [19%]).\n\n\n\nPazopanib had clinically meaningful antitumour activity in patients with progressive and advanced extraskeletal myxoid chondrosarcoma, and could be considered a suitable option after failure to respond to first-line anthracycline-based chemotherapy in these patients.\n\n\n\nSpanish Group for Research on Sarcomas, Italian Sarcoma Group, French Sarcoma Group, GlaxoSmithKline, and Novartis.",
"affiliations": "Department of Cancer Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy. Electronic address: silvia.stacchiotti@istitutotumori.mi.it.;Chemotherapy Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.;Department of Medical Oncology, University Hospital La Paz, Hospital La Paz Institute for Health Research, Madrid, Spain.;Department of Medical Oncology, University Hospital Virgen del Rocio, Seville, Spain; Institute of Biomedicine of Sevilla, Universidad de Sevilla, Seville, Spain.;Chemotherapy Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.;Department of Medical Oncology, University Hospital Ramón y Cajal, Madrid, Spain.;Department of Cancer Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy.;Department of Cancer Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy; Department of Medical Oncology and Hemato-Oncology, University of Milan, Milan, Italy.;Hematology Department, University Hospital Son Espases, Palma, Illes Baleares, Spain.;Department of Medical Oncology, Sant Pau Hospital, Barcelona, Spain.;Division of Medical Oncology, Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia, IRCCS, Candiolo, Italy.;Department of Oncology, Institut Bergonié, Bordeaux, France.;Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.;Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.;Department of Medical Oncology, Centre Léon Bérard, Lyon, France; Université Claude Bernard Lyon I, Lyon, France.;Medical Oncology Department, Centre Oscar Lambret, Lille, France.;Musculoskeletal Imaging Section, University Hospital La Paz, Hospital La Paz Institute for Health Research, Madrid, Spain.;Institute of Biomedicine of Sevilla, Universidad de Sevilla, Seville, Spain; Department of Pathology, University Hospital Virgen del Rocio, Seville, Spain.;Department of Pathology, Centre Léon Bérard, Lyon, France.;Department of Radiology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy.;Department of Diagnostic Pathology and Laboratory Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy.;Department of Diagnostic Pathology and Laboratory Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy.;Department of Research, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy.;Department of Research, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy.;Oncogenetics and Oncogenomics Unit, Centro di Riferimento Oncologico di Aviano IRCCS, Aviano, Italy.;Oncogenetics and Oncogenomics Unit, Centro di Riferimento Oncologico di Aviano IRCCS, Aviano, Italy.;Oncogenetics and Oncogenomics Unit, Centro di Riferimento Oncologico di Aviano IRCCS, Aviano, Italy.;Department of Diagnostic Pathology and Laboratory Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy.;Department of Medical Oncology, University Hospital of Canarias, Tenerife, Spain.;Department of Medical Oncology, University Hospital Virgen del Rocio, Seville, Spain; Institute of Biomedicine of Sevilla, Universidad de Sevilla, Seville, Spain.",
"authors": "Stacchiotti|Silvia|S|;Ferrari|Stefano|S|;Redondo|Andres|A|;Hindi|Nadia|N|;Palmerini|Emanuela|E|;Vaz Salgado|Maria Angeles|MA|;Frezza|Anna Maria|AM|;Casali|Paolo Giovanni|PG|;Gutierrez|Antonio|A|;Lopez-Pousa|Antonio|A|;Grignani|Giovanni|G|;Italiano|Antoine|A|;LeCesne|Axel|A|;Dumont|Sarah|S|;Blay|Jean Yves|JY|;Penel|Nicolas|N|;Bernabeu|Daniel|D|;de Alava|Enrique|E|;Karanian|Marie|M|;Morosi|Carlo|C|;Brich|Silvia|S|;Dagrada|Gian Paolo|GP|;Vallacchi|Viviana|V|;Castelli|Chiara|C|;Brenca|Monica|M|;Racanelli|Dominga|D|;Maestro|Roberta|R|;Collini|Paola|P|;Cruz|Josefina|J|;Martin-Broto|Javier|J|",
"chemical_list": "D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(19)30319-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "20(9)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002813:Chondrosarcoma; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D018204:Neoplasms, Connective and Soft Tissue; D011743:Pyrimidines; D012189:Retrospective Studies; D012983:Soft Tissue Neoplasms; D013449:Sulfonamides; D016896:Treatment Outcome",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "1252-1262",
"pmc": null,
"pmid": "31331701",
"pubdate": "2019-09",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pazopanib for treatment of advanced extraskeletal myxoid chondrosarcoma: a multicentre, single-arm, phase 2 trial.",
"title_normalized": "pazopanib for treatment of advanced extraskeletal myxoid chondrosarcoma a multicentre single arm phase 2 trial"
} | [
{
"companynumb": "PHHY2019IT196731",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PAZOPANIB"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "Buprenorphine is abused in several countries notwithstanding its benefits as an analgesic and as an opioid agonist treatment medication. Benzodiazepines and alcohol have previously been associated with buprenorphine toxicity. This study elucidates the role of emerging concomitant drugs in different groups of buprenorphine user deaths.\n\n\n\nAll cases in the Finnish national post-mortem toxicology database from 2016-2019 in which buprenorphine or norbuprenorphine was a laboratory finding in any post-mortem specimen and age at death of 15-64 years were investigated for cause and manner of death, concurrent drug and alcohol findings, age, and gender.\n\n\n\nThere were 792 deaths with a buprenorphine finding, of which buprenorphine was implicated in poisoning without other opioids in 271 cases (34 %). In this group of buprenorphine poisoning deaths, concomitant benzodiazepines were found in 94 % (clonazepam 53 %), illicit drugs in 63 %, gabapentinoids in 50 % (pregabalin 41 %), alcohol in 41 %, antidepressants in 32 %, and antipsychotics in 28 % of cases; only three deaths showed no benzodiazepines, alcohol, or gabapentinoids. Polydrug use was common regardless of the cause of death. In the age group 15 to 24 years, concomitant use of benzodiazepines and illicit drugs, and buprenorphine poisoning were more prevalent than in the age group 25-64 years.\n\n\n\nThe unprecedentedly high concomitant use of benzodiazepines in buprenorphine user deaths obscures other possible pharmacological risk factors for buprenorphine poisoning that could be relevant for prevention. Higher mortality in the younger age group suggests particularly unsafe drug use patterns that should be addressed.",
"affiliations": "Department of Forensic Medicine, University of Helsinki, P.O. Box 40, 00014 Helsinki, Finland; Forensic Toxicology Unit, Finnish Institute for Health and Welfare, P.O. Box 30, 00271 Helsinki, Finland.;Department of Forensic Medicine, University of Helsinki, P.O. Box 40, 00014 Helsinki, Finland; Forensic Toxicology Unit, Finnish Institute for Health and Welfare, P.O. Box 30, 00271 Helsinki, Finland.;Department of Forensic Medicine, University of Helsinki, P.O. Box 40, 00014 Helsinki, Finland; Forensic Toxicology Unit, Finnish Institute for Health and Welfare, P.O. Box 30, 00271 Helsinki, Finland. Electronic address: ilkka.ojanpera@helsinki.fi.",
"authors": "Mariottini|Claudia|C|;Kriikku|Pirkko|P|;Ojanperä|Ilkka|I|",
"chemical_list": "D000700:Analgesics; D000701:Analgesics, Opioid; D013287:Illicit Drugs; D001569:Benzodiazepines; D000431:Ethanol; D002047:Buprenorphine; D000069583:Pregabalin; C043585:norbuprenorphine",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.drugalcdep.2020.108345",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0376-8716",
"issue": "218()",
"journal": "Drug and alcohol dependence",
"keywords": "Alcohol; Benzodiazepines; Buprenorphine-related death; Concomitant use; Pregabalin",
"medline_ta": "Drug Alcohol Depend",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000700:Analgesics; D000701:Analgesics, Opioid; D001344:Autopsy; D001569:Benzodiazepines; D002047:Buprenorphine; D062787:Drug Overdose; D000431:Ethanol; D005260:Female; D005387:Finland; D006801:Humans; D013287:Illicit Drugs; D008297:Male; D008875:Middle Aged; D000069583:Pregabalin; D012307:Risk Factors; D019966:Substance-Related Disorders; D055815:Young Adult",
"nlm_unique_id": "7513587",
"other_id": null,
"pages": "108345",
"pmc": null,
"pmid": "33127184",
"pubdate": "2021-01-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Concomitant drugs with buprenorphine user deaths.",
"title_normalized": "concomitant drugs with buprenorphine user deaths"
} | [
{
"companynumb": "FI-TEVA-2021-FI-1914733",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional": "... |
{
"abstract": "BACKGROUND\nOnly sparse information exists on the use of direct oral anticoagulant (DOAC) testing and the impact on clinical management. Here, we evaluated the clinical impact of DOAC measurements in a real-life clinical setting. Moreover, number of tests performed in relation to number of DOAC-treated patients was evaluated.\n\n\nMETHODS\nClinical data was systematically retrieved from medical records on all patients who had undergone a DOAC testing at Aarhus University Hospital, Denmark from 2014 until March 2018. Data on consumption of DOACs and DOAC tests during 2012-2017 was retrieved from the MEDical STATistics database and from involved laboratories.\n\n\nRESULTS\nA total of 241 DOAC measurements were performed in 234 patients from 2014 to 2018 at our institution. In 88% of patients, DOAC testing was performed in an acute clinical situation; most frequently in patients with acute stroke (53%) or bleedings (26%). Clinical management was explicitly affected by the DOAC testing in 77% of patients. Number of DOAC tests performed in relation to number of DOAC-treated patients in Denmark varied between 0.05% and 0.39% from 2012 to 2015. However, the number increased in 2017 to 2.10% for rivaroxaban-treated, 1.43% for apixaban-treated and 0.74% for dabigatran-treated patients.\n\n\nCONCLUSIONS\nDOAC testing had a significant impact on clinical management in the majority of patients. The study highlights the importance of availability to specific DOAC tests, especially in institutions handling emergent settings.",
"affiliations": "Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark. Electronic address: anlarsen@rm.dk.;Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.",
"authors": "Winther-Larsen|Anne|A|;Hvas|Anne-Mette|AM|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1016/j.thromres.2019.01.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-3848",
"issue": "175()",
"journal": "Thrombosis research",
"keywords": "Clinical management; Direct oral anticoagulants; Hemostasis; Laboratory testing; Measuring",
"medline_ta": "Thromb Res",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D005260:Female; D006801:Humans; D008297:Male",
"nlm_unique_id": "0326377",
"other_id": null,
"pages": "40-45",
"pmc": null,
"pmid": "30703700",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical impact of direct oral anticoagulant measuring in a real-life setting.",
"title_normalized": "clinical impact of direct oral anticoagulant measuring in a real life setting"
} | [
{
"companynumb": "DK-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-006149",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "South African patients with rifampicin-resistant tuberculosis (TB) and resistance to fluoroquinolones and/or injectable drugs (extensively drug-resistant (XDR) and preXDR-TB) were granted access to bedaquiline through a clinical access programme with strict inclusion and exclusion criteria.PreXDR-TB and XDR-TB patients were treated with 24 weeks of bedaquiline within an optimised, individualised background regimen that could include levofloxacin, linezolid and clofazimine as needed. 200 patients were enrolled: 87 (43.9%) had XDR-TB, 99 (49.3%) were female and the median age was 34 years (interquartile range (IQR) 27-42). 134 (67.0%) were living with HIV; the median CD4+ count was 281 cells·μL-1 (IQR 130-467) and all were on antiretroviral therapy.16 out of 200 patients (8.0%) did not complete 6 months of bedaquiline: eight were lost to follow-up, six died, one stopped owing to side effects and one was diagnosed with drug-sensitive TB. 146 out of 200 patients (73.0%) had favourable outcomes: 139 (69.5%) were cured and seven (3.5%) completed treatment. 25 patients (12.5%) died, 20 (10.0%) were lost from treatment and nine (4.5%) had treatment failure. 22 adverse events were attributed to bedaquiline, including a QT interval corrected using the Fridericia formula (QTcF) >500 ms (n=5), QTcF increase >50 ms from baseline (n=11) and paroxysmal atrial flutter (n=1).Bedaquiline added to an optimised background regimen was associated with a high rate of successful treatment outcomes for this preXDR-TB and XDR-TB cohort.",
"affiliations": "National TB Programme, National Dept of Health, Pretoria, South Africa.;Health Economics Unit, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.;King Dinuzulu Hospital Complex, Kwazulu Natal Dept of Health, Durban, South Africa.;Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.;Division of Clinical Pharmacology, Dept of Medicine, University of Cape Town, Cape Town, South Africa.;Northern Cape Dept of Health, Namakwa, South Africa.;Sizwe Tropical Diseases Hospital, Gauteng Dept of Health, Johannesburg, South Africa.;Amity Health Consortium, Johannesburg, South Africa.;King Dinuzulu Hospital Complex, Kwazulu Natal Dept of Health, Durban, South Africa.;King Dinuzulu Hospital Complex, Kwazulu Natal Dept of Health, Durban, South Africa.;Desmond Tutu TB Centre, Dept of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.;Klerksdorp Tshepong Hospital, North West Dept of Health, Klerksdorp, South Africa.;Klerksdorp Tshepong Hospital, North West Dept of Health, Klerksdorp, South Africa.;Brooklyn Chest Hospital, Western Cape Dept of Health, Cape Town, South Africa.;Centre for Tuberculosis, National Institute for Communicable Diseases, National Health Laboratory Services, Johannesburg, South Africa.;Médecins sans Frontières, Khayelitsha, Cape Town, South Africa.;Medical Research Council, Durban, South Africa.;University of the Witwatersrand, Faculty of Health Sciences, Johannesburg, South Africa.",
"authors": "Ndjeka|Norbert|N|;Schnippel|Kathryn|K|;Master|Iqbal|I|;Meintjes|Graeme|G|;Maartens|Gary|G|;Romero|Rodolfo|R|;Padanilam|Xavier|X|;Enwerem|Martin|M|;Chotoo|Sunitha|S|;Singh|Nalini|N|;Hughes|Jennifer|J|0000-0002-5349-9509;Variava|Ebrahim|E|;Ferreira|Hannetjie|H|;Te Riele|Julian|J|;Ismail|Nazir|N|;Mohr|Erika|E|;Bantubani|Nonkqubela|N|;Conradie|Francesca|F|",
"chemical_list": "D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D064687:Diarylquinolines; D024841:Fluoroquinolones; D064704:Levofloxacin; C493870:bedaquiline; D002991:Clofazimine; D000069349:Linezolid",
"country": "England",
"delete": false,
"doi": "10.1183/13993003.01528-2018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0903-1936",
"issue": "52(6)",
"journal": "The European respiratory journal",
"keywords": null,
"medline_ta": "Eur Respir J",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D002991:Clofazimine; D064687:Diarylquinolines; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D054908:Extensively Drug-Resistant Tuberculosis; D005260:Female; D024841:Fluoroquinolones; D015658:HIV Infections; D006801:Humans; D064704:Levofloxacin; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D016012:Poisson Distribution; D013019:South Africa; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant",
"nlm_unique_id": "8803460",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30361246",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "High treatment success rate for multidrug-resistant and extensively drug-resistant tuberculosis using a bedaquiline-containing treatment regimen.",
"title_normalized": "high treatment success rate for multidrug resistant and extensively drug resistant tuberculosis using a bedaquiline containing treatment regimen"
} | [
{
"companynumb": "ZA-JNJFOC-20190201724",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BEDAQUILINE FUMARATE"
},
"drugadditional": null,
... |
{
"abstract": "Acute rerupture after coil embolization is defined as rerupture within three days after treatment; its prognosis is worse than that of rebleeding at other time periods. However, to date, little is known about complications during the acute phase. Therefore, we used the PubMed database to perform a review of acute rerupture after coil embolization of ruptured intracranial saccular aneurysms and increase our understanding. After reviewing the complications, we found that the cause of acute rerupture is unclear, but the following risk factors are involved: incomplete occlusion of the initial aneurysm, the presence of a hematoma adjacent to a ruptured aneurysm, an aneurysmal outpouching, poor Hunt-Hess grade at the time of treatment, and the location of the aneurysm in an anterior communicating artery. In addition, intraoperative rupture is a non-negligible cause. Acute rerupture after coil embolization mainly occurs within the first 24 hours after the procedure. Brain computed tomography is the gold standard for diagnosing acute rebleeding of a coiled aneurysm. For acute rerupture after coil embolization, prevention is critical, and complete occlusion of the aneurysm in the first session is the best protection against acute rebleeding. In addition, a restricted postembolization anticoagulation strategy is recommended for patients with high-risk aneurysms. For patients with an adjacent hematoma, surgical clipping is recommended. Most patients present no changes immediately after acute rebleeding because of their poor condition. However, surgical or endovascular treatments can be attempted if the patient is in an acceptable condition. Even so, the outcomes are typically unsatisfactory.",
"affiliations": "1 Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China.;1 Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China.;2 Department of Training, The First Hospital of Jilin University, Changchun, China.;1 Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China.;1 Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China.;1 Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China.",
"authors": "Li|Kailing|K|;Guo|Yunbao|Y|;Zhao|Ying|Y|;Xu|Baofeng|B|;Xu|Kan|K|;Yu|Jinlu|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1591019917747245",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1591-0199",
"issue": "24(2)",
"journal": "Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences",
"keywords": "Intracranial aneurysm; acute rerupture; coil embolization; review",
"medline_ta": "Interv Neuroradiol",
"mesh_terms": "D000208:Acute Disease; D017542:Aneurysm, Ruptured; D004621:Embolization, Therapeutic; D006801:Humans; D007049:Iatrogenic Disease; D002532:Intracranial Aneurysm; D011379:Prognosis; D012008:Recurrence; D012307:Risk Factors; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9602695",
"other_id": null,
"pages": "117-124",
"pmc": null,
"pmid": "29231793",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "21332293;17345112;28716568;26104272;28580532;18048860;11478068;28000128;16627789;12802695;28824313;28382536;16286399;26508130;26526272;21969241;16091523;28791434;20099070;25658785;15031075;19299485;26471748;26052880;28298025;11396746;27836654;23512976;26069261;20849318;20672900;26354945;16159052;12775880;20591272;24994079;27759680;21926852;12414200;25564539",
"title": "Acute rerupture after coil embolization of ruptured intracranial saccular aneurysms: A literature review.",
"title_normalized": "acute rerupture after coil embolization of ruptured intracranial saccular aneurysms a literature review"
} | [
{
"companynumb": "CN-BAYER-2018-071837",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Warfarin is a well-established cause of gross hematuria. However, impaired kidney function does not occur except in the rare instance of severe blood loss or clot formation that obstructs the urinary tract. It has been recently described an entity called warfarin-related nephropathy, in which acute kidney injury is caused by glomerular hemorrhage and renal tubular obstruction by red blood cell casts. We report a patient under warfarin treatment with chronic kidney disease, macroscopic hematuria and acute kidney injury. A renal biopsy showed massive occlusion of renal tubules by red blood cells and casts. The possible relationship of the warfarin therapy, intratubular hemorrhage and acute kidney injury is discussed.",
"affiliations": "Department of Nephrology, Centro Hospitalar Vila Nova de Gaia, Vila Nova de Gaia, Portugal. mclaracsantos@gmail.com",
"authors": "Santos|Clara|C|;Gomes|Ana M|AM|;Ventura|Ana|A|;Almeida|Clara|C|;Seabra|Joaquim|J|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "Spain",
"delete": false,
"doi": "10.3265/Nefrologia.pre2012.Oct.11617",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0211-6995",
"issue": "33(3)",
"journal": "Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia",
"keywords": null,
"medline_ta": "Nefrologia",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000925:Anticoagulants; D006417:Hematuria; D006801:Humans; D007678:Kidney Glomerulus; D008297:Male; D051436:Renal Insufficiency, Chronic; D014859:Warfarin",
"nlm_unique_id": "8301215",
"other_id": null,
"pages": "400-3",
"pmc": null,
"pmid": "23712226",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An unusual cause of glomerular hematuria and acute kidney injury in a chronic kidney disease patient during warfarin therapy.",
"title_normalized": "an unusual cause of glomerular hematuria and acute kidney injury in a chronic kidney disease patient during warfarin therapy"
} | [
{
"companynumb": "PT-MYLAN-2014S1017197",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMINOPHYLLINE"
},
"drugadditional": null,
... |
{
"abstract": "Disseminated infections due to Mycobacterium bovis Bacillus Calmette-Guérin (BCG) are unusual and occur mostly in patients with inborn error of immunity (IEI) or acquired immunodeficiency. However, cases of secondary BCGosis due to intravesical BCG instillation have been described. Herein, we present a case of severe BCGosis occurring in an unusual situation.\n\n\n\nWe report one case of severe disseminated BCG disease occurring after hematological malignancy in a 48-year-old man without BCG instillation and previously vaccinated in infancy with no complication. Laboratory investigations demonstrated that he was not affected by any known or candidate gene of IEI or intrinsic cellular defect involving IFNγ pathway. Whole genome sequencing of the BCG strain showed that it was most closely related to the M. bovis BCG Tice strain, suggesting an unexpected relationship between the secondary immunodeficiency of the patient and the acquired BCG infection.\n\n\n\nThis case highlights the fact that, in addition to the IEI, physicians, as well as microbiologists and pharmacists should be aware of possible acquired disseminated BCG disease in secondary immunocompromised patients treated in centers that administrate BCG for bladder cancers.",
"affiliations": "Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France.;Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France.;APHP.Sorbonne Université, Hôpital Pitié-Salpêtrière, Laboratoire de Bactériologie-Hygiène, Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux (CNR-MyRMA), Paris, France.;APHP.Sorbonne Université, Hôpital Pitié-Salpêtrière, Laboratoire de Bactériologie-Hygiène, Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux (CNR-MyRMA), Paris, France.;Université de Strasbourg, INSERM UMR-S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Faculté de médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.;Department of Infectiology, Strasbourg University Hospital, Strasbourg, France.;Departement of Pathology, Strasbourg University Hospital, Strasbourg, France.;Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France.;Departement of Nuclear Medicine and Molecular Imaging, ICANS, University Hospital of Strasbourg, Strasbourg, France.;Department of Internal Medicine, Strasbourg University Hospital, Strasbourg, France.;Université de Strasbourg, INSERM UMR-S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Faculté de médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.;Laboratory of Bacteriology, Strasbourg University Hospital, Virulence bactérienne Précoce UR7290-Lyme Borreliosis Group, FMTS-CHRU Strasbourg, Institut de Bactériologie, Strasbourg, France.;Laboratory of Bacteriology, Strasbourg University Hospital, Virulence bactérienne Précoce UR7290-Lyme Borreliosis Group, FMTS-CHRU Strasbourg, Institut de Bactériologie, Strasbourg, France.;Department of Infectiology, Strasbourg University Hospital, Strasbourg, France.;Department of Infectiology, Strasbourg University Hospital, Strasbourg, France.;Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France.;Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France.",
"authors": "Gies|Vincent|V|;Dieudonné|Yannick|Y|;Morel|Florence|F|;Sougakoff|Wladimir|W|;Carapito|Raphaël|R|;Martin|Aurélie|A|;Weingertner|Noëlle|N|;Jacquel|Léa|L|;Hubele|Fabrice|F|;Kuhnert|Cornelia|C|;Jung|Sophie|S|;Schramm|Frederic|F|;Boyer|Pierre|P|;Hansmann|Yves|Y|;Danion|François|F|;Korganow|Anne-Sophie|AS|;Guffroy|Aurélien|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2021.696268",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.696268\nImmunology\nCase Report\nCase Report: Acquired Disseminated BCG in the Context of a Delayed Immune Reconstitution After Hematological Malignancy\nGies Vincent 1 2 3\n\nDieudonné Yannick 1 2\n\nMorel Florence 4 5\n\nSougakoff Wladimir 4 5\n\nCarapito Raphaël 2 6\n\nMartin Aurélie 7\nWeingertner Noëlle 8\nJacquel Léa 1 2\nHubele Fabrice 9\nKuhnert Cornelia 10\nJung Sophie 2 11\n\nSchramm Frederic 12\nBoyer Pierre 12\nHansmann Yves 7\nDanion François 7\nKorganow Anne-Sophie 1 2\nGuffroy Aurélien 1 2 *\n\n1Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France\n2Université de Strasbourg, INSERM UMR-S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Faculté de médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France\n3Université de Strasbourg, Faculty of Pharmacy, Illkirch, France\n4APHP.Sorbonne Université, Hôpital Pitié-Salpêtrière, Laboratoire de Bactériologie-Hygiène, Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux (CNR-MyRMA), Paris, France\n5Sorbonne Universités, Inserm, Centre d'Immunologie et des Maladies Infectieuses (Cimi-Paris), UMR 1135, Paris, France\n6Immunology Laboratory, Strasbourg University Hospital, Strasbourg, France\n7Department of Infectiology, Strasbourg University Hospital, Strasbourg, France\n8Departement of Pathology, Strasbourg University Hospital, Strasbourg, France\n9Departement of Nuclear Medicine and Molecular Imaging, ICANS, University Hospital of Strasbourg, Strasbourg, France\n10Department of Internal Medicine, Strasbourg University Hospital, Strasbourg, France\n11Hôpitaux Universitaires de Strasbourg, Centre de Référence Maladies Rares Orales et Dentaires (O-Rares), Pôle de Médecine et de Chirurgie Bucco-Dentaires, Strasbourg, France\n12Laboratory of Bacteriology, Strasbourg University Hospital, Virulence bactérienne Précoce UR7290-Lyme Borreliosis Group, FMTS-CHRU Strasbourg, Institut de Bactériologie, Strasbourg, France\nEdited by: Sergio Rosenzweig, National Institutes of Health (NIH), United States\n\nReviewed by: Saul Oswaldo Lugo Reyes, National Institute of Pediatrics, Mexico; Hassan Abolhassani, Karolinska University Hospital, Sweden\n\n*Correspondence: Aurélien Guffroy, aurelien.guffroy@chru-strasbourg.fr\nThis article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology\n\n03 8 2021\n2021\n12 69626816 4 2021\n15 7 2021\nCopyright © 2021 Gies, Dieudonné, Morel, Sougakoff, Carapito, Martin, Weingertner, Jacquel, Hubele, Kuhnert, Jung, Schramm, Boyer, Hansmann, Danion, Korganow and Guffroy\n2021\nGies, Dieudonné, Morel, Sougakoff, Carapito, Martin, Weingertner, Jacquel, Hubele, Kuhnert, Jung, Schramm, Boyer, Hansmann, Danion, Korganow and Guffroy\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nContext\n\nDisseminated infections due to Mycobacterium bovis Bacillus Calmette-Guérin (BCG) are unusual and occur mostly in patients with inborn error of immunity (IEI) or acquired immunodeficiency. However, cases of secondary BCGosis due to intravesical BCG instillation have been described. Herein, we present a case of severe BCGosis occurring in an unusual situation.\n\nCase Description\n\nWe report one case of severe disseminated BCG disease occurring after hematological malignancy in a 48-year-old man without BCG instillation and previously vaccinated in infancy with no complication. Laboratory investigations demonstrated that he was not affected by any known or candidate gene of IEI or intrinsic cellular defect involving IFNγ pathway. Whole genome sequencing of the BCG strain showed that it was most closely related to the M. bovis BCG Tice strain, suggesting an unexpected relationship between the secondary immunodeficiency of the patient and the acquired BCG infection.\n\nConclusion\n\nThis case highlights the fact that, in addition to the IEI, physicians, as well as microbiologists and pharmacists should be aware of possible acquired disseminated BCG disease in secondary immunocompromised patients treated in centers that administrate BCG for bladder cancers.\n\nBCG\nBCGosis-susceptible PIDs\nImmunodeficiency\nhematological malignancies\ncontamination\ncase report\n==== Body\nIntroduction\n\nDisseminated infections due to Mycobacterium bovis Bacillus Calmette-Guérin (BCG) are rare and occur in three types of conditions. First, it occurs in rare cases of inborn errors of immunity (IEI) involving phagocytosis, such as chronic granulomatous diseases (CGD), or interferon-gamma (IFNγ) pathways (called Mendelian susceptibility to mycobacterial diseases or MSMD) at the time of BCG vaccination. The second situation concerns cases associated with acquired immunodeficiency to IFNγ pathways that are described as a phenocopy of IEI. They lead to opportunistic infections (fungi, parasites, and bacteria), tuberculosis, and infection due to non-tuberculosis mycobacteria (1–4). Finally, reactivations are described in immunocompromised patients with human immunodeficiency virus (HIV) (5, 6), and cases of secondary disseminated BCG disease (BCGosis) are also reported under BCG therapy for bladder malignancy (7, 8). Here, we described a case of severe secondary BCGosis occurring after hematological malignancy in an adult without BCG instillation and previously vaccinated in infancy with no complication.\n\nCase Description\n\nA 48-year-old Caucasian man was referred to our department for progressive asthenia, anorexia, and cachexia (−12 kg in 9 months).\n\nHis main medical history was a hematological malignancy (OMS 2008 grade 1–2 follicular lymphoma) diagnosed 3 years before and involving the lacrimal gland and the bowel. Biopsies (right part of the colon) revealed a monotypic lymphoid infiltrate made of CD20+, CD5−, CD10+, and Bcl6+ lymphocytes with a Ki67 index at 50%. Lungs were not involved at this time (Supplementary Figure S1). He was treated with combined chemotherapy (R-CHOP) and a maintenance therapy with Rituximab every 2 months, for 18 months. He had experienced neither opportunistic and severe infections nor autoimmune diseases. Timeline of his medical history is resumed in Figure 1.\n\nFigure 1 Clinical history (Timeline). R, Rituximab; CHOP: C, cyclophosphamide; H, hydroxyadriamycine; O, oncovin®; P, prednisone; CT, computerized tomography; ATB, antibiotherapy.\n\nSeven months after the last Rituximab therapy, the patient presented fever, splenomegaly (17 cm), and fine dry crackles at pulmonary auscultation with dyspnea (New York Heart Association Classification class II–IV). An interstitial lung disease with nodular lesions was diagnosed on CT-scan with a decline of alveolar exchanges on breath tests (Figure 2A). Broncho-alveolar lavage (BAL) revealed an alveolar lymphocytosis (230,000 cells/ml, 67% lymphocytes, 28% macrophages) with inverted CD4/CD8 ratio and without any virus (screened by PCR), bacteria, or parasite in culture. Biology showed inflammatory syndrome, acute renal failure, pancytopenia with severe lymphopenia, mild neutropenia, thrombopenia and anemia, as well as hypogammaglobulinemia (Supplementary Table S1). Bone marrow aspiration revealed a poor cellularity and fat involution (reflecting likely the nutritional deficiency state) without malignant cells. Considering kidney failure, a biopsy was made and revealed an acute interstitial nephritis without glomerular lesions. 18F-FDG PET/CT-scan showed several hypermetabolic lesions (tonsil, lung nodules, and parenchyma) but no hypermetabolism of the spleen. Within a couple of days, the condition of the patient worsened with hypoxemia requiring increasing level of oxygen despite probabilistic antibiotherapy (sulfamethoxazole/trimethoprim for Pneumocysis jirovecii PCR+ in BAL and large-spectrum antibacterial therapy with piperacillin/tazobactam). Corticosteroids were added and transiently improved the respiratory state. A lung biopsy was performed that finally revealed invasive infection by M. bovis BCG, suspected by Ziehl-Neelsen coloration and confirmed by PCR and culture (Figure 2B). The M. bovis BCG strain was also found in the bone marrow and blood cultures. The strain was phenotypically susceptible to rifampicin, isoniazid, and ethambutol. Cryptococcus neoformans was also identified in lung biopsy but without central nervous system involvement. HIV PCR and serology were negative. Phagocytosis assays were normal, discarding the hypothesis of chronic granulomatous disease.\n\nFigure 2 Clinical evolution and histological analysis of the patient. (A) 18F-FDG-TEP-CT-scan revealing an interstitial lung disease with nodular lesions (left). CT-scan normalization after 3 months (right). (B) Histological analysis showing a peri-bronchial granulomatous inflammation with ulceration (upper left), a perivascular granuloma (upper right), giant multinucleated cells (lower left), and BAAR with Ziehl-Neelsen staining (lower right).\n\nDespite a treatment regimen of isoniazid, rifampin, pyrazinamide, and ethambutol for BCGosis, initiated before the strain identification, and fluconazole for Cryptococcus, the patient state worsened with need for intensive care unit support. Corticosteroids were re-introduced, and G-CSF therapy was added two times per week. We hypothesized a primary or secondary defect in IFNγ pathway, such as an autoimmunization against IFNγ, and we decided to introduce Imukin® as an add-on therapy (50 µg S.C. three times/week and after 2 weeks at 100 µg S.C. three times/week) (Supplementary Table S1). This strategy finally allowed an improvement of the patient’s condition with CT-scan and TEP-scan complete normalization after 3 and 6 months, respectively (Figure 2A). Interferon therapy was maintained during 12 months with bi-antibiotherapy (rifampcin and isoniazid) and fluconazole after the complete remission in order to avoid any relapse, and 12 months after treatment’s discontinuation, the patient remained in complete remission.\n\nFunctional Analysis\n\nThe patient harbored a severe post-chemotherapy lymphopenia with delayed immune reconstitution of B-cell and T-cell compartment, i.e., very low level of CD19+ cells with a selective lack of IgM production, and low levels of naive CD45RA+ T cells. CD4/CD8 ratio was conserved in proportion (Supplementary Table S1). The absolute number of monocytes was normal with 55% of classical, 18% of intermediate, and 27% non-classical monocytes.\n\nPotential IFN pathway defects that may lead to ineffective response towards BCG were explored. IFNγ stimulation of peripheral mononuclear cells (PBMCs) from a healthy donor (HD) in the presence of 25% (v/v) allogenic HD or patient’s serum (from different time points, i.e., before, during, and after IFNγ therapy) did not impair STAT1 phosphorylation. Similarly, no significant difference in STAT1 phosphorylation was observed when we mixed the IFNγ and the patient’s serum before using it to stimulate PBMCs from HD. These results suggested for the absence of anti-IFNγ autoantibodies or any other autoantibodies that may directly hinder/block IFNγ signaling (Figures 3A–C). Absence of anti-GM-CSF autoantibodies was also confirmed (data not shown). STAT1 phosphorylation, after IFNγ stimulation of monocytes from the patient, was preserved (Figure 3D). CD4+ T cells from the patient responded to BCG (Figure 3E) and showed no apparent defect of IFNγ production after BCG ± IL12 stimulation (Figure 3F). Altogether, these results did not support the hypothesis of an IEI or acquired immunodeficiency related to defective host defense mechanisms against BCG.\n\nFigure 3 Absence of IFNγ or other autoantibodies that may directly hinder/block IFNγ signaling and normal response to IFNγ or BCG stimulation. STAT1 phosphorylation (Y701) of HD monocytes after stimulation for 15 min (A) with 25% (v/v) allogenic HD or patient’s serum (from different time points: P1, P2, and P3) and (B) with IFNγ previously mixed with 25% (v/v) allogenic HD or patient’s serum (from different time points: P1, P2, and P3). (C) STAT1 phosphorylation (Y701) of HD monocytes after IFNγ stimulation for 15 min. Cells were preincubated 30 min at room temperature in the presence of 25% (v/v) HD or patient’s serum (from different time points: P1, P2, and P3) and washed before IFNγ stimulation. (D) STAT1 phosphorylation (Y701) of monocytes from the patient after IFNγ stimulation for 15 min. (E) Frequency of IFNγ+ and/or TNFα+ CD4+ T cells from the patient after no stimulation or stimulation with heat inactivated BCG for 48 h. (F) IFNγ concentration in culture supernatant after no stimulation, IL12, heat-inactivated BCG, or PMA/IONO stimulation of PBMC from the patient and one HD for 48 h. BCG: bacillus Calmette-Guérin; HD, healthy donor; IFNγ, interferon gamma; NS, non-stimulated; P1, patient’s serum before BCGosis diagnosis and IFNγ therapy (2018-08); P2, patient’s serum at the time of BCGosis diagnosis and during IFNγ therapy (2018-11); P3, patient’s serum after BCGosis diagnosis and IFNγ therapy (2019-02).\n\nGenomic Analysis\n\nWhole exome sequencing (WES) was performed but did not reveal/detect any known mutations or unknown variants with high in silico predicted consequence (CADD > 10, MAF < 0.005%) involved in MSMD (i.e., IL12RB1, IL12B, IL12RB2, IL23R, IFNGR1, IFNGR2, STAT1, CYBB, IRF8, SPPL2A, TYK2, ISG15, RORC, JAK1, and NEMO) (9). Similarly, no candidate genes of IEI were found (Supplementary Table S2).\n\nWhole genome sequencing (WGS) of M. bovis BCG strain and comparative phylogenomic analysis with the genomes of reference M. bovis BCG strains were performed at the National Reference Center for Mycobacteria and Resistance of Mycobacteria to Antituberculosis (CNR-MyRMA). The results showed that the patient’s strain (M. bovis BCG_ 1811074784, Figure 4) was most closely related to the M. bovis BCG Tice strain.\n\nFigure 4 Maximum likelihood phylogenetic tree representing the relationship between the clinical M. bovis BCG strain (M. bovis BCG_1811074784) and reference M. bovis BCG strains. Bootstrap values of each branch are indicated.\n\nDiscussion\n\nBecause of the opportunistic features of infection (severe BCGosis, Cryptococcus) and considering the remission of the patient after IFNγ therapy introduction, we suspected a late-onset IEI. However, no rare monogenic causes of genetic susceptibility to tuberculosis, or genetic risk factor such as P1104A TYK2 allele (10), were found; neither did we find other known pathogenic variants involved in IEI. Although we cannot totally exclude the existence of some unknown genetic susceptibility factors not evidenced by our WES analysis, the fact that the patient was vaccinated several times (because of anergy to the intradermoreaction test) with BCG vaccine during infancy and did not develop any symptom argues against an IEI. Moreover, none of his relatives were infected by BCG or other mycobacteria, even after exposition to BCG for vaccination. Additionally, no intrinsic defect in IFNγ production or IFNγ response was detected. Anti-cytokine autoantibodies are known to be a cause of adult-onset infection susceptibility (also called “phenocopies” of IEI) (1, 11–13), but the presence of anti-IFNγ or anti-GM-CSF has been excluded.\n\nFinally, WGS and comparative phylogenomic analysis of the isolated M. bovis BCG revealed that this clinical strain was more closely related to the M. bovis BCG Tice. M. bovis BCG vaccine strains were derived by the repeated in vitro passage of M. bovis leading to its attenuation. The original BCG strain was distributed to many laboratories all around the world, which, in turn, carried out subcultures, generating daughter strains named according to their geographical origin. The BCG Tice strain is actually used as adjunctive therapy for superficial bladder cancer (OncoTICE®). Intravesical instillation of BCG for bladder cancer has been previously reported to be responsible for disseminated BCGosis in both immunocompromised and immunocompetent patients (7, 8, 14–16). The delay for BCGosis development is usually lower than 1 year, and some authors argued that the strain used in bladder installation could correlate with the frequency and severity of BCGosis (17). However, no vesical instillations were performed in our case and the results of the phylogenomic comparison might suggest the possibility of an acquired BCG infection during one of the chemotherapy sessions with an infection that remained latent during several months before becoming invasive. Interestingly, some cases of BCGosis have also been reported in patients with hematological malignancies who had never received intravesical BCG instillation (18–21), and a possible role of iatrogenic infection through central catheter was suggested (22) (Supplementary Table S3). Most of these cases were already linked to BCG Tice strain; the possible mechanism could be environmental contamination through aerosol generation during intra-vesical instillation or colonization of the outside of the central catheter by colonized gloves (18–21).\n\nPerspectives\n\nWe report herein one case of severe BCGosis, possibly linked to intrahospital acquisition of the BCG Tice strain. We excluded the possibility of an underlying IEI and we showed an unexpected relationship between the secondary immunodeficiency of the patient, due to the lymphoma and its treatment, and the acquired BCG infection. Using IFNγ therapy in association with antibiotherapy, corticosteroids, and G-CSF, the patient progressively recovered with a complete remission after several months. Although only assumptions about the origin of this contamination can be made from this single case, physicians, especially hematologists and oncologists, as well as pharmacists and microbiologists should be aware of the risk of disseminated BCGosis in immunocompromised patients treated in centers that administrate BCG for bladder cancers.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nThe patient’s written consent was obtained.\n\nAuthor Contributions\n\nVG, A-SK, and AG contributed to conception and design of the study. YD, FM, WS, AM, NW, LJ, FH, CK, SJ, FS, PB, YH, FD, A-SK, and AG contributed to the collection of the data. VG, YD, FM, WS, RC, FS, PB, and AG performed the analysis. VG and AG wrote the first draft of the manuscript. YD, FM, WS, RC, AM, NW, LJ, FH, CK, SJ, FS, PB, YH, FD, A-SK, and AG wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nAcknowledgments\n\nWe thank the physicians who helped us to take care of the patient reported in the manuscript. We thank the “Hôpitaux Universitaires de Strasbourg” for their support; the ERNs (European Reference Networks for rare disease), RITA (Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases), and ReCONNET (European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases); and the INTERREG V program [PERSONALIS project, co-financed by the European regional development fund (ERDF)].\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.696268/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Liew W-K Thoon K-C Chong C-Y Tan NWH Cheng D-T Chan BSW . Juvenile-Onset Immunodeficiency Secondary to Anti-Interferon-Gamma Autoantibodies. J Clin Immunol (2019) 39 :512–8. 10.1007/s10875-019-00652-1\n2 Bustamante J Boisson-Dupuis S Abel L Casanova J-L . Mendelian Susceptibility to Mycobacterial Disease: Genetic, Immunological, and Clinical Features of Inborn Errors of IFN-γ Immunity. Semin Immunol (2014) 26 :454–70. 10.1016/j.smim.2014.09.008\n3 Al-Muhsen S Casanova J-L . The Genetic Heterogeneity of Mendelian Susceptibility to Mycobacterial Diseases. J Allergy Clin Immunol (2008) 122 :1043–51. 10.1016/j.jaci.2008.10.037\n4 Fekrvand S Yazdani R Olbrich P Gennery A Rosenzweig SD Condino-Neto A . Primary Immunodeficiency Diseases and Bacillus Calmette-Guérin (Bcg)-Vaccine-Derived Complications: A Systematic Review. J Allergy Clin Immunol Pract (2020) 8 :1371–86. 10.1016/j.jaip.2020.01.038\n5 Saharia KK Koup RA . T Cell Susceptibility to HIV Influences Outcome of Opportunistic Infections. Cell (2013) 155 :505–14. 10.1016/j.cell.2013.09.045\n6 Girardi E Sabin CA d’Arminio Monforte A Hogg B Phillips AN Gill MJ . Incidence of Tuberculosis Among HIV-Infected Patients Receiving Highly Active Antiretroviral Therapy in Europe and North America. Clin Infect Dis (2005) 41 :1772–82. 10.1086/498315\n7 Oladiran O Nwosu I Oladunjoye A Oladunjoye O . Disseminated BCG Sepsis Following Intravesical Therapy for Bladder Carcinoma: A Case Report and Review of Literature. J Community Hosp Internal Med Perspect (2020) 10 :168–70. 10.1080/20009666.2020.1742475\n8 To U Kim J Chia D . Disseminated BCG: Complications of Intravesical Bladder Cancer Treatment. Case Rep Med (2014) 2014 :e362845. 10.1155/2014/362845\n9 Bousfiha A Jeddane L Picard C Al-Herz W Ailal F Chatila T . Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification. J Clin Immunol (2020) 40 :66–81. 10.1007/s10875-020-00758-x 32048120\n10 Boisson-Dupuis S Ramirez-Alejo N Li Z Patin E Rao G Kerner G . Tuberculosis and Impaired IL-23-Dependent IFN-γ Immunity in Humans Homozygous for a Common TYK2 Missense Variant. Sci Immunol (2018) 3 (30)eaau8714. 10.1126/sciimmunol.aau8714\n11 Browne SK Holland SM . Anticytokine Autoantibodies in Infectious Diseases: Pathogenesis and Mechanisms. Lancet Infect Dis (2010) 10 :875–85. 10.1016/S1473-3099(10)70196-1\n12 Uchida K Beck DC Yamamoto T Berclaz P-Y Abe S Staudt MK . Gm-Csf Autoantibodies and Neutrophil Dysfunction in Pulmonary Alveolar Proteinosis. N Engl J Med (2007) 356 :567–79. 10.1056/NEJMoa062505\n13 Kampmann B Hemingway C Stephens A Davidson R Goodsall A Anderson S . Acquired Predisposition to Mycobacterial Disease Due to Autoantibodies to IFN-γ. J Clin Invest (2005) 115 :2480–8. 10.1172/JCI19316\n14 Pérez-Jacoiste Asín MA Fernández-Ruiz M López-Medrano F Lumbreras C Tejido Á San Juan R . Bacillus Calmette-Guérin (Bcg) Infection Following Intravesical Bcg Administration as Adjunctive Therapy For Bladder Cancer. Med (Baltimore) (2014) 93 (17)236–54. 10.1097/MD.0000000000000119\n15 Lukacs S Tschobotko B Szabo NA Symes A . Systemic BCG-Osis as a Rare Side Effect of Intravesical Bcg Treatment for Superficial Bladder Cancer. Case Rep Urol (2013) 2013 :821526. 10.1155/2013/821526 23844314\n16 Westhovens IM Vanden Abeele M-E Messiaen PE van der Hilst JC . Systemic BCG Infection in a Patient With Pancytopaenia and Fever 9 Years After Intravesical BCG Administration for Bladder Cancer. BMJ Case Rep (2016) 2016 bcr2016215599. 10.1136/bcr-2016-215599\n17 Levi LI Schlemmer F de Castro N Brun O Veziris N Argemi X . Bacillus Calmette-Guerin Infection Following Intravesical Instillation: Does the Strain Matter? Med Mal Infect (2019) 49 :350–5. 10.1016/j.medmal.2018.11.014\n18 Coppes MJ Olivieri NF Howes M Pusic M Gold R Richardson SE . Mycobacterial Brain Abscess Possibly Due to Bacille Calmette-Guérin in an Immunocompromised Child. Clin Infect Dis (1992) 14 :662–5. 10.1093/clinids/14.3.662\n19 Stone MM Vannier AM Storch SK Peterson C Nitta AT Zhang Y . Meningitis Due to Iatrogenic Bcg Infection in Two Immunocompromised Children. New Engl J Med (1995) 333 :561–3. 10.1056/NEJM199508313330905\n20 Waecker NJ Stefanova R Cave MD Davis CE Dankner WM . Nosocomial Transmission of Mycobacterium Bovis Bacille Calmette-Guerin to Children Receiving Cancer Therapy and to Their Health Care Providers. Clin Infect Dis (2000) 30 :356–62. 10.1086/313652\n21 Vos MC de Haas PEW Verbrugh HA Renders NHM Hartwig NG de Man P . Nosocomial Mycobacterium Bovis-Bacille Calmette-Guérin Infections Due to Contamination of Chemotherapeutics: Case Finding and Route of Transmission. J Infect Dis (2003) 188 :1332–5. 10.1086/379034\n22 Meije Y Martínez-Montauti J Caylà JA Loureiro J Ortega L Clemente M . Healthcare-Associated Mycobacterium Bovis-Bacille Calmette-Guérin (Bcg) Infection in Cancer Patients Without Prior BCG Instillation. Clin Infect Dis (2017) 65 :1136–43. 10.1093/cid/cix496\n\n",
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"keywords": "BCG; BCGosis-susceptible PIDs; Immunodeficiency; case report; contamination; hematological malignancies",
"medline_ta": "Front Immunol",
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"title": "Case Report: Acquired Disseminated BCG in the Context of a Delayed Immune Reconstitution After Hematological Malignancy.",
"title_normalized": "case report acquired disseminated bcg in the context of a delayed immune reconstitution after hematological malignancy"
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"abstract": "Acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms are all severe hypersensitivity reactions to medications. While each of these reactions is a well-established entity with specific diagnostic criteria, clinicians see cases that fulfill criteria for more than one form, prompting discussion on the possibility of combined forms. Such overlapping clinical pictures meeting the criteria for 2 conditions have thus become a topic of debate in dermatology in recent years. We describe 2 patients with cutaneous drug reactions having the characteristics of both acute generalized exanthematous pustulosis and Stevens-Johnson syndrome -toxic epidermal necrolysis. We also review previously published cases and current thinking on such overlapping conditions.",
"affiliations": "Servicio de Dermatología, Hospital General Universitario Gregorio Marañón, Madrid, España. Electronic address: celiahr@hotmail.com.;Servicio de Dermatología, Hospital General Universitario Gregorio Marañón, Madrid, España.;Servicio de Dermatología, Hospital General Universitario Gregorio Marañón, Madrid, España.",
"authors": "Horcajada-Reales|C|C|;Pulido-Pérez|A|A|;Suárez-Fernández|R|R|",
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"keywords": "Acute generalized exanthematous pustulosis; Cutaneous adverse drug reactions; Necrólisis epidérmica tóxica; Pustulosis exantemática generalizada aguda; Stevens-Johnson syndrome; Síndrome de Stevens-Johnson; Toxic epidermal necrolysis; Toxicodermias",
"medline_ta": "Actas Dermosifiliogr",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000368:Aged; D000369:Aged, 80 and over; D064420:Drug-Related Side Effects and Adverse Reactions; D004802:Eosinophilia; D005260:Female; D006801:Humans; D013262:Stevens-Johnson Syndrome",
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"title": "Severe Cutaneous Drug Reactions: Do Overlapping Forms Exist?",
"title_normalized": "severe cutaneous drug reactions do overlapping forms exist"
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"abstract": "Patients with multiple myeloma (MM) have improved treatment options, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Despite their efficacy, increased rates of cardiovascular (CV) complications occur in patients exposed to some of these therapies. While previous research has focused on identifying the toxicities inherent to each specific agent, the CV side effects may be potentiated by the combination of PIs and IMiDs plus dexamethasone. We present a patient with MM with recurrent cardiotoxicity only when exposed to combination PI and IMiD-based therapy. We also review the literature in this context, and propose a potential algorithm for cardiotoxicity prevention in this population.",
"affiliations": "Cardio-Oncology Program, Department of Cardiovascular Sciences, University of South Florida Morsani College of Medicine and H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.;Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;H. Lee Moffitt Cancer Center and Research Institute, University of South Florida Morsani College of Medicine, Tampa, FL, USA.;Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.;Cardio-Oncology Program, Vanderbilt University School of Medicine, Nashville, TN, USA.;Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;H. Lee Moffitt Cancer Center and Research Institute, University of South Florida Morsani College of Medicine, Tampa, FL, USA.;Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.",
"authors": "Fradley|Michael G|MG|0000-0001-8352-8975;Groarke|John D|JD|;Laubach|Jacob|J|0000-0001-7565-2052;Alsina|Melissa|M|;Lenihan|Daniel J|DJ|;Cornell|Robert F|RF|0000-0002-2011-1475;Maglio|Michelle|M|;Shain|Kenneth H|KH|;Richardson|Paul G|PG|0000-0002-7426-8865;Moslehi|Javid|J|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D061988:Proteasome Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.14970",
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"issn_linking": "0007-1048",
"issue": "180(2)",
"journal": "British journal of haematology",
"keywords": "cardio-oncology; cardiotoxicity; immunomodulatory drugs; multiple myeloma; proteasome inhibitor",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D066126:Cardiotoxicity; D004562:Electrocardiography; D005260:Female; D006331:Heart Diseases; D006801:Humans; D008279:Magnetic Resonance Imaging; D009101:Multiple Myeloma; D061988:Proteasome Inhibitors",
"nlm_unique_id": "0372544",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent cardiotoxicity potentiated by the interaction of proteasome inhibitor and immunomodulatory therapy for the treatment of multiple myeloma.",
"title_normalized": "recurrent cardiotoxicity potentiated by the interaction of proteasome inhibitor and immunomodulatory therapy for the treatment of multiple myeloma"
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"abstract": "Staphylococcus aureus produces numerous toxins, such as toxic shock syndrome toxin 1 (TSST-1) and Panton-Valentine leukocidin (PVL). We isolated community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) strains producing both TSST-1 and PVL isolated from severe necrotizing pneumonia cases in a Nepali family. Detection of these CA-MRSA strains is rare in the world, and infection with these strains can take a rapidly progressive and lethal course. In this study, we traced the clinical course of this case and conducted a genetic analysis of the isolated strains.\nWe described 2 familial cases (a 20-year-old male and 61-year-old female) of severe necrotizing pneumonia caused by CA-MRSA with the TSST-1 and PVL genes. A 20-year-old Nepalese male was admitted to our hospital after a 3-day history of high fever and coughing. Despite resuscitation efforts, he died of multiple organ failure. A 61-year-old Nepalese female was admitted to our hospital with a complaint of high fever and dyspnea for 1 day. She was the grandmother of the male subject and mostly stayed at his residence in Japan. We administered intravenous antibiotics, including anti-MRSA antibiotics, and she improved in 2 weeks. The sequence type of the isolates was ST22/SCCmec type IVa, and the spa type was t005. The virulence genes detected were as follows: PVL gene (lukSF-pv), TSST-1 gene (tst-1), sec, seg, sei, sel, sem, sen, seo, and seu. ST22 was not the dominant CA-MRSA clone type in Japan. Some of the reports demonstrated that PVL-/TSST-1-positive ST22-MRSA strains are prevalent in Nepal. Therefore, the MRSA strains were thought to be acquired from Nepal.\nThese cases highlight the emergence of TSST-1- and PVL-positive CA-MRSA infection and its association with life-threatening community-acquired necrotizing pneumonia. Clinicians should note the possibility of introducing MRSA strains from abroad and be aware of this illness to initiate appropriate treatment.",
"affiliations": "Department of Emergency and Critical Care Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Microbiology and Infection Diseases, Toho University School of Medicine, Tokyo, Japan.;Department of Microbiology and Infection Diseases, Toho University School of Medicine, Tokyo, Japan.;Department of Emergency and Critical Care Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Emergency and Critical Care Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Emergency and Critical Care Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Emergency and Critical Care Medicine, Saitama Red Cross Hospital, Saitama, Japan.",
"authors": "Hayakawa|Katsura|K|0000-0003-3680-7407;Yamaguchi|Tetsuo|T|0000-0002-6220-1890;Ono|Daisuke|D|;Suzuki|Hajime|H|;Kamiyama|Jiro|J|0000-0001-5956-4511;Taguchi|Shigemasa|S|;Kiyota|Kazuya|K|0000-0003-4423-4434",
"chemical_list": null,
"country": "New Zealand",
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"doi": "10.2147/IDR.S262123",
"fulltext": "\n==== Front\nInfect Drug Resist\nInfect Drug Resist\nidr\nidr\nInfection and Drug Resistance\n1178-6973 Dove \n\n262123\n10.2147/IDR.S262123\nCase Series\nTwo Cases of Intrafamilial Transmission of Community-Acquired Methicillin-Resistant Staphylococcus aureus Producing Both PVL and TSST-1 Causing Fatal Necrotizing Pneumonia and Sepsis\nHayakawa et alHayakawa et alhttp://orcid.org/0000-0003-3680-7407Hayakawa Katsura 1 http://orcid.org/0000-0002-6220-1890Yamaguchi Tetsuo 2 Ono Daisuke 2 Suzuki Hajime 1 http://orcid.org/0000-0001-5956-4511Kamiyama Jiro 1 Taguchi Shigemasa 1 http://orcid.org/0000-0003-4423-4434Kiyota Kazuya 1 1 Department of Emergency and Critical Care Medicine, Saitama Red Cross Hospital, Saitama, Japan\n2 Department of Microbiology and Infection Diseases, Toho University School of Medicine, Tokyo, Japan\nCorrespondence: Katsura Hayakawa Department of Emergency and Critical Care Medicine, Saitama Red Cross Hospital, 1-5 Shintoshin, Chu-o-Ku, Saitama City330-8553, JapanTel +81-48-852-1111Fax +81-48-852-3120 Email gene1982jp@gmail.com\n20 8 2020 \n2020 \n13 2921 2927\n10 5 2020 06 8 2020 © 2020 Hayakawa et al.2020Hayakawa et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Introduction\nStaphylococcus aureus produces numerous toxins, such as toxic shock syndrome toxin 1 (TSST-1) and Panton–Valentine leukocidin (PVL). We isolated community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) strains producing both TSST-1 and PVL isolated from severe necrotizing pneumonia cases in a Nepali family. Detection of these CA-MRSA strains is rare in the world, and infection with these strains can take a rapidly progressive and lethal course. In this study, we traced the clinical course of this case and conducted a genetic analysis of the isolated strains.\n\nCase Report\nWe described 2 familial cases (a 20-year-old male and 61-year-old female) of severe necrotizing pneumonia caused by CA-MRSA with the TSST-1 and PVL genes. A 20-year-old Nepalese male was admitted to our hospital after a 3-day history of high fever and coughing. Despite resuscitation efforts, he died of multiple organ failure. A 61-year-old Nepalese female was admitted to our hospital with a complaint of high fever and dyspnea for 1 day. She was the grandmother of the male subject and mostly stayed at his residence in Japan. We administered intravenous antibiotics, including anti-MRSA antibiotics, and she improved in 2 weeks. The sequence type of the isolates was ST22/SCCmec type IVa, and the spa type was t005. The virulence genes detected were as follows: PVL gene (lukSF-pv), TSST-1 gene (tst-1), sec, seg, sei, sel, sem, sen, seo, and seu. ST22 was not the dominant CA-MRSA clone type in Japan. Some of the reports demonstrated that PVL-/TSST-1-positive ST22-MRSA strains are prevalent in Nepal. Therefore, the MRSA strains were thought to be acquired from Nepal.\n\nConclusion\nThese cases highlight the emergence of TSST-1- and PVL-positive CA-MRSA infection and its association with life-threatening community-acquired necrotizing pneumonia. Clinicians should note the possibility of introducing MRSA strains from abroad and be aware of this illness to initiate appropriate treatment.\n\nKeywords\ncommunity-acquired methicillin-resistant Staphylococcus aureusCA-MRSAtoxic shock syndrome toxin 1TSST-1Panton–Valentine leukocidinPVLnecrotizing pneumoniaNo external fundingNo external funding was acquired for this study. All investigations were funded internally.\n==== Body\nIntroduction\nStaphylococcus aureus is one of the most common pathogens causing various human infections, including skin, soft tissue, respiratory, bone, joint, and endovascular infections.1 Methicillin-resistant S. aureus (MRSA) strains are also known to be hospital- or healthcare-associated pathogens [hospital- or healthcare-associated MRSA (HA-MRSA)].2 Since the mid-1990s, the healthcare system has reported many MRSA infections in patients lacking risk factors for exposure. This new MRSA strain is called community-associated MRSA (CA-MRSA).3 Molecular typing studies have shown that CA-MRSA differs from HA-MRSA.4 CA-MRSA belongs to distinct genetic lineages, and it usually carries smaller staphylococcal cassette chromosome mec (SCCmec) cassettes such as type IV SCCmec and specific virulence factors such as Panton–Valentine leukocidin (PVL).5 PVL is a cytotoxin that causes leukocyte destruction and tissue necrosis, including severe necrotizing fasciitis and necrotizing pneumonia.6–8 PVL is thought to be the important factor for the virulence of CA-MRSA. Among CA-MRSA, USA300 clone (ST8/SCCmec IV/PVL+) is a major CA-MRSA clone that is endemic in the United States and causes various types of infectious diseases, from skin and soft-tissue infections to more invasive diseases, such as pneumonia, bacteremia, and osteomyelitis.5,9 Meanwhile, other CA-MRSA clones are prevalent in other parts of the world, such as the Southwest Pacific clone (ST30/SCCmec IV/PVL +), the Taiwanese clone (ST59/SCCmec IV or V/PVL +), and the European clone (ST80/SCCmec IV/PVL +).4,5,10 In Japan, PVL-producing CA-MRSA is less common, while toxic shock syndrome toxin-1 (TSST-1)-producing CA-MRSA and exfoliative toxin (ET)-producing CA-MRSA have been found to be common. Analysis of CA-MRSA isolated from the skin showed that among SCCmec type IV-MRSA strains, 18.8% were PVL-producing strains, 7.9% were ET-producing strains and 43.2% were TSST-1-producing strains.11 TSST-1 is a superantigen that causes toxic shock syndrome (TSS) characterized by high fever, erythematous rash, hypotension and multiple organ failure; it is commonly known as a toxin produced by the New York/Japan clone (ST5/SCCmec type II), a representative clone of HA-MRSA.12 In summary, TSST-1-producing CA-MRSA is common in Japan, but the incidence of PVL-producing CA-MRSA is gradually on the rise.11,13\n\nRecently, we obtained CA-MRSA strains producing both PVL and TSST-1 isolated from severe necrotizing pneumonia cases in a Nepali family. Detection of CA-MRSA with this characteristic is rare not only in Japan but also in the world. There has been a report that methicillin-sensitive Staphylococcus aureus (MSSA), which produces both toxins, has caused severe pneumonia; thus, this MRSA clone may be highly virulent.14 Because we considered the experience of this case to be valuable and important, in this study, we traced the exact clinical course of this case and conducted a genetic analysis of the isolated strains.\n\nCase Report\nCase 1\nA 20-year-old Nepalese male was admitted to our hospital after a 3-day history of a high fever and cough. He had been previously seen at another local clinic where he was diagnosed with influenza and treated with oral oseltamivir for the first 3 days. On the fourth day, he developed dyspnea and was admitted to our hospital on the same day. He did not have any relevant past history and had not been prescribed any medications. He came to Japan for employment almost five years ago with his parents and took his residence in Saitama Prefecture.\n\nHis vital signs on the day of admission were as follows: level of consciousness, E3V4M6/Glasgow Coma Scale; blood pressure, 100/72 mmHg; heart rate, 133 beats per minute; body temperature, 38.4 °C; respiratory rate, 24 breaths per minute; and peripheral capillary oxygen saturation level at an O2 flow rate of 2 liters per minute, 94%. Physical examination revealed lower respiratory sounds, and a few moist rales were heard in both lungs on chest auscultation. Laboratory data revealed a white blood cell (WBC) count of 700/mm3, a blood platelet count of 82,000/mm3, a C-reactive protein (CRP) level of 23.2 mg/dl, a blood urea nitrogen (BUN) level of 26.3 mg/dl, and a serum creatinine level of 2.2 mg/dl. The results of liver function tests were normal except for a lactate dehydrogenase (LDH) level of 618 IU/l. A chest computed tomography (CT) scan showed infiltrative and nodular shadows with pneumatocele formation in the right upper lobe (Figure 1).Figure 1 A chest computed tomography (CT) scan in Case 1 shows infiltrative and nodular shadows with pneumatocele formation in the right upper lobe.\n\n\n\nAt first, we diagnosed severe bacterial pneumonia after influenza and septic shock and initiated the administration of lactate Ringer’s solution, noradrenalin infusion, and intravenous tazobactam/piperacillin (TAZ/PIPC) (4.5 g, 4 times daily) and azithromycin (AZM) (500 mg, once a day). However, his vital signs did not improve, and he developed respiratory failure requiring mechanical ventilation support. After rapid deterioration of his arterial oxygenation level, we introduced veno-veno extracorporeal membrane oxygenation support. Because gram-positive staphylococci were detected from sputum and blood samples collected on admission, we added linezolid (600 mg, 2 times daily, intravenously) on day 2. On the same day, we performed a bronchoscopy, which showed diffuse inflammatory changes and easy bleeding (Figure 2). Therefore, we suspected necrotizing pneumonia caused by CA-MRSA. He underwent multidisciplinary treatment; however, his respiratory condition gradually worsened. Despite resuscitation efforts, he died of multiple organ failure on day 7. The isolates from the culture of blood and sputum samples on the day of hospital admission were MRSA strains TUM18988 and TUM18989. Additionally, his father, who lived with him in Japan, had a negative nasal swab test for MRSA.Figure 2 Bronchoscopy in Case 1 shows diffuse inflammatory changes and easy bleeding.\n\n\n\nCase 2\nA 61-year-old Nepalese female was admitted to our hospital with a complaint of a high fever and dyspnea for 1 day. She was admitted 5 days later than the admission of Case 1. She did not have any relevant past medical history and had not been prescribed any medications, including antibiotics. She and her husband had come to tour Japan 3 months previously. She was the grandmother of Case 1 and mostly stayed at his residence.\n\nHer vital signs on the day of admission were as follows: blood pressure, 139/86 mmHg; heart rate, 139 beats per minute; body temperature, 39.0 °C; respiratory rate, 35 breaths per minute; and a peripheral capillary oxygen saturation level on 3 liters of O2 per minute, 96%. Laboratory data revealed a WBC count of 23,680/mm3 and a CRP level of 43.2 mg/dl. A rapid test performed on a nasal swab was negative for influenza virus. A chest CT scan showed irregular consolidations and ground glass opacity and bilateral pleural effusion (Figure 3).Figure 3 A chest CT scan in Case 2 shows irregular consolidations, ground glass opacity and bilateral pleural effusion.\n\n\n\nFirst, we suspected pneumonia associated with S. aureus because we had information about the medical history of Case 1. We started intravenous ceftriaxone (1 g, 2 times daily) and linezolid (600 mg, 2 times daily). On day 2 of admission, we changed the linezolid to vancomycin (1 g, 2 times daily, intravenously) due to allergy complications. She improved in 2 weeks and was discharged on day 13. She then flew back to Kathmandu-Nepal and had a full recovery.\n\nMicrobiological Test\nStrain TUM18988 and strain TUM18989 were identified as S. aureus using the VITEK 2 system with the GP ID card panel (bioMérieux Japan Ltd., Tokyo, Japan). Determination of the minimum inhibitory concentration (MIC) of each antibiotic for the isolated strain was performed using a MicroScan WalkAway 96 Plus system with the Pos MIC 3.3J panel (Beckman Coulter, Inc., Brea, California, USA) according to the CLSI guidelines (2016).15 Strain TUM18988 and strain TUM18989 were resistant to oxacillin (MIC >2 mg/l), penicillin (MIC >8 mg/l), ampicillin (MIC >8 mg/l), meropenem (MIC =8 mg/l), cefazolin (MIC =16 mg/l), gentamicin (MIC >8 mg/l), erythromycin (MIC >4 mg/l), clindamycin (MIC ≤0.5 mg/l), and levofloxacin (MIC >4 mg/dl), but susceptible to minocycline (MIC ≤1 mg/l), arbekacin (MIC ≤1 mg/l), vancomycin (MIC =1 mg/l), teicoplanin (MIC ≤2 mg/l), linezolid (MIC =1 mg/l), and trimethoprim/sulfamethoxazole (MIC ≤0.5 mg/l). The isolate from the culture of sputum samples of Case 2 was also MRSA (strain TUM18990) and showed the same properties as strain TUM18988 and strain TUM18989.\n\nThe Genetic Features in These Cases\nBacterial genomic DNA of strain TUM18988 and strain TUM18990 were extracted using the DNeasy Blood & Tissue Kit (Qiagen, Aarhus, Denmark) with lysostaphin (Wako) as previously described.16 Genomic DNAs were used as a template for whole-genome sequencing by next-generation sequencing (NGS) using MiSeq (Illumina, San Diego, CA, USA). DNA-libraries for NGS were prepared with Nextera XT DNA sample preparation kits (Illumina) in accordance with the manufacturer’s protocol. The read data from each strain were assembled using CLC Genomics Workbench v 12.0 software (Qiagen, Aarhus, Denmark), and the obtained contigs were analyzed using the SCCmecFinder service, multilocus sequence typing (MLST) service, spaTyper service, Resfinder service, and VirulenceFinder service on the Center for Genomic Epidemiology website.17 The sequence type was ST22/SCCmec type IVa, and the spa type was t005. The virulence genes detected were as follows: PVL gene (lukSF-pv), TSST-1 gene (tst-1), sec, seg, sei, sel, sem, sen, seo, and seu (Table 1.). Furthermore, reads from each strain were mapped to the sequence of the EMRSA-15 strain (accession no. CP007659.1, the same sequence type strain as TUM18988; ST22), and the mutations between each isolate were identified by comparing the mapping sequence using CLC Genomics Workbench software. Only four SNPs were detected between TUM18988 and TUM18990 in a whole-genome comparison. The sequence data for strain TUM18988 and strain TUM18990 were deposited in the DNA Data Bank of Japan (DDBJ) under BioProject Accession number PRJDB8964.Table 1 Genetic Characteristics and Virulence Factors in Two Isolates in This Study\n\nIsolates\tGenotype\tResistant Gene\tAntimicrobial Susceptibility (μg/mL)\t\nSCCmec\tMLST\tspa\tcoa\tagr\tVirulent Gene\tAcquired\tMutations\tEM\tCLDM\tLVFX\tMINO\tST\tABK\tVCM\tLZD\t\nTUM18988 and TUM18990\tIVa\tST22\tt005\tXIa\tI\tlukSF-pv, tst-1, sec, seg, sei, sel, sem, sen, seo, seu\tblaZ, mecA, aadD, aac(6ʹ)-aph(2”), erm(C), tem(M)\tgrlA (S80F), gyrA (S84L)\t>4\t≤0.5\t>4\t≤1\t≤0.5\t≤1\t1\t1\t\n\n\n\nDiscussion\nWe present a case of intrafamilial transmission of CA-MRSA infection with severe pneumonia in a healthy person with no medical history. The genotype of both strains isolated from this case was ST22/SCCmec typeIV/TSST-1+/PVL+, which was unique in that it harbored both the TSST-1 and PVL genes. ST22 is the same clone type as the EMRSA-15 clone, which is known as the HA-MRSA clone in Europe.18 The EMRSA-15 clone was PVL-negative/TSST-1-negative, suggesting that the isolates in this study were different from the EMRSA-15 clone. Furthermore, ST22 clones are rarely isolated in Japan. ST22/SCCmec type IV clones have been detected from familial infection in Japan;19 however, ST22 was not the dominant CA-MRSA clone type in Japan,11 and this clone was PVL-positive but TSST-1-negative. Furthermore, MRSA isolates harboring PVL genes were demonstrated in Nepal and classified into ST22/SCCmec type IV and ST772/SCCmec type V.20 Some of these ST22-MRSA strains were reported to be harboring TSST-1 genes. ST22/SCCmec type IV-MRSA strains have been isolated from domestic swine and wild macaques residing in Nepal.21 Therefore, the ST22/SCCmec type IV-MRSA strain that is positive for PVL-/TSST-1 can be one of the prevailing clones in Nepal. The MRSA strains obtained from Case 1 and Case 2 were the same clones based on whole-genome comparisons. Because Case 1 who lived in Japan and developed symptoms after Case 2 from Nepal visited him, the MRSA strain was thought to be brought from Nepal and transmitted to the grandson (Case 1) from the grandmother (Case 2). Clinicians should note the possibility of introducing MRSA strains from abroad, even if the strains are not prevalent in their country, as in these cases.\n\nIn Australia, an increasing incidence of CA-MRSA infections has resulted in the addition of vancomycin to standard empiric therapy in patients with suspected CA-MRSA bacteremia.22 Because skin infection caused by CA-MRSA is common in the United States, vancomycin, trimethoprim/sulfamethoxazole in combination with rifampin, and linezolid are thought to be the first line of antimicrobial therapy for cutaneous abscesses.23 Particularly after influenza infection, MRSA pneumonia may occur even in healthy adults without any immunological abnormality.24 Our clinicians should consider the administration of anti-MRSA antibiotics to patients with suspected necrotizing pneumonia, even if it is a community-acquired infection. PVL toxin produced by CA-MRSA is not associated with superantigenic toxins, and TSST-1 genes are thought to be rarely found in PVL-positive strains.25 Although the prevalence of PVL- and TSST-1-positive MSSA/MRSA, such as in our cases, is still rare, there have been some reports in recent years.26 Most MSSA/MRSA is generally detected in skin infections.27 However, there is a report describing a fatal case of necrotizing pneumonia due to both TSST-1- and PVL-positive MSSA. This report indicated that early diagnosis and appropriate antimicrobial treatment are crucial to achieve positive results in patients infected with TSST-1 and PVL-positive MSSA.14 Linezolid is recommended for the treatment of necrotizing pneumonia caused by MRSA as it can inhibit exotoxin production.28 In our cases, we had clinical information about the culture of the sputum and blood samples of Case 1, and we could administer anti-MRSA antibiotics for Case 2 at an earlier phase.\n\nFinally, it is important to emphasize that the association between PVL and TSST-1 genes and particular clinical manifestations requires further research because other combinations of exotoxin genes could also be important pathogenic factors. However, clinicians should know about CA-MRSA with PVL and TSST-1 as a possible cause of life-threatening community-acquired necrotizing pneumonia.\n\nConclusion\nIn conclusion, we described 2 familial cases of severe necrotizing pneumonia caused by CA-MRSA with TSST-1 and PVL genes in Japan. This MRSA strain was thought to be brought from Nepal. CA-MRSA necrotizing pneumonia should be considered in the differential diagnosis of severe community-associated pneumonia, particularly in healthy adults. Additionally, the CA-MRSA strains can be brought from abroad, even if they are not prevalent in one’s own country, as in our cases. Appropriate early treatment with antibiotics, including anti-MRSA antibiotics such as vancomycin or linezolid, should be initiated when severe necrotizing pneumonia is suspected.\n\nAcknowledgment\nThe author thanks American Journal Experts for English proofreading of this manuscript.\n\nAbbreviations\nMRSA, methicillin-resistant Staphylococcus aureus; HA-MRSA, hospital- or healthcare-associated MRSA; CA-MRSA, community-acquired MRSA; SCCmec, staphylococcal cassette chromosome mec; PVL, Panton–Valentine leucocidin; TSST-1, toxic shock syndrome toxin 1; MSSA, methicillin-sensitive Staphylococcus aureus; WBC, white blood cell; CRP, C-reactive protein; BUN, blood urea nitrogen; LDH, lactate dehydrogenase; CT, computed tomography; TAZ/PIPC, tazobactam/piperacillin; AZM, azithromycin; MIC, minimum inhibitory concentration; DNA, deoxyribonucleic acid; MLST, multilocus sequence typing.\n\nEthical Approval and Consent for Publication\nInformed consent has been obtained from patient one’s father and patient two. And written consent (including for the accompanying images) has been obtained for publication in an online journal. The institutional approval was not required to publish the case details.\n\nDisclosure\nThe authors report no conflicts of interest for this work.\n==== Refs\nReferences\n1. Lowy \nFD . Staphylococcus aureus infections\n. N Engl J Med . 1998 ;339 (8 ):520 –532\n. doi:10.1056/NEJM199808203390806 9709046 \n2. Moellering \nRC \nJr. MRSA: the first half century\n. J Antimicrob Chemother . 2012 ;67 (1 ):4 –11\n. doi:10.1093/jac/dkr437 22010206 \n3. David \nMZ , Daum \nRS . Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic\n. Clin Microbiol Rev . 2010 ;23 (3 ):616 –687\n.20610826 \n4. Lee \nAS , de Lencastre \nH , Garau \nJ , et al. Methicillin-resistant Staphylococcus aureus\n. Nat Rev Dis Primers . 2018 ;4 :18033 . doi:10.1038/nrdp.2018.33 29849094 \n5. 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"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6973",
"issue": "13()",
"journal": "Infection and drug resistance",
"keywords": "CA-MRSA; PVL; Panton–Valentine leukocidin; TSST-1; community-acquired methicillin-resistant Staphylococcus aureus; necrotizing pneumonia; toxic shock syndrome toxin 1",
"medline_ta": "Infect Drug Resist",
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"other_id": null,
"pages": "2921-2927",
"pmc": null,
"pmid": "32903848",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "25789579;10524952;20206987;29849094;30579658;20610826;15325596;15153884;31523765;7901274;22010206;18532937;29668933;12967497;16914702;18064027;9709046;23824366;22160592;23827369;17234914;20173050;24073746;15872271;27014464;25781188",
"title": "Two Cases of Intrafamilial Transmission of Community-Acquired Methicillin-Resistant Staphylococcus aureus Producing Both PVL and TSST-1 Causing Fatal Necrotizing Pneumonia and Sepsis.",
"title_normalized": "two cases of intrafamilial transmission of community acquired methicillin resistant staphylococcus aureus producing both pvl and tsst 1 causing fatal necrotizing pneumonia and sepsis"
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"abstract": "Prostate cancer usually metastasizes to regional lymph nodes and bone. Laryngeal cartilage metastases are very rare and only few cases have been published so far describing thyroid cartilage metastatic lesions from prostate cancer. Here, we describe 5 cases of carcinoma prostate, 3 staging and 2 follow-up, where 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography (PET/CT) scan revealed multiple skeletal lesions along with thyroid cartilage metastasis. Initially, laryngeal cartilage metastases remain asymptomatic and in later stages patients present with symptoms. These metastatic lesions to thyroid cartilage are rare entities and can often easily be missed on conventional imaging. PET-CT imaging has overcome this diagnostic problem due to its ability to provide for both anatomical and functional imaging.",
"affiliations": "Department of Nuclear Medicine, Mahajan Imaging Centre, Sir Ganga Ram Hospital, New Delhi, India.;Department of Nuclear Medicine, Mahajan Imaging Centre, Sir Ganga Ram Hospital, New Delhi, India.;Department of Nuclear Medicine, Mahajan Imaging Centre, Sir Ganga Ram Hospital, New Delhi, India.",
"authors": "Gupta|Nitin|N|;Verma|Ritu|R|;Belho|Ethel Shangne|ES|",
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"doi": "10.4103/ijnm.ijnm_218_20",
"fulltext": "\n==== Front\nIndian J Nucl Med\nIndian J Nucl Med\nIJNM\nIndian Journal of Nuclear Medicine : IJNM : The Official Journal of the Society of Nuclear Medicine, India\n0972-3919\n0974-0244\nWolters Kluwer - Medknow India\n\nIJNM-36-183\n10.4103/ijnm.ijnm_218_20\nCase Report\nMetastatic Thyroid Cartilage Lesion from Prostatic Adenocarcinoma on 68Ga-Prostate-Specific Membrane Antigen Positron Emission Tomography-Computed Tomography Scan: Case Series\nGupta Nitin\nVerma Ritu\nBelho Ethel Shangne\nDepartment of Nuclear Medicine, Mahajan Imaging Centre, Sir Ganga Ram Hospital, New Delhi, India\nAddress for correspondence: Dr. Nitin Gupta, Department of Nuclear Medicine, Mahajan Imaging Centre, Sir Ganga Ram Hospital, New Delhi, India. E-mail: drnitingpt@gmail.com\nApr-Jun 2021\n21 6 2021\n36 2 183188\n26 10 2020\n02 12 2020\n07 12 2020\nCopyright: © 2021 Indian Journal of Nuclear Medicine\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nProstate cancer usually metastasizes to regional lymph nodes and bone. Laryngeal cartilage metastases are very rare and only few cases have been published so far describing thyroid cartilage metastatic lesions from prostate cancer. Here, we describe 5 cases of carcinoma prostate, 3 staging and 2 follow-up, where 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography (PET/CT) scan revealed multiple skeletal lesions along with thyroid cartilage metastasis. Initially, laryngeal cartilage metastases remain asymptomatic and in later stages patients present with symptoms. These metastatic lesions to thyroid cartilage are rare entities and can often easily be missed on conventional imaging. PET-CT imaging has overcome this diagnostic problem due to its ability to provide for both anatomical and functional imaging.\n\n68Ga prostate-specific membrane antigen positron emission tomography/computed tomography scan\nadenocarcinoma prostate gland\nthyroid cartilage\n==== Body\nIntroduction\n\nProstate cancer is primarily a disease of the elderly with majority of patients presenting with age above 65 years.[1] It is the most common cancer in men worldwide and fifth most common cancer overall. Most metastatic prostate cancer patients present with high serum prostate-specific antigen (PSA) levels and often metastases occur at sites such as pelvic lymph nodes (LNs), bones, lungs, and liver in advanced cases. In literature, very few cases have been described of metastatic lesions from prostate carcinoma to thyroid cartilage. Here, we describe 5 cases with rare presentation of metastatic lesions to thyroid cartilage detected on 68Ga prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) scan.\n\nCase Reports\n\nThe salient features of all 5 cases are described in Table 1.\n\nTable 1 Clinical and imaging details of patients\n\n\tAge (years)\tHistory\tScan findings\tThyroid cartilage lesions findings\t\nCase 1\t65\tStaging scan, serum PSA >100 ng/mL, Gleason’s score 4+5=9\tPSMA avid lesions in primary prostate gland and metastatic abdominal and pelvic lymph nodes, lung lesions and sclerotic skeletal lesions\tPSMA avid sclerotic lesions in both laminas of the thyroid cartilage (more in right lamina) with SUVmax of 8.7\t\nCase 2\t92\tStaging scan, serum PSA 3983.85 ng/mL, Gleason’s score 4+5=9\tPSMA avid lesions in primary prostate gland and metastatic abdominal and pelvic lymph nodes and sclerotic skeletal lesions\tPSMA avid sclerotic lesion in the left lamina of the thyroid cartilage posteriorly with associated soft-tissue component with SUVmax of 40.0\t\nCase 3\t54\tStaging scan, serum PSA 210 ng/mL, Gleason’s score 4+4=8\tPSMA avid lesions in primary prostate gland and metastatic left cervical, left supraclavicular, abdominal and pelvic lymph nodes and sclerotic skeletal lesions\tPSMA avid subtle sclerotic lesion in the right lamina of the thyroid cartilage posteriorly with SUVmax of 21.1\t\nCase 4\t72\tFollow-up case of carcinoma prostate gland, on Injection Denosumab and hormonal therapy, being evaluated for rising serum PSA levels, with recent value of 411 ng/mL\tPSMA avid lesions in primary prostate gland and metastatic mildly PSMA avid liver lesions, left adrenal gland lesion, and sclerotic skeletal lesions\tPSMA avid mixed lytic-sclerotic lesion in the left lamina of the thyroid cartilage with SUVmax of 8.8\t\nCase 5\t69\tFollow up case of carcinoma prostate gland, on hormonal therapy, being evaluated for rising serum PSA levels with recent value of 180 ng/ml\tPSMA avid lesions in primary prostate gland and metastatic liver lesions, abdominal lymph nodes and skeletal lesions\tPSMA avid sclerotic lesion in the right lamina of thyroid cartilage with SUVmax of 11.6\t\nPSA: Prostate-specific antigen, SUVmax: Maximum standardized uptake values, PSMA: Prostate-specific membrane antigen\n\nCase 1\n\nA 65-year-old male patient, recently diagnosed case of carcinoma prostate gland, was referred for staging whole body 68Ga-PSMA PET/CT scan. Anterior and lateral maximal intensity projection (MIP) [Figure 1a and b] images revealed multiple PSMA avid lesions. Axial CT and fused PET/CT images [Figure 1c–f] in bone and soft-tissue window showed PSMA avid sclerotic lesions in the bilateral laminae of the thyroid cartilage. Axial CT and fused PET/CT images [Figure 1g and h] also showed PSMA avid primary lesion in the prostate gland.\n\nFigure 1 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography scan, anterior and lateral maximal intensity projection (a and b) suggestive of multiple prostate-specific membrane antigen avid lesions. Axial computed tomography and fused positron emission tomography/computed tomography images (c-f) showing prostate-specific membrane antigen avid lesions in the thyroid cartilage and multiple prostate-specific membrane antigen avid sclerotic skeletal metastases. Axial computed tomography and fused positron emission tomography/computed tomography images (g and h) showing prostate-specific membrane antigen avid primary lesion in the prostate gland\n\nCase 2\n\nA 92-year-old male, recently diagnosed case of carcinoma prostate gland was referred for staging 68Ga-PSMA PET/CT scan. Anterior and lateral MIP [Figure 2a and b] image showed multiple PSMA avid lesions. Axial CT and fused PET/CT images [Figure 2c–f] in bone and soft-tissue window showed PSMA avid sclerotic lesion in the left lamina of the thyroid cartilage. Axial CT and fused PET/CT images [Figure 2g and h] also showed PSMA avid primary lesion in the prostate gland.\n\nFigure 2 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography scan, anterior and lateral maximal intensity projection (a and b) image showing multiple prostate-specific membrane antigen avid lesions. Axial computed tomography and fused positron emission tomography/computed tomography images (c-f) showing prostate-specific membrane antigen avid lesion in the left lamina of the thyroid cartilage posteriorly and few prostate-specific membrane antigen avid sclerotic skeletal metastasis. Axial computed tomography and fused positron emission tomography/computed tomography images (g and h) showing prostate-specific membrane antigen avid primary lesion in the prostate gland\n\nCase 3\n\nA 54-year-old male patient, recently diagnosed case of carcinoma prostate gland, was referred for staging 68Ga-PSMA PET/CT scan. Anterior and lateral MIP [Figure 3a and b] images showed multiple PSMA avid lesions. Axial CT and fused PET/CT images [Figure 3c–f] in bone and soft-tissue window showed PSMA avid subtle sclerotic lesion in the right lamina of the thyroid cartilage. Axial CT and fused PET/CT images [Figure 3g and h] also showed PSMA avid primary lesion in the prostate gland.\n\nFigure 3 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography scan, anterior and lateral maximal intensity projection (a and b) image showing extensive prostate-specific membrane antigen avid metastatic lesions. Axial computed tomography and fused positron emission tomography/computed tomography images (c-f) showing prostate-specific membrane antigen avid lesion in the right lamina of the thyroid cartilage posteriorly. Axial computed tomography and fused positron emission tomography/computed tomography images (g and h) showing prostate-specific membrane antigen avid primary lesion in the prostate gland and multiple prostate-specific membrane antigen avid sclerotic skeletal metastases\n\nCase 4\n\nA 72-year-old male patient, follow-up case of carcinoma prostate gland, on injection denosumab and hormonal therapy, being evaluated for rising serum PSA levels, was referred for 68Ga-PSMA PET/CT scan. Anterior and lateral MIP [Figure 4a and b] images showed multiple PSMA avid lesions. Axial CT and fused PET/CT images [Figure 4c–f] in bone and soft-tissue window showed PSMA avid mixed lytic-sclerotic lesion in the left lamina of the thyroid cartilage with maximum standardized uptake values (SUVmax) of 8.8. Axial CT and fused PET/CT images [Figure 4g and h] also showed PSMA avid primary lesion in the prostate gland.\n\nFigure 4 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography scan, anterior and lateral maximal intensity projection (a and b) image suggestive of multiple PSMA avid metastatic lesions. Axial computed tomography and fused positron emission tomography/computed tomography images (c-f) showing prostate-specific membrane antigen avid lesion in left lamina of the thyroid cartilage and few prostate-specific membrane antigen avid sclerotic skeletal lesions. Axial computed tomography and fused positron emission tomography/computed tomography images (g and h) showing prostate-specific membrane antigen avid primary lesion in the prostate gland and few prostate-specific membrane antigen avid sclerotic skeletal lesions\n\nCase 5\n\nA 69-year-old male patient, follow-up case of carcinoma prostate gland, on hormonal therapy, being evaluated for rising serum PSA levels, was referred for 68Ga-PSMA PET/CT scan. Anterior and lateral MIP [Figure 5a and 5b] images showed multiple PSMA avid lesions. Axial CT and fused PET/CT images [Figure 5c–f] in bone and soft-tissue window showed PSMA avid sclerotic lesion in the thyroid cartilage with SUVmax of 11.6. Axial CT and fused PET/CT images [Figure 5g–h] also showed PSMA avid primary lesion in the prostate gland.\n\nFigure 5 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography scan, Anterior and lateral maximal intensity projection (a and b) suggestive of multiple prostate-specific membrane antigen avid lesions. Axial computed tomography and fused positron emission tomography/computed tomography images (c-f) showing prostate-specific membrane antigen avid lesion in the right lamina of the thyroid cartilage. Axial computed tomography and fused positron emission tomography/computed tomography images (g and h) suggestive of prostate-specific membrane antigen avid primary lesion in the prostate gland and prostate-specific membrane antigen avid skeletal metastases\n\nDiscussion\n\nProstate cancer is mainly a disease of the elderly with majority of the cases occurring in men above 65 years of age. Prostate cancer is the most common cancer in men and is the second leading cause of cancer deaths among men.[2] PSMA is a Type II integral membrane glycoprotein with a large extracellular domain,[3] with increased expression in metastatic disease and disease recurrence. Accurate staging of prostate cancer is of high importance for treatment decisions and patient management. Prostate cancer most often spreads to LNs and bone, and high PSMA expression has been demonstrated in adenocarcinoma of the prostate and its metastatic sites.\n\nMelanomas and hypernephromas have been found to be the most common tumors in case of laryngeal metastasis diagnosis, followed by breast, lung, and colon tumors.[4] Although prostate cancer can metastasize to any part of the body, thyroid cartilage metastases are extremely rare and only few reports are available in literature describing the same. Metastatic involvement of the larynx is very uncommon due to the absence of vessels within the cartilaginous tissue. The thyroid cartilage involvement is suggestive of poor prognosis as it means extensive metastases.[5] In case of advanced prostatic cancer, the ossified laryngeal cartilage can be affected, like any other bone of the skeleton. The tumor cells first metastasize to the hematopoietic tissue within the laryngeal cartilages, followed by local destruction and subsequent development of a perilaryngeal soft-tissue mass.[5] The various symptoms with which the patient can present are hoarseness of voice, neck pain, or respiratory distress.[6] The first fully documented case was from an adenocarcinoma of the kidney.[7] The first case report describing thyroid cartilage metastasis from prostate cancer was published in 1954.[6] Few cases have been described in literature previously of metastasis to cartilages of larynx.[89101112] The laryngeal metastases usually remain unnoticed and may or may not present with clinical symptoms. The same was seen in our series and none of the patient had any thyroid cartilage involvement symptoms and since multiple metastases were seen, the histopathological confirmation of the thyroid cartilage lesions was not done. Out of 5 patients discussed in our series, 3 had thyroid cartilage involvement in staging and only and in other 2 the metastatic lesions in thyroid cartilage were detected on follow-up.\n\nThe CT characteristics features for detecting cartilage involvement by neoplastic lesion are sclerosis, erosion, lysis, and presence of extralaryngeal tissue. While sclerosis has high sensitivity (83%), it has low specificity (40% for thyroid cartilage).[13] Erosion or lysis are highly specific criteria (86–95%) for neoplastic cartilage disease, however, their sensitivity varies, as they occur in late course of disease. Magnetic resonance imaging has high sensitivity (89–95%) but lower specificity (74–84%) as compared to CT for the detection of cartilage invasion.[14] The recent fusion imaging PSMA PET/CT scan can help in staging carcinoma prostate and detecting common and uncommon sites of metastasis due to high sensitivity. This case series highlights the great potential of PSMA PET/CT in detecting anatomically occult lesions which would have been otherwise missed on conventional imaging.\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\n1 Hariharan K Padmanabha V Demography and disease characteristics of prostate cancer in India Indian J Urol 2016 32 103 8 27127351\n2 Siegel RL Miller KD Jemal A Cancer statistics, 2020 CA Cancer J Clin 2020 70 7 30 31912902\n3 Jadvar H PSMA PET in prostate cancer J Nucl Med 2015 56 1131 2 25977465\n4 Batsakis JG Luna MA Byers RM Metastases to the larynx Head Neck Surg 1985 7 458 60 4044264\n5 Prescher A Schick B Stütz A Brors D Laryngeal prostatic cancer metastases: An underestimated route of metastases? Laryngoscope 2002 112 1467 73 12172264\n6 EHRLICH A Tumor involving the laryngeal cartilages AMA Arch Otolaryngol 1954 59 178 85 13123639\n7 Turner AL Metastatic malignant tumour of the larynx, secondary to adenocarcinoma of the right kidney J Laryngol Otol 1924 39 181 94\n8 Tupalli A Damle NA Thankarajan AS Mangu BS Kumar A Khan D An unusual case of simultaneous cricoid and thyroid cartilage metastases from prostatic adenocarcinoma on 68Ga-PSMA PET/CT Nucl Med Mol Imaging 2020 54 61 2 32206134\n9 Annovazzi A Faiella A Pescarmona E Sanguineti G Sciuto R Asymptomatic metastasis to thyroid cartilage detected by 18F-choline and 64Cu-PSMA PET/CT as a single site of disease relapse in a patient with castration-resistant prostate carcinoma Clin Nucl Med 2020 45 214 6 31652161\n10 Escudero RM Amo FH Martínez MC Jiménez JT Alonso AH Piniés GO Metastatic prostate cancer on the thyroid cartilage: Unusual symptoms of prostatic adenocarcinoma.Case report Arch Esp Urol 2011 64 132 5 21422500\n11 Olvera M Delgado M Vázquez M Zavala J Macedo V Puentes M Unusual presentation of prostate cancer metastatic to the cricoid cartilage and oral cavity Case Rep Med 2018 2018 5207204 29692814\n12 Ng SJ Sinha AK Loi HY Khor LK Asymptomatic metastasis to cricoid from prostate carcinoma: An incidental finding detected on 18F-choline PET/CT Jpn J Radiol 2015 33 298 301 25820451\n13 Beitler JJ Muller S Grist WJ Corey A Klein AM Johns MM Prognostic accuracy of computed tomography findings for patients with laryngeal cancer undergoing laryngectomy J Clin Oncol 2010 28 2318 22 20368569\n14 Zbären P Becker M Läng H Pretherapeutic staging of laryngeal carcinoma.Clinical findings, computed tomography, and magnetic resonance imaging compared with histopathology Cancer 1996 77 1263 73 8608501\n\n",
"fulltext_license": "CC BY-NC-SA",
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"issue": "36(2)",
"journal": "Indian journal of nuclear medicine : IJNM : the official journal of the Society of Nuclear Medicine, India",
"keywords": "68Ga prostate-specific membrane antigen positron emission tomography/computed tomography scan; adenocarcinoma prostate gland; thyroid cartilage",
"medline_ta": "Indian J Nucl Med",
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"title": "Metastatic Thyroid Cartilage Lesion from Prostatic Adenocarcinoma on 68Ga-Prostate-Specific Membrane Antigen Positron Emission Tomography-Computed Tomography Scan: Case Series.",
"title_normalized": "metastatic thyroid cartilage lesion from prostatic adenocarcinoma on 68ga prostate specific membrane antigen positron emission tomography computed tomography scan case series"
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"abstract": "A 62-year-old patient diagnosed with pulmonary blastoma with submandibular, scrotum and adrenal metastases was admitted to Sotiria General Hospital in Athens. No other such case has been published to date. The patient started receiving chemotherapy, but the scrotum metastasis grew rapidly and erupted. This led to sepsis despite surgical excision of infected and necrotic tissues and intravenous antibiotics. Treatment strategy in pulmonary blastoma should be defined by a multidisciplinary team, and surgical treatment should be considered as quickly as possible when such a tumor is suspected.",
"affiliations": "Oncology Unit, 3rd Department of Medicine, Sotiria General Hospital, Athens University School of Medicine, Athens, Greece. knsyrigos@usa.net",
"authors": "Syrigos|Kostas N|KN|;Katirtzoglou|Nikolaos|N|;Ntomi|Vasileia|V|;Pierrakou|Aikaterini|A|;Chorti|Maria|M|;Stratakos|Grigorios|G|;Dannos|Ioannis|I|;Saif|Muhammad W|MW|",
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"mesh_terms": "D000310:Adrenal Gland Neoplasms; D001706:Biopsy; D001999:Bronchoscopy; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005834:Genital Neoplasms, Male; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D018202:Pulmonary Blastoma; D012611:Scrotum; D013365:Submandibular Gland Neoplasms; D014057:Tomography, X-Ray Computed",
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"references": null,
"title": "Pulmonary blastoma with submandibular, scrotum and adrenal metastases: case report.",
"title_normalized": "pulmonary blastoma with submandibular scrotum and adrenal metastases case report"
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"abstract": "We retrospectively analyzed late small bowel toxicity in patients who received abdominal or pelvic intensity modulated radiation therapy (IMRT) to the small bowel with a maximum dose greater than the generally accepted maximal tolerable dose of 45 Gy.\nAll patients (N = 94) who received IMRT with a point dose of at least 45 Gy to tightly contoured small bowel between 2005 and 2014 at our institution were included. The median prescribed treatment dose was 70.2 Gy. The median follow-up was 20.1 months. Late small bowel toxicity was assessed using the Common Terminology Criteria for Adverse Events Version 3.0. Dosimetric variables and clinical factors were assessed for their relationship to small bowel toxicity.\nThe median maximal small bowel point dose (Dmax) was 6546.5 cGy. The estimated 5-year rates of freedom from at least grade 1, at least grade 2, and at least grade 3 late small bowel toxicity were 72.4% (95% confidence interval [CI], 60.7%-86.5%), 91.9% (95% CI, 84.1%-100%), and 93.6% (95% CI, 86.2%-100%), respectively. One patient (1.1%) developed grade 3 late toxicity, and 2 patients (2.1%) developed grade 4 late toxicity. Use of capecitabine/5-fluorouracil treatment was a significant predictor (P < 0.001) of at least grade 1 and at least grade 2 small bowel toxicity. No other clinical factors were associated with toxicity. None of the dose-volume parameters were significant predictors of small bowel toxicity.\nIt may be possible with IMRT to deliver high doses to small volumes of small bowel with low rates of significant long-term complications. Further studies should explore tolerable dose-volume relationships in cases in which aggressive abdominal or pelvic treatment may be warranted to treat the underlying malignancy.",
"affiliations": "Department of Radiation Oncology, Mount Sinai West Hospital, New York, New York.;Department of Radiation Oncology, Mount Sinai West Hospital, New York, New York.;Department of Radiation Oncology, Mount Sinai West Hospital, New York, New York.;Department of Radiation Oncology, Mount Sinai West Hospital, New York, New York.",
"authors": "Ling|Andrew|A|;Furhang|Eli|E|;Ryemon|Shannon N|SN|;Ennis|Ronald D|RD|",
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"fulltext": "\n==== Front\nAdv Radiat OncolAdv Radiat OncolAdvances in Radiation Oncology2452-1094Elsevier S2452-1094(17)30191-410.1016/j.adro.2017.09.005Side EffectLate small bowel toxicity after aggressive abdominopelvic intensity modulated radiation therapy Ling Andrew BAaFurhang Eli PhD, DABMPaRyemon Shannon N. MSaEnnis Ronald D. MDre230@cinj.rutgers.eduab*a Department of Radiation Oncology, Mount Sinai West Hospital, New York, New Yorkb Icahn School of Medicine at Mount Sinai, New York, New York* Corresponding author. Rutgers Cancer Institute of NJ, 195 Little Albany St, New Brunswick, NJ 08901Rutgers Cancer Institute of NJ195 Little Albany StNew BrunswickNJ08901 re230@cinj.rutgers.edu08 9 2017 Oct-Dec 2017 08 9 2017 2 4 615 623 15 5 2017 17 8 2017 6 9 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nWe retrospectively analyzed late small bowel toxicity in patients who received abdominal or pelvic intensity modulated radiation therapy (IMRT) to the small bowel with a maximum dose greater than the generally accepted maximal tolerable dose of 45 Gy.\n\nMethods and materials\nAll patients (N = 94) who received IMRT with a point dose of at least 45 Gy to tightly contoured small bowel between 2005 and 2014 at our institution were included. The median prescribed treatment dose was 70.2 Gy. The median follow-up was 20.1 months. Late small bowel toxicity was assessed using the Common Terminology Criteria for Adverse Events Version 3.0. Dosimetric variables and clinical factors were assessed for their relationship to small bowel toxicity.\n\nResults\nThe median maximal small bowel point dose (Dmax) was 6546.5 cGy. The estimated 5-year rates of freedom from at least grade 1, at least grade 2, and at least grade 3 late small bowel toxicity were 72.4% (95% confidence interval [CI], 60.7%-86.5%), 91.9% (95% CI, 84.1%-100%), and 93.6% (95% CI, 86.2%-100%), respectively. One patient (1.1%) developed grade 3 late toxicity, and 2 patients (2.1%) developed grade 4 late toxicity. Use of capecitabine/5-fluorouracil treatment was a significant predictor (P < 0.001) of at least grade 1 and at least grade 2 small bowel toxicity. No other clinical factors were associated with toxicity. None of the dose-volume parameters were significant predictors of small bowel toxicity.\n\nConclusion\nIt may be possible with IMRT to deliver high doses to small volumes of small bowel with low rates of significant long-term complications. Further studies should explore tolerable dose-volume relationships in cases in which aggressive abdominal or pelvic treatment may be warranted to treat the underlying malignancy.\n==== Body\nSummary\nDose-volume thresholds that are strongly associated with late small bowel toxicity to guide clinical care are not well established, especially at the low volume–high dose range. A retrospective analysis of associations between dose-volume statistics, clinical factors, and the incidence of late small bowel toxicity in a cohort of 94 patients was conducted. Our data suggest that it may be possible to treat small volumes of small bowel above 45 to 50 Gy with acceptably low long-term toxicity risk.\n\nAlt-text: Unlabelled box\n\n\n\nIntroduction\nRadiation therapy for abdominal or pelvic malignancies can result in small bowel toxicity. Previous estimatesof the incidence of late small bowel toxicity, based on expert opinions in the pre–intensity modulated radiation therapy (IMRT) era, suggest that the complication probability of 5% after 5 years (TD5/5) for severe toxicity is at a dose of 50 Gy for irradiating one third of the small bowel.1\n\nRelationships between dose-volume statistics and the incidence of acute small bowel toxicity have been assessed in patients with rectal and gynecologic cancers who received concurrent chemotherapy.2, 3, 4, 5 On the basis of these earlier studies, the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines recommend limiting V15 to <120 cc if individual loops are contoured and V45 to <195 cc if the entire peritoneal cavity is contoured.6 Although the QUANTEC guidelines also found some consistency with the aforementioned TD5/5 estimate for late small bowel toxicity, detailed dose-volume data for late small bowel toxicity were lacking.\n\nAdditionally, data with regard to late toxicity involving patients with irradiation of the small bowel to doses above 45 Gy are extremely limited. Previously published studies involved different fractionation schedules and non-IMRT radiation therapy, thus creating challenges in establishing guidelines that minimize late small bowel toxicity in IMRT treatment with higher maximum point dosages than the generally accepted 45 Gy.7, 8, 9, 10 Such guidelines are especially important in cases in which treatment of the underlying malignancy might benefit from more aggressive abdominal or pelvic radiation therapy.\n\nAmbiguity also exists regarding whether contouring small bowel loops or the bowel bag is a more accurate predictor of late small bowel toxicity. Although some studies have used the entire bowel bag to account for bowel motion, 1 recent study has demonstrated that volumes measured by loop contouring were better predictors of overall gastrointestinal toxicity in a cohort of patients with cervical cancer.11 Other factors, such as the volume of liquid in the bladder, may also affect bowel motion and the accuracy of loop or bowel bag contouring methods.12\n\nThe aim of this study was to characterize the dose-volume relationship of late small bowel toxicity in patients who were treated with IMRT and whose malignancies warranted a maximum point dosage to the small bowel that was higher than 45 Gy. Additionally, we aimed to characterize any relationships between clinical variables or treatment factors and late small bowel toxicity.\n\nMethods and materials\nAfter institutional review board approval was obtained, we retrospectively reviewed 338 patients who were diagnosed with pelvic or abdominal malignancies and treated by one of the investigators (RDE) with IMRT alone (no brachytherapy) to prescribed doses of more than 45 Gy between January 2005 and June 2014. A total of 94 patients met the inclusion criteria of receiving a maximum point dose of at least 45 Gy to the small bowel.\n\nClinical data were extracted from the radiation oncology department records. Data on previous malignancies, presence of diabetes mellitus, vascular disease, previous gastrointestinal conditions, previous abdominal or pelvic surgeries, receipt of chemotherapy or hormone therapy (concurrent or sequential), date of completion of IMRT, prescribed dose of IMRT, use of daily image guidance, and the nature and severity of gastrointestinal symptoms in follow-up were collected. Toxicity was assessed using Common Terminology Criteria for Adverse Events Version 3.0. Small bowel toxicities included diarrhea, small bowel obstruction, enteritis, fistula, and stool incontinence. Any stool incontinence recorded was not confirmed to be a small bowel complication, but we elected to be conservative and assumed that any stool incontinence was a consequence of the radiation to the small bowel. Follow-up time was defined as the time between the completion of IMRT treatment and either the most recent follow-up or the incidence of small bowel toxicity. Severity of late toxicity was grouped into at least grade 1, at least grade 2, and at least grade 3 toxicity.\n\nThe individual loops of the small bowel were contoured on each computed tomography slice of the treatment-planning computed tomography scan. All patients received small bowel contrast to distinguish the small bowel from the large bowel. All contours were performed by a single experienced physician (RDE). Patients were treated with 180 to 200 cGy per fraction to a total prescribed dose between 5400 and 7560 cGy (median, 7020 cGy). A small bowel dose-volume histogram (DVH) was generated for each patient. We applied an internally developed guideline of 60 Gy to a maximum of 10 cc and 70 Gy to 5 cc when the physician felt this aggressive treatment was clinically warranted. These guidelines often were exceeded, however, with 25 instances above the 60 Gy limit and 4 of those 25 instances above the 70 Gy limit. The total volume of small bowel irradiated and the volume of small bowel receiving at least 10 Gy up to at least 80 Gy at 5 Gy intervals (V10, V15, etc.) were recorded. The maximum, minimum, and median point doses of the small bowel (Dmax, Dmin, and Dmean) were also recorded.\n\nTo assess the incidence over time, Kaplan-Meier analyses were conducted. Patients were divided into groups based on whether they did or did not have V80 >0 cc, V75 >1 cc, V75 >0 cc, V70 >1 cc down to V60. Groups were also constructed by dividing patients into those who were above and those who were below the cohort median of V10 up to V60 and of Dmax, Dmin, and Dmean. One group was created for V15 >120 cc to test the QUANTEC guideline on our patient cohort. Two groups were also created to evaluate toxicity in patients whose doses exceeded the internally developed guidelines of V60 <10 cc and V70 <5 cc. Toxicity differences between groups on the basis of the clinical variables, treatment factors, and the constructed dose groups described were conducted using the Kaplan-Meier estimator and the log-rank test.\n\nFor each clinical variable, treatment factor, or dosimetric group that showed a statistically significant difference with the log-rank test, a subset analysis of DVH statistics was performed to compare patients with or without that condition. The Kaplan-Meier method was also used to assess the time course of late small bowel toxicity for at least grade 1, at least grade 2, and at least grade 3 toxicity. Two patients had incomplete medical histories; their data were excluded from analyses that involved the missing information. One patient had an incomplete DVH and was excluded from analyses involving the missing DVH statistics. Additionally, 2 patients received multiple sets of abdominopelvic IMRT treatment and were excluded from all DVH statistics analyses because an accurate summation of the 2 treatment plans was not possible.\n\nThe Kaplan-Meier comparison was done for all constructed groups described and all clinical variables listed in Table 1 that could be divided into nonzero groupings. We considered a P-value <.05 as our significance threshold for the clinical variables, treatment factors, and binary dosimetric comparisons. However, because 26 separate dosimetric and 28 separate clinical comparisons were made, we applied the Bonferroni correction and set a significance level at P < .0019 for the dosimetric comparisons and at .0018 for the clinical comparisons. Statistical analyses were performed with R, Version 3.2.5.Table 1 Patient/treatment characteristics\n\nTable 1Clinical variable/treatment factor\tNumber of patients\t%\t\nSex\t\t\t\nMale\t63\t67.0\t\nFemale\t31\t33.0\t\nMalignancy\t\t\t\nProstate\t50\t53.2\t\n Primary\t37\t39.4\t\n Postoperative\t11\t11.7\t\n Recurrence\t2\t2.1\t\nBladder\t12\t12.8\t\n Primary\t8\t8.5\t\n Postoperative\t0\t0\t\n Recurrence\t4\t4.3\t\nUterus\t7\t7.4\t\n Primary\t5\t5.3\t\n Postoperative\t0\t0\t\n Recurrence\t2\t2.1\t\nOvary\t6\t6.4\t\n Primary\t1\t1.1\t\n Postoperative\t0\t0\t\n Recurrence\t5\t5.3\t\nPancreas\t6\t6.4\t\n Primary\t4\t4.3\t\n Postoperative\t1\t1.1\t\n Recurrence\t1\t1.1\t\nOther\t13\t13.8\t\nImage Guided Radiation Therapy\t\t\t\nYes\t32\t34.0\t\n Cone beam computed tomography\t23\t24.5\t\n kV\t9\t9.6\t\nNo\t62\t66.0\t\nDiabetes Mellitus\t\t\t\nYes\t23\t24.5\t\nNo\t69\t73.4\t\nNot available\t2\t2.1\t\nHypertension\t\t\t\nYes\t36\t38.3\t\nNo\t56\t59.6\t\nNot available\t2\t2.1\t\nChemotherapy\t\t\t\nAny\t37\t39.4\t\n Cisplatin\t17\t18.1\t\n Capecitabine/5-fluorouracil\t12\t12.8\t\n Other\t8\t8.5\t\nConcurrent\t29\t30.9\t\n Cisplatin\t14\t14.9\t\n Capecitabine/5-fluorouracil\t9\t9.6\t\n Other\t6\t6.4\t\nNone\t57\t60.6\t\nAndrogen Deprivation Therapy\n(Male Patients Only)\t\t\t\nAny\t34\t36.2\t\n Concurrent\t32\t34.0\t\nNone\t29\t30.1\t\nPrevious Gastrointestinal Conditions\t\t\t\nYes\t35\t37.2\t\nNo\t57\t60.6\t\nNot available\t2\t2.1\t\nPrevious Abdominal Surgery\t\t\t\nYes\t37\t39.4\t\nNo\t55\t58.5\t\nNot available\t2\t2.1\t\nVascular Disease\t\t\t\nYes\t16\t17.0\t\nNo\t76\t80.9\t\nNot available\t2\t2.1\t\nConstructed Dose-Volume Histogram Groups\t\t\t\nV80 >0 cc\t2\t2.2a\t\nV75 >1 cc\t5\t5.4a\t\nV75 >0 cc\t12\t13.0a\t\nV70 >1 cc\t13\t14.1a\t\nV70 >0 cc\t22\t23.9a\t\nV65 >1 cc\t33\t35.9a\t\nV65 >0 cc\t50\t54.3a\t\nV60 >1 cc\t49\t53.3a\t\nV60 >0 cc\t65\t70.7a\t\na These percentages were calculated using 92 in the denominator because 2 patients received multiple sets of radiation therapy and their dose-volume histograms could not be appropriately summed together.\n\n\n\nResults\nPatient characteristics and treatment factors are summarized in Table 1. DVH statistics are summarized in Table 2. Of the 92 patients who received 1 set of abdominopelvic IMRT treatment, 2 patients (2.2%) received point doses to the small bowel of >80 Gy; 22 (23.9%) received point doses to the small bowel >70 Gy.Table 2 Small bowel dose-volume histogram statistics summary\n\nTable 2Dose-volume histogram statistic\tn\tMinimum\tMedian\tMaximum\t\nDmax, cGy\t92\t4530.1\t6546.5\t8142.2\t\nDmina, cGy\t92\t51.6\t346.0\t1531.1\t\nDmeana, cGy\t92\t890.5\t2622.2\t4486.1\t\nTotal Small Bowel Volume Contoured, cc\t92\t7.8\t145.7\t1554.7\t\nV80, cc\t91\t0.0\t0.0\t0.1\t\nV75, cc\t91\t0.0\t0.0\t22.2\t\nV70, cc\t91\t0.0\t0.0\t37.5\t\nV65, cc\t91\t0.0\t0.001\t49.9\t\nV60, cc\t91\t0.0\t1.8\t62.1\t\nV55, cc\t91\t0.0\t5.0\t101.3\t\nV50, cc\t91\t0.0\t11.4\t127.8\t\nV45, cc\t91\t0.001\t19.3\t231.9\t\nV40, cc\t91\t0.006\t26.7\t430.6\t\nV35, cc\t91\t0.03\t39.3\t518.0\t\nV30, cc\t91\t0.09\t52.1\t691.0\t\nV25, cc\t91\t0.2\t66.0\t899.0\t\nV20, cc\t91\t0.3\t81.3\t1231.2\t\nV15, cc\t91\t0.6\t95.8\t1379.4\t\nV10, cc\t91\t1.6\t112.1\t1419.8\t\na These are minimum and mean doses to the small bowel that was contoured.\n\n\n\nOverall, 17 patients (18.1%) experienced at least grade 1 late small bowel toxicity. Five patients (5.3%) experienced at least grade 2 late small bowel toxicity. Of the cases with at least grade 2 toxicity, 2 patients (2.1%) experienced grade 4 late toxicity with small bowel obstruction. The small bowel obstruction in one of these patients was in the high-dose area, but we could not assess the site of obstruction in the other patient because the images were not retrievable. One other patient (1.1%) experienced grade 3 stool incontinence. As previously mentioned, it was unclear if the stool incontinence was a small bowel complication, but we elected to be conservative and assumed that any stool incontinence was a consequence of radiation to the small bowel. If these stool incontinence cases were not small bowel complications, then our small bowel toxicity rates would be even lower than reported.\n\nRelevant patient characteristics, treatment factors, and DVH statistics for the 3 patients who experienced at least grade 3 late small bowel toxicity are summarized in Table 3. Kaplan-Meier estimates of freedom and 95% confidence intervals (CIs) from at least grade 1, at least grade 2, and at least grade 3 late small bowel toxicity at 5 years were 72.4% (95% CI, 60.7%-86.5%), 91.9% (95% CI, 84.1%-100%), and 93.6% (95% CI, 86.2%-100%), respectively (Fig 1). Scatter plot of dose vs at least grade 1 and at least grade 2 toxicity is displayed in Fig 2.Figure 1 Kaplan-Meier plots for freedom from (A) at least grade 1, (B) at least grade 2, and (C) at least grade 3 late small bowel toxicity. Tick marks denote censored observations.\n\nFigure 1Figure 2 Volume of small bowel receiving 45 to 80 Gy in 5-Gy intervals. Red asterisks denote patients who experienced (A) at least grade 1 late small bowel toxicity and (B) at least grade 2 late small bowel toxicity. Magnified plots of small bowel volume up to 20 cc of the same dose range with patients who experienced (C) at least grade 1 late small bowel toxicity and (D) at least grade 2 small bowel toxicity marked similarly.\n\nFigure 2Table 3 Summary of patients with at least grade 3 late small bowel toxicity\n\nTable 3Characteristics\tPatient 1\tPatient 2\tPatient 3\t\nAge, y\t53\t72\t87\t\nTreatment Setting\tPostoperative\tPrimary treatment\tLocal recurrence\t\nMalignancy\tProstate\tPancreas\tRectum\t\nPrescribed IMRT Dose, cGy\t6480\t5400\t6300\t\nDrug Treatment\tPrior 5-FU + cisplatin for esophageal cancer; leuprolide before prostate IMRT\tPrior gemcitabine treatment; concurrent 5-FU treatment\tConcurrent 5-FU treatment\t\nTime of Complication after End of Radiation Therapy, mo\t15.1\t7.3\t46.0\t\nComplication Details\tGrade 3 stool incontinence\tGrade 4 small bowel obstruction + resection\tGrade 4 small bowel obstruction\t\nMedical History\tHypercholesterolemia; past esophageal cancer with IMRT treatment\tDiarrhea; past breast cancer with IMRT treatment\tGERD; aortic valve disease; HTN\t\nPrior Surgeries\tRadical prostatectomy; esophagectomy\tNone\tAbdominal perineal resection\t\nDmax, cGy\t6813.3\t5928.9\t6548.9\t\nDmeana, cGy\t3354.9\t3193.4\t3286.8\t\nV80, cc\t0.0\t0.0\t0.0\t\nV75, cc\t0.0\t0.0\t0.0\t\nV70, cc\t0.0\t0.0\t0.0\t\nV65, cc\t1.5\t0.0\t0.05\t\nV60, cc\t5.0\t0.0\t12.0\t\nV55, cc\t9.2\t31.9\t25.3\t\nV50, cc\t13.0\t46.4\t45.8\t\nV45, cc\t17.6\t58.5\t93.4\t\n5-FU, 5-fluorouracil; IMRT, intensity modulated radiation therapy; GERD, gastroesophageal reflux disease; HTN, hypertension.\n\na This is the mean dose to the small bowel that was contoured.\n\n\n\nLog-rank tests for toxicity of all clinical variables, treatment factors, and dosimetric divisions showed only 1 statistically significant association (Table 4). Specifically, capecitabine/5-fluorouracil (5-FU) treatment (concurrent or sequential) was a significant predictor for at least grade 1 and at least grade 2 toxicity (Table 4), with 4 of 12 patients experiencing any toxicity, 3 of whom had higher than grade 2 toxicity. One of these patients developed grade 3 stool incontinence and had received 5-FU treatment for an esophageal malignancy within 6 months of initiating abdominopelvic radiation therapy (Table 3). Even after excluding this patient, capecitabine/5-FU treatment (concurrent or sequential) was still significant for at least grade 1 and at least grade 2 toxicity (P < .001 for both, even when excluding this patient). However, cisplatin treatment or the use of any chemotherapy (concurrent or sequential) were not significant (Table 4). Three of 12 patients who received capecitabine/5-FU treatment experienced at least grade 2 toxicity, versus only 1 of 16 patients who received cisplatin who experienced at least grade 2 toxicity.Table 4 Log-rank test for small bowel toxicity on groups\n\nTable 4Predictor\tGrade ≥1\n(P-value)\tGrade ≥2\n(P-value)\t\nCapecitabine/5-FU\t< .001\t< .001\t\nCisplatin\t.808\t.4\t\nAny Chemotherapy\t.191\t.00589\t\nDmax >median\t.789\t.47\t\nDmina >median\t.681\t.878\t\nDmeana >median\t.13\t.0866\t\nV15 >120 cc\t.784\t.447\t\nV60 >10 cc\t.511\t.85\t\nV70 >5 cc\t.289\t.787\t\nV10 >median\t.844\t.484\t\nV15 >median\t.774\t.447\t\nV20 >median\t.78\t.447\t\nV25 >median\t.819\t.457\t\nV30 >median\t.814\t.457\t\nV35 >median\t.827\t.457\t\nV40 >median\t.961\t.522\t\nV45 >median\t.94\t.518\t\nV50 >median\t.991\t.0929\t\nV55 >median\t.31\t.0183\t\nV60 >median\t.935\t.458\t\nV80 >0 cc\t.257\t.767\t\nV75 >1 cc\t.699\t.334\t\nV75 >0 cc\t.681\t.672\t\nV70 >1 cc\t.904\t.697\t\nV70 >0 cc\t.873\t.394\t\nV65 >1 cc\t.627\t.692\t\nV65 >0 cc\t.663\t.74\t\nV60 >1 cc\t.193\t.986\t\nV60 >0 cc\t.898\t.649\t\na These are minimum and mean doses to the small bowel that was contoured.\n\n\n\nNotably, none of our dosimetric comparisons were statistically significant, including the groups for V15 >120 cc and for our internally developed guidelines. However, some of the variables, including the use of any chemotherapy, were close to our significance threshold. The log-rank test of any chemotherapy for higher than grade 2 toxicity had a P-value of .00589, but this likely was driven by the capecitabine patients (Table 4). Of the dosimetric variables, only the V55 median group came relatively close to our Bonferroni significance threshold.\n\nA separate subset analysis was conducted for patients who did or did not receive capecitabine/5-FU treatment. These tests also showed no significant associations between the median DVH groups and small bowel toxicity.\n\nDiscussion\nWe found that despite delivering doses to the small bowel that were above the generally accepted maximum of 45 Gy, our patients experienced low rates of toxicity. Although past studies have quantified a relationship between acute small bowel toxicity and certain DVH parameters, we did not find that relationship with late small bowel toxicity in our overall patient cohort. Other studies that have explored late small bowel toxicity have had large inconsistencies with fractionation schedule and the type of radiation therapy used.7, 8, 9, 10\n\nA sizeable number of patients received point doses of >70 Gy (n = 22), warranting an examination of the variables at least through V70 in our dataset. The insignificance of V60, V65, and V70 in the log-rank tests for the constructed groups (Table 1) is especially worth noting. These results suggest that it may be possible to deliver these doses without high rates of significant complications to the small bowel. Similarly, Green et al found a low incidence of grade 3 + acute or chronic small bowel toxicity when using IMRT or VMAT techniques in a cohort of patients with prostate cancer, 25 of whom received doses of >52 Gy to the small bowel with no incidence of late toxicity.13 Although it may be desirable to limit the maximum small bowel dose to <45 Gy if possible, it may be safe to increase the dose above this threshold without significant additional complications if treatment of the underlying malignancy would benefit. In particular, limiting the volume that receives 60 Gy to 10 cc and the volume that receives 70 Gy to 5 cc, as we have tried with most patients, may be appropriate in clinical situations that warrant aggressive treatment. Our results suggest that it may even be reasonable to raise these thresholds in certain situations.\n\nAdditionally, we observed that the 3 patients who experienced grade 3 or higher complications all received 5-FU treatment and had a prior gastrointestinal condition. As mentioned previously, 1 of these patients received 5-FU within 6 months of abdominopelvic radiation therapy for a different malignancy, but capecitabine/5-FU treatment remained significantly associated with at least grade 2 toxicity even when this patient was excluded. Past studies have also supported the potential need for clinicians to consider a wider variety of clinical variables and treatment factors when planning pelvic IMRT treatment.14 However, statistical analyses are greatly limited without a larger number of patients with these severe complications and unique medical histories.\n\nIt must also be noted that the retrospective nature of this study, with treatment by a single investigator (RDE) and a small number of grade 2 or higher complications, makes it difficult to draw definitive conclusions. The large 10-year range in which patients were considered, inconsistent periods between follow-up visits, patients who were lost to follow-up, and the inhomogeneity of our patient cohort further complicate any potential conclusions. The use of physician-reported outcomes, which are routinely lower than patient-reported outcomes, particularly for lower-grade toxicities, is also a limitation.\n\nFuture prospective studies from other investigators should consider including patient-reported outcomes and ideally should be conducted with larger cohorts using standard fractionation, uniform use of IMRT and image guidance, and a defined long-term follow-up schedule. These prospective studies are necessary to eliminate potential confounding variables and correlations between different factors in a retrospective study that may have biased our results. These studies are important to more accurately define the dose-volume relationship of small bowel toxicity and interactions with clinical variables and to establish appropriate thresholds for elevating radiation dosage in severe cases. Additionally, although many of our treatment plans show maximum small bowel doses well above 60 or 70 Gy, the true maximum small bowel dose may be substantially lower than reported in the plan due to the mobility of most of the small bowel. Patients who have fixed loops of small bowel within the high-dose region may be more susceptible to high levels of small bowel injury.\n\nFinally, it must be noted that various genetic factors are likely to underlie individual patient risk of late radiation therapy toxicity. Variants in genes associated with DNA repair pathways, cell cycle arrest, and immune response have been thought to possibly increase the radiosensitivity of certain cells that are exposed during treatment.15 With the formation of a radiogenomics consortium, genome-wide association studies are becoming increasingly important in identifying single nucleotide polymorphisms that may contribute to the increased risk of radiation toxicity.16 Although replication of results and false positives remain large problems, recent analyses with increased power have found greater success in identifying single nucleotide polymorphism associations.15, 17 One recent study identified an additional risk locus for radiation toxicity compared with an earlier genome-wide association study of patients with prostate cancer, which highlights the need for more collaborative efforts.18 Further investigation into any differences in dose tolerance, specifically in patients receiving high maximal doses to the small bowel, should take these genetic risk factors into consideration. This type of prospective study remains extremely important in accurately evaluating the risk-reward tradeoff for patients whose underlying malignancies warrant aggressive pelvic or abdominal radiation treatment.\n\nConclusion\nOur retrospective, hypothesis-generating data suggest that small volumes of small bowel can be treated above 45 to 50 Gy with acceptable long-term toxicity risk, but extra caution is advised in the setting of capecitabine/5-FU. The widespread acceptance of 45 to 50 Gy as the maximal dose to the small bowel may not be warranted and indeed might impede optimal patient care in situations in which a higher dose might provide improved tumor control. Additional research is needed, ideally with large numbers of patients to account for confounding factors and with prospectively collected data to minimize selection bias, to better determine the optimal dose-volume constraints for long-term small bowel toxicity.\n\nAcknowledgments\nThe authors thank Frieda Trichter DSc, Rosemary Giuliano MSN, Omar Morales, Ira Leykin, and Anissa Muller for their assistance with data collection.\n\nConflicts of interest: None.\n==== Refs\nReferences\n1 Emami B. Lyman J. Brown A. Tolerance of normal tissue to therapeutic irradiation Int J Radiat Oncol Biol Phys 21 1991 109 122 2032882 \n2 Robertson J.M. Lockman D. Yan D. Wallace M. The dose-volume relationship of small bowel irradiation and acute grade 3 diarrhea during chemoradiotherapy for rectal cancer Int J Radiat Oncol Biol Phys 70 2008 413 418 17904305 \n3 Baglan K.L. Frazier R.C. Yan D. Huang R.R. Martinez A.A. Robertson J.M. The dose-volume relationship of acute small bowel toxicity from concurrent 5-FU-based chemotherapy and radiation therapy for rectal cancer Int J Radiat Oncol Biol Phys 52 2002 176 183 11777636 \n4 Roeske J.C. Bonta D. Mell L.K. Lujan A.E. Mundt A.J. A dosimetric analysis of acute gastrointestinal toxicity in women receiving intensity-modulated whole-pelvic radiation therapy Radiother Oncol 69 2003 201 207 14643959 \n5 Huang E.Y. Sung C.C. Ko S.F. Wang C.J. Yang K.D. The different volume effects of small-bowel toxicity during pelvic irradiation between gynecologic patients with and without abdominal surgery: A prospective study with computed tomography-based dosimetry Int J Radiat Oncol Biol Phys 69 2007 732 739 17531397 \n6 Kavanagh B.D. Pan C.C. Dawson L.A. Radiation dose-volume effects in the stomach and small bowel Int J Radiat Oncol Biol Phys 76 2010 101 107 \n7 Nuyttens J.J. Prevost J.B. Van der Voort van Ziip N.C. Hoogeman M. Levendag P.C. Curative stereotactic robotic radiotherapy treatment for extracranial, extrapulmonary, extrahepatic, and extraspinal tumors: Technique, early results, and toxicity Technol Cancer Res Treat 6 2007 605 610 17994790 \n8 Kelly P. Das P. Pinnix C.C. Duodenal toxicity after fractionated chemoradiation for unresectable pancreatic cancer Int J Radiat Oncol Biol Phys 85 2013 143 149 \n9 Schneider R.A. Vitolo V. Albertini F. Small bowel toxicity after high dose spot scanning-based proton beam therapy for paraspinal/retroperitoneal neoplasms Strahlenther Onkol 189 2013 1020 1025 24052010 \n10 Sprawka A. Pietrzak L. Garmol D. Tyc-Szczepaniak D. Kepka L. Bujko K. Definitive radical external beam radiotherapy for rectal cancer: Evaluation of local effectiveness and risk of late small bowel damage Acta Oncol 52 2013 816 823 22860980 \n11 Isohashi F. Mabuchi S. Akino Y. Dose-volume analysis of predictors for chronic gastrointestinal complications in patients with cervical cancer treated with postoperative concurrent and whole-pelvic radiation therapy J Radiat Res 57 2016 668 676 27342839 \n12 Xu M.J. Kirk M. Zhai H. Lin L.L. Bag and loop small bowel contouring strategies differentially estimate small bowel dose for post-hysterectomy women receiving pencil beam scanning proton therapy Acta Oncologia 55 2016 900 908 \n13 Green G. Williams R. Zhang J. Azawi S. Dose-volume relationship of acute and late small bowel toxicity from radiation therapy for prostate cancer: A veteran affairs study Int J Radiat Oncol Biol Phys 90 2014 S456 \n14 Kuku S. Fragkos C. McCormack M. Forbes A. Radiation-induced bowel injury: The impact of radiotherapy on survivorship after treatment for gynaecological cancers Br J Cancer 109 2013 1504 1512 24002603 \n15 West C.M. Bartnett G.C. Genetics and genomics of radiotherapy toxicity: Towards prediction Genome Med 3 2011 52 21861849 \n16 West C. Rosenstein B.S. Establishment of a radiogenomics consortium Int J Radiat Oncol Biol Phys 76 2010 1295 1296 20338472 \n17 Bartnett G.C. Coles C.E. Elliot R.M. Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: A prospective analysis study Lancet Oncol 13 2012 65 77 22169268 \n18 Kerns S.L. Dorling L. Fachal L. Meta-analysis of genome wide association studies identifies genetic markers of late toxicity following radiotherapy for prostate cancer EBioMedicine 10 2016 150 163 27515689\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2452-1094",
"issue": "2(4)",
"journal": "Advances in radiation oncology",
"keywords": null,
"medline_ta": "Adv Radiat Oncol",
"mesh_terms": null,
"nlm_unique_id": "101677247",
"other_id": null,
"pages": "615-623",
"pmc": null,
"pmid": "29204529",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "14643959;11777636;17904305;20338472;27515689;22169268;24052010;26927612;21861849;17531397;2032882;23200173;27342839;22860980;20171503;17994790;24002603",
"title": "Late small bowel toxicity after aggressive abdominopelvic intensity modulated radiation therapy.",
"title_normalized": "late small bowel toxicity after aggressive abdominopelvic intensity modulated radiation therapy"
} | [
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"companynumb": "US-ACCORD-061922",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEUPROLIDE ACETATE"
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{
"abstract": "OBJECTIVE\nTo determine antiretroviral (ARV) pharmacokinetics in a patient who previously underwent Roux-en-Y gastric bypass (RYGB) surgery.\n\n\nMETHODS\nWe describe a 38-year-old Hispanic man who tested positive for human immunodeficiency virus (HIV) 11 months following RYGB surgery. When the patient presented for care of his HIV, his HIV-1 RNA was 146 138 copies/mL (5.20 log) and his CD4 T cell count was 320 cells/mm(3) (25%). He was initiated on tenofovir disoproxil fumarate (TDF) 300 mg once daily, emtricitabine (FTC) 200 mg once daily, and darunavir/ritonavir (DRV/r) 600/100 mg twice daily. ARV concentrations were similar to historical data. Six months following ARV initiation, HIV-1 RNA was <48 copies/mL and CD4 count had increased to 562 cells/mm(3) (39%).\n\n\nCONCLUSIONS\nBariatric surgery has been successfully performed in obese persons infected with the HIV, but data are limited on ARV drug selection and pharmacokinetics in this group. Optimal suppression of HIV replication requires appropriate concentrations of ARV drugs, and in a patient who has undergone RYGB, this can be challenging not only because of a decreased absorptive surface area but also because of an increased intragastric pH.\n\n\nCONCLUSIONS\nWe found that once daily TDF/FTC and twice daily DRV/r produced trough concentrations similar to historic data in a patient who previously underwent RYGB with virologic suppression and immunologic recovery.",
"affiliations": "University of Colorado Anschutz Medical Campus, Aurora, CO, USA.",
"authors": "MacBrayne|Christine E|CE|;Blum|Joshua D|JD|;Kiser|Jennifer J|JJ|",
"chemical_list": "D019380:Anti-HIV Agents; D063065:Organophosphonates; D013449:Sulfonamides; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; D019438:Ritonavir; D000069454:Darunavir",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028014525034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "48(6)",
"journal": "The Annals of pharmacotherapy",
"keywords": "HIV; Roux-en-Y; antiretroviral; darunavir; emtricitabine; gastric bypass; tenofovir",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000225:Adenine; D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D000069454:Darunavir; D003841:Deoxycytidine; D000068679:Emtricitabine; D015390:Gastric Bypass; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D063065:Organophosphonates; D019438:Ritonavir; D013449:Sulfonamides; D000068698:Tenofovir",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "816-9",
"pmc": null,
"pmid": "24615629",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Tenofovir, emtricitabine, and darunavir/ritonavir pharmacokinetics in an HIV-infected patient after Roux-en-Y gastric bypass surgery.",
"title_normalized": "tenofovir emtricitabine and darunavir ritonavir pharmacokinetics in an hiv infected patient after roux en y gastric bypass surgery"
} | [
{
"companynumb": "US-JNJFOC-20140603539",
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"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DARUNAVIR"
},
"drugadditional": null,
"... |
{
"abstract": "Colistin-induced nephrotoxicity is commonly associated with elevation of serum creatinine level or a reduction of urine output. Uncommonly, tubulopathy associated with colistin has been reported. Here we present a unique case of a 46-year-old man who developed polyuria, hypokalaemia, hypocalcaemia, hypomagnesemia and metabolic alkalosis after 3 days of therapy with intravenous colistimethate sodium. After ruling out other causes, a diagnosis of colistin-induced acquired Bartter syndrome was made. The patient required daily aggressive intravenous repletion of fluids and electrolytes. However, polyuria and metabolic abnormalities abated only after drug discontinuation.",
"affiliations": "Medicine, All India Institute of Medical Sciences, New Delhi, India.;Medicine, All India Institute of Medical Sciences, New Delhi, India.;Medicine, All India Institute of Medical Sciences, New Delhi, India doctoranimeshray@gmail.com.;Medicine, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Tabish|Mohammad|M|http://orcid.org/0000-0001-5192-6901;Mahendran|Manjit|M|;Ray|Animesh|A|http://orcid.org/0000-0001-7498-9112;Vikram|Naval Kishore|NK|",
"chemical_list": "C004691:colistinmethanesulfonic acid; D003091:Colistin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-232630",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(2)",
"journal": "BMJ case reports",
"keywords": "drugs: infectious diseases; fluid electrolyte and acid-base disturbances; infections",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000471:Alkalosis; D001477:Bartter Syndrome; D003091:Colistin; D003937:Diagnosis, Differential; D006801:Humans; D006996:Hypocalcemia; D007008:Hypokalemia; D008297:Male; D008875:Middle Aged; D011141:Polyuria",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32029515",
"pubdate": "2020-02-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Colistin-induced acquired Bartter-like syndrome: an unusual cause of meltdown.",
"title_normalized": "colistin induced acquired bartter like syndrome an unusual cause of meltdown"
} | [
{
"companynumb": "IN-AXELLIA-002984",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PYRAZINAMIDE"
},
"drugadditional": null,
"... |
{
"abstract": "Mucormycosis is a fatal opportunistic fungal infection. Rarely it can occur in immunocompetent patients. Here, we present a case of colonic mucormycosis in immunocompetent patients.",
"affiliations": "University of Arkansas for Medical Sciences, Fayetteville, AR, United States.;University of Arkansas for Medical Sciences, Fayetteville, AR, United States.;University of Arkansas for Medical Sciences, Fayetteville, AR, United States.;University of Arkansas for Medical Sciences, Fayetteville, AR, United States.",
"authors": "Shah|Chintav|C|;Zimmerman|Stewart|S|;Mckinney|Jason|J|;Ebers|Andrew|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2020.e00773",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30081-0\n10.1016/j.idcr.2020.e00773\ne00773\nArticle\nColonic mucormycosis in an immunocompetent patient with endocarditis\nShah Chintav chintavshah65@gmail.com⁎ Zimmerman Stewart Mckinney Jason Ebers Andrew University of Arkansas for Medical Sciences, Fayetteville, AR, United States\n⁎ Corresponding author. chintavshah65@gmail.com\n11 5 2020 \n2020 \n11 5 2020 \n20 e0077326 3 2020 14 4 2020 14 4 2020 © 2020 Published by Elsevier Ltd.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Mucormycosis is a fatal opportunistic fungal infection. Rarely it can occur in immunocompetent patients. Here, we present a case of colonic mucormycosis in immunocompetent patients.\n\nKeywords\nColonic mucormycosisUncommon findingImmunocompetent individualHigh mortality rate\n==== Body\nIntroduction\nMucormycosis is a fatal opportunistic infection that typically occurs in immunocompromised patients [1]. Most commonly, it manifests as a rhinocerebral infection [1]. Primary gastrointestinal mucormycosis is rarely reported in literature [3]. Immunosuppression is the main risk factor associated with mucormycosis infections, however there are other factors that have been shown to increase the incidence of primary GI mucormycosis mainly in patients predisposed to acute or chronic gastric ulcers secondary to smoking or alcohol use [2]. It is more often reported with transplant recipients who are on corticosteroids and immunosuppressant drugs [2]. In the absence of immunosuppression, breach in the gastric mucosa has been thought to be an important predisposing factor for this condition [2]. Primary gastrointestinal Mucormycosis is an uncommon disease associated with high mortality rate [3]. The most common site involved is stomach [3]. The patient with gastrointestinal mucormycosis has mortality rate of 85 % [3]. Mucormycosis is the second most common mold after aspergillus for invasive infections [3].\n\nCase report\nA 72-year-old male with a history of Type 2 Diabetes mellitus well controlled, Benign Prostatic Hypertrophy, Gout, and splenectomy in 2011 due to trauma, originally presented to an outside Emergency department with complaints of having shaking/rigors and few days of what he described as “a cold”. At that facility, he had a temperature of 102.8 F and was hypotensive and hypoxic. His blood pressure improved with fluid resuscitation, however he was emergently intubated due to worsening respiratory failure. Propofol was started for sedation and the subsequent drop in pressure resulted in the need for pressors, so norepinephrine was started. Additional workup included a CT Angiography of Chest which showed no Pulmonary Embolism. He was then transferred to our facility.\n\nUpon arrival, he was found to have acute kidney injury with Creatinine of 1.79 mg/dl and an elevated lactic acid at 4.5 mmol/l. Norepinephrine was continued, but vasopressin and stress dose Corticosteroids were needed to help the patient maintain an adequate MAP. Vancomycin, cefepime, and metronidazole were started. Given his hemodynamic instability without a clear cause, a bedside Transthoracic echocardiogram was performed to assess tamponade, but it was essentially normal. His hemodynamics improved and his pressors were able to be titrated off over the next 72 h. His creatinine continued to worsen during this time. Blood cultures (two bottles) collected at the outside facility returned positive for Streptococcus infantarius (formerly Bovis). Broad spectrum antibacterials were continued. His creatinine did not improve and the patient had to be transitioned to continuous renal replacement therapy. Ultimately, he required hemodialysis. His blood cultures cleared, but the patient had continued leukocytosis. A TEE was performed which showed a 5 mm aortic valve vegetation. The patient was transitioned to ceftriaxone for endocarditis. He continued to be febrile with temperatures of 101.0 F and his rectal tube began to have melanotic stools, followed by bright red bloody output, which prompted further investigation with a CT of his abdomen and pelvis. Imaging revealed circumferential colonic wall thickening consistent with infectious, inflammatory, or ischemic colitis. Due to this finding, metronidazole was added to ceftriaxone for additional anaerobic coverage. A subsequent drop in hemoglobin resulted in the patient being transfused 2 units Packed Red Blood Cells.\n\nGastroenterology was consulted who performed bedside EGD and flexible sigmoidoscopy. The patient was still sedated with propofol at this time and remained on the ventilator. Flex sigmoidoscopy showed localized severe inflammation characterized by erosions, erythema, and granularity in the sigmoid colon. Biopsies were taken for histology. Endoscopy showed grade C reflux esophagitis with some non-bleeding gastric ulcers. Surgery was then consulted due to the biopsy findings of the sigmoidoscopy and a total colectomy was performed. Overall, the procedure was well tolerated. Over the next several days, the patient was weaned off the ventilator and transitioned to nasal cannula. The surgical pathology and sigmoid biopsies returned positive for fulminant colitis with full thickness necrosis secondary to mucormycosis. Fungal culture grew Lichtheimia (Absidia). CT of abdomen, pelvis, chest, and sinuses was performed to investigate for any other possible manifestations of mucormycosis. All further imaging was essentially unremarkable. Patient was started on IV liposomal amphotericin B 500 mg every 24 h. After one week of therapy, repeat upper endoscopy and colonoscopy was repeated to search for persistent mucormycosis in the ileum or rectal stump in addition to ruling out malignancy. These biopsies were negative for infection as well as malignancy. Overall treatment plan was discussed at length, as the patient does not have known immunodeficiency and it was hypothesized that the endocarditis led to the ischemic colitis which harbored a reservoir for mucormycosis to grow. Regardless, the final plan was to treat with 14 days liposomal amphotericin B, followed by isavuconazole for several months with frequent Infectious Disease follow up appointments. He had infusion set up for ceftriaxone to finish the antibacterial therapy for endocarditis.\n\nPatient was discharged to a long term acute care facility for rehabilitation (LTACH). However during a follow up with infectious disease, the patient complained of abdominal pain. CT of the abdomen and pelvis was done which showed small abscess formation. Patient was admitted to the hospital and two drains were placed by interventional radiology(IR). The culture from abscess that was sent out once again grew Lichtheimia (Absidia). Patient had been on isavuconazole at discharge which was changed to posaconazole at the follow up. After this finding, the patient was put back on amphotericin B. General surgery was consulted who recommended that the patient be transferred to a tertiary care center for surgical intervention. No surgical Intervention was done at the tertiary care center. The patient was discharged to a long term acute care facility (LTACH) and he continues to do well.\n\nDiscussion\nColonic mucormycosis accounts for 9% cases of mucormycosis and it carries a high mortality [4]. The first case of mucormycosis was reported by Paultauf in 1885 [3,5]. Standard treatment of mucormycosis involves treating with intravenous liposomal amphotericin B initially, followed by a course of posaconazole/isavuconazole. There have not been standardized treatment guidelines for GI mucormycosis, however it is common to start with amphotericin B. The role of combination therapy has not been elucidated [5]. An added confounder in this case is that the patient was not immune-suppressed unlike the typical mucormycosis patient. This posed additional questions when developing a treatment plan for the patient, as most research has been performed on immunocompromised individuals.\n\nDeclaration of Competing Interest\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n==== Refs\nReferences\n1 Choi Han Lim Shin Yoon M.i Lee KiMan Choe Kang Hyeon Jeon Hyun Jeong Sung Ro Hyun Bowel infarction due to intestinal mucormycosis in an immunocompetent patient J Korean Surg Soc 83 November (5) 2012 325 329 10.4174/jkss.2012.83.5.325 October 29, 2012 23166893 \n2 Benjamin S. Primary gastric mucormycosis: role of preexisting ulcerative and erosive lesions J Postgrad Med 55 2009 73 74 [serial online] [cited 2020 Jan 14] Available from: http://www.jpgmonline.com/text.asp?2009/55/1/73/48447 \n3 Shiva Prasad B.N. Shenoy A. Nataraj K.S. Primary gastrointestinal mucormycosis in an immunocompetent person J Postgrad Med 54 2008 211 213 [serial online] [cited 2020 Jan 14] Available from: http://www.jpgmonline.com/text.asp?2008/54/3/211/41805 18626171 \n4 Verma G.R. Lobo D.R. Walker R. Bose S.M. Gupta K.L. Disseminated mucormycosis in healthy adults J Postgrad Med 41 1995 40 [serial online] [cited 2020 Jan 14] Available from: http://www.jpgmonline.com/text.asp?1995/41/2/40/501 10707707 \n5 Paultauf A. Mycosis mucorina Arch Pathol Anat 102 1885 543\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "20()",
"journal": "IDCases",
"keywords": "Colonic mucormycosis; High mortality rate; Immunocompetent individual; Uncommon finding",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e00773",
"pmc": null,
"pmid": "32435589",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "10707707;18626171;19242086;23166893",
"title": "Colonic mucormycosis in an immunocompetent patient with endocarditis.",
"title_normalized": "colonic mucormycosis in an immunocompetent patient with endocarditis"
} | [
{
"companynumb": "US-009507513-2006USA003635",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "POSACONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Post-stem cell transplantation (SCT) relapsed acute lymphoblastic leukemia (ALL) has extremely poor prognosis with median survival of less than 1 year. Donor lymphocyte infusion, second transplantation, chemotherapy or cytokine treatment have been tried as a salvage regimen without significant clinical benefit. Recently, blinatumomab, a bispecific monoclonal antibody targeting CD3-expressing T cells and CD19-expressing B-cell lineage malignant cells demonstrated promising outcomes in relapsed/refractory ALL patients. Literature on blinatumomab use in biphenotypic ALL along with Philadelphia chromosome positive (Ph(+)) ALL is limited. We report a case of post-SCT relapsed CD19 expressing biphenotypic lymphoblastic leukemia patient who achieved complete remission after blinatumomab treatment and has lasting remission for 1 year.",
"affiliations": "Research Assistant, Hematology Department of Medicine, University of Arizona, AZ, USA.;Department of Medicine, University of Arizona, AZ, USA.;Department of Pathology, University of Arizona, AZ, USA.;Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, MN, USA.;Research Assistant, Hematology Department of Medicine, University of Arizona, AZ, USA.;Research Assistant, Hematology Department of Medicine, University of Arizona, AZ, USA.;Research Assistant, Hematology Department of Medicine, University of Arizona, AZ, USA.;Department of Medicine, University of Arizona, AZ, USA.",
"authors": "Alcharakh|Mohammed|M|;Yun|Seongseok|S|;Dong|Yimin|Y|;Vincelette|Nicole D|ND|;Daud|Madiha|M|;Manzoor|Saima|S|;Riaz|Irbaz Bin|IB|;Anwer|Faiz|F|",
"chemical_list": "D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D000970:Antineoplastic Agents; D017252:CD3 Complex; C510808:blinatumomab",
"country": "England",
"delete": false,
"doi": "10.2217/imt-2015-0023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1750-743X",
"issue": "8(8)",
"journal": "Immunotherapy",
"keywords": "Blinatumomab; CD19; biphenotypic acute leukemia",
"medline_ta": "Immunotherapy",
"mesh_terms": "D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D000970:Antineoplastic Agents; D001402:B-Lymphocytes; D017252:CD3 Complex; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012008:Recurrence; D012074:Remission Induction; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes; D014019:Tissue Donors",
"nlm_unique_id": "101485158",
"other_id": null,
"pages": "847-52",
"pmc": null,
"pmid": "27381683",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Blinatumomab-induced donor T-cell activation for post-stem cell transplant-relapsed acute CD19-positive biphenotypic leukemia.",
"title_normalized": "blinatumomab induced donor t cell activation for post stem cell transplant relapsed acute cd19 positive biphenotypic leukemia"
} | [
{
"companynumb": "US-AMGEN-USASP2017109737",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "Detection of the FIP1L1-PDGFRA fusion gene or the corresponding cryptic 4q12 deletion supports the diagnosis of chronic eosinophilic leukemia (CEL) in patients with chronic hypereosinophilia. We retrospectively characterized 17 patients fulfilling WHO criteria for idiopathic hypereosinophilic syndrome (IHES) or CEL, using nested RT-PCR and interphase fluorescence in situ hybridization (FISH). Eight had FIP1L1-PDGFRA (+) CEL, three had FIP1L1-PDGFRA (-) CEL and six had IHES. FIP1L1-PDGFRA (+) CEL responded poorly to steroids, hydroxyurea or interferon-alpha, and had a high probability of eosinophilic endomyocarditis (n=4) and disease-related death (n=4). In FIP1L1-PDGFRA (+) CEL, palpable splenomegaly was present in 5/8 cases, serum vitamin B(12) was always markedly increased, and marrow biopsies revealed a distinctively myeloproliferative aspect. Imatinib induced rapid complete hematological responses in 4/4 treated FIP1L1-PDGFRA (+) cases, including one female, and complete molecular remission in 2/3 evaluable cases. In the female patient, 1 log reduction of FIP1L1-PDGFRA copy number was reached as by real-time quantitative PCR (RQ-PCR). Thus, correlating IHES/CEL genotype with phenotype, FIP1L1-PDGFRA (+) CEL emerges as a homogeneous clinicobiological entity, where imatinib can induce molecular remission. While RT-PCR and interphase FISH are equally valid diagnostic tools, the role of marrow biopsy in diagnosis and of RQ-PCR in disease and therapy monitoring needs further evaluation.",
"affiliations": "The Center for Human Genetics, University Hospital Leuven, Leuven, Belgium. peter.vandenberghe@uz.kuleuven.ac.be",
"authors": "Vandenberghe|P|P|;Wlodarska|I|I|;Michaux|L|L|;Zachée|P|P|;Boogaerts|M|M|;Vanstraelen|D|D|;Herregods|M-C|MC|;Van Hoof|A|A|;Selleslag|D|D|;Roufosse|F|F|;Maerevoet|M|M|;Verhoef|G|G|;Cools|J|J|;Gilliland|D G|DG|;Hagemeijer|A|A|;Marynen|P|P|",
"chemical_list": "D001549:Benzamides; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D039221:mRNA Cleavage and Polyadenylation Factors; D000068877:Imatinib Mesylate; C479819:FIP1L1-PDGFRA fusion protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha",
"country": "England",
"delete": false,
"doi": "10.1038/sj.leu.2403313",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "18(4)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000328:Adult; D001549:Benzamides; D002894:Chromosomes, Human, Pair 4; D002999:Clone Cells; D005260:Female; D006801:Humans; D017681:Hypereosinophilic Syndrome; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion; D010641:Phenotype; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D020796:Receptor, Platelet-Derived Growth Factor alpha; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D039221:mRNA Cleavage and Polyadenylation Factors",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "734-42",
"pmc": null,
"pmid": "14973504",
"pubdate": "2004-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias.",
"title_normalized": "clinical and molecular features of fip1l1 pdfgra chronic eosinophilic leukemias"
} | [
{
"companynumb": "PHHY2018BE065019",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadditional": null,
"drugad... |
{
"abstract": "Infections caused by Mycobacterium wolinskyi have rarely been reported, and essentially all were cellulitis and/or osteomyelitis related with traumatic event or surgical wound. Here, we present the 1st case of septic complication due to this organism in a patient with chronic myelogenous leukemia of the 1st but late chronic phase.",
"affiliations": "Division of Hematology and Immunology, Department of Internal Medicine, Ohtsu Red Cross Hospital, Ohtsu 520-8511, Japan. tatsohno@ja2.so-net.ne.jp",
"authors": "Ohno|Tatsuharu|T|;Kishimoto|Wataru|W|;Chihara|Dai|D|;Sakamoto|Takashi|T|;Arimoto-Miyamoto|Kazue|K|;Takeoka|Tomoharu|T|;Tsuji|Masaaki|M|;Kida|Kaneyuki|K|;Ohkusu|Kiyofumi|K|;Ezaki|Takayuki|T|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.diagmicrobio.2008.07.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-8893",
"issue": "62(4)",
"journal": "Diagnostic microbiology and infectious disease",
"keywords": null,
"medline_ta": "Diagn Microbiol Infect Dis",
"mesh_terms": "D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008875:Middle Aged; D009161:Mycobacterium; D009165:Mycobacterium Infections, Nontuberculous; D018805:Sepsis",
"nlm_unique_id": "8305899",
"other_id": null,
"pages": "433-6",
"pmc": null,
"pmid": "18929459",
"pubdate": "2008-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "First case report of sepsis caused by Mycobacterium wolinskyi in chronic myelogenous leukemia.",
"title_normalized": "first case report of sepsis caused by mycobacterium wolinskyi in chronic myelogenous leukemia"
} | [
{
"companynumb": "PHBS2008JP06082",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": "3",
... |
{
"abstract": "Rhabdomyolysis is a rare, but serious complication of statin therapy, and represents the most severe end of the spectrum of statin-induced myotoxicity. We report a case where coenzyme Q10 facilitated recovery from statin-induced rhabdomyolysis and acute renal failure, which had initially persisted despite statin cessation and haemodialysis. This observation is biologically plausible due to the recognised importance of coenzyme Q10 in mitochondrial bioenergetics within myocytes, and the fact that statins inhibit farnesyl pyrophosphate production, a biochemical step crucial for coenzyme Q10 synthesis. Coenzyme Q10 is generally well tolerated, and may potentially benefit patients with statin-induced rhabdomyolysis.",
"affiliations": "Department of Cardiology, St Vincent's Hospital, Darlinghurst, New South Wales, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.",
"authors": "Wang|L W|LW|;Jabbour|A|A|;Hayward|C S|CS|;Furlong|T J|TJ|;Girgis|L|L|;Macdonald|P S|PS|;Keogh|A M|AM|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014451:Ubiquinone; C024989:coenzyme Q10",
"country": "Australia",
"delete": false,
"doi": "10.1111/imj.12712",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1444-0903",
"issue": "45(4)",
"journal": "Internal medicine journal",
"keywords": "coenzyme Q10; lipid; renal failure; rhabdomyolysis; statin",
"medline_ta": "Intern Med J",
"mesh_terms": "D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D008875:Middle Aged; D020127:Recovery of Function; D012206:Rhabdomyolysis; D014451:Ubiquinone",
"nlm_unique_id": "101092952",
"other_id": null,
"pages": "451-3",
"pmc": null,
"pmid": "25827512",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Potential role of coenzyme Q10 in facilitating recovery from statin-induced rhabdomyolysis.",
"title_normalized": "potential role of coenzyme q10 in facilitating recovery from statin induced rhabdomyolysis"
} | [
{
"companynumb": "PHHY2015AU041390",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
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"drug... |
{
"abstract": "The diagnosis of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is rare in pregnancy but potentially life threatening. There are no randomized controlled trials to guide the management of AAV in pregnancy and fetal safety data remains limited. Rituximab administration, a treatment for AAV, has been reported in pregnant women with reassuring fetal outcomes in the oncology and rheumatology literature; however, no published reports describe its use in AAV.\n\n\n\nWe present a case of de novo myeloperoxidase positive (MPO) AAV diagnosed at 22 weeks gestation. Clinical presentation included elevated serum creatinine at 177 μmol/L, hematuria and nephrotic range proteinuria along with high-titre MPO. Diagnosis was confirmed by renal biopsy. Patient was treated with methylprednisolone IV followed by oral prednisone 70 mg daily and Rituximab 650 mg IV weekly for four weeks followed by azathioprine maintenance therapy and prednisone taper. Delivery occurred at 29 weeks gestation via cesarean section for maternal neurologic symptoms concerning for preeclampsia. Maternal and fetal CD + 19 cells were depleted at time of delivery with associated fetal lymphopenia in the absence of infection or other complications related to Rituximab use. The patient experienced a reduction in proteinuria and inflammatory markers following Rituximab therapy; however, serum creatinine increased to 375 μmol/L by 11 weeks post-partum.\n\n\n\nWe report the first use, to our knowledge, of Rituximab with corticosteroids for induction therapy of AAV in pregnancy.",
"affiliations": "Division of Nephrology, University of British Columbia, Vancouver, BC, Canada.;St. Paul's Hospital, 1081 Burrard St. Vancouver BC, Vancouver, Canada.;Division of Nephrology, University of British Columbia, Vancouver, BC, Canada. MBeaulieu@providencehealth.bc.ca.",
"authors": "Harris|Claire|C|;Marin|Judith|J|;Beaulieu|Monica C|MC|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D019268:Antibodies, Antineutrophil Cytoplasmic; D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1186/s12882-018-0949-7",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 94910.1186/s12882-018-0949-7Case ReportRituximab induction therapy for de novo ANCA associated vasculitis in pregnancy: a case report Harris Claire claire.harris@alumni.ubc.ca 1Marin Judith JMarin@providencehealth.bc.ca 2Beaulieu Monica C. 1-604-681-7191MBeaulieu@providencehealth.bc.ca 1231 0000 0001 2288 9830grid.17091.3eDivision of Nephrology, University of British Columbia, Vancouver, BC Canada 2 0000 0000 8589 2327grid.416553.0St. Paul’s Hospital, 1081 Burrard St. Vancouver BC, Vancouver, Canada 3 BC Provincial Renal Agency, Vancouver, BC Canada 28 6 2018 28 6 2018 2018 19 15211 9 2017 17 6 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe diagnosis of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is rare in pregnancy but potentially life threatening. There are no randomized controlled trials to guide the management of AAV in pregnancy and fetal safety data remains limited. Rituximab administration, a treatment for AAV, has been reported in pregnant women with reassuring fetal outcomes in the oncology and rheumatology literature; however, no published reports describe its use in AAV.\n\nCase presentation\nWe present a case of de novo myeloperoxidase positive (MPO) AAV diagnosed at 22 weeks gestation. Clinical presentation included elevated serum creatinine at 177 μmol/L, hematuria and nephrotic range proteinuria along with high-titre MPO. Diagnosis was confirmed by renal biopsy. Patient was treated with methylprednisolone IV followed by oral prednisone 70 mg daily and Rituximab 650 mg IV weekly for four weeks followed by azathioprine maintenance therapy and prednisone taper. Delivery occurred at 29 weeks gestation via cesarean section for maternal neurologic symptoms concerning for preeclampsia. Maternal and fetal CD + 19 cells were depleted at time of delivery with associated fetal lymphopenia in the absence of infection or other complications related to Rituximab use. The patient experienced a reduction in proteinuria and inflammatory markers following Rituximab therapy; however, serum creatinine increased to 375 μmol/L by 11 weeks post-partum.\n\nConclusion\nWe report the first use, to our knowledge, of Rituximab with corticosteroids for induction therapy of AAV in pregnancy.\n\nKeywords\nAntineutrophil cytoplasmic antibody (ANCA)PregnancyCase reportRituximabMyeloperoxidase (MPO)Vasculitisissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nThe de novo diagnosis of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is rare in pregnancy. Treatment of AAV in pregnancy poses a therapeutic dilemma as the risks of teratogenicity and adverse fetal outcomes are weighed against the potential fatal maternal outcomes of untreated severe disease. We report the first use, to our knowledge, of Rituximab with corticosteroids for induction therapy in MPO associated ANCA vasculitis with severe renal involvement diagnosed in the second trimester of pregnancy.\n\nCase presentation\nA 20 year old gravida 1, para 0, female of Salvadoran descent was referred to nephrology for deteriorating kidney function and the nephrotic syndrome at 22 weeks gestational age (GA). Past medical history included a diagnosis of juvenile rheumatoid arthritis at age 12 treated with nonsteroidal anti-inflammatory drugs (NSAIDs) with resolution of symptoms into adulthood without therapy. The patient also endorsed pre-conception use of intranasal cocaine and cigarettes with no use (documented on urine drug screen) post conception. Medication use included prenatal vitamins, diclectin and acetaminophen. The patient reported a family history of rheumatoid arthritis diagnosed in her mother and maternal grandmother.\n\nAt presentation the patient’s serum creatinine was 177 μmol/L compared to a previous creatinine of 82 μmol/L three months earlier and a pre-pregnancy value of 56 μmol/L. She endorsed progressive lower limb edema beginning in early pregnancy. A history of tea coloured urine, epistaxis and sinus pressure was elicited. She did not have hemoptysis or rash but endorsed arthralgias in her shoulders, wrists, distal interphalangeal joints and ankles.\n\nOn examination her blood pressure was 116/60 mmHg. Relevant examination findings included pitting edema to the knees bilaterally. There were no active joints or rash.\n\n24-h urine for protein yielded 9.81 g with > 100 RBC/hpf seen on microscopy. Urine albumin to creatinine ratio was 450 mg/mmol. Urine drug screen was negative for cocaine. Serum albumin was 20 g/L, antinuclear antibody 1:80, double stranded DNA negative, extractable nuclear antigen negative, C3, C4, normal and rheumatoid factor, cyclic citrullinated peptide negative, C-reactive protein 13 (normal < 10). HIV, Hepatitis B and C serology were negative. ANCA serology was positive with MPO antibody tire of 107.7 Antibody Index (AI) (normal < 20).\n\nRenal ultrasound revealed structurally normal kidneys. Obstetrical ultrasound revealed mild intrauterine growth restriction (IUGR). Chest x-ray was unremarkable.\n\nRenal biopsy was performed urgently with a diagnosis of pauci immune glomerulonephritis. Three of 14 glomeruli on light microscopy contained cellular crescents, 4 glomeruli fibrous crescents, 1 globally sclerosed. Up to six glomeruli contained segmental sclerosis with only five to 10 % interstitial fibrosis and tubular atrophy.\n\nThe patient was counselled regarding the maternal and fetal risks associated with her diagnosis and her therapeutic options including termination and elected to continue with the pregnancy. In particular, the risk of progression of renal impairment and potential requirement of dialysis during pregnancy were discussed, in addition to the high risk of preeclampsia and preterm labour if the pregnancy was continued. The patient was treated with methylprednisolone 1 g IV daily × 3 followed by oral prednisone 70 mg daily dosed by ideal weight and then Rituximab 650 mg IV weekly for four weeks. No infusion reactions to Rituximab were noted. The patient developed diffuse striae distensae which may have been a result of the high dose prednisone in the context of pregnancy and weight gain. Serum creatinine continued to rise throughout pregnancy to 250 μmol/L, despite a reduction in proteinuria to a urine albumin creatinine ratio of 125 mg/mmol and improvement in symptoms. At 27 weeks GA, the patient became hypertensive necessitating use of labetalol therapy. She was initiated on erythropoietin for anemia. The patient developed thrombocytopenia which was felt to be immune mediated in nature with a nadir of 64. Repeat obstetrical ultrasounds revealed normalization of fetal growth.\n\nDelivery occurred at 29 weeks GA via caesarean section for worsening maternal headache and visual disturbance concerning for preeclampsia and worsening renal function with serum creatinine of 275 μmol/L. Maternal CD19+ cells were depleted at time of delivery. Neonatal birth weight was 1010 g and the neonate spent 10 weeks in the neonatal intensive care unit before discharge in healthy condition. Neonatal CD19+ cell levels were depleted at birth with associated transient lymphopenia without infectious complications. After delivery, the patient’s creatinine rose to a value of 375 μmol/L (eGFR 14 ml/min) at 11 weeks post partum. Prednisone was tapered slowly to 10 mg daily and the patient was initiated on azathioprine maintenance therapy four months after Rituximab induction and titrated up to a dose of 2 mg/kg/day. At the time of maintenance therapy initiation, the MPO titer was 5.8 Units (normal < 1).\n\nDiscussion\nWithout specific treatment ANCA associated vasculitis is associated with high mortality and poor renal outcomes. The most recent KDIGO guidelines suggest the use of cyclophosphamide and corticosteroids as induction treatment with grade 1A evidence [1]. Rituximab and corticosteroids may be used as an alternative initial treatment in patients without severe disease or in whom cyclophosphamide is contraindicated (1B) [1]. The evidence for treatment of ANCA associated vasculitis in pregnancy is limited to case report and case series data.\n\nRenal dysfunction is a well-established risk factor for pregnancy complications including preeclampsia, preterm labour and pregnancy loss [2]. It is generally accepted that active autoimmune disease such as vasculitis in pregnancy further increase these risks but the literature is limited to case reports in this area and thus attributable risk is unknown [3].\n\nThe literature describing ANCA associated vasculitis in pregnancy is heterogeneous and is dominated by descriptions of patients with known ANCA vasculitides in remission prior to conception. In one case study, Presta et al. reported the pre-conception use of plasma exchange, cyclophosphamide and prednisone for MPO-ANCA vasculitis 1 month prior to unplanned conception and there was no fetal complications [4].\n\nDe novo ANCA associated vasculitis in pregnancy is rare. A case series of 12 patients with de novo ANCA associated vasculitis in pregnancy was reported by Alfhaily et al. in 2009 [5]. Treatment regimens included combinations of prednisone plus cyclophosphamide, Intravenous immunoglobulin (IVIG) or azathioprine. One fetal death was reported, 2 pregnancies were terminated for medical indications with a mean live birth gestational age of 34 weeks and good fetal outcomes. One patient developed pre-eclampsia. There was one maternal death in this series with the majority of women achieving clinical remission.\n\nRituximab is listed as a Food and Drug Administration (FDA) category C drug per the previous FDA drug classification system [6]. As an IgG isotype antibody, it crosses the placenta beginning at 16 weeks gestation [7]. Pregnancy outcomes after maternal exposure to rituximab have been described in primarily in the oncology literature with some reports of use in autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosus. A review of Rituximab exposure during 9 pregnancies for oncology (6 lymphoma) and autoimmune (1 idiopathic thrombocytopenic purpura, 1 thrombotic thrombocytopenic purpura, 1 autoimmune hemolytic anemia) indications reported no serious neonatal outcomes [6]. Although B cell depletion occurred in 4/5 neonates tested during the first week of life, recovery of B cell populations occurred by 6 months and no serious infections were reported even in the 2 neonates with low white blood cell counts at birth. A possible explanation for the absence of infections reported thus far in the literature is that neonates depend on maternal IgG for immunity during the first few months of life while B-cell function still developing during this time frame even in unexposed normal neonates [8].\n\nA case series by Chakravarty reviewed 153 pregnancies with maternal exposure to rituximab and 90 live births including 21 pregnancies with antenatal exposure [9]. The rate of preterm labor was 19%, compared to 10–12% in the general population however this rate is comparable to women with chronic medical diseases. The rate of congenital malformations was the same as the general population. The rate of miscarriage was higher possibly due to frequent testing detecting early pregnancies or again due to maternal comorbidities. Four neonatal infections occurred but no pattern was identified regarding timing of rituximab exposure and no infections occurred in the 7 neonates who developed cytopenias.\n\nWith respect to the use of rituximab for AAV prior to conception, Pendergraft et al. reported maternal and fetal outcomes in patients who received rituximab pre conception [10]. This retrospective analysis reported 8 pregnancies in 6 women with vasculitis who received rituximab prior to conception. Mean rituximab exposure was 5.2 months prior to estimated date of confinement (EDC), with 4 of 8 pregnancies conceived within one month of most recent rituximab infusion. Rituximab was discontinued at time of pregnancy diagnosis and patients were maintained on prednisone and/or azathioprine. There was one fetal demise due to a congenital anomaly unrelated to rituximab and maternal disease activity was quiescent in all but one pregnancy where prednisone was up titrated due to respiratory symptoms. At delivery 6 of 8 women had undetectable CD20+ B lymphocytes however 3 of 3 of fetal samples had present CD20+ B lymphocytes. Mean delivery occurred at 38 wks GA for the 7 live births.\n\nReview of the literature reveals one prior case report of the use of rituximab for induction therapy in a case of de novo pauci immune glomerulonephritis which was ANCA negative [11]. The pregnancy was ended with termination and patient was switched to cyclophosphamide after receiving two doses of rituximab in addition to corticosteroids and plasmapheresis, therefore no neonatal outcomes are reported.\n\nAs a result of this case, we report the first known use of rituximab for induction therapy of ANCA associated vasculitis during an established pregnancy with continuation of the pregnancy to delivery. Although Rituximab exposure in the second and third trimester appears to cause neonatal B cell depletion this does not appear to be associated with adverse events in the neonate. Rituximab exposure does not appear to increase congenital malformations even when exposure occurs in the first trimester or just prior to conception. Further investigation is still required to determine the adequacy of the immune response to vaccination in the offspring and it is recommended that live vaccines should be avoided during the first 6 months of life if exposure occurred after the first trimester [12].\n\nConclusion\nAlthough more evidence is required, Rituximab can be considered for the treatment of ANCA vasculitis during pregnancy. The decision to use any immunosuppressive medication in pregnancy requires careful counselling of the patient regarding the limitations of our knowledge in this area and the possible expected fetal outcomes. However, the importance of adequate treatment of a potentially life threatening maternal condition must be highlighted. Our patient developed preeclampsia and premature delivery even with improvement in markers of her vasculitis with rituximab therapy. This outcome emphasizes the high risk nature of pregnancies in patients with severe renal impairment and systemic inflammatory conditions and the need for specialized obstetrical care from a highly trained interprofessional team.\n\nAbbreviations\nAAVANCA associated vasculitis\n\nAIAntibody Index\n\nANCAAntineutrophil cytoplasmic antibody\n\nEDCEstimated date of confinement\n\nFDAFood and Drug Administration\n\nGAGestational Age\n\nIUGRsMild intrauterine growth restriction\n\nIVIGIntravenous immunoglobulin\n\nMPOMyeloperoxidase\n\nNSAIDsNonsteroidal anti-inflammatory drugs\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed for this case report.\n\nAuthors’ contributions\nCH, MB and JM were involved in the index case and literature review. CH collected the data and drafted the manuscript. MB and JM were involved in revising the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. KDIGO KDIGO Clinical Practice Guideline for Glomerulonephritis Kidney Int Suppl 2012 2 209 10.1038/kisup.2012.23 \n2. Zhang JJ Ma XX Hao L Liu LJ Lv JC Zhang H A systematic review and meta-analysis of outcomes of pregnancy in CKD and CKD outcomes in pregnancy Clin J Am Soc Nephol 2015 10 1964 1978 10.2215/CJN.09250914 \n3. Doria A Bajocchi G Tonon M Salvarani C Pre-pregnancy counselling of patients with vasculitis Rheumatology 2008 47 iii13 iii15 10.1093/rheumatology/kem250 18504277 \n4. Presta P Presta P Fuiano G Successful conception and pregnancy in p-ANCA associated vasculitis in course of treatment with immunosuppressive drugs and renal replacement therapy Int J Rheum Dis 2015 18 470 472 10.1111/1756-185X.12454 25195538 \n5. Alfhaily F Watts R Leather A Wegener’s granulomatosis occurring de novo during pregnancy Clin Exp Rheumatol 2009 27 Suppl 52 S86 S88 19646353 \n6. Vinet E Pineau C Gordon C Clarke AE Biologic therapy and pregnancy outcomes in women with rheumatic diseases Arthritis Rheum (Arthritis Care & Research) 2009 61 5 587 592 10.1002/art.24462 \n7. Østensen M Lockshin M Doria A Update on safety during pregnancy of biological agents and some immunosuppressive anti-rheumatic drugs Rheumatology 2008 47 Suppl 3 iii28 iii31 18504282 \n8. Klink DT, van Elburg RM, Schreurs MWJ, van Well GTJ. Rituximab administration in third trimester of pregnancy suppresses neonatal B-cell development. Clin Devel Immunol. 2008;2008:6.\n9. Chakravarty EF Murray ER Kelman A Farmer P Pregnancy outcomes after maternal exposure to rituximab Blood 2011 117 5 1499 1506 10.1182/blood-2010-07-295444 21098742 \n10. Pendergraft WF McGrath MM Murphy AP Fetal outcomes after rituximab exposure in women with autoimmune vasculitis Ann Rheum Dis 2013 72 12 2051 2053 10.1136/annrheumdis-2013-203833 23864238 \n11. Conduit C Yew S Jose M Jayne D Kirkland G A case of diagnosis anti-neutrophil cytoplasmic antibody-negative pauci-immune necrotising glomerulonephritis in pregnancy Intern Med J 2017 47 5 600 601 10.1111/imj.13405 28503881 \n12. Götestam Skorpen C Hoeltzenbein M Tincani A The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation Ann Rheum Dis 2016 75 795 810 10.1136/annrheumdis-2015-208840 26888948\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "19(1)",
"journal": "BMC nephrology",
"keywords": "Antineutrophil cytoplasmic antibody (ANCA); Case report; Myeloperoxidase (MPO); Pregnancy; Rituximab; Vasculitis",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D019268:Antibodies, Antineutrophil Cytoplasmic; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic; D012074:Remission Induction; D000069283:Rituximab; D055815:Young Adult",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "152",
"pmc": null,
"pmid": "29954345",
"pubdate": "2018-06-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19404999;23864238;25195538;18504282;18504277;28503881;26888948;19646353;18596903;26487769;21098742",
"title": "Rituximab induction therapy for de novo ANCA associated vasculitis in pregnancy: a case report.",
"title_normalized": "rituximab induction therapy for de novo anca associated vasculitis in pregnancy a case report"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2018US-179886",
"fulfillexpeditecriteria": "1",
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"actiondrug": "5",
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"activesubstancename": "AZATHIOPRINE"
},
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{
"abstract": "Despite advances in the treatment of patients with pulmonary arterial hypertension (PAH), survival has not improved greatly (is still very affected). Imatinib, an antagonist of platelet-derived growth factor with antiproliferative activity, has been effective in experimental models and clinically in several published reports. We report the results of imatinib therapy in 4 patients with PAH (functional class IV) who were refractory to treatment with drug combinations for this condition. The final outcome was favorable in only 1 of the 4 cases. In this case, the patient was in functional class III and his hemodynamic parameters had improved significantly within 5 months after starting therapy. However, the patient died as a result of severe toxic hepatitis in which imatinib may have played a role. The present report adds to the few already in the literature (4 cases) and suggests that care should continue to be shown when using imatinib to treat PAH.",
"affiliations": "Unidad de Colagenosis e Hipertensión Pulmonar, Servicio de Medicina Interna, Hospital Universitario Virgen del Rocío, Sevilla, España. fjgarciah@eresmas.com",
"authors": "García Hernández|Francisco José|FJ|;Castillo Palma|María Jesús|MJ|;González León|Rocío|R|;Garrido Rasco|Rocío|R|;Ocaña Medina|Celia|C|;Sánchez Román|Julio|J|",
"chemical_list": "D001549:Benzamides; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D000068877:Imatinib Mesylate",
"country": "Spain",
"delete": false,
"doi": "10.1016/s1579-2129(09)60008-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2896",
"issue": "44(12)",
"journal": "Archivos de bronconeumologia",
"keywords": null,
"medline_ta": "Arch Bronconeumol",
"mesh_terms": "D000328:Adult; D001549:Benzamides; D056486:Chemical and Drug Induced Liver Injury; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D000068877:Imatinib Mesylate; D008875:Middle Aged; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines",
"nlm_unique_id": "0354720",
"other_id": null,
"pages": "689-91",
"pmc": null,
"pmid": "19091239",
"pubdate": "2008-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Experience with imatinib to treat pulmonary arterial hypertension.",
"title_normalized": "experience with imatinib to treat pulmonary arterial hypertension"
} | [
{
"companynumb": "ES-CONCORDIA PHARMACEUTICALS INC.-E2B_00016041",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TREPROSTINIL"
},
"drugad... |
{
"abstract": "OBJECTIVE\nWe report five cases of optic neuropathy (ON) identified over a 2-year period within an island population of 140 000. These cases display characteristics possibly related to long-term treatment with selective serotonin reuptake inhibitors (SSRIs).\n\n\nMETHODS\nRetrospective analysis of casenotes. Each case has been assessed using the Naranjo algorithm to indicate likelihood of adverse drug reaction (ADR).\n\n\nRESULTS\nClinical assessment and investigation confirmed ON in all cases with a vascular origin suspected. SSRI cessation may help protect the unaffected eye and in some cases recovery of vision seems possible. The Naranjo scores indicated possible ADR in four cases and probable ADR in one case.\n\n\nCONCLUSIONS\nIn 2004, ~7% of the UK adult population was receiving SSRI treatment for a range of 4.8-7.7 years. The most common ophthalmic side effect is acute glaucoma. Currently, there remain no reports of SSRI associated ON, although papilloedema has been reported. A potential mechanism for ischaemic optic neuropathy (ION) has been described in relation to raised serotonin levels. A single case of central retinal vein occlusion exists along with reports of deep vein thrombosis (DVT) and ischaemic stroke. We recommend a review of SSRI treatment in cases of acute ON.",
"affiliations": "Department of Ophthalmology, St Mary's Hospital, Newport, IOW, UK.",
"authors": "Lochhead|J|J|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1038/eye.2015.119",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0950-222X",
"issue": "29(9)",
"journal": "Eye (London, England)",
"keywords": null,
"medline_ta": "Eye (Lond)",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009901:Optic Nerve Diseases; D012189:Retrospective Studies; D017367:Serotonin Uptake Inhibitors; D014786:Vision Disorders",
"nlm_unique_id": "8703986",
"other_id": null,
"pages": "1233-5",
"pmc": null,
"pmid": "26139049",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17854756;21677222;9932283;15534605;21519224;18545940;19587851;11190017;15567215;7249508;21350282;16690637",
"title": "SSRI-associated optic neuropathy.",
"title_normalized": "ssri associated optic neuropathy"
} | [
{
"companynumb": "PHHY2015GB117207",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Neurosurgical interventions are rarely associated with meningitis with a very low incidence rate ranging from 1.1% to 2.5%. Gram negative bacillary meningitis first described in the 1940's, previously uncommon has been increasing in the recent past associated with advanced age, immunosuppression and neurosurgery. Enterobacter meningitis though relatively uncommon is recently increasing in incidence and treatment is frequently complicated due to resistance to antibiotics making this a challenging, difficult to treat infection that may be associated with adverse clinical outcomes. Here, we describe a case of a 27-year-old patient diagnosed with brain sarcoma at the age of four years, who presented with Enterobacter meningitis following a neurosurgical intervention for resection of a recurrent brain tumor (meningioma on pathology) and had a prolonged hospital stay with a difficult to treat infection.",
"affiliations": "Resident Physician, Department of Internal Medicine, Rutgers Robert Wood Johnson Medical School, Saint Peter's University Hospital , New Jersey, USA .;Research Assistant, Department of Pulmonology, New York Methodist , USA .;Attending Physician, Department of Internal Medicine, Rutgers Robert Wood Johnson Medical School, Saint Peter's University Hospital , New Jersey, USA .;Epidemiology-Biostatistics, City University of New York , USA .",
"authors": "Chauhan|Shaylika|S|;Noor|Jawad|J|;Yegneswaran|Balaji|B|;Kodali|Hanish|H|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2016/20759.9081",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "10(12)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Bi-frontal craniotomies; Immunosuppression; Neurosurgical interventions",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "OD10-OD11",
"pmc": null,
"pmid": "28208914",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports",
"references": "9105752;15798816;10807247;15793111;12709321;15936376;12856206;16460547",
"title": "Enterobacter Meningitis and Challenges in Treatment.",
"title_normalized": "enterobacter meningitis and challenges in treatment"
} | [
{
"companynumb": "US-UCBSA-2017002972",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PRIMIDONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Hypertension is common in hemolytic uremic syndrome (HUS) and often difficult to control. Local renin-angiotensin activation is believed to be an important part of thrombotic microangiopathy, leading to a vicious cycle of progressive renal injury and intractable hypertension. This has been demonstrated in vitro via enhanced tissue factor expression on glomerular endothelial cells which is enhanced by angiotensin II. We report two pediatric cases of atypical HUS with severe refractory malignant hypertension, in which we targeted the renin-angiotensin system by using intravenous (IV) enalaprilat, oral aliskiren, and oral enalapril with quick and dramatic response of blood pressure. Both drugs, aliskiren and IV enalaprilat, were effective in controlling hypertension refractory to multiple antihypertensive medications. These appear to be promising alternatives in the treatment of severe atypical HUS-induced hypertension and hypertensive emergency.",
"affiliations": "Pediatric Critical Care Unit, Medanta - The Medicity, Gurgaon, Haryana, India.;Kidney Institute, Medanta - The Medicity, Gurgaon, Haryana, India.;Department of Immunology, Georges Pompidou European Hospital, APHP, Paris, France.;Pediatric Critical Care Unit, Medanta - The Medicity, Gurgaon, Haryana, India.;Department of Pediatric Nephrology, Akron Children's Hospital, Akron, Ohio, USA.;Kidney Institute, Medanta - The Medicity, Gurgaon, Haryana, India.;Kidney Institute, Medanta - The Medicity, Gurgaon, Haryana, India.;Kidney Institute, Medanta - The Medicity, Gurgaon, Haryana, India.",
"authors": "Raghunathan|V|V|;Sethi|S K|SK|;Dragon-Durey|M A|MA|;Dhaliwal|M|M|;Raina|R|R|;Jha|P|P|;Bansal|S B|SB|;Kher|V|V|",
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"doi": "10.4103/0971-4065.181462",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-27-13610.4103/0971-4065.181462Case ReportTargeting renin-angiotensin system in malignant hypertension in atypical hemolytic uremic syndrome Raghunathan V. *Sethi S. K. 1*Dragon-Durey M. A. 2Dhaliwal M. Raina R. 3Jha P. 1Bansal S. B. 1Kher V. 1Pediatric Critical Care Unit, Medanta - The Medicity, Gurgaon, Haryana, India1 Kidney Institute, Medanta - The Medicity, Gurgaon, Haryana, India2 Department of Immunology, Georges Pompidou European Hospital, APHP, Paris, France3 Department of Pediatric Nephrology, Akron Children's Hospital, Akron, Ohio, USA* These authors contributed equally to this work.\n\nAddress for correspondence: Dr. S. K. Sethi, Consultant, Pediatric Nephrology, Kidney Institute, Medanta - The Medicity, Gurgaon - 122 001, Haryana, India. E-mail: sidsdoc@gmail.comMar-Apr 2017 27 2 136 140 Copyright: © 2017 Indian Journal of Nephrology2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Hypertension is common in hemolytic uremic syndrome (HUS) and often difficult to control. Local renin-angiotensin activation is believed to be an important part of thrombotic microangiopathy, leading to a vicious cycle of progressive renal injury and intractable hypertension. This has been demonstrated in vitro via enhanced tissue factor expression on glomerular endothelial cells which is enhanced by angiotensin II. We report two pediatric cases of atypical HUS with severe refractory malignant hypertension, in which we targeted the renin-angiotensin system by using intravenous (IV) enalaprilat, oral aliskiren, and oral enalapril with quick and dramatic response of blood pressure. Both drugs, aliskiren and IV enalaprilat, were effective in controlling hypertension refractory to multiple antihypertensive medications. These appear to be promising alternatives in the treatment of severe atypical HUS-induced hypertension and hypertensive emergency.\n\nKey words\nEnalaprilenalaprilathemolytic uremic syndromemalignant hypertensionrenin\n==== Body\nIntroduction\nHypertension is common in hemolytic uremic syndrome (HUS), and often difficult to control in an acute stage. Malignant hypertension associated with HUS leads to reversible posterior encephalopathy syndrome, seizures, heart failure, and other adverse consequences which increase the morbidity and mortality of the disease. Renin-mediated mechanism is believed to be the main factor responsible for hypertension seen in these cases.[123] Drugs that act by blocking renin-angiotensin axis (RAS) are thus ideal for such cases, however, due to concern of progression of renal failure and lack of experience of these agents in children, these are not preferred or used commonly in acute stages. We hereby report two cases of HUS with severe refractory malignant hypertension in which we targeted RAS by using intravenous (IV) enalaprilat, oral aliskiren, and oral enalapril with quick and dramatic response of blood pressure (BP).\n\nCase Reports\nCase 1\nA 6-year-old male was admitted with a history of vomiting, fever since 2 weeks, hematuria and decreased urine output since 1 week. On evaluation by his local practitioner, he was found to have anemia (hemoglobin [Hb] 6.3 g/dl), thrombocytopenia (platelet 72,000/mm3), active urine sediment (red blood cell [RBC] 40–60/hpf, albumin 3+), and azotemia (blood urea 200 mg/dl, creatinine 4.2 mg/dl). He had an episode of seizure (due to accelerated hypertension), hence was brought to our hospital for further management. On evaluation, he was hypertensive (BP 150/100 mmHg) with generalized edema, oliguria, and a normal systemic examination. Investigations were suggestive of HUS (Hb 4.8 g/dl, white blood cell [WBC] 11,190 cmm, platelet 1.84/mm3, peripheral smear: schistocytes positive, reticulocyte count 6.8%, lactate dehydrogenase [LDH] 4300 U/L, Direct Coombs test and Indirect Coombs tests were negative, urea 67 mg/dl, creatinine 2.6 mg/dl). Septic work up, dengue serology, and malarial antigen were negative, and he became afebrile on the 4th day of admission. His antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibody (ANCA) were negative. He was started on empiric antibiotics (injection ceftriaxone) and daily plasmapheresis for HUS. Echocardiography and fundus were normal. Detailed complement regulator assay showed very high anti-Factor H antibody (41,000 IU). C3, C4, antigenic levels of Factor H, Factor I, Factor B, and CD46 were normal [Table 1]. He was given a blood transfusion and initiated on hemodialysis and daily plasma exchanges in view of oligo-anuric acute kidney injury (AKI).\n\nTable 1 Complement assay in cases*\n\nFor the child's height percentile, the BP percentiles were: 90th percentile: 113/72 mmHg and 95th percentile 117/76 mmHg (Blood pressure references used were as per the fourth report[4]). For arterial hypertension [Figure 1], he was started on sustained release nifedepine, clonidine, and metoprolol and subsequently prazosin with a gradual increase in dosage. However, arterial BP remained persistently high (>99th centile; up to 170/120 mmHg), and he developed blurring of vision, with abdominal pain and vomiting on the 3rd day of admission necessitating need for IV nitroglycerine (up to 5 mcg/kg/min) and subsequently labetolol infusion (up to 2 mg/kg/h) for refractory hypertension. Child had persistent arterial hypertension (>99th centile for his age), despite vigorous fluid removal in hemodialysis sessions.\n\nFigure 1 Response to antihypertensive medications in case 1\n\nOral enalapril and minoxidil were also added and dosage of other oral antihypertensives optimized to the maximal doses [Figure 1] but arterial BP remained high and was difficult to control. Oral enalapril was added on the same day of oral minoxidil. The starting dose was 0.2 mg/kg/day and was increased gradually. But since within 48 h of adding oral enalapril and oral minoxidil, child went into hypertensive emergency (BP 180/120 mmHg), with hallucinations and visual blurring, IV enalaprilat was added. Hypertension showed a significant improvement after addition of IV enalaprilat (10 µg/kg/dose q 8 hourly) on the 5th day of admission. There was a consistent fall of BP within hours of giving individual IV enalaprilat boluses (average fall in mean BP 9.5 mmHg). Arterial BP decreased to 110/78 mmHg; patient became asymptomatic, and nitroglycerine and labetolol infusions were tapered off successfully.\n\nHe developed neutropenia a week following enalaprilat therapy (WBC 1500 cmm, 50% neutrophils), which could not be attributed to any other cause; hence, it was stopped followed by a rebound in hypertension (arterial BP 190/136 mmHg). He was not dialysis dependent at this stage with a good urine output, and serum creatinine had fallen to 0.6 mg/dl, and his hemodialysis catheter was removed.\n\nAliskiren (2 mg/kg/dose) was then added with good response (arterial BP decreased to 150/110 mmHg over 24 h, and 138/110 mmHg over 48 h); however, it was withdrawn after 4 days due to hyperkalemia (serum potassium 6.5 mmol/L). After improvement of neutopenia, oral enalapril was reintroduced along with telmisartan. BP control improved within 48 h on this angiotensin-converting enzyme inhibitor-angiotensin receptor blockade (ACEI-ARB) combination (BP <90th percentile for age) along with other oral antihypertensive agents. Metoprolol and prazosin could be tapered off thereafter.\n\nHe received seven daily plasmapheresis sessions till active hemolysis subsided followed by alternate day sessions. He received prednisolone (1 mg/kg/day) and IV immunoglobulin 2 g/day (day 10 of admission), IV cyclophosphamide during his hospital stay. He was discharged after 3 weeks after achieving good BP control. He received total six doses of IV cyclophosphamide followed by maintenance azathioprine. At his 1 year of follow-up, he is doing well, normotensive (BP <90th percentile for age) and no proteinuria (urine protein/creatinine ratio <0.2) and a normal urine examination on angiotensin-converting enzyme (ACE) and ARB combination.\n\nCase 2\nA 7-month-old male was admitted with a history of vomiting, fever since 5 days and anuria since 2 days. There was no history of diarrhea or dysentery in the past. On admission, he was hypertensive (BP 130/60 mmHg), with pallor, facial puffiness, and normal systemic examination. Investigations were suggestive of atypical HUS-microangiopathic hemolytic anemia with AKI (Hb 7 g/dl, WBC 13,280/mm3, platelets 100,000/mm3, peripheral smear: schistocytes, elliptocytes, reticulocyte count 5.6%, LDH 4300 U/L) and active urine sediment (RBC 10–20/hpf, albumin 2+). The child had no evidence of pneumonia or sepsis, on clinical evaluation, and all cultures were sterile. The child had advanced azotemia (urea 216 mg/dl, creatinine 7.2 mg/dl) with severe hyperkalemia and metabolic acidosis. He was initiated on hemodialysis in view of anuric AKI. For HUS with evidence of ongoing hemolysis and dialysis dependence, he was started on daily plasmapheresis. A detailed complement assay (including C3, C4, antigenic levels of Factor H, Factor I, Factor B, CD46, and autoantibodies to Factor H) were normal [Table 1]. His ANA and ANCA were negative. BP was observed to be high since admission and increased up to 160/110 mmHg on serial monitoring, although patient remained asymptomatic. Echocardiography and fundus were normal.\n\nFor his arterial hypertension (>99th centile for age) [Figure 2], he was started on amlodipine and prazosin initially; dosage was increased to the maximal dose, and clonidine and oral enalapril were added on the 3rd and 4th day of admission, respectively. Despite the addition of multiple antihypertensive agents and dosage optimization and aggressive ultrafiltration in hemodialysis sessions, arterial BP showed only marginal decrease and mean arterial BP remained high (>99th centile for age; 100–110 mmHg). Intravenous enalaprilat (10 µg/kg/dose q 8 hourly) was added on day 6 of admission. The mean arterial BP improved (80 mmHg) within 12 h of addition of enalaprilat. Once arterial BP was controlled with no further increase, dose of oral enalapril was maximized, while tapering off IV enalaprilat and other antihypertensive medications were continued.\n\nFigure 2 Response to antihypertensive medications in case 2\n\nDaily hemolytic parameters and renal function were monitored. Both improved gradually on plasmapheresis. He received 5 daily and 3 alternate day plasmapheresis sessions. Hemodialysis was stopped by day 9 of admission. He was discharged in 2 weeks time in a stable condition, with adequate urine output and BP controlled on oral antihypertensive therapy. At a follow-up of 1 year, currently the infant is doing well, with serum creatinine 0.7 mg/dl, urine protein/creatinine ratio 1.5, and normal BP (BP <90th percentile for age) on oral enalapril 0.4 mg/kg/day.\n\nDiscussion\nThe extent of renal microangiopathic involvement appears to be responsible for the development of hypertension and renal failure in atypical HUS.[1] Renal ischemia is triggered which leads to maximal activation of RAS resulting in accelerated hypertension which is often very severe and resistant to antihypertensive therapy. Local RAS activation is believed to be an important key factor in the thrombotic microangiopathy in HUS leading to intractable hypertension. This has been demonstrated to occur via enhanced tissue factor expression on glomerular endothelial cells which is enhanced by angiotension II.[2] On the other hand, there are conflicting reports of plasma renin activity in HUS.[567] Two studies have shown elevated plasma renin levels in children with HUS, irrespective of systemic hypertension.[67]\n\nSevere hypertension that ensues is a clinician's nightmare as it is hard to control despite use of multiple drug combinations and careful drug titration. In extreme cases, bilateral nephrectomy is ultimately required as a life-saving measure for achieving control of BP, thus again underlining the pivotal role of hyperreninemia in the development of hypertension in HUS.[13]\n\nAlthough there is plenty of evidence in favor of renin-mediated mechanism in the pathogenesis of hypertension in HUS, in practice there is hesitation to use RAS inhibitors or their combinations in the acute stage for hypertension. This is due to fear of worsening of renal failure and lack of pediatric experience with newer RAS inhibitors. Oral ACEIs (enalapril, captopril) have been shown to be renoprotective and of benefit for long-term BP control and reduction in proteinuria in patients with persistent disease.[8] However, they are not preferred in the acute stage of disease, used with great caution and generally initiated after improvement of renal function. Moreover, ACEIs including enalaprilat are seldom used in hypertensive emergencies due to concerns regarding slow onset of action and variable effectiveness, especially in children.[9]\n\nWe used IV enalaprilat in both patients for acute hypertension who showed significant and consistent decline in BP. It helped in successful reversal of hypertensive urgency in the older child whose BP remained high and was extremely difficult to control despite multiple drugs including IV nitroglycerine and labetolol. Enalaprilat is the active metabolite of enalapril. The onset of action begins in 15 min, but the peak effect may take 1–4 h. The duration of action is usually 4–6 h. The half life of the drug is usually 11.1 h in infants and children.[10] There is one case series reporting the neonatal use of enalaprilat that reported that doses even at the lower end of what was used in this cohort may lead to significant, prolonged hypotension and oliguric acute renal failure.[11] If it is used in the newborn or children, it should be used with caution with ongoing monitoring of BP, serum potassium, and renal function. The adverse effects of enalaprilat are hyperkalemia, hypotension, cough, diarrhea, angioedema, and leucopenia (agranulocytosis). We encountered neutropenia in one of our patients a week after initiation of IV enalaprilat which reversed quickly on drug withdrawal. However, severe rebound hypertension also occurred on stopping enalaprilat, while other drugs were continued, which reiterates its effectiveness in the management of the hypertensive urgency. Hirschl et al. studied the BP response to IV enalaprilat in 35 patients with hypertensive crisis, and found that the extent of systolic and diastolic BP reduction correlated well with the pretreatment plasma renin and angiotensin II levels.[12] Thus, it appears that the status of RAS determines the efficacy of IV enalaprilat, and hence it was successful in both our patients with HUS-induced hypertension. Therapeutic enalaprilat levels can probably be achieved with 1/4th total cumulative dose of enalapril, administered as 6 hourly enalaprilat: recommended pediatric dosing is 5–10 mcg/kg/dose.[13] We used a dose of 10 mcg/kg/dose q 8 hourly in both of our cases based on the previous report.\n\nWe used aliskiren in the older child which too was very effective in lowering BP. Aliskiren is the first direct renin inhibitor available in an oral form approved for adults by the US Food and Drug Administration in 2007.[1415] As renin is the first and rate-limiting step in angiotensin II synthesis in RAS, its direct inhibition is theoretically more advantageous as compared to ACE inhibition/ARB. As it is a nonpeptide molecule, it has better bioavailability and a long half-life and can, therefore, lower BP effectively. It is available in the form of 150 mg and 300 mg doses. Once administered orally, the effect of the drug peaks in 1–3 h, achieves its steady state in 5–7 days and has a half-life of 40 h.[15] Aliskiren produces dose-dependent BP reduction and its potency has been shown to be equivalent or better than ACEIs, ARBs in various trials.[151617] Moreover, when administered as a combination with ACEI, it helps to block an increase in plasma renin activity induced by ACEI monotherapy. Combination therapy (aliskiren + ACEI) has been demonstrated to have greater BP-lowering potential as compared to either alone.[16] Dual RAS blockade however must be cautiously monitored as there is a higher chance of adverse effects. A case series of children with chronic kidney disease receiving combination aliskiren/ACEI showed >45% proteinuria reduction, however side effects in the form of hyperkalemia, worsening of renal function, and hypotension were seen.[17] Mild hyperkalemia was seen in our patient but was asymptomatic, and potassium normalized quickly on stopping the drug. Other adverse effects including nausea, angioedema, diarrhea, abdominal pain, and headache may be seen with aliskiren but are usually mild and not dose related. Adult studies have shown aliskiren to be a safe and effective antihypertensive drug; however, its use in children has been restricted so far due to the paucity of data. A recent prospective, randomized controlled in children between ages 6 and 17 years concluded that aliskiren in once daily doses of 2 mg/kg or 6 mg/kg was well tolerated and safe.[18] We used a dose of 2 mg/kg in case 1.\n\nIn the above two patients, we used two unconventional drugs: aliskiren and IV enalaprilat, both of which were very quick and effective in controlling high BP refractory to multiple antihypertensive medications and aggressive ultrafiltration during dialysis sessions. The limitation of the report is small number, multiple antihypertensives in these patients, and simultaneous use of plasma exchanges and immunosuppression in anti-Factor H antibody positive case 1 to help resolution of illness, which might make interpretation difficult. These appear to be promising alternatives in the treatment of severe atypical HUS-induced hypertension and hypertensive emergency, and there is a need to have more trials targeting renin in these cases.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Ruggenenti P Remuzzi G Malignant vascular disease of the kidney: Nature of the lesions, mediators of disease progression, and the case for bilateral nephrectomy Am J Kidney Dis 1996 27 459 75 8678055 \n2 Nestoridi E Kushak RI Tsukurov O Grabowski EF Ingelfinger JR Role of the renin angiotensin system in TNF-alpha and Shiga-toxin-induced tissue factor expression Pediatr Nephrol 2008 23 221 31 18060435 \n3 Habib R Gagnadoux MF Broyer M Hemolytic-uremic syndrome in children and arterial hypertension Arch Mal Coeur Vaiss 1981 74 37 43 \n4 National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents Pediatrics 2004 114 2 Suppl 555 76 15286277 \n5 Proesmans W VanCauter A Thijs L Lijnen P Plasma renin activity in haemolytic uraemic syndrome Pediatr Nephrol 1994 8 444 6 7947036 \n6 Grunfeld B Gimenez M Liapchuc S Mendilaharzu J Gianantonio C Systemic hypertension and plasma renin activity in children with the hemolytic-uremic syndrome Int J Pediatr Nephrol 1982 3 211 4 6754646 \n7 Powell HR Rotenberg E Williams AL McCredie DA Plasma renin activity in acute poststreptococcal glomerulonephritis and the haemolytic-uraemic syndrome Arch Dis Child 1974 49 802 7 4372955 \n8 Van Dyck M Proesmans W Renoprotection by ACE inhibitors after severe hemolytic uremic syndrome Pediatr Nephrol 2004 19 688 90 15064939 \n9 Temple ME Nahata MC Treatment of pediatric hypertension Pharmacotherapy 2000 20 140 50 10678292 \n10 Nakamura H Ishii M Sugimura T Chiba K Kato H Ishizaki T The kinetic profiles of enalapril and enalaprilat and their possible developmental changes in pediatric patients with congestive heart failure Clin Pharmacol Ther 1994 56 160 8 8062492 \n11 Wells TG Bunchman TE Kearns GL Treatment of neonatal hypertension with enalaprilat J Pediatr 1990 117 664 7 2170612 \n12 Hirschl MM Binder M Bur A Herkner H Woisetschläger C Bieglmayer C Impact of the renin-angiotensin-aldosterone system on blood pressure response to intravenous enalaprilat in patients with hypertensive crises J Hum Hypertens 1997 11 177 83 9175570 \n13 Reams GP Lal SM Whalen JJ Bauer JH Enalaprilat: An intravenous substitute for oral enalapril therapy. Humoral and pharmacokinetic effects J Clin Hypertens 1986 2 245 53 3023555 \n14 Gradman AH Kad R Renin inhibition in hypertension J Am Coll Cardiol 2008 51 519 28 18237679 \n15 Bhatti AB Gazali ZA Can aliskiren be considered as a new novel drug for hypertension? Cureus 2015 7 e375 26677425 \n16 Uresin Y Taylor AA Kilo C Tschöpe D Santonastaso M Ibram G Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension J Renin Angiotensin Aldosterone Syst 2007 8 190 8 18205098 \n17 Stanton A Jensen C Nussberger J O'Brien E Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren Hypertension 2003 42 1137 43 14597641 \n18 Sullivan JE Keefe D Zhou Y Satlin L Fang H Yan JH Pharmacokinetics, safety profile, and efficacy of aliskiren in pediatric patients with hypertension Clin Pediatr (Phila) 2013 52 599 607 23610239\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "27(2)",
"journal": "Indian journal of nephrology",
"keywords": "Enalapril; enalaprilat; hemolytic uremic syndrome; malignant hypertension; renin",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "136-140",
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"pmid": "28356668",
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"title": "Targeting renin-angiotensin system in malignant hypertension in atypical hemolytic uremic syndrome.",
"title_normalized": "targeting renin angiotensin system in malignant hypertension in atypical hemolytic uremic syndrome"
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"abstract": "BACKGROUND\nThe incidence of neurological complications related to ventricular assist devices (VAD) remains high and includes life-threatening conditions such as intracranial hemorrhage or ischemic stroke. Although no definitive management guidelines exist, operative interventions may be required for major neurological injuries.\n\n\nOBJECTIVE\nThis case series describes the perioperative management of children at a single center who underwent neurosurgical procedures for major intracranial bleeds or ischemic strokes while on VAD support.\n\n\nMETHODS\nA database review identified all pediatric VAD patients who underwent a neurosurgical procedure for an intracranial hemorrhage or ischemic stroke from April 2014 to January 2020. Data regarding patient characteristics, preoperative medical management, intraoperative anesthetic management, and postoperative outcomes were collected using retrospective chart review.\n\n\nRESULTS\nNinety VADs were implanted in 78 patients. Five neurosurgical interventions were performed: four for intracranial hemorrhages and one for an ischemic stroke. All four patients with hemorrhages were receiving anticoagulation at the time of their event and the three patients on warfarin received emergent reversal with prothrombin concentrate complex and vitamin K. Three patients also received pre-procedural platelet transfusions. Two of the five procedures were emergent bedside external ventricular drain placements, and three were surgical operations. All three patients who underwent operative procedures received invasive hemodynamic monitoring and were supported with a combination of inotropes and afterload reduction. One patient required a massive blood product transfusion. The two patients who underwent external ventricular drain placement had no further surgical interventions and died from the severity of their neurological injuries. All three patients who underwent operative procedures survived to transplantation and discharge home.\n\n\nCONCLUSIONS\nPerioperative concerns for the anesthesiologist include VAD hemodynamic management, bleeding, VAD thrombosis, and prevention of secondary brain injury. A systematic, multidisciplinary approach to management is paramount to attain favorable outcomes.",
"affiliations": "Department of Pediatric Anesthesiology, Lurie Children's Hospital, Chicago, IL, USA.;Division of Pediatric Cardiology, Stanford University, Stanford, CA, USA.;Division of Pediatric Anesthesiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Division of Pediatric Cardiology, Stanford University, Stanford, CA, USA.;Division of Child Neurology, Stanford University, Stanford, CA, USA.;Division of Pediatric Cardiology, Stanford University, Stanford, CA, USA.;Division of Cardiothoracic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Division of Pediatric Anesthesiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.",
"authors": "Yu|Jane|J|https://orcid.org/0000-0002-0516-9580;Murray|Jenna|J|;Ramamoorthy|Chandra|C|https://orcid.org/0000-0003-0541-9903;Chen|Sharon|S|;Lee|Sarah|S|;Ryan|Kathleen|K|;Maeda|Katsuhide|K|;Navaratnam|Manchula|M|https://orcid.org/0000-0001-6524-6640",
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"journal": "Paediatric anaesthesia",
"keywords": "intracranial hemorrhage; neurosurgery; stroke; ventricular assist device",
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"mesh_terms": "D002648:Child; D006353:Heart-Assist Devices; D006470:Hemorrhage; D006801:Humans; D019635:Neurosurgical Procedures; D012189:Retrospective Studies; D013927:Thrombosis",
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"title": "Neurosurgical intervention in children with ventricular assist devices: A single-center case series review.",
"title_normalized": "neurosurgical intervention in children with ventricular assist devices a single center case series review"
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"abstract": "There has been only a few reports regarding aripiprazole causing false positive urine amphetamine drug screens, exclusively on children accidently ingesting aripiprazole. Herein, we present the first reported case of a 40 year old woman affected by Bipolar I Disorder, treated with aripirazole at therapeutic oral dose ranging from 15 mg/day to 30 mg/day, in the context of a depressive episode with mixed and psychotic features, showing a false positive urine amphetamine drug screen. We document the relationship between aripiprazole-dose, plasma concentration and amphetamines values in toxicologic urine examinations over time. Awareness of potential false positive urine amphetamine drug screens during aripiprazole treatment can condition therapeutic choices and prevent legal implications.",
"affiliations": "University of Milan, Dipartmento di Scienze Biomediche e Cliniche Luigi Sacco, Milano, Italy.;University of Milan, Dipartmento di Scienze Biomediche e Cliniche Luigi Sacco, Milano, Italy.;University of Milan, Dipartmento di Scienze Biomediche e Cliniche Luigi Sacco, Milano, Italy.;University of Milan, Dipartmento di Scienze Biomediche e Cliniche Luigi Sacco, Milano, Italy.;University of Milan, Dipartmento di Scienze Biomediche e Cliniche Luigi Sacco, Milano, Italy.;University of Milan, Dipartmento di Scienze Biomediche e Cliniche Luigi Sacco, Milano, Italy; CRC \"Aldo Ravelli\", University of Milan, Milano, Italy; Department of Psychiatry and Behavioral Sciences, Stanford University, CA, USA. Electronic address: bernardo.dellosso@unimi.it.",
"authors": "Caricasole|Valentina|V|;Spagnolo|Giuseppe|G|;Di Bernardo|Ilaria|I|;Cirnigliaro|Giovanna|G|;Piccoli|Eleonora|E|;Dell'Osso|Bernardo|B|",
"chemical_list": "D000662:Amphetamines; D014150:Antipsychotic Agents; D000068180:Aripiprazole",
"country": "United States",
"delete": false,
"doi": "10.1016/j.comppsych.2019.152126",
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"issue": "94()",
"journal": "Comprehensive psychiatry",
"keywords": "Aripiprazole; False positive; Urine drug screen",
"medline_ta": "Compr Psychiatry",
"mesh_terms": "D000328:Adult; D000662:Amphetamines; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D001714:Bipolar Disorder; D005189:False Positive Reactions; D005260:Female; D006801:Humans; D015813:Substance Abuse Detection",
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"title": "Aripiprazole causing false positive urine amphetamine drug screen in an adult patient with bipolar disorder.",
"title_normalized": "aripiprazole causing false positive urine amphetamine drug screen in an adult patient with bipolar disorder"
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"abstract": "The association of bevacizumab and irinotecan has been shown to display a quick efficacy in low-grade glioma (LGG), but most patients relapse within months after cessation of therapy. From October 2012 to March 2014, four patients have been treated with irinotecan-bevacizumab followed by a metronomic maintenance with weekly vinblastine to try to prevent relapses. After a median follow-up of 23 months after the end of the bevacizumab-irinotecan induction, no patient relapsed. These observations suggest that maintenance chemotherapy with weekly vinblastine after an induction by irinotecan-bevacizumab can improve progression-free survival in children with LGG.",
"affiliations": "Service d'hématologie et Oncologie Pédiatrique, Centre Hospitalo-Universitaire Timone Enfants, AP-HM, Marseille, France.;Service de Radiothérapie, Centre Hospitalo-Universitaire Timone Enfants, AP-HM, Marseille, France.;Service de Radiologie, Centre Hospitalo-Universitaire Timone Enfants, AP-HM, Marseille, France.;Service d'hématologie et Oncologie Pédiatrique, Centre Hospitalo-Universitaire Timone Enfants, AP-HM, Marseille, France.;Service d'hématologie et Oncologie Pédiatrique, Centre Hospitalo-Universitaire Timone Enfants, AP-HM, Marseille, France.;Metronomics Global Health Initiative, Marseille, France.;Aix-Marseille Université, INSERM, CRO2 UMR_S 911, Marseille, 13385, France.;Service Neurochirurgie Pédiatrique, Centre Hospitalo-Universitaire Timone Enfants, AP-HM, Marseille, France.;Service d'hématologie et Oncologie Pédiatrique, Centre Hospitalo-Universitaire Timone Enfants, AP-HM, Marseille, France.",
"authors": "Heng|Marie Amélie|MA|;Padovani|Laetitia|L|;Dory-Lautrec|Philippe|P|;Gentet|Jean Claude|JC|;Verschuur|Arnaud|A|;Pasquier|Eddy|E|;Figarella-Branger|Dominique|D|;Scavarda|Didier|D|;André|Nicolas|N|",
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"doi": "10.1002/cam4.699",
"fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 10.1002/cam4.699CAM4699Short ReportClinical Cancer ResearchShort ReportsCan metronomic maintenance with weekly vinblastine prevent early relapse/progression after bevacizumab–irinotecan in children with low‐grade glioma? Heng Marie Amélie \n1\nPadovani Laetitia \n2\nDory‐Lautrec Philippe \n3\nGentet Jean Claude \n1\nVerschuur Arnaud \n1\n\n4\nPasquier Eddy \n4\n\n5\nFigarella‐Branger Dominique \n5\n\n6\nScavarda Didier \n7\nAndré Nicolas \n1\n\n4\n\n5\n1 Service d'hématologie et Oncologie PédiatriqueCentre Hospitalo‐Universitaire Timone Enfants, AP‐HMMarseilleFrance2 Service de RadiothérapieCentre Hospitalo‐Universitaire Timone EnfantsAP‐HMMarseilleFrance3 Service de RadiologieCentre Hospitalo‐Universitaire Timone EnfantsAP‐HMMarseilleFrance4 Metronomics Global Health InitiativeMarseilleFrance5 Aix‐Marseille UniversitéINSERMCRO2 UMR_S 911Marseille13385France6 Service d'AnatomopathologieCentre Hospitalo‐Universitaire Timone EnfantsAP‐HMMarseilleFrance7 Service Neurochirurgie PédiatriqueCentre Hospitalo‐Universitaire Timone EnfantsAP‐HMMarseilleFrance* Correspondence\n\nNicolas André, Service d'Hématologie et Oncologie Pédiatrique, CHU Timone Enfants, AP‐HM, Bd Jean Moulin, Marseille, France. Tel: 0491384420; Fax: 0491386820; E‐mail: nicolas.andre@ap-hm.fr\n31 3 2016 7 2016 5 7 10.1002/cam4.2016.5.issue-71542 1545 04 12 2015 29 1 2016 16 2 2016 © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nThe association of bevacizumab and irinotecan has been shown to display a quick efficacy in low‐grade glioma (LGG), but most patients relapse within months after cessation of therapy. From October 2012 to March 2014, four patients have been treated with irinotecan–bevacizumab followed by a metronomic maintenance with weekly vinblastine to try to prevent relapses. After a median follow‐up of 23 months after the end of the bevacizumab–irinotecan induction, no patient relapsed. These observations suggest that maintenance chemotherapy with weekly vinblastine after an induction by irinotecan–bevacizumab can improve progression‐free survival in children with LGG.\n\nAngiogenesiscancerchildrenlow‐grade gliomamalignancies metronomic chemotherapyLNlavieLes Copains de Charles source-schema-version-number2.0component-idcam4699cover-dateJuly 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:14.07.2016\n\nCancer Medicine \n2016 ; 5 (7 ):1542 –1545\n==== Body\nIntroduction\nLow‐grade glioma (LGG) represents a third of primary central nervous system tumors in children, making it the most common brain tumor in childhood 1. Most patients with LGG have a prolonged survival, and for them LGG can be regarded as a chronic disease 2. Consequently, it is crucial to find treatments with less acute and long‐term toxicities. Previous studies have reported that a treatment with the association of bevacizumab with irinotecan could quickly improve symptoms 3, 4, 5, 6, which is highly relevant in case of visual impairment. However, most patients relapse within a median of 5 months after treatment cessation 4, 5. To prevent early relapses, we proposed a maintenance protocol with metronomic weekly vinblastine following irinotecan–bevacizumab induction therapy. The choice of vinblastine was based on evidence of antitumor activity of Vinca alkaloids in pediatric LGG 7, 8, 9, 10 and their good safety profile. Among anti‐ tubulin agents, vinblastine has been demonstrated to be an active drug even when used as a second line or more treatment 9. Lastly, vinblastine does not display auditory toxicity that is associated with carboplatin and which should be avoided in children with visual impairment. We report here a preliminary experience in four patients.\n\nPatients and Methods\nPatients\nThis is a retrospective analysis of four consecutive patients aged less than 18 years of age, treated with the association of bevacizumab–irinotecan as a first line treatment or for relapse of hypothalamo‐chiasmatic LGG from October 2012 to March 2014. Details about the patients, their underlying disease, and treatments are given in Table 1.\n\nTable 1 Patients' characteristics and treatment\n\nPatient ID\tGender\tNF1\tAge treated\tPrimary location\tMetastasis\tPathology/Braf mutation\tPrevious therapies\tClinical status at treatment\tTreatment response\tFU\t\n1\tM\t+\t7\tVisual pathway; Thalamus\tNo\tNot done\tNone\tVisual impairement\tPR\t16 months\t\n2\tF\t−\t13\tVisual pathway\tNo\tPilocytic astrocytomaNo mutation Braf\tNone\tVisual impairement\tSD\t16 months\t\n3\tF\t−\t16\tVisual pathway\tNo\tNot done\tNone\tVisual impairement\tSD\t23 months\t\n4\tF\t−\t14\tPosterior fossa; Pineal region\tYes (lepto‐meningeal)\tPilocytic astrocytomaMutation Braf.\t(1) BB‐SFOP chemotherapya(2) Surgery(3) Temozolomide(4) Carboplatinum‐Vincristine(5) Fluvastatin‐Celecoxib(6) Irinotecan‐bevacizumab (×2)(7) Metro‐SFCE01b\n\tVisual impairementAtaxia Paraplegia\tSD\t5 months\t\nNF, neurofibromatosis type 1; PR, partial response; SD, stable disease; FU, follow‐up.\n\na BBSFOP chemotherapy protocol consists in 3 week's cycles with alternating cyclophosphamide‐ vincristine; cisplatin‐etoposide; carboplatin‐procarbazine.\n\nb Metro‐SFCE01 metronomic chemotherapy protocol consists ins: celecoxib‐vinblastine with alternating cyclophosphamide and methotrexate.\n\nJohn Wiley & Sons, LtdTreatment\nPatients were treated with the association of bevacizumab (10 mg/kg) and irinotecan (125 mg/m2) on day 1 and 15 of 2 weeks cycles 3, 4, during 6 months or until maximization of radiological or clinical benefit. Vinblastine was administered at the dose of 6 mg/m2 per week 8 and decreased to 3 mg/m2 in case of hematological toxicity. The planned total duration was 18 months. Patient no. 4 received oral vinorelbine (60 mg/m2) 10 instead of vinblastine since she progressed when receiving vinblastine with concomitant methotrexate, celecoxib, and cyclophosphamide as part of a phase II trial during the previous line of treatment 11.\n\nEvaluation\nCerebral and medullar MRI assessments were performed every 3 months. Responses were evaluated according to the RANO criteria.\n\nResults\nOverall, treatment lasted 15 months (range: 13–24 months). The mean duration of induction was 9 months (7, 8, 10, and 12 months, respectively). The mean duration of maintenance with vinblastine was 7.5 months (8, 6, 3, and 12 months, respectively). Clinical improvement was noted in all patients, including vision improvement (n = 3) and ataxia (n = 1). In addition, after 3 months of treatment, one patient achieved objective response, and 3 patients had a stable disease, which were confirmed on following MRI. One patient who had stable disease while receiving the bevacizumab–irinotecan induction, responded to weekly vinblastine. The other 3 patients had a stable disease following vinblastine maintenance. No further visual improvement was noted during the maintenance phase. Most importantly, with a median follow‐up of 15 months (range: 5–23 months) after completion of maintenance therapy, no progression was noted.\n\nOverall treatment was well tolerated. Toxicities observed during the irinotecan–bevacizumab was mild. No renal toxicity or hypertension was observed nor wound healing defect/delay. One patient (patient no. 3) had to stop irinotecan after 3 months because of grade III vomiting and nausea and grade II abdominal pain. The same patient also needed to stop vinblastine because of sustained grade II vomiting/nausea during maintenance therapy. For one patient (patients no. 1) vinblastine dose had to be reduced from 6 to 3 mg/m2 because of hematologic toxicity (grade III neutropenia).\n\nDiscussion\nAchieving to maintain sustained stable disease in pediatric patient with LGG, while limiting both acute and long‐term toxicities is challenging 2, 3, 4, 5, 6, 7, 8, 9, 10. Recently, the combination of bevacizumab and irinotecan has been reported to produce rapid tumor response in some children with recurrent LGG 3, 4, 5, 6, but patients frequently relapse shortly after stopping treatment 4. Indeed, Hwang and co‐workers reported that 13 out of 14 patients progressed after stopping bevacizumab at a median time of 5 months 4. In this report, a maintenance therapy with metronomic weekly vinblastine was added after induction with bevacizumab–irinotecan to prevent early relapses. Noteworthy, the visual improvement obtained during the induction phase was maintained during the vinblastine metronomic treatment. Overall, this approach lead to the stability or improvement of symptoms in the four patients with a median follow‐up of 16 months after completion of treatment, and 23 months after the end of induction therapy with bevacizumab–irinotecan. Although the number of patients and follow‐up are limited, the results we report herein compare favorably with the different studies investigating the use of bevacizumab–irinotecan in patients with LGG 4.\n\nThis treatment was well tolerated, which is in line with previous reports of good safety profile of bevacizumab–irinotecan 3, 4, 5, 6 and vinblastine 8, 9 in children with LGG. In this study, irinotecan had to be stopped in one patient after 7 months of treatment because of digestive toxicity, and single agent bevacizumab was continued for 3 more months. Vinblastine maintenance had to be stopped prematurely in this patient due to general bad tolerance of the treatment. Vinblastine dose reduction was also necessary in another patient because of hematologic toxicity. Side effects were quickly reversible after treatment cessation and tolerance was improved after dose reduction.\n\nThe maintenance phase relies on IV injections because of the lack of oral formulation of vinblastine. Vinorelbine has been recently reported to be an active drug for the treatment of relapsing/refractory LGG 10. It is orally available, thus paving the way for an oral maintenance metronomic regimen. This approach would eventually reduce the cost of treatment and the number of stays in hospital. In this study, one patient was treated with oral vinorelbine for 12 months. Treatment was well tolerated.\n\nHere, the maintenance regimen with weekly vinblastine is based on frequent administration of chemotherapy at relatively low dose and can therefore be regarded as a metronomic treatment 12. This approach has already been reported to be active in LGG 13, 14. Acknowledging that maintenance therapy is metronomic brings new light on the mechanisms of action that can contribute to long‐term control of the disease 15. Metronomic chemotherapy has been reported to be antiangiogenic and to restore some level of antitumor immune response 12, thus potentially re‐inducing tumor dormancy, which can be beneficial in patients with LGG.\n\nWe report here, preliminary observation of the potential clinical benefit of adding metronomic maintenance with vinblastine after initial treatment with an association of bevacizumab–irinotecan to try to prevent early relapse. Larger randomized studies aiming at demonstrating the value of a vinblastine‐based maintenance regimen in patients with LGG after irinotecan–bevacizumab induction are mandatory. Alternatively, using oral vinorelbine instead of vinblastine might contribute to improvement of patient's quality of life.\n\nConflict of Interest\nThe authors have no conflict of interest to declare.\n\nAcknowledgment\nWe thank LNlavie, Les Copains de Charles for their support.\n==== Refs\nReferences\n1 \nCBTRUS \n. 2008 \nStatistical report: primary brain tumors in the United Stated, 2000–2004 . Published by the central brain tumor; registry of the United States , Hinsdale, IL .\n2 \n\nColin , C. \n, \nL. \nPadovani \n, \nC. \nChappé \n, \nS. \nMercurio \n, \nD. Scavarda \n, \nA. \nLoundou \n, et al. 2013 \nOutcome analysis of childhood pilocytic astrocytomas: a retrospective study of 148 cases at a single institution . Neuropathol. Appl. Neurobiol. \n39 :693 –705 .23278243 \n3 \n\nPacker , R. J. \n, \nR. \nJakati \n, \nM. \nHorn \n, \nB. \nRood \n, \nG. \nVezina \n, \nT. \nMacDonald \n, et al. 2009 \nObjective response of multiply recurrent low‐grade glioma to bevacizumab and irinotecan . Pediatr. Blood Cancer \n52 :791 –795 .19165892 \n4 \n\nHwang , E. \n, \nR. \nJakati \n, \nL. B. \nKilburn \n, \nM. \nHorn \n, \nG. \nVezina \n, \nB. R. \nRood \n, et al. 2013 \nLong‐term efficacy and toxicity of bevacizumab‐based therapy in children with recurrent low‐grade gliomas . Pediatr. Blood Cancer \n60 :776 –782 .22976922 \n5 \n\nCouec , M. L. \n, \nN. \nAndré \n, \nE. \nThebaud \n, \nO. \nMinckes \n, \nX. Rialland \n, \nN. \nCorradini \n, et al. 2012 \nBevacizumab and irinotecan in children with recurrent or refractory brain tumors: toxicity and efficacity trends . Pediatr. Blood Cancer \n59 :34 –38 .22287258 \n6 \n\nGururangan , S. \n, \nJ. \nFanguraso \n, \nT. Y. \nPoussaint \n, \nR. E. McLendon \n, \nA. \nOnar‐Thomas \n, \nS. \nWu \n, et al. 2014 \nEfficacy of bevacizumab plus irinotecan in children recurrent low‐grade gliomas‐ a pediatric brain tumor consortium study . Neuro‐Oncology \n16 :310 –317 .24311632 \n7 \n\nPacker , R. J. \n\n1999 \nBrain tumor in children . Arch. Neurol. \n56 :421 –425 .10199329 \n8 \n\nLafay‐Cousin , L. \n, \nS. \nHolm \n, \nI. \nQaddoumi \n, \nG. \nNicolin \n, \nU. Bartels \n, \nU. \nTabori \n, et al. 2005 \nWeekly vinblastine in pediatric low‐grade glioma patient with carboplatin allergic reaction . Cancer \n103 :2636 –2642 .15861409 \n9 \n\nBouffet , E. \n, \nR. \nJakacki \n, \nS. \nGoldman \n, \nD. \nHargrave \n, \nC. Hawkins \n, \nM. \nShroff \n, et al. 2012 \nPhase II study of weekly vinblastine in recurrent or refractory pediatric low‐grade glioma . J. Clin. Oncol. \n30 :1358 –1363 .22393086 \n10 \n\nCapellano , A. M. \n, \nA. S. \nPetrilli \n, \nN. S. \nda Silva \n, \nF. A. \nSilva \n, \nP. M. \nPaiva \n, \nS. \nCavalheiro \n, et al. 2015 \nSingle agent vinorelbine in pediatric patient with progressive optic pathway glioma . J. Neurooncol. \n121 :105 –112 .\n11 \n\nAndré , N. \n, \nS. \nAbed \n, \nD. \nOrbach \n, \nC. A. \nAlla \n, \nL. \nPadovani \n, \nE. \nPasquier \n, et al. 2011 \nPilot study of a pediatric metronomic 4‐drug regimen . Oncotarget \n2 :960 –965 .22156656 \n12 \n\nAndré , N. \n, \nM. \nCarré \n, and \nE. \nPasquier \n. 2014 \nMetronomics: towards personalized chemotherapy? \nNat. Rev. Clin. Oncol. \n11 :413 –431 .24913374 \n13 \n\nRobison , N. J. \n, \nF. \nCampigotto \n, \nS. N. \nChi \n, \nP. E. \nManley \n, \nC. D. \nTurner \n, \nM. A. \nZimmerman \n, et al. 2014 \nA phase II trial of a multi‐agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer . Pediatr. Blood Cancer \n61 :636 –642 .24123865 \n14 \n\nZapletalova , D. \n, \nN. \nAndré \n, \nL. \nDeak \n, \nM. \nKyr \n, \nV. \nBajciova \n, \nP. \nMudry \n, et al. 2012 \nMetronomic chemotherapy with the COMBAT regimen in advanced pediatric malignancies: a multicenter experience . Oncology \n82 :249 –260 .22538363 \n15 \n\nAndré , N. \n, \nS. \nCointe \n, \nV. \nBarlogis \n, \nL. \nArnaud \n, \nR. \nLacroix \n, \nE. \nPasquier \n, et al. 2015 \nMaintenance chemotherapy in children with ALL exerts metronomic‐like thrombospondin‐1 associated anti‐endothelial effect . Oncotarget \n6 :23008 –23014 .26284583\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "5(7)",
"journal": "Cancer medicine",
"keywords": "Angiogenesis; cancer; children; low-grade glioma; malignancies metronomic chemotherapy",
"medline_ta": "Cancer Med",
"mesh_terms": "D059250:Administration, Metronomic; D000293:Adolescent; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin; D002648:Child; D003131:Combined Modality Therapy; D018450:Disease Progression; D005260:Female; D005910:Glioma; D006801:Humans; D000077146:Irinotecan; D060046:Maintenance Chemotherapy; D008297:Male; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D019233:Retreatment; D012189:Retrospective Studies; D014747:Vinblastine",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "1542-5",
"pmc": null,
"pmid": "27037940",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article",
"references": "24311632;27037940;24123865;22393086;22287258;23278243;19165892;10199329;24913374;22538363;15861409;22156656;26284583;22976922",
"title": "Can metronomic maintenance with weekly vinblastine prevent early relapse/progression after bevacizumab-irinotecan in children with low-grade glioma?",
"title_normalized": "can metronomic maintenance with weekly vinblastine prevent early relapse progression after bevacizumab irinotecan in children with low grade glioma"
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"companynumb": "FR-ACTAVIS-2016-09269",
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"abstract": "Eribulin, a non-taxane inhibitor of microtubule dynamics, is approved for the treatment of metastatic breast cancer patients after progression with anthracyclines and taxanes. Nevertheless, to our knowledge, information on its use in dialytic patients is not available to date. This report describes the case of a chemo-pretreated dialytic woman with lung, bone, and liver metastasis from breast cancer, who experienced stable disease with a response < 20% with eribulin in fifth line after 3 hormonal lines and 1 chemotherapy line. This case suggests the feasibility and good tolerability of eribulin in this peculiar setting.",
"affiliations": null,
"authors": "Nettuno|Raffaele|R|;Menditto|Carmine|C|",
"chemical_list": "D000970:Antineoplastic Agents; D005663:Furans; D007659:Ketones; D043823:Taxoids; C490954:eribulin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000489064",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-2414",
"issue": "94 Suppl 1()",
"journal": "Oncology",
"keywords": "Chemotherapy; Dialysis; Eribulin; Metastatic breast cancer; Taxanes",
"medline_ta": "Oncology",
"mesh_terms": "D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D005663:Furans; D006801:Humans; D007659:Ketones; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "0135054",
"other_id": null,
"pages": "16-18",
"pmc": null,
"pmid": "30036877",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15313917;27659911;18645010;21376385;27403097;21493087;16020666;16255135;21859830;20030375;11221827",
"title": "Eribulin as a Feasible and Safe Monotherapy in a Dialytic Pretreated Woman with Metastatic Breast Cancer: A Case Report.",
"title_normalized": "eribulin as a feasible and safe monotherapy in a dialytic pretreated woman with metastatic breast cancer a case report"
} | [
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"companynumb": "IT-ACCORD-071038",
"fulfillexpeditecriteria": "1",
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"abstract": "Hepatic sinusoidal obstruction syndrome (SOS) is a life-threatening state generally occurring as a complication of conditioning regimens used for hematopoietic stem cell transplant. Hepatic SOS after a standard dose of chemotherapy in malignancies is rare, and there are only a few cases in pediatric literature. We report a 56-year-old man with multiple myeloma who experienced SOS after being initiated on chemotherapy including cyclophosphamide, dexamethasone, and bortezomib and who experienced a delay in treatment with defibrotide, because it is currently approved by the Food and Drug Administration for only patients who develop SOS after hematopoietic stem cell transplant.",
"affiliations": "Department of Internal Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI.;Department of Internal Medicine, Detroit Medical Center/Wayne State University, Detroit, MI.;Department of Gastroenterology, Detroit Medical Center/Wayne State University, Detroit, MI.;Department of Gastroenterology, Detroit Medical Center/Wayne State University, Detroit, MI.;Department of Internal Medicine, Detroit Medical Center/Wayne State University, Detroit, MI.;Department of Gastroenterology, Detroit Medical Center/Wayne State University, Detroit, MI.;Department of Gastroenterology, Detroit Medical Center/Wayne State University, Detroit, MI.",
"authors": "Tariq|Tooba|T|;Dawdy|John|J|;Goyal|Sachin|S|;Mohamad|Bashar|B|;Singh|Manmeet|M|;Mutchnick|Milton|M|;Ehrinpreis|Murray|M|",
"chemical_list": null,
"country": "United States",
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"doi": "10.14309/crj.0000000000000103",
"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JACGCRJACGCRJAC9ACG Case Reports Journal2326-3253Wolters Kluwer Maryland, MD ACGCR-19-033910.14309/crj.000000000000010300031Case ReportLiverHepatic Sinusoidal Obstruction Syndrome in a Patient With Multiple Myeloma Treated With CyBorD Tariq Tooba MD1Dawdy John MD, MHS2Goyal Sachin MD3Mohamad Bashar MD3Singh Manmeet MD2Mutchnick Milton MD3Ehrinpreis Murray MD31 Department of Internal Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI2 Department of Internal Medicine, Detroit Medical Center/Wayne State University, Detroit, MI3 Department of Gastroenterology, Detroit Medical Center/Wayne State University, Detroit, MICorrespondence: Tooba Tariq, MD, Department of Internal Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI 49008 (tooba.tariq@med.wmich.edu).25 7 2019 7 2019 6 7 e0010311 11 2018 05 3 2019 © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.2019This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.ABSTRACT\nHepatic sinusoidal obstruction syndrome (SOS) is a life-threatening state generally occurring as a complication of conditioning regimens used for hematopoietic stem cell transplant. Hepatic SOS after a standard dose of chemotherapy in malignancies is rare, and there are only a few cases in pediatric literature. We report a 56-year-old man with multiple myeloma who experienced SOS after being initiated on chemotherapy including cyclophosphamide, dexamethasone, and bortezomib and who experienced a delay in treatment with defibrotide, because it is currently approved by the Food and Drug Administration for only patients who develop SOS after hematopoietic stem cell transplant.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nSinusoidal obstruction syndrome (SOS), previously known as veno-occlusive disease (VOD), is a potentially serious complication of conditioning regimens used for hematopoietic stem cell transplant (HSCT) in the western world.1 Presentation classically includes weight gain, painful hepatomegaly, ascites, and hyperbilirubinemia.2 The underlying pathogenesis of SOS in the HSCT population involves enhanced radiation or chemotherapy-induced toxic injury to the sinusoidal endothelial cells and hepatocytes in zone 3 of the liver acinus. Subsequently, there is extensive cytokine production, depletion of cellular antioxidants, release of endothelial growth factors, and activation of clotting factors, which leads to sinusoidal obstruction and widespread liver disruption.13 This same mechanism is suspected to occur in the non-HSCT population.4 We represent a unique case of hepatic SOS in a patient with multiple myeloma after starting treatment with a standard dosage of cyclophosphamide.\n\nCASE REPORT\nA 56-year-old African-American man presented with progressive confusion, fatigue, right upper quadrant abdominal pain of 1-week duration. Two months earlier, the patient was diagnosed with kappa light-chain multiple myeloma (International Staging System, stage 3) and was initiated on CyBorD therapy (cyclophosphamide 300 mg/m2, bortezomib 1.5 mg/m2, and dexamethasone 40 mg). He had already developed end-stage renal disease from multiple myeloma, was anuric, and had been started on hemodialysis. He had completed day 1 of cycle 2 of CyBorD treatment regimen 14 days before presentation.\n\nPhysical examination revealed stable vitals, icteric sclera, tender hepatomegaly, and asterixis. There was no ascites appreciated. The patient had a weight gain of 4 kg from hospital measurement 2 weeks before, marking a 5.5% increase. Laboratory work revealed alanine transaminase 80 IU/L, aspartate transaminase 108 IU/L, alkaline phosphatase 432 IU/L, total bilirubin 10.5 mg/dL, international normalized ratio >10, and partial thromboplastin time 82.7. Abdominal ultrasound demonstrated mild hepatomegaly without ductal dilation or cholelithiasis, and there was no evidence of hepatic or portal vein thrombosis. Serologic testing for hepatitis B and C were negative. Ultrasound-guided percutaneous liver biopsy showed an increase in pericentral and sinusoidal collagen fibers, marked cholestasis, focal drop out of hepatocytes with fibrosis, and minimal inflammatory cells in the portal triad and pericentral veins consistent with SOS (Figure 1). Conservative management with vitamin K and lactulose for hepatic encephalopathy was administered.\n\nFigure 1. (A) Hematoxylin and eosin stain showing sinusoidal dilatation with atrophy and disruption of hepatocyte plates. (B) Trichrome stain showing perivenular and perisinusoidal fibrosis.\n\nThe care teams involved decided that therapy with defibrotide was warranted and inquired about procuring this medication from specialty pharmacy and insurance before authorization. An extensive administrative review of this case was performed which lasted over 2 weeks before the medication was approved and administered to the patient. The delay was due to initial rejection of therapy based on the Food and Drug Administration (FDA) indication for the medication being strictly for treatment of pediatric and adult patients who received HSCT and developed hepatic VOD/SOS with concomitant renal or pulmonary dysfunction. After initiation of defibrotide, on day 5 of therapy, the patient developed significant lower gastrointestinal (GI) bleed, requiring blood transfusions and urgent endoscopic intervention. Unfortunately, defibrotide had to be discontinued due to the increased risk of GI hemorrhage and resultant unfavorable risk-benefit equation in this patient.\n\nDISCUSSION\nHepatic SOS is primarily a clinical diagnosis observed in patients who present within 30 days of HSCT and exposure to high dose of immunosuppressive therapy. Two diagnostic criteria are in common use: the Baltimore Criteria and the Modified Seattle Criteria, which require 2 of the following to make the diagnosis of SOS—bilirubin of ≥2 mg/dL, hepatomegaly or right upper quadrant pain, and weight gain of ≥5%.2,3\n\nAlthough the vast majority of patients who develop VOD/SOS are indeed HSCT patients, it is a syndrome that also occurs in non-HSCT patients treated with similar medications. Literature review revealed 3 major VOD/SOS cohorts: a Japanese cohort, the compassionate use program cohort, and the treatment-investigational new drug (T-IND) cohort.5–7 The T-IND cohort has recently published a post-hoc analysis of its non–transplant-associated VOD/SOS patients. Of 1,137 patients enrolled in the T-IND cohort, 137 (12%) were identified as having VOD/SOS after non–HSCT-associated chemotherapy, 16 of which were adults (aged >16 years).8 Similarly, non-HSCT patients made up 11% (79 of 710) of the compassionate use program cohort.6\n\nIn the non-HSCT setting, a number of inciting agents have been identified, including inotuzumab and gemtuzumab ozogamicin and vincristine.9,10 Cyclophosphamide was part of our patient's treatment regimen, which was identified as the most common medication in the T-IND trial nontransplant subgroup.8 Previous instances of suspected VOD/SOS involving cyclophosphamide were with high-dose therapy.11 To the best of our knowledge, this is one of the very few cases describing hepatic SOS after conventional chemotherapy doses of cyclophosphamide in a patient with multiple myeloma. The higher doses of cyclophosphamide used for HSCT are associated with an array of toxicities, which include hemorrhagic cystitis, VOD, lung damage, and cardiac necrosis.\n\nCyclophosphamide is the inactive form of the drug which is activated by cytochrome P450 enzymes to form 4-hydroxycyclophosphamide and eventually phosphoramide mustard, the actual alkylating agent. Studies have shown that increased exposure and high local concentration of 4-hydroxycyclophosphamide may lead to damage to sinusoidal endothelial cells and ultimately VOD.12 In our patient, the toxicity of cyclophosphamide could have been enhanced by drug-drug (dexamethasone and bortezomib) interactions or the underlying disease (multiple myeloma).\n\nDefibrotide is the only FDA-indicated medication for VOD/SOS. The proposed mechanism of action of defibrotide involves reduction in endothelial cell activation and protection of endothelial cells from inflammatory and prothrombotic cascade. An early initiation of defibrotide therapy has demonstrated better clinical outcomes at +100 days and is now recommended in patients with VOD/SOS.13 Hemorrhage, hypotension, and GI disturbances are some of the most common side effects associated with defibrotide treatment. Richardson et al showed that pulmonary hemorrhage was the most common type of hemorrhage, with GI hemorrhage being the second most common type occurring in 3.3% of the patients who received defibrotide treatment.14\n\nA study involving patients with severe SOS and multiorgan failure showed that the rates and types of adverse events among defibrotide-treated patients were similar to those in control subjects. However, it was noted that although the rates of hemorrhage were similar between the 2 groups, the rate of fatal hemorrhage was slightly higher in the defibrotide group.15\n\nWithin the United States, FDA indication for defibrotide is for the treatment of hepatic VOD/SOS in post-HSCT patients with renal or pulmonary dysfunction.7 As evidenced by the T-IND trial, there is a non-negligible number of non-HSCT patients who develop VOD/SOS and strong consideration should be made to expand FDA indication to include non-HSCT patients with confirmed VOD/SOS.8 Furthermore, physicians should be on the alert for hepatic SOS in patients receiving cyclophosphamide as it can be especially toxic in the presence of underlying hepatic disease and interaction with other drugs that increase its potency and toxicity.\n\nThis case report not only describes a rare case of VOD/SOS in a patient with multiple myeloma but also reports its development at a standard chemotherapy dosing of cyclophosphamide. Furthermore, broadened FDA indication for defibrotide therapy to include non-HSCT patients should be considered to prevent future treatment delays, such as that experienced by our patient.\n\nDISCLOSURES\nAuthor contributions: T. Tariq and J. Dawdy wrote the manuscript. S. Goyal, B. Mohamad, M. Singh, M. Mutchnick, and M. Ehrinpreis edited the manuscript. S. Goyal and T. Tariq are the article guarantors.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n1. Sakumura M Tajiri K Miwa S \nHepatic sinusoidal obstruction syndrome induced by non-transplant chemotherapy for non-Hodgkin lymphoma . Intern Med \n2017 ;56 (4 ):395 –400 .28202860 \n2. Jones RJ Lee KS Beschorner WE \nVenoocclusive disease of the liver following bone marrow transplantation . Transplantation \n1987 ;44 (6 ):778 –83 .3321587 \n3. Elli M Pinarli FG Dagdemir A Acar S \nVeno-occlusive disease of the liver in a child after chemotherapy for brain tumor . Pediatr Blood Cancer \n2006 ;46 (4 ):521 –3 .16317738 \n4. Shulman HM Gown AM Nugent DJ \nHepatic veno-occlusive disease after bone marrow transplantation: Immunohistochemical identification of the material within occluded central venules . Am J Pathol \n1987 ;127 (3 ):549 –58 .2438942 \n5. Yakushijin K Atsuta Y Doki N \nSinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation: Incidence, risk factors and outcomes . Bone Marrow Transpl \n2016 ;51 (3 ):403 –9 .\n6. Corbacioglu S Carreras E Mohty M \nDefibrotide for the treatment of hepatic veno-occlusive disease: Final results from the international compassionate-use program . Biol Blood Marrow Transplant \n2016 ;22 (10 ):1874 –82 .27397724 \n7. Kernan NA Grupp S Smith AR \nFinal results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome . Br J Haematol \n2018 ;181 (6 ):816 –27 .29767845 \n8. Kernan NA Richardson PG Smith AR \nDefibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome following nontransplant-associated chemotherapy: Final results from a post hoc analysis of data from an expanded-access program . Pediatr Blood Cancer \n2018 ;65 (10 ):e27269 .29873895 \n9. Wadleigh M Richardson PG Zahrieh D \nPrior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation . Blood \n2003 ;102 (5 ):1578 –82 .12738663 \n10. Tang C Lindsay J Gill A Kerridge I \nDefibrotide use in vincristine-induced hepatic sinusoidal obstruction syndrome . Clin Lymphoma Myeloma Leuk \n2017 ;17 :539 –41 .28842141 \n11. Beltinger J Haschke M Kaufmann P Michot M Terracciano L Krähenbühl S \nHepatic veno-occlusive disease associated with immunosuppressive cyclophosphamide dosing and roxithromycin . Ann Pharmacother \n2006 ;40 (4 ):767 –70 .16595573 \n12. de Jonge ME Huitema ADR Beijnen JH Rodenhuis S \nHigh exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy . Br J Cancer \n2006 ;94 (9 ):1226 –30 .16622453 \n13. Richardson PG Smith AR Triplett BM \nEarlier defibrotide initiation post-diagnosis of veno-occlusive disease/sinusoidal obstruction syndrome improves day +100 survival following haematopoietic stem cell transplantation . Br J Haematol \n2017 ;178 (1 ):112 –8 .28444784 \n14. Richardson PG Smith AR Triplett BM \nDefibrotide for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome: Interim results from a treatment IND study . Biol Blood Marrow Transplant \n2017 ;23 (6 ):997 –1004 .28285079 \n15. Richardson PG Riches ML Kernan NA \nPhase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure . Blood \n2016 ;127 (13 ):1656 –65 .26825712\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2326-3253",
"issue": "6(7)",
"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "e00103",
"pmc": null,
"pmid": "31620512",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports",
"references": "29767845;16317738;28842141;16622453;29873895;3321587;28444784;27397724;28202860;16595573;26825712;12738663;26595082;28285079;2438942",
"title": "Hepatic Sinusoidal Obstruction Syndrome in a Patient With Multiple Myeloma Treated With CyBorD.",
"title_normalized": "hepatic sinusoidal obstruction syndrome in a patient with multiple myeloma treated with cybord"
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"activesubstancename": "CYCLOPHOSPHAMIDE"
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{
"abstract": "Voriconazole is a triazole antifungal agent superior to amphotericin B in the treatment of invasive aspergillosis. It is generally well tolerated and has excellent oral bioavailability, providing significant benefit in the treatment of invasive fungal infections. There have been numerous reports of dermatologic reactions to this agent, including erythroderma, cheilitis, Stevens-Johnson syndrome, discoid lupus erythematosus, pseudoporphyria, squamous cell carcinoma, and photosensitivity reactions. Pseudoporphyria, a dermatologic condition mimicking porphyria cutanea tarda, has been described as an adverse effect of voriconazole use. Clinical findings include photosensitivity, vesicles, bullae, milia, and scarring in sun-exposed areas. Photo-onycholysis is a phenomenon of nail discoloration and onycholysis that has been described in the setting of a phototoxic drug reaction and pseudoporphyria. Implicated drugs have most commonly been tetracyclines, fluoroquinolones, and psoralens; others have been reported as well. We report a case of a pediatric patient with leukemia who developed symptoms consistent with pseudoporphyria and later photo-onycholysis while being treated with voriconazole. To our knowledge, this is the first reported case of pseudoporphyria due to voriconazole in a pediatric patient and the first reported case of photo-onycholysis as a consequence of voriconazole use.",
"affiliations": "Infectious Diseases Division, Department of Pediatrics.;Department of Medicine, Division of Dermatology; Department of Pathology, Vanderbilt University, Nashville, Tennessee.;Infectious Diseases Division, Department of Pediatrics.",
"authors": "Willis|Zachary I|ZI|;Boyd|Alan S|AS|;Di Pentima|M Cecilia|MC|",
"chemical_list": "D002511:Cephalosporins; D054714:Echinocandins; D055666:Lipopeptides; D002981:Clindamycin; D064704:Levofloxacin; D014640:Vancomycin; D000077723:Cefepime; D065819:Voriconazole; D000077551:Micafungin",
"country": "England",
"delete": false,
"doi": "10.1093/jpids/piu065",
"fulltext": null,
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"issn_linking": "2048-7193",
"issue": "4(2)",
"journal": "Journal of the Pediatric Infectious Diseases Society",
"keywords": "photo-onycholysis; phototoxicity; pseudoporphyria; voriconazole",
"medline_ta": "J Pediatric Infect Dis Soc",
"mesh_terms": "D000842:Ankle; D001228:Aspergillosis; D001768:Blister; D055499:Catheter-Related Infections; D000077723:Cefepime; D002511:Cephalosporins; D002613:Cheilitis; D002648:Child; D002921:Cicatrix; D002981:Clindamycin; D017484:Dermatitis, Phototoxic; D054714:Echinocandins; D006801:Humans; D007008:Hypokalemia; D016867:Immunocompromised Host; D064704:Levofloxacin; D055666:Lipopeptides; D008275:Magnesium Deficiency; D008297:Male; D000077551:Micafungin; D054039:Onycholysis; D010787:Photosensitivity Disorders; D011164:Porphyrias; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D014640:Vancomycin; D065819:Voriconazole",
"nlm_unique_id": "101586049",
"other_id": null,
"pages": "e22-4",
"pmc": null,
"pmid": "26407422",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Phototoxicity, Pseudoporphyria, and Photo-onycholysis Due to Voriconazole in a Pediatric Patient With Leukemia and Invasive Aspergillosis.",
"title_normalized": "phototoxicity pseudoporphyria and photo onycholysis due to voriconazole in a pediatric patient with leukemia and invasive aspergillosis"
} | [
{
"companynumb": "US-MYLANLABS-2016M1004745",
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"activesubstancename": "VORICONAZOLE"
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... |
{
"abstract": "Differential treatment strategies are applied in thrombotic microangiopathy (TMA) according to the sub-classifications. Hence, it is worthwhile to overview clinical manifestations and outcomes of overall TMA patients according to sub-classifications. We analyzed TMA patients whose serum lactate dehydrogenase levels >250 IU/L, with the presence of schistocytes in their peripheral blood smear, or with typical vascular pathologic abnormalities in their renal biopsy. We compared clinical manifestations including overall survival (OS) and renal survival according to TMA causes. A total of 117 TMA patients (57 primary and 60 secondary TMA) were analyzed. Renal symptom was the most common manifestation in whole patients, while renal function at diagnosis was worst in pregnancy-related TMA group. Primary TMA patients had more frequent CNS symptom and hematologic manifestation compared to secondary TMAs. Among secondary TMAs, pregnancy- and HSCT-related TMA patients showed prevalent hemolytic features. During 150.2 months of follow-up, 5-year OS rate was 64.8%. Poor prognostic factors included older age, combined hematologic and solid organ malignancies, lower hemoglobin levels, and lower serum albumin levels. There was no significant difference in OS between primary and secondary TMAs. Seventy-eight percent of patients experienced AKI during TMA. Five-year death-censored renal survival rate was poor with only 69.2%. However, excellent renal outcome was observed in pregnancy-associated TMA. TMA showed various clinical manifestations according to their etiology. Notably, both OS and renal survival were poor regardless of their etiologies except pregnancy-associated TMA. Physicians should differentiate a variety of TMA categories and properly manage this complex disease entity.",
"affiliations": "Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.;Division of Hematology-oncology, Department of Internal Medicine, CHA University School of Medicine, Seongnam, South Korea.;Division of Nephrology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.;Division of Nephrology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.;Division of Hematology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.;Division of Hematology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.;Division of Hematology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.;Division of Nephrology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea. mdhjlee@gmail.com.;Division of Hematology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea. go01@snu.ac.kr.",
"authors": "Kang|Eunjeong|E|;Yoo|Shin Hye|SH|;Oh|Doyeun|D|;Joo|Kwon Wook|KW|;Kim|Yon Su|YS|;Yoon|Sung-Soo|SS|;Kim|Inho|I|;Park|Seonyang|S|;Lee|Hajeong|H|;Koh|Youngil|Y|",
"chemical_list": "D006454:Hemoglobins; D012709:Serum Albumin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-017-3063-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "96(10)",
"journal": "Annals of hematology",
"keywords": "Clinical manifestation; Hemolytic uremic syndrome; Thrombotic microangiopathy",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D005260:Female; D006454:Hemoglobins; D006801:Humans; D008297:Male; D008875:Middle Aged; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic; D012189:Retrospective Studies; D012307:Risk Factors; D012709:Serum Albumin; D015996:Survival Rate; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1715-1726",
"pmc": null,
"pmid": "28752391",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical dissection of thrombotic microangiopathy.",
"title_normalized": "clinical dissection of thrombotic microangiopathy"
} | [
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"companynumb": "PHHY2017KR114079",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
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"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadditional": "3",
"drugadm... |
{
"abstract": "Adenosine deaminase 2 (ADA2) deficiency is an auto-inflammatory disease due to mutations in cat eye syndrome chromosome region candidate 1 (CECR1) gene, currently named ADA2. The disease has a wide clinical spectrum encompassing early-onset vasculopathy (targeting skin, gut and central nervous system), recurrent fever, immunodeficiency and bone marrow dysfunction. Different therapeutic options have been proposed in literature, but only steroids and anti-cytokine monoclonal antibodies (such as tumor necrosis factor inhibitor) proved to be effective. If a suitable donor is available, hematopoietic stem cell transplantation (HSCT) could be curative. Here we describe a case of ADA2 deficiency in a 4-year-old Caucasian girl. The patient was initially classified as autoimmune neutropenia and then she evolved toward an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. The diagnosis of ALPS became uncertain due to atypical clinical features and normal FAS-induced apoptosis test. She was treated with G-CSF first and subsequently with immunosuppressive drugs without improvement. Only HSCT from a 9/10 HLA-matched unrelated donor, following myeloablative conditioning, completely solved the clinical signs related to ADA2 deficiency. Early diagnosis in cases presenting with hematological manifestations, rather than classical vasculopathy, allows the patients to promptly undergo HSCT and avoid more severe evolution. Finally, in similar cases highly suspicious for genetic disease, it is desirable to obtain molecular diagnosis before performing HSCT, since it can influence the transplant procedure. However, if HSCT has to be performed without delay for clinical indication, related donors should be excluded to avoid the risk of relapse or partial benefit due to a hereditary genetic defect.",
"affiliations": "Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Paediatric Hematology-Oncology, Ospedale della Donna e del Bambino, Verona, Italy.;Paediatric Hematology-Oncology, Ospedale della Donna e del Bambino, Verona, Italy.;Paediatric Hematology-Oncology, Ospedale della Donna e del Bambino, Verona, Italy.;Paediatric Hematology-Oncology, Ospedale della Donna e del Bambino, Verona, Italy.;Paediatric Hematology-Oncology, Ospedale della Donna e del Bambino, Verona, Italy.;Paediatric Hematology-Oncology, Ospedale della Donna e del Bambino, Verona, Italy.;Paediatric Hematology-Oncology, Ospedale della Donna e del Bambino, Verona, Italy.;San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.;San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.;San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Biocrystallography Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Department of Medicine and Biochemistry, Duke University School of Medicine, Durham, NC, United States.;Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Department of Pediatric Infectious Diseases and Immunology, Medical Academy of Postgraduate Education, Kiev, Ukraine.;Paediatric Hematology-Oncology, Ospedale della Donna e del Bambino, Verona, Italy.;Paediatric Hematology-Oncology, Ospedale della Donna e del Bambino, Verona, Italy.",
"authors": "Barzaghi|Federica|F|;Minniti|Federica|F|;Mauro|Margherita|M|;Bortoli|Massimiliano De|M|;Balter|Rita|R|;Bonetti|Elisa|E|;Zaccaron|Ada|A|;Vitale|Virginia|V|;Omrani|Maryam|M|;Zoccolillo|Matteo|M|;Brigida|Immacolata|I|;Cicalese|Maria Pia|MP|;Degano|Massimo|M|;Hershfield|Michael S|MS|;Aiuti|Alessandro|A|;Bondarenko|Anastasiia V|AV|;Chinello|Matteo|M|;Cesaro|Simone|S|",
"chemical_list": "C491901:FAS protein, human; D036341:Intercellular Signaling Peptides and Proteins; D019014:fas Receptor; D016179:Granulocyte Colony-Stimulating Factor; C408373:ADA2 protein, human; D000243:Adenosine Deaminase",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2018.02767",
"fulltext": "\n==== Front\nFront ImmunolFront ImmunolFront. Immunol.Frontiers in Immunology1664-3224Frontiers Media S.A. 10.3389/fimmu.2018.02767ImmunologyCase ReportALPS-Like Phenotype Caused by ADA2 Deficiency Rescued by Allogeneic Hematopoietic Stem Cell Transplantation Barzaghi Federica 123*†Minniti Federica 4†Mauro Margherita 4Bortoli Massimiliano De 4Balter Rita 4Bonetti Elisa 4Zaccaron Ada 4Vitale Virginia 4Omrani Maryam 2Zoccolillo Matteo 23Brigida Immacolata 2Cicalese Maria Pia 12Degano Massimo 5Hershfield Michael S. 6Aiuti Alessandro 127Bondarenko Anastasiia V. 8Chinello Matteo 4Cesaro Simone 41Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy2San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy3Department of Systems Medicine, Tor Vergata University, >Rome, Italy4Paediatric Hematology-Oncology, Ospedale della Donna e del Bambino, Verona, Italy5Biocrystallography Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy6Department of Medicine and Biochemistry, Duke University School of Medicine, Durham, NC, United States7Vita-Salute San Raffaele University, Milan, Italy8Department of Pediatric Infectious Diseases and Immunology, Medical Academy of Postgraduate Education, Kiev, UkraineEdited by: Sergio Rosenzweig, National Institutes of Health (NIH), United States\n\nReviewed by: V. Koneti Rao, National Institutes of Health (NIH), United States; Ivona Aksentijevich, National Human Genome Research Institute (NHGRI), United States\n\n*Correspondence: Federica Barzaghi barzaghi.federica@hsr.itThis article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology\n\n†These authors have contributed equally to this work\n\n14 1 2019 2018 9 276710 8 2018 12 11 2018 Copyright © 2019 Barzaghi, Minniti, Mauro, De Bortoli, Balter, Bonetti, Zaccaron, Vitale, Omrani, Zoccolillo, Brigida, Cicalese, Degano, Hershfield, Aiuti, Bondarenko, Chinello and Cesaro.2019Barzaghi, Minniti, Mauro, De Bortoli, Balter, Bonetti, Zaccaron, Vitale, Omrani, Zoccolillo, Brigida, Cicalese, Degano, Hershfield, Aiuti, Bondarenko, Chinello and CesaroThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Adenosine deaminase 2 (ADA2) deficiency is an auto-inflammatory disease due to mutations in cat eye syndrome chromosome region candidate 1 (CECR1) gene, currently named ADA2. The disease has a wide clinical spectrum encompassing early-onset vasculopathy (targeting skin, gut and central nervous system), recurrent fever, immunodeficiency and bone marrow dysfunction. Different therapeutic options have been proposed in literature, but only steroids and anti-cytokine monoclonal antibodies (such as tumor necrosis factor inhibitor) proved to be effective. If a suitable donor is available, hematopoietic stem cell transplantation (HSCT) could be curative. Here we describe a case of ADA2 deficiency in a 4-year-old Caucasian girl. The patient was initially classified as autoimmune neutropenia and then she evolved toward an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. The diagnosis of ALPS became uncertain due to atypical clinical features and normal FAS-induced apoptosis test. She was treated with G-CSF first and subsequently with immunosuppressive drugs without improvement. Only HSCT from a 9/10 HLA-matched unrelated donor, following myeloablative conditioning, completely solved the clinical signs related to ADA2 deficiency. Early diagnosis in cases presenting with hematological manifestations, rather than classical vasculopathy, allows the patients to promptly undergo HSCT and avoid more severe evolution. Finally, in similar cases highly suspicious for genetic disease, it is desirable to obtain molecular diagnosis before performing HSCT, since it can influence the transplant procedure. However, if HSCT has to be performed without delay for clinical indication, related donors should be excluded to avoid the risk of relapse or partial benefit due to a hereditary genetic defect.\n\nADA2 deficiencyHSCTALPSADA2CECR1autoimmunityimmunodeficiencyneutropenia\n==== Body\nIntroduction\nDeficiency of adenosine deaminase 2 (DADA2) is a genetic auto-inflammatory disease caused by autosomal recessive mutations in adenosine deaminase 2 (ADA2) gene, mapped on chromosome 22q11 (1). Adenosine deaminase 2 (ADA2) is an enzyme secreted in the plasma by myeloid cells that catalyzes the conversion of adenosine to inosine (2). The pathomechanism of DADA2 remains unclear, but immunomodulatory function of ADA2 is crucial. Indeed, in vitro studies suggest that ADA2 works as an autocrine factor activating cells of the immune system (3). Thus, deficiency of ADA2 results in multiple immune abnormalities, such as increased pro-inflammatory M1 macrophages (as opposed to anti-inflammatory M2 macrophages), upregulation of genes associated with neutrophil activation, increased secretion of pro-inflammatory cytokines including TNF and interleukin-1b (IL-1b) and endothelial damage (4, 5).\n\nDADA2 was described for the first time in 2014 by two independent studies (4, 6). The predominant clinical presentation includes recurrent fever, early-onset vasculopathy involving skin, gut and central nervous system (1, 7, 8). Blood tests usually show elevation of acute phase reactants (erythrocyte sedimentation rate and C-reactive protein) (1). Recent evidences suggest a broader clinical spectrum encompassing also features of autoimmunity, immunodeficiency and bone marrow dysfunction (1, 8–14). The diagnosis of DADA2 is based on the measurement of plasma ADA2 enzymatic activity and on the identification of biallelic mutations in ADA2.\n\nSplenomegaly or hepatosplenomegaly are frequently reported in patients with DADA2 deficiency (1, 4, 11, 15, 16) as well as cytopenia (1, 4, 11, 17). Nevertheless, their presence in addition to clinical and biological features defining an Autoimmune Lymphoproliferative Syndrome (ALPS)-like phenotype is less common. Only two cases of DADA2 presenting with clinical features resembling ALPS have been recently described (17, 18). Another patient experienced hemophagocytic lymphohistocytosis on a background of ALPS-like manifestations (19).\n\nWe describe a case of ADA2 deficiency presenting as ALPS-like disease, unresponsive to immunosuppressive therapy, successfully treated with allogeneic hematopoietic stem cell transplantation (HSCT).\n\nCase Presentation\nA 4-year old Caucasian female child was referred to our Center for diagnostic assessment of severe neutropenia lasting for 6 months that was not responsive to the administration of granulocyte-colony stimulating factor (G-CSF) up to a maximum dose of 20 mcg/kg daily.\n\nThe patient was born after a full-term gestation, from non-consanguineous parents. The birth weight was 3,600 g. Familial medical history was unremarkable. Parents reported recurrent infections of upper respiratory tract and stomatitis during the first years of life, before the occurrence of severe neutropenia.\n\nPhysical examination was normal, except for the presence of splenomegaly (long axis 11.5 cm at ultrasound scan), whereas blood count revealed profound neutropenia (absolute neutrophil count, ANC, 0.02 × 109/L) without anemia and thrombocytopenia. Bone marrow examination showed the presence of rare myeloid precursors with normal representation of the erythroid and megakaryocyte lineages. The clonogenic study of bone marrow progenitors in vitro showed a normal growth of erythroid cells whereas the growth of myeloid cells was below the normal range: CFU-E/BFU-E 37 (normal range 27–81/2 × 104); CFU-GEMM 1 (normal range 0–10/2 × 104); CFU-GM 30 (normal range 33–100/2 × 104). Interestingly the patient bone marrow plasma markedly inhibited the growth of progenitor cells obtained from healthy voluntary bone marrow donors: CFU-E/BFU-E/(2 × 105) from 88 (controls) to 4 (controls + patient plasma), CFU-GEMM/(2 × 105) from 17 to 9. An extensive diagnostic work-up excluded other potential causes of neutropenia such as Kostmann disease, Shwachman-Diamond syndrome, Fanconi anemia and paroxysmal nocturnal hemoglobinuria. Finally, a misdiagnosed form of autoimmune neutropenia was hypothesized. Indeed, anti-neutrophil IgG were 171.1 mg/dL (normal value < 33.5 mg/dL), IgM were 24.9 mg/dL (normal value < 32.2 mg/dL). Hence, the patient underwent a 4-week trial with prednisone at 2.5 mg/kg/day that led to complete remission of neutropenia (ANC 3.360 × 109/L). Prednisone was slowly tapered. Nevertheless, fever occurred at every attempt of reducing the dose of prednisone below 1 mg/kg/day. Given the significant side effects after 3 months of steroid therapy, introduction of steroid-sparing agents (cyclosporine first and mycophenolate mofetil later) was attempted. However, neutropenia did not improve and the patient remained steroid dependent.\n\nAfter 4 months, she experienced a single episode of livedo reticularis at the lower limbs. The histological examination showed a livedoid thrombotic vasculopathy. Moreover, the patient was hospitalized eight times due to episodes of fever, abdominal pain and neutropenia with elevated inflammation markers. Abdominal CT scan, esophagogastroduodenoscopy (EGDS) and colonoscopy showed no abnormalities, as well as gastrointestinal biopsies.\n\nThe patient was assessed also for ALPS (Table 1) (20) because of autoimmune neutropenia and splenomegaly: she displayed increased double negative T-lymphocytes in the peripheral blood (2.5%, normal value <1.7% of total lymphocytes), IL-18 (1.125 pg/ml, normal value 36–258 pg/ml), IL-10 (7.2 pg/ml, normal value < 1 pg/ml). However, vitamin B12 levels where only mildly elevated as compared to patients with classical ALPS (775 pg/mL, normal value 191–663) (21); similarly, FAS-induced apoptosis test was normal (survivor T-lymphocytes after FAS antigenic stimulation 42%) (22). Sirolimus was started (23, 24) and withdrawn after 2 months, due to the occurrence of fever and abdominal pain. Prednisone was continued alone. No mutations were found in ALPS-disease causative genes (FAS, FASL, CAS10). The control of clonogenic tests 7 months after starting immunosuppression showed a good growth of CFU-E/BFU-E (120/2 × 104) and CFU-GEMM (52/2 × 104); the growth of bone marrow progenitor cells derived from healthy donors was no more inhibited by the patient's bone marrow plasma.\n\nTable 1 Diagnostic criteria for ALPS defined by 2009 NIH consensus (20).\n\nRequired\t\n1. Chronic (6 months), nonmalignant, noninfectious lymphadenopathy or splenomegaly or both\t\n2. Elevated CD3 + TCRαβ + CD4-CD8- DNT cells (1.5% of total lymphocytes or 2.5% of CD3 lymphocytes) in the setting of normal or elevated lymphocyte counts\t\nAccessory\t\nPrimary\t\n1. Defective lymphocyte apoptosis (in 2 separate assays)\t\n2. Somatic or germline pathogenic mutation in FAS, FASL, or CASP10\t\nSecondary\t\n1. Elevated plasma sFASL levels (>200 pg/mL) OR elevated plasma IL-10 levels (>20 pg/mL) OR elevated serum or plasma vitamin B12 levels (>1,500 ng/L) OR elevated plasma IL-18 levels (>500 pg/mL)\t\n2. Typical immunohistological findings as reviewed by an experienced hematopathologist\t\n3. Autoimmune cytopenias (hemolytic anemia, thrombocytopenia, or neutropenia) AND elevated immunoglobulin G levels (polyclonal hypergammaglobulinemia)\t\n4. Family history of a nonmalignant/noninfectious lymphoproliferation with or without autoimmunity\t\nDefinitive diagnosis: required criteria plus one primary accessory criterion.\n\nProbable diagnosis: required criteria plus one secondary criterion.\n\nCASP10 caspase 10, DNT double-negative T cell, FASL Fas-ligand, Ig immunoglobulin, IL interleukin, NIH National Institutes of Health, sFasL soluble Fas ligand.\n\nConsidering the persistence of neutropenia despite the administration of G-CSF and immunosuppressive therapy, the patient was candidate to allogeneic HSCT. During pre-transplant workup, brain magnetic resonance (MRI) revealed a 5-mm signal alteration in the right cortical-subcortical frontal basal region consistent with a petechial spot.\n\nHSCT was performed at 5 years and 4 months of age. The patient underwent a myeloablative conditioning with busulfan, thiotepa, fludarabine and rituximab (Table 2). Graft-vs.-host disease (GVHD) prophylaxis consisted of anti-thymocite globulin, short methotrexate, cyclosporine (from day 0 to day +28) than replaced by tacrolimus (from day +29). Neutrophil engraftment occurred on day +26, and platelet engraftment occurred on day +34. Complete donor chimerism was detected on day +33. Main complications after HSCT were gut and skin grade II acute GVHD requiring additional therapy with prednisone at 2 mg/kg/day, tapered slowly due to frequent relapses. Further complications were: CMV reactivation (on day + 31) treated successfully with valganciclovir and osteonecrosis of the knees (on day + 138), treated with vitamin D, calcium, bisphosphonates, physio-kinesiotherapy and hyperbaric oxygen therapy.\n\nTable 2 Conditioning regimen.\n\nDrug\tDosage\t\nFludarabine\t3 × 50 mg/m2/day\t\nThiotepa\t2 × 5 mg/kg/day\t\nBusulfan\t16 × 0.8 mg/kg (every 6 h)\t\nATG Genzyme\t3 × 4 mg/kg/day\t\nRituximab\t1 × 375 mg/m2/day\t\nConsidering the atypical clinical evolution, the inadequate response to therapy and the absence of mutations, the diagnosis of ALPS was questioned. We performed molecular analysis by Haloplex target system platform (Illumina) on the patient's buccal swab obtained after HSCT. The patient resulted compound heterozygous for two novel mutations in ADA2 gene. The variant located at exon 9 determines an amino acidic substitution (c.1367 A>G, p.Y456C) and the variant located in exon 8 introduces a premature stop codon causing the synthesis of a truncated protein (c.1196. G>A, p.W399*). Both parents were healthy heterozygous carriers. These new mutations are reported as detrimental for the protein according to different prediction tools (e.g., PROVEAN, PolyPhen).\n\nThe high-resolution crystal structure of the homodimeric wild type protein was previously determined (PDB ID 3LGD, corresponding to UniProt Q9NZK5 amino acid residues 29-510, Zavialov et al.,http://dx.doi.org/10.1074/jbc.M109.083527). To address the effects of the two mutations, we performed a structural and energetic analysis of the enzyme. The p.Y456C mutation affects a hydrophobic pocket of ADA2 (Figure 1A). Of note, this is a novel mutation but the p.Y453C mutation, which affects the same hydrophobic pocket, is one of the most common found in patients with DADA2 (1). The p.Y456C mutation carried by our patient heavily destabilizes the ADA2 structure (ΔΔ G = 4.53 ± 0.12 kcal/mol from n = 5 independent simulations) as calculated using the program FoldX (25). The p.W399* mutation instead leads to a truncation of the protein C-terminus, removing key residues required for the correct folding of the active site, and resulting in a solvent-exposed catalytic Zn2+ ion (Figure 1B). Thus, both mutations are predicted to dramatically reduce the enzymatic activity of ADA2 through structural destabilization of the protein.\n\nFigure 1 (A) Location of the p.Y456C mutation. The Y456 residue is located in an α-helical segment and inserted between hydrophobic residues. (B) Structural abnormality of the ADA2 protein generated by the p.W399* mutation. In yellow, the portion of the protein that is lacking due to the stop codon introduced by the mutation. Figures generated with Pymol (http://www.pymol.org).\n\nPre-HSCT plasma of the patient was not available but we could assess ADA2 activity in the parents, which resulted lower than healthy controls as expected in carriers, supporting the deleterious effect of the mutations on the protein function. Moreover, patient's ADA2 plasma activity after HSCT was normal, in the absence of clinical manifestations of the disease and in the presence of full donor chimerism (Table 3). These results strongly suggest DADA2 as cause of the hematological manifestations of the patient.\n\nTable 3 Plasma ADA2 activity in the index family.\n\nSample\tAge (year)\tPlasma ADA2 activity* (mU/mL)\t\nPatient post-HSCT\t7\t21.4\t\nMother\t32\t4.2\t\nFather\t36\t4.9\t\nReference values for plasma ADA2 activity*\n(mU/mL), mean ± SD (range)\t\nADA2 deficient (n = 36)\t\t0.4 ± 0.5 (0.02 – 1.9)\t\nADA2 carriers (n = 25)\t\t5.5 ± 1.7 (2.9 – 8.8)\t\nControls (N = 23 + pooled human plasma)\t\t13.8 ± 5.1 (4.8 – 27.2)\t\n* obtained using the HPLC assay described in Zhou et al. (4).\n\nThe patient gradually recovered from HSCT complications and immunosuppressive therapy was withdrawn. She is now alive and well 28 months after HSCT enjoying a normal life.\n\nDiscussion\nClinical phenotype and age at onset of DADA2 vary widely without clear correlation to ADA2 genotype (8).\n\nAlthough not described initially, hematological disorders appear to be an emergent clinical manifestation of DADA2. A various degree of hematological dysfunction affects approximately 43% of patients, in the absence of evident vasculitis (14). Anemia, including pure red cell aplasia, and lymphopenia are the most frequent findings, while neutropenia is a rare clinical manifestation (1, 13, 14).\n\nInitially, our patient was classified as an ALPS-like based on autoimmune neutropenia, splenomegaly and positive biomarkers. Subsequently, the diagnosis of ALPS became less certain because of the lack of response to immunosuppressive drugs, atypical clinical features (livedo reticularis and recurrent severe abdominal pain), normal FAS-induced apoptosis test, and lack of mutations of ALPS-related genes. Only widening the genetic evaluation after HSCT in the index case and in the parents, DADA2 was diagnosed. Of note, clinical presentation of DADA2 as ALPS-like disease have been reported in two patients (17, 18) who were successfully treated with HSCT and anti-TNF medications respectively.\n\nOf note, during the active phase of the disease, the patient's bone marrow plasma markedly inhibited the growth of progenitor cells obtained from healthy bone marrow donors. This finding and the reversion of inhibition after administration of steroids, suggests the presence of pro-inflammatory mediators inhibiting the growth of bone marrow progenitor cells, as observed in the setting of acquired aplastic anemia, where plasma pro-inflammatory cytokines block the differentiation of bone marrow progenitor cells (26). This further supports the possible benefit derived by the administration of TNF-inhibitors in ADA2 patients before transplant, in order to reduce the inflammatory burden also in the bone marrow niches (14). Current literature suggests different therapeutic options for DADA2: the choice between medical therapy and HSCT depends on predominant symptoms and severity of the clinical phenotype. Being an inflammatory condition, high doses of steroids are usually useful to control the disease, although a steroid-dependence often occurs (5), as in the case herein described. If inflammatory symptoms and vasculitis are predominant, anti–tumor necrosis factor agents are usually beneficial (6, 7, 11, 14). HSCT is a potential definitive treatment, since it provides ADA2 producing monocytes, which are able to restore ADA2 plasma activity and control the disease manifestations (15, 17, 19, 27). Moreover, as recently reported by Hashem et al. (28), bone marrow dysfunction and immunodeficiency are the most frequent indications leading to transplant.\n\nOur experience suggests that ADA2 deficiency should be considered as differential diagnosis in cases of severe autoimmune neutropenia evolving to ALPS-like disease not responsive to standard immunosuppressive approaches. Early diagnosis based on these manifestations could allow prompt therapeutic intervention anticipating the onset of vasculopathy and related severe complications.\n\nImportantly, clinicians should aim at obtaining the molecular diagnosis of putative genetic diseases before transplant, since it could influence the management of patients candidate to HSCT. This particularly applies in ADA2 deficiency, considering the high risk of complications due to the persisting inflammation and the impaired endothelial integrity (17, 19, 29). In this light, anti-TNF therapy administered before the conditioning can reduce vascular inflammation (14). With the same aim, conditioning should be tailored, for example replacing Busulfan with Treosulfan or other agents displaying lower endothelial toxicity. Another strategy can foresee prophylactic Defibrotide to reduce the risk of sinusoidal obstruction syndrome. In addition, the selection of the donor can favor unrelated donor avoiding carrier familial donors who might display partial reduction of ADA2 activity. This partial defect can be amplified in the presence of mixed chimerism, leaving a residual and potentially clinically significant enzymatic defect (28). Finally, evaluating ADA2 activity after transplant, especially in case of mixed chimerism, allows monitoring the efficacy and promptly detect the disease recurrence (27). Further studies are needed to define the appropriate timing of HSCT and as well as intensity of conditioning regimen.\n\nConcluding Remarks\nEarly diagnosis of DADA2 in cases presenting with hematological manifestations, rather than classical vasculopathy, is crucial, allowing the patients to undergo HSCT, if indicated, before the arousal of more severe manifestations of the disease. Moreover, physicians can adjust the transplant procedure based on the features of the disease, in order to minimize complications and create the most favorable conditions to allow an efficacious control of the disease. Finally, this case highlights the importance of reaching a genetic diagnosis before HSCT. If transplant cannot be delayed, a related donor should be excluded in all cases of genetic disease suspicion without precise molecular diagnosis: an unrelated donor would give the possibility to avoid relapse or partial benefit due to a common genetic defect.\n\nEthics Statement\nThe study was performed in accordance with the Declaration of Helsinki. The patient was enrolled in a study approved by the San Raffaele Ethical Committee (TIGET06). Written informed consent was obtained from parents for biological sample collection and data publication.\n\nAuthor Contributions\nFM, MM, MC, MDB, RB, EB, AZ, VV, and SC participated to clinical care of the patient and related clinical data. IB, MZ, and MO performed the molecular analysis by Haloplex. IB, MZ, MO, FB, and MPC contributed to the selection of variants. MD analyzed the effect of mutations on the protein structure. MH performed the dosage of ADA2 enzymatic activity. FB, FM, MM, AA, and SC designed the study, analyzed results and wrote the paper. AVB referred the patient and participated in the clinical management.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nWe thank the patient and her family for their trust and for allowing publication of clinical information.\n\nFunding. The study was supported by grants of the Italian Ministero della Salute (Programma di rete, NET-2011-02350069), the European Commission (ERARE-3-JTC 2015 EUROCID) and Fondazione Telethon (TIGET Core grant C6). FB and MZ conducted this study as part of their Ph.D. in Immunologia Medicina Molecolare e Biotecnologie Applicate, Tor Vergata University, Rome, Italy.\n==== Refs\nReferences\n1. Meyts I Aksentijevich I . 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(2016 ) 177 :316 –20 . 10.1016/j.jpeds.2016.06.058 27514238 \n10. Schepp J Bulashevska A Mannhardt-Laakmann W Cao H Yang F Seidl M . Deficiency of adenosine deaminase 2 causes antibody deficiency . J Clin Immunol. (2016 ) 36 :179 –86 . 10.1007/s10875-016-0245-x 26922074 \n11. Schepp J Proietti M Frede N Buchta M Hubscher K Rojas Restrepo J . Screening of 181 patients with antibody deficiency for deficiency of adenosine deaminase 2 sheds new light on the disease in adulthood . Arthritis Rheumatol. (2017 ) 69 :1689 –700 . 10.1002/art.40147 28493328 \n12. Skrabl-Baumgartner A Plecko B Schmidt WM Konig N Hershfield M Gruber-Sedlmayr U . Autoimmune phenotype with type I interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation . Pediatr Rheumatol Online J. (2017 ) 15 :67 . 10.1186/s12969-017-0193-x 28830446 \n13. Cipe FE Aydogmus C Serwas NK Keskindemirci G Boztug K . Novel Mutation in CECR1 Leads to Deficiency of ADA2 with Associated Neutropenia . 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Blood (2016 ) 127 :17 –28 . 10.1182/blood-2015-07-657981 26504182 \n25. Schymkowitz J Borg J Stricher F Nys R Rousseau F Serrano L . The FoldX web server: an online force field . Nucleic Acids Res. ( 2005) 33 :W382 –388 . 10.1093/nar/gki387 15980494 \n26. Zeng Y Katsanis E . The complex pathophysiology of acquired aplastic anaemia . Clin Exp Immunol. (2015 ) 180 :361 –70 . 10.1111/cei.12605 25683099 \n27. Bucciol G Delafontaine S Segers H Bossuyt X Hershfield MS Moens L . Hematopoietic Stem Cell Transplantation in ADA2 Deficiency: Early Restoration of ADA2 Enzyme Activity and Disease Relapse upon Drop of Donor Chimerism . J Clin Immunol. (2017 ) 37 :746 –50 . 10.1007/s10875-017-0449-8 28993957 \n28. Hashem H Kumar AR Muller I Babor F Bredius R Dalal J . Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2 . Blood (2017 ) 130 :2682 –8 . 10.1182/blood-2017-07-798660 28974505 \n29. 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"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "9()",
"journal": "Frontiers in immunology",
"keywords": "ADA2; ADA2 deficiency; ALPS; CECR1; HSCT; autoimmunity; immunodeficiency; neutropenia",
"medline_ta": "Front Immunol",
"mesh_terms": "D000243:Adenosine Deaminase; D017209:Apoptosis; D056735:Autoimmune Lymphoproliferative Syndrome; D002675:Child, Preschool; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D009503:Neutropenia; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D061349:Unrelated Donors; D019014:fas Receptor",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "2767",
"pmc": null,
"pmid": "30692987",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "26867732;29951947;28830446;29271561;27514238;27663683;28983775;28993957;24552284;28516235;24552285;15980494;28805790;27609179;29564582;28974505;20227752;20453107;25457153;28493328;29411230;27059682;26504182;21885601;26922074;28522451;20538792;22306884;25683099",
"title": "ALPS-Like Phenotype Caused by ADA2 Deficiency Rescued by Allogeneic Hematopoietic Stem Cell Transplantation.",
"title_normalized": "alps like phenotype caused by ada2 deficiency rescued by allogeneic hematopoietic stem cell transplantation"
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"occurcountry": "IT",
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"abstract": "Thyroid lymphomas are rare clinical entities that may result from either the primary intrathyroid de novo or secondary thyroid gland involvement of a lymphoma. Among these, the Hodgkin's subtype is quite uncommon, accounting for 0.6-5% of all thyroid malignancies. The authors report on a 76-year-old female presenting with a thyroid nodule that, upon surgical excision, was found to be a nodular lymphocyte predominant Hodgkin lymphoma of the thyroid. So far, thyroid involvement by this variant has never been reported. Upon reporting on this clinical case, the authors emphasize the difficulties usually found in establishing the diagnosis and in defining the best management strategy. A thorough review of the available literature is done.",
"affiliations": "Endocrinology Department, Hospital de Egas Moniz, Lisboa, Portugal.;Pathology Department, Hospital de Egas Moniz, Lisboa, Portugal.;Endocrinology Department, Instituto Português de Oncologia Francisco Gentil, Lisboa, Portugal.;Endocrinology Department, Hospital de Egas Moniz, Lisboa, Portugal.",
"authors": "Tavares Bello|Carlos|C|0000-0001-5676-5115;Cassis|João|J|;Simões|Helder|H|;Sequeira Duarte|João|J|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1155/2016/8756723",
"fulltext": "\n==== Front\nCase Rep EndocrinolCase Rep EndocrinolCRIECase Reports in Endocrinology2090-65012090-651XHindawi Publishing Corporation 10.1155/2016/8756723Case ReportNodular Lymphocyte Predominant Hodgkin Lymphoma of the Thyroid http://orcid.org/0000-0001-5676-5115Tavares Bello Carlos \n1\n\n*\nCassis João \n2\nSimões Helder \n3\nSequeira Duarte João \n1\n1Endocrinology Department, Hospital de Egas Moniz, Lisboa, Portugal2Pathology Department, Hospital de Egas Moniz, Lisboa, Portugal3Endocrinology Department, Instituto Português de Oncologia Francisco Gentil, Lisboa, Portugal*Carlos Tavares Bello: bello.carlos04@gmail.comAcademic Editor: Osamu Isozaki\n\n2016 1 12 2016 2016 87567232 9 2016 14 11 2016 Copyright © 2016 Carlos Tavares Bello et al.2016This 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.Thyroid lymphomas are rare clinical entities that may result from either the primary intrathyroid de novo or secondary thyroid gland involvement of a lymphoma. Among these, the Hodgkin's subtype is quite uncommon, accounting for 0.6–5% of all thyroid malignancies. The authors report on a 76-year-old female presenting with a thyroid nodule that, upon surgical excision, was found to be a nodular lymphocyte predominant Hodgkin lymphoma of the thyroid. So far, thyroid involvement by this variant has never been reported. Upon reporting on this clinical case, the authors emphasize the difficulties usually found in establishing the diagnosis and in defining the best management strategy. A thorough review of the available literature is done.\n==== Body\n1. Introduction\nHodgkin's lymphoma (HL) is a malignant lymphoproliferative disease encompassing a wide spectrum of lymphoid neoplasms. It accounts for 8.2% of all lymphomas [1] and 0.5% of all cancers diagnosed in the developed world annually [2]. In Europe, the incidence is approximately 2.4 per 100.000 per year [3]. It has a bimodal age distribution with the highest peak affecting young adults (around 20 years of age) and a second peak in the elderly (older adults, approximately 65 years). Males are more frequently affected than female patients [1]. Risk factors include the socioeconomic status (high for nodular sclerosis and low for mixed cellularity and lymphocyte depleted subtypes), Epstein-Barr virus infection, immunosuppression (iatrogenic or HIV, 5–25-fold higher risk), genetic background (HLA-DRB1 and HLA-DQB1 genotypes), and autoimmunity (Rheumatoid Arthritis, OR 2.7; Systemic Lupus Erythematosus, OR 5.8; Sarcoidosis, OR 14) [4]. HL arises from germinal center or postgerminal center B cells and has a unique cellular composition consisting of a variable amount of neoplastic cells in an inflammatory background. Reed-Sternberg cells and their variants (Hodgkin's, mummified, lacunar, lymphocytic, and histiocytic cells) are diagnostic. The phenotype of the inflammatory cell background infiltrate, along with the neoplastic cell morphological and immunophenotypical features, subdivides HL in 2 subgroups: classical and nodular lymphocyte predominant HL. Classical HL is further subdivided in 4 subtypes: nodular sclerosis (70% of all HL), mixed cellularity (20%), lymphocyte-rich (5%), and lymphocyte-depleted (<1%) HL. Nodular lymphocyte predominant HL (NLPHL) accounts for less than 10% of all HL cases and is considered a distinct clinical entity [4].\n\nHL usually presents with painless lymphadenopathy (70%), mostly cervical in location (60–80%). B symptoms (fever, chills, and weight loss) are present in 20% of patients, may alert systemic involvement, and constitute a poor prognostic marker. Extranodal disease, as opposed to non-Hodgkin lymphomas (present in 33% of cases), is less frequent with HL (5–10%) [3].\n\nPrimary Malignant Lymphoma of the Thyroid is uncommon, accounting for less than 5% of all thyroid malignancies and up to 7% of all extranodal lymphomas [5–8]. It tends to be of B cell origin, with the majority being of non-Hodgkin's subtype (MALT and diffuse large B cell subtype). It predominantly affects elderly female patients in their 7th decade of life. Its etiology remains largely unknown but lymphocytic thyroiditis, by allowing lymphoid cell infiltration of the thyroid bed (a lymphoid cell deprived organ), may well be involved. It is often difficult to establish the primary source of HL in patients with both nodal and extranodal involvement; however, primary extranodal forms are extremely rare [9].\n\nThe case of a patient bearing a nodular lymphocyte predominant Hodgkin's lymphoma affecting the thyroid gland is reported.\n\n2. Case Report\nThe patient was a 76-year-old female followed up in the Thyroid Clinic for a thyroid nodule and primary hypothyroidism. The patient also had type 2 diabetes mellitus, arterial hypertension, and hypercholesterolemia. Regular medication included levothyroxine, ramipril, and simvastatin, diabetes being controlled with dietary measures only. Family and personal history were noncontributory and there was no previous radiation or iodine exposure. A thyroid nodule was first diagnosed upon clinical suspicion and ultrasound confirmation 2 years previous to her first Endocrinology Clinic visit. Imaging documented a large (29 × 44 × 31 mm transverse, longitudinal, and anteroposterior diameters, resp.), hypoechogenic, heterogeneous thyroid nodule of the left lobe with regular borders (Figure 1) superimposed on a micronodular background and multiple locoregional (left posterior and internal jugular) lymphadenopathies of large dimensions (the largest with 48 × 20 mm diameter) (Figure 2).\n\nLaboratory studies were compatible with compensated primary hypothyroidism (TSH 2.32 IU/mL (normal range 0.4–4.68 IU/mL); free thyroxine 13 pmol/L (normal range 10–28 pmol/L)) along with marginally elevated thyroid autoantibody titer (antithyroid peroxidase, 71.8 IU/mL; negative antithyroglobulin results). No changes were seen on the complete blood count, lactate dehydrogenase, or erythrocyte sedimentation rate. No thyroid scintigraphy was done due to the absence of hyperthyroidism.\n\nFine needle aspirations (FNA) of the thyroid nodule were inconclusive; however, upon repetition, suspicion of papillary thyroid carcinoma (follicular and Hürthle cells with moderate degree anisokaryosis and nuclear grooves, Thy Class 4) on a thyroiditis background (mixed lymphoid population with predominance of small lymphocytes) arose. FNA of a suspicious lymph node was, on the other hand, suggestive of a lymphoproliferative disorder (monomorphic population of small lymphocytes and rare macrophages). Flow cytometry of both the thyroid nodule and a suspicious lymph node cytology specimen did not show any monoclonal lymphoid cells although there was a greatly increased CD4/CD8 ratio.\n\nUpon suspicion of a differentiated thyroid cancer, total thyroidectomy with cervical lymph node dissection was performed.Intraoperative pathology consultation was requested for the thyroid specimen that showed a well delimitated, nonencapsulated, homogeneous, elastic, whitish nodule occupying the left thyroid lobe with 44 mm of greatest diameter. Frozen sections of the nodule revealed a nodular lymphoid proliferation suggestive of a malignant lymphoma. No evidence of papillary carcinoma was present. On paraffin sections the findings were similar to the those found on the lymph node.\n\nRegional cervical lymph node dissection revealed extensive HL involvement (16 out of 18 lymph nodes with evidence of HL). The lymph nodes had a macroscopically homogeneous whitish surface. Microscopy revealed architectural distortion induced by proliferation of multiple small nodules with irregular borders composed of dendritic cells (CD21+), numerous small CD4+ T lymphocytes, and few histiocytes and B lymphocytes. In this highly cellular background, a few large neoplastic cells with scant cytoplasm and large lobulated vacuolated nuclei with one or more red nucleoli (“popcorn cells”) were present. Very few mitotic figures could be seen and no necrosis could be appreciated. Immunohistochemistry of the neoplastic cells showed positivity for CD20 and negativity for CD30 and CD15 (Figure 2). In situ hybridization for EBV was negative.\n\nDiagnostic conclusion: both specimens were compatible with Nodular Lymphocyte Predominant Hodgkin's Lymphoma (NLPHL).\n\n\n\n\nBone marrow biopsy and full body CT-scan revealed no further evidence of extranodal disease. Taken together, these results allowed classifying our patient's HL in the stage IA.\n\nBesides thyroidectomy and cervical lymphadenectomy, the patient subsequently underwent systemic chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). With treatment, a favorable neoplastic response was observed. A total of 5 cycles were completed. Unfortunately, because of significant cardiac toxicity from anthracyclines, hospital admission for acute congestive heart failure and significant performance status deterioration, chemotherapy was suspended (after 5 cycles). The patient is presently well and displays no evidence of disease recurrence, upon 30 months of follow-up.\n\n3. Discussion\nThyroid malignancies are increasingly being diagnosed in the current era of the “Incidentalomas,” differentiated thyroid cancer accounting for the majority of them. Thyroid lymphomas are very rare [5–7], both primary and secondary forms. Primary Malignant Thyroid Lymphoma (TL) is a rare thyroid neoplasm representing less than 5% of all thyroid cancers and 2.5% of all NHL [10]. The peak incidence is in the 7th decade and affects more frequently the female gender. TL are almost always of B cell lineage. Most being initially MALT lymphomas, the majority may ultimately progress to Diffuse Large B Cell Lymphoma (DLBCL), which account for 70–80% of all TL at the time of diagnosis.\n\nConcerning Primary Thyroid Lymphomas, Hashimoto thyroiditis is considered a risk factor predisposing to its development and, in fact, in up to 40% of cases, concomitant primary hypothyroidism has been reported. Clinically, compressive symptoms are present in one-third and accompanying locoregional lymphadenopathy in 50% of cases. Regarding therapy, surgery may be indicated in some cases despite chemotherapy (with or without Radiation therapy) the being most frequently employed treatment modality [9].\n\nOur literature search revealed thirty-nine cases of Hodgkin's lymphoma located in the thyroid gland reported to date. Thyroid Hodgkin lymphoma affects mostly female patients (75–80% patients) with a median age of 42 years at the time of diagnosis [8]. Thyroid gland, a lymphoid cell deprived organ, requires an inflammatory insult for local lymphocyte allocation [11]. This is one theory supporting a possible association between lymphocytic thyroiditis and HL. In 80% of patients, thyroid HL became manifest as a rapidly enlarging neck mass, compressive symptoms being somewhat frequent, hoarseness (35%), dyspnea (65%), and dysphagia (53%). Classical B symptoms, fever (>38°C) for 3 or more days, drenching night sweats, and significant weight loss (>10% body weight in 6 months), are rare and may herald systemic involvement and disease progression, representing a predictor of poor outcome [3]. Classical Hodgkin's Lymphoma, namely, nodular sclerosis subtype, is the most frequently described variant to affect the thyroid gland [8].\n\nNodular lymphocyte predominant HL (NLPHL) constitutes a rare subtype of HL, accounting for no more than 10% of all cases of HL. It is considered a distinct clinical entity in that it differs from classical forms of HL in many aspects: Median age at presentation tends to be higher than in classical HL (30–40 years) and it has a greater male predominance (3 : 1). 70–80% of patients present with stage I-II disease and tend to have a higher propensity for peripheral lymph node involvement (neck and axilla). “B symptoms” are less frequent, being present in up to 10% of cases, which possibly reflects a lower systemic cytokine release (IL-2, -4, and -13). Extranodal involvement is rare, the spleen being the most commonly involved organ (10–15%). Bone marrow infiltration is found in less than 5% of cases.\n\nIts hallmark histologic feature is the presence of malignant LP cells (histiocytic Reed-Sternberg cell variants) embedded within a nodular pattern of infiltrating lymphocytes. Malignant cells are described as “popcorn cells,” an illustrative description of their morphology (containing a single, large, folded, or multilobated nucleus with multiple small basophilic nucleoli). In contrast with Reed-Sternberg cells, LP cells do not express CD 15 or CD30, being rather positive for CD19, CD20, CD22, CD45, and CD79a along with expression of Oct-2 and B cell Oct-binding protein 1 transcription factors. Reed-Sternberg cells are identified in more than half of NLPHL cases; however, these tend to be scarce, positive for CD20, and negative for CD15 and CD30. Markers for EBV are typically negative.\n\nRecommended management involves field or regional radiotherapy for patients with limited stage disease and combined modality therapy or chemotherapy for advanced stage disease. Response rates are very high, complete remission being achieved in 90–100% of patients. Relapses are unfortunately common within 3–6 years (10–35%); however, prognosis remains overall favorable (10-year survival rates of 80–90%) [12].\n\nThe patient described is, to our knowledge, the first documented case of nodular lymphocyte predominant HL involving the thyroid. Patient was older than was expected from what has been described with this HL subtype. Lymphocytic thyroiditis was definitely present which may have been a decisive risk factor and a possible factor underlying difficulty in establishing the definite diagnosis. Primary Malignant Lymphoma of the thyroid diagnosis was assumed postoperatively justifying the adjuvant postoperative conventional chemotherapy for HL (ABVD regimen). Lymphoma free survival is reported after 2 years of follow-up despite possible significant treatment toxicity (heart failure).\n\n4. Conclusions\nThyroid nodules are frequent clinical and radiological findings, the majority being benign in nature. Among thyroid malignancies, lymphomas are quite rare and are usually of non-Hodgkin's subtype. Hodgkin lymphomas of the thyroid are even more unusual, only 40 cases being described so far (mostly of the nodular sclerosis subtype). Nodular lymphocyte predominant HL is considered to represent a distinct form of HL regarding epidemiological distribution, biological behavior, histological hallmarks, and prognosis. The authors report on the first described case of a nodular lymphocyte predominant Hodgkin lymphoma of the thyroid.\n\nAdditional Points\n\nTake-Home Messages. (i) Hodgkin lymphomas of the thyroid gland are very rare. (ii) Nodular sclerosis HL is the most frequent HL subtype described to affect the thyroid. (iii) Nodular lymphocyte predominant HL is a distinct form of HL and so far had not been reported to affect the thyroid. (iv) Thyroid HL usually presents as a space occupying lesion, B symptoms and systemic involvement being rare. (v) In this subtype of HL, Reed-Sternberg cells are rare and are immunophenotypically distinct (CD20 positive, CD15 and CD30 negative). (vi) Treatment options range from field or regional radiotherapy for limited stage disease to combined modality therapy or chemotherapy for advanced stage disease.\n\nCompeting Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 (a) Thyroid nodule, large (29 × 44 × 31 mm transverse, longitudinal, and anteroposterior diameters, resp.) hypoechogenic heterogeneous thyroid nodule with regular borders; (b) lymph node, large (48 × 20 mm), hypoechoic, partly cystic lymph node.\n\nFigure 2 3: FNA of the thyroid with follicular cells with suspicious nuclei (anisokaryosis, longitudinal grooves) on the background of a lymphocytic thyroiditis (Papanicolaou stain, 400x); 4: macroscopy features of the surgical specimens: left hemithyroidectomy (on top) and left cervical lymph node (on the bottom); 5: thyroid parenchyma with a diffuse infiltration of a lymphoid neoplasm (HE, 40x). These features were also found on the lymph node (not shown); 6: the neoplasm consisted of irregular nodules of follicular dendritic cells (CD21, 40x); 7: extensive background of CD4+ T-lymphocytes (CD4, 40x); 8: intermingled scattered large “popcorn cells” could be observed (HE, 200x); 9: the neoplastic popcorn cells were positive for CD20 (CD20, 200x); 10: they were negative for CD30 (CD30, 200x) and CD15 (not shown).\n==== Refs\n1 Longo D. L. Malignancies of Lymphoid Cells. Harrison's Principles of Internal Medicine 2015 19th McGraw-Hill Education \n2 National Cancer Insititute Hodgkin Lymphoma-SEER Stat Fact Sheets http://seer.cancer.gov/statfacts/html/hodg.html \n3 Szczepanek-Parulska E. Szkudlarek M. Majewski P. Breborowicz J. Ruchala M. Thyroid nodule as a first manifestation of Hodgkin lymphoma-report of two cases and literature review Diagnostic Pathology 2013 8 1 p. 116 10.1186/1746-1596-8-116 2-s2.0-84907280164 \n4 Lash B. W. Hodgkin Lymphoma: Practice Essentials, Background, Pathophysiology, Medscape Drugs & Diseases, http://emedicine.medscape.com/article/201886-overview#a4 \n5 Forconi F. Bocchia M. Marconcini S. CD30 positive (non-anaplastic) peripheral T-cell lymphoma of the thyroid gland Haematologica 1999 84 10 946 948 2-s2.0-0032743624 10509044 \n6 Gupta N. Nijhawan R. Srinivasan R. Fine needle aspiration cytology of primary thyroid lymphoma: a report of ten cases CytoJournal 2005 2, article 21 10.1186/1742-6413-2-21 2-s2.0-30344461859 \n7 Derringer G. A. Thompson L. D. R. Frommelt R. A. Bijwaard K. E. Heffess C. S. Abbondanzo S. L. Malignant lymphoma of the thyroid gland: a clinicopathologic study of 108 cases The American Journal of Surgical Pathology 2000 24 5 623 639 10.1097/00000478-200005000-00001 2-s2.0-0034099339 10800981 \n8 Wang S. A. Rahemtullah A. Faquin W. C. Roepke J. Harris N. L. Hasserjian R. P. Hodgkin's lymphoma of the thyroid: a clinicopathologic study of five cases and review of the literature Modern Pathology 2005 18 12 1577 1584 10.1038/modpathol.3800501 2-s2.0-27944442467 16258502 \n9 Schlumberger M. Filetti S. Hay I. D. Nontoxic Diffuse and Nodular Goiter and Thyroid Neoplasia 2011 12th Philadelphia, Pa, USA Saunders Williams Textbook of Endocrinology \n10 Thieblemont C. Mayer A. Dumontet C. Primary thyroid lymphoma is a heterogeneous disease The Journal of Clinical Endocrinology & Metabolism 2002 87 1 105 111 10.1210/jc.87.1.105 2-s2.0-18244406321 11788631 \n11 Pedersen R. K. Pedersen N. T. Primary non-Hodgkin's lymphoma of the thyroid gland: a population based study Histopathology 1996 28 1 25 32 10.1046/j.1365-2559.1996.268311.x 2-s2.0-0030065545 8838117 \n12 Lee I. A. LaCasce A. S. Nodular lymphocyte predominant Hodgkin lymphoma The Oncologist 2009 14 7 739 751 10.1634/theoncologist.2009-0099 2-s2.0-68449094570 19605845\n\n",
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"title": "Nodular Lymphocyte Predominant Hodgkin Lymphoma of the Thyroid.",
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"abstract": "The COVID-19 pandemic has caused multiple deaths worldwide. Since no specific therapies are currently available, treatment for critically ill patients with COVID-19 is supportive. The most severe patients need sustained life support for recovery. We herein describe the course of a critically ill COVID-19 patient with multi-organ failure, including acute respiratory failure, acute kidney injury, and fulminant cytokine release syndrome (CRS), who required mechanical ventilation and extracorporeal membrane oxygenation support. This patient with a predicted high mortality risk was successfully managed with a careful strategy of oxygenation, uremic toxin removal, hemodynamic support, and most importantly, cytokine-targeted intervention for CRS, including cytokine/endotoxin removal, anti-cytokine therapy, and immune modulation. Comprehensive cytokine data, CRS parameters, and biochemical data of extracorporeal removal were provided to strengthen the rationale of this strategy. In this report, we demonstrate that timely combined hemoperfusion with cytokine adsorptive capacity and anti-cytokine therapy can successfully treat COVID-19 patients with fulminant CRS. It also highlights the importance of implementing cytokine-targeted therapy for severe COVID-19 guided by the precise measurement of disease activity.",
"affiliations": "Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.;Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.;Department of Anesthesiology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.;Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.;Division of Nephrology, University of Alabama, Birmingham, AL, United States.",
"authors": "Huang|Thomas Tao-Min|TT|;Chien|Ying-Chun|YC|;Wang|Chih-Hsien|CH|;Chang|Sui-Yuan|SY|;Wang|Jann-Tay|JT|;Hsieh|Song-Chou|SC|;Yeh|Yu-Chang|YC|;Ku|Shih-Chi|SC|;Yu|Chong-Jen|CJ|;Chiang|Bor-Luen|BL|;Chang|Shan-Chwen|SC|;Tolwani|Ashita|A|",
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"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.649583\nMedicine\nCase Report\nSuccessful Treatment of a Critically Ill COVID-19 Patient Using Continuous Renal Replacement Therapy With Enhanced Cytokine Removal and Tocilizumab: A Case Report\nHuang Thomas Tao-Min 1†\n\nChien Ying-Chun 1†\n\nWang Chih-Hsien 2\n\nChang Sui-Yuan 3\nWang Jann-Tay 1\nHsieh Song-Chou 1\nYeh Yu-Chang 4\nKu Shih-Chi 1*\nYu Chong-Jen 1\nChiang Bor-Luen 5\nChang Shan-Chwen 1\nTolwani Ashita 6\n1Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan\n2Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan\n3Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan\n4Department of Anesthesiology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan\n5Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan\n6Division of Nephrology, University of Alabama, Birmingham, AL, United States\nEdited by: Ata Murat Kaynar, University of Pittsburgh, United States\n\nReviewed by: Longxiang Su, Peking Union Medical College Hospital (CAMS), China; Yihua Dong, Wenzhou Medical University, China\n\n*Correspondence: Shih-Chi Ku scku1015@ntu.edu.tw\nThis article was submitted to Intensive Care Medicine and Anesthesiology, a section of the journal Frontiers in Medicine\n\n†These authors have contributed equally to this work\n\n07 6 2021\n2021\n07 6 2021\n8 64958305 1 2021\n19 4 2021\nCopyright © 2021 Huang, Chien, Wang, Chang, Wang, Hsieh, Yeh, Ku, Yu, Chiang, Chang and Tolwani.\n2021\nHuang, Chien, Wang, Chang, Wang, Hsieh, Yeh, Ku, Yu, Chiang, Chang and Tolwani\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nThe COVID-19 pandemic has caused multiple deaths worldwide. Since no specific therapies are currently available, treatment for critically ill patients with COVID-19 is supportive. The most severe patients need sustained life support for recovery. We herein describe the course of a critically ill COVID-19 patient with multi-organ failure, including acute respiratory failure, acute kidney injury, and fulminant cytokine release syndrome (CRS), who required mechanical ventilation and extracorporeal membrane oxygenation support. This patient with a predicted high mortality risk was successfully managed with a careful strategy of oxygenation, uremic toxin removal, hemodynamic support, and most importantly, cytokine-targeted intervention for CRS, including cytokine/endotoxin removal, anti-cytokine therapy, and immune modulation. Comprehensive cytokine data, CRS parameters, and biochemical data of extracorporeal removal were provided to strengthen the rationale of this strategy. In this report, we demonstrate that timely combined hemoperfusion with cytokine adsorptive capacity and anti-cytokine therapy can successfully treat COVID-19 patients with fulminant CRS. It also highlights the importance of implementing cytokine-targeted therapy for severe COVID-19 guided by the precise measurement of disease activity.\n\nCOVID-19\ncytokine release syndrome\nextracorporeal membrane oxygenation\ncontinuous renal replacement therapy\ntocilizumab\nNational Taiwan University Hospital10.13039/501100005762NTUH-109-P13\n==== Body\nIntroduction\n\nThe emerging and rapid transmission of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with its associated syndrome, coronavirus disease (COVID-19), has spread worldwide after its outbreak in Wuhan, China in late 2019 (1). Although most patients may be asymptomatic, patients with advanced ages or multiple comorbidities can develop\n\nfatal illnesses and rapidly succumb to them. It is estimated that 2–10% of the patients may develop critical illness and may need intensive care and advanced life support (1–5). The associated pathophysiology is diverse and might range from transient organ dysfunction to deadly multi-organ failure. The organs involved include the cardiovascular system, kidneys, lungs, hematologic system, and immune system. Severely ill patients may have cytokine release syndrome (CRS) (6), presenting with refractory hypotension, hemophagocytic lymphohistiocytosis (7), anti-phospholipid activity (8), and kidney damage (9). Since effective antiviral therapy is not available at this time; life-supportive measures and effective complication management are pivotal measures for patient survival. We report herein a successful treatment strategy using cytokine-targeted therapy, including CRS management and extracorporeal cytokine removal, in a critically ill COVID-19 patient with a devastating clinical course.\n\nCase Description\n\nA 53-year-old man with a history of colon cancer and bladder cancer with disease-free status for more than 5 years developed watery diarrhea 3 d after close contact with a confirmed COVID-19 patient. Fever (body temperature, 37.7°C), general malaise, myalgia, and poor appetite prompted him to seek medical advice on the 11th day, and he was admitted to a regional hospital. The hemogram was normal (white blood cell count: 4,900/μL, hemoglobin concentration: 16.6 g/dL, and platelet count: 203 k/μL). The aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were 44 and 45 U/L, respectively. There was an elevation in the C-reactive protein (CRP) level (12.5 mg/dL), although the procalcitonin level was within normal limits (0.15 ng/mL). Polymerase chain reaction (PCR) from a nasal swab for SARS-CoV-2 was positive. Moxifloxacin (400 mg daily) and hydroxychloroquine were administered.\n\nOn day 16, he developed respiratory distress with an escalation of his oxygen needs from nasal prongs to a non-rebreathing mask. A chest radiograph revealed rapid progression of pulmonary infiltrates (Figure 2A). He underwent tracheal intubation for severe hypoxemia with an arterial oxygen partial pressure to fractional inspired oxygen ratio of 109 mmHg. In addition, he had lactic acidosis (lactic acid level 2.3 mg/dL), rhabdomyolysis (creatinine kinase level 261 U/L), high CRP level (14.6 mg/dL), and hyperferritinemia (ferritin level 2,957 ng/mL). His urine volume was ~840 mL in 24 h, and the renal reserve was adequate with a serum creatinine level of 1.1 mg/dL. With this presentation, he was transferred to our intensive care unit (ICU) for advanced life support (Figure 1).\n\nFigure 1 The time course of ferritin levels, IL-6 levels, vasoactive-inotropic equivalent (VIE) scores, and urine amount in a severe COVID-19 patient with multi-organ failures. IL-6, interleukin 6; VIE, vasoactive-inotropic equivalent; CVVHDF, continuous venovenous hemodiafiltration; AN69ST/PEI: hemofilter with AN69 and polyethyleneimine.\n\nDisease Assessment\n\nClinical Parameters and SARS-CoV-2 Detection\n\nAcute disease severity was assessed using Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II scores collected on ICU admission and the next day of ICU stay (10). Sequential organ failure assessment (SOFA) scores were collected daily (11). Vasoactive-Inotropic Equivalent (VIE) scores were calculated from the infusion rates of vasopressors and inotropes and automatically summed up in the computerized database (12). Acute kidney injury was defined using the Kidney Disease: Improving Global Outcomes 2012 criteria (13). We also calculated the kinetic glomerular filtration rate (GFR), which forecasts future renal dysfunction derived from two consecutive days' serum creatinine data (14). Collection and detection of SARS-CoV-2 from biological samples were compliant with the World Health Organization guidance (15). Sputum, nasopharyngeal swabs, and oropharyngeal swabs were obtained for real-time PCR (RT-PCR). We determined the SARS-CoV-2 viral loads in each biological sample.\n\nContinuous Renal Replacement Therapy\n\nThe indication for continuous renal replacement therapy (CRRT) was oliguria for more than 12 h, with clinical evidence of fluid overload and hemodynamic compromise. We used a standard CRRT machine (PlasmaflexⓇ, BaxterⓇ, France) with either a standard AN69 based hemofilter (M150, BaxterⓇ, France) or a specialized hemofilter composed of AN69 and polyethyleneimine (AN69ST/PEI, oXirisⓇ, BaxterⓇ France) used for increased clearance of cytokines and endotoxins in patients with sepsis (16). The CRRT prescription was compatible with the current standard (13). We used continuous veno-venous hemodiafiltration (CVVHDF) with a dialysate flow of 10–15 mL/kg/h along with a filtration flow of 15–20 mL/kg/h via a 14 Fr-uncuffed tunneled catheter. To decrease filtration fraction and prolong circuit lives, we chose CVVHDF as the main treatment modality. The filtration fraction was set to below 20% to avoid pre-mature dysfunction of the circuit. The AN69ST/PEI hemofilter with increased adsorptive capacity for cytokines and endotoxins has been emergently approved by the United States in response to the COVID-19 pandemic under EUA200164 and has been granted permission for use in Taiwan in recent years. We set up CRRT with an AN69ST/PEI along with heparin or regional citrate anticoagulation (RCA) (17). We targeted the activated prothrombin time around 50–70 s while using heparin and targeted a post-filter ionized calcium around 0.3–0.45 mmol/L while using RCA (18).\n\nVeno-Venous Extracorporeal Membrane Oxygenation Life Support\n\nThe indication for veno-venous extracorporeal membrane oxygenation (VV-ECMO) support was refractory hypoxemia. We cannulated the patient via the right internal jugular and femoral vein using the cut-down method. The VV-ECMO comprised a circuit with heparin-bound surfaces, an oxygenator (Affinity NT, Medtronic), a centrifugal pump (BPX-80 Bio-Pump Plus, Medtronic, Anaheim, CA, USA), and an oxygen-air blender (Model 3500 CP-G gas mixer, Sechrist, Anaheim, CA, USA) (19).\n\nCytokine Measurement\n\nWe used the cytometric bead array (CBA) method to determine cytokine levels (20). Approximately 5 mL peripheral blood samples were obtained from patients at each time point. Plasma was isolated after centrifugation at 1,500 rpm for 10 min. The concentrations of cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, IL-17, interferon-γ, and tumor necrosis factor in plasma were determined using cytometric bead array (CBA; BD Biosciences), according to the manufacturer's protocol. Briefly, 350 μL samples were subjected to analysis in duplicate using the CBA kit on BD caliber cytometry. The concentrations of cytokines in culture supernatants were quantified using FCAP Array software v3.0 (20). We determined cytokine levels in samples collected from plasma and CRRT effluent. Plasma cytokine levels were checked at three-time points (before CRRT, hour 12, and 24) to determine the number of total cytokines removed using the area under the curve method. Because it was impossible to check the adsorptive capacity of AN69ST/PEI hemofilter, we checked cytokine levels from the CRRT effluent collected in the first 24 h on CRRT with the AN69ST/PEI hemofilter. The differences between these two values could approximate the number of cytokines absorbed by the hemofilter.\n\nMedications for Immune Modulation\n\nThe patient was prescribed tocilizumab, tofacitinib, hydroxychloroquine, and belimumab during his hospital course. Tocilizumab acts as an IL-6 receptor blockade and has been approved for rheumatoid arthritis, giant cell arteritis, and chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (21). Tofacitinib is an inhibitor of Janus kinase (JAKs) 1 and 3. It also has partial selectivity to JAK 2. Tofacitinib may suppress pro-inflammatory signaling including IL-6. It has not been tested in COVID-19 patients for cytokine blockade (22). Hydroxychloroquine is an anti-malarial drug and in vitro study confirmed its ability to inhibit SARS-CoV-2 (23). Antiphospholipid activities may be detected in COVID-19 patients. The mechanism of belimumab is to inhibit the binding of soluble circulating B lymphocyte stimulator to surface ligands of B cells, which may downregulate the anti-phospholipid activities (24).\n\nResults\n\nUpon arrival to the ICU, the patient experienced rapid deterioration of oxygenation and hemodynamics. The body temperature was high (38.3°C), arterial blood pressure was low (79/51 mmHg), and he had tachycardia (heart rate, 136 bpm). He needed vasopressors with a VIE of 29.80: norepinephrine at 0.26 mcg/kg/min, and dopamine at 3.7 μg/kg/min were administered to maintain adequate mean artery pressure. The APACHE II score was 40 (corresponding to an estimated mortality rate of 85%), and the SOFA score was 17. There was a severe acute kidney injury (AKI) with an absence of urine output for more than 12 h and an increase in creatinine level to 3.1 mg/dL. The kinetic GFR was calculated to be 0 mL/min (14). Urinalysis showed dysmorphic red blood cells (RBCs) and renal tubular cells (RTCs), which indicated glomerulonephritis and acute tubular necrosis. A VV-ECMO circuit was promptly set for refractory hypoxemia (2). His laboratory values indicated a relative lymphopenia (lymphocyte percentage: 6.1%, with an absolute count of 722/μL). The ferritin level increased to 13,317 ng/mL, and the triglyceride level was 446 mg/dL. The AST level was 121 U/L, along with an ALT level of 47 U/L. The cytokine profiles displayed an extremely high IL-6 level (12,049.07 pg/mL). A rapidly evolving CRS was likely. In addition, with rapidly elevating procalcitonin levels (from 0.15 to >100 pg/mL), ceftazidime and levofloxacin were prescribed empirically for concern of a superimposed bacterial infection, although the bacterial cultures did not yield until discharge. CRRT with an AN69ST/PEI hemofilter was delivered using a separate uncuffed tunneled catheter. Intravenous immunoglobulin (1 g/kg/day) was administered for two consecutive days for hypogammaglobulinemia (immunoglobulin G: 629 mg/dL).\n\nThe poor renal reserve precluded the patient from remdesivir therapy. Hydroxychloroquine with 400 mg twice daily was continued, and tocilizumab with a total dose of 400 mg (5.2 mg/kg) was prescribed 2 h after the initiation of CRRT. Tofacitinib (5 mg twice daily) was also prescribed for suspected antiphospholipid activity. We changed the AN69ST/PEA hemofilter circuit every 24 h for better clearance of cytokine/endotoxin. After 26-h treatment, the patient's hemodynamics improved. On day 20, we changed the CRRT hemofilter to an AN69 based hemofilter, after 3 days of cytokine adsorptive treatment. The viral load from the sputum was 2,762 copies/mL. Dopamine and norepinephrine were tapered off on day 22 (after 6-day cytokine-targeted therapy). The ferritin level declined from 13,317 ng/mL on day 16 to 3,875 ng/mL on day 21. The total bilirubin level was 2.28 mg/dL, and the triglyceride level decreased to 320 mg/dL. Another dose of tocilizumab with the same dosage of 400 mg was administered on day 25. The viral load at that time from sputum was 1.35 million copies/mL (Table 1).\n\nTable 1 Baseline characteristics, treatment courses, and relevant data of the reported patient.\n\nDate (day of symptom onset)\t1 April (11th)\t5 April (16th)\t13 April (24th)\t22 April (33rd)\t27 April (38th)\t4 May (45th)\t11 May (52nd)\t\nClinical status\t\t\t\t\t\t\t\t\nBP (mmHg)\t153/75\t79/51\t131/72\t130/69\t165/84\t154/75\t136/85\t\nPulse rates (bpm)\t\t136\t113\t106\t60\t123\t73\t\nUrine output (mL/kg/h)\t0\t0.09\t0.09\t1.11\t1.37\t2.26\t1.91\t\nViral loads (copies/mL)\t\t\t\t\t\t\t\t\nSputum\tPositive\t2,762\t1,354,580\n(Day 26)\t99.65\t83.26\t51.78\t932.27\t\nThroat swab\tPositive\t267\t232,822\t\t\t\t\t\nNasal swab\t\t\t595,075\n(Day 28)\t72.46\t1,128.65\t6.59\t65.67\n(Day50)\t\nVasopressors\t\t\t\t\t\t\t\t\nNorepinephrine (mcg/kg/min)\t–\t0.26\t0.02\t0.01\t–\t–\t–\t\nDopamine (mcg/kg/min)\t–\t3.70\t1.45\t0.00\t–\t–\t–\t\nVIS\t0\t29.80\t2.95\t1.40\t0\t0\t0\t\nHemogram\t\t\t\t\t\t\t\t\nHemoglobin (g/dL)\t16.6\t15.4\t10.2\t8.8\t9.9\t9.5\t8.7\t\nWhite blood cell (/μL)\t4,900\t12,430\t19,430\t11,480\t6,610\t13,180\t11,660\t\nLymphocyte (/μL)\t\t723\t1,263\t787\t568\t667 (D42)\t1,118 (D51)\t\nLymphocyte (%)\t\t6.1\t6.5\t7.4\t8.6\t8.5 (D42)\t8.7 (D51)\t\nPlatelet (K/μL)\t203\t255\t221\t165\t198\t174\t379\t\nBiochemistry\t\t\t\t\t\t\t\t\nALT (U/L)\t44\t47\t27\t18\t25\t89\t107\t\nAST(U/L)\t45\t121\t83\t47\t40\t57\t58\t\nBUN (mg/dL)\t10\t26.5\t40\t58.3\t44.8\t29.1\t32.9\t\nCreatinine (mg/dL)\t1.12\t3.1\t2.7\t4.1\t1.6\t1.9\t1.1\t\nSodium (mmol/L)\t–\t144\t133\t137\t137\t142\t138\t\nTotal Bilirubin (mg/dL)\t1.1\t2.18\t1.39\t1.76\t2.43\t4.76\t2.77\t\nCK (U/L)\t261\t820\t1,672\t288\t128\t107\t219 (D49)\t\nCK-MB (U/L)\t–\t8.53\t7.35 (D23)\t4.18\t3.38 (D35)\t3.14 (D42)\t–\t\nFerritin (ng/mL)\t–\t13,317.09\t3,993.02\t2,461.61\t1,636.28\t2,690.1\t3,200.13\t\nFibrinogen (mg/dL)\t–\t527.6 (D17)\t363\t240.5\t227\t233.1\t178.2 (D53)\t\nLactic Acid (mmol/L)\t–\t5.83\t1.44\t2.54\t0.9\t0.94\t0.77 (D51)\t\nLDH (U/L)\t–\t813\t663\t412\t358\t427\t302\t\nTG (mg/dL)\t–\t446\t320\t116 (D34)\t–\t–\t–\t\nD-dimer (mg/L)\t–\t21.9\t>35\t>35\t12.95\t>35\t6.81\t\nInflammatory markers\t\t\t\t\t\t\t\t\nProcalcitonin (ng/mL)\t0.15\t>100.0\t4.03\t2.15\t0.587\t0.645\t0.128\t\nCRP (mg/dL)\t12.5\t20.1\t12.24\t1.06\t0.27\t2.94\t1.12\t\nCytokines (pg/mL)\t\t\t\t\t\t\t\t\nIL-6\t–\t12,049.1\t3,546.5\t2,535.4\t154.0\t1,579.02\t\t\nIL-4\t–\t0.46\t0\t0.66\t0.07\t0.1\t\t\nIL-10\t–\t2.45\t2.22\t5.24\t3.71\t4.77\t\t\nIL-17\t–\t0\t0\t0\t0.55\t0.88\t\t\nTNF\t–\t0\t0\t0\t0\t0\t\t\nIFN-gamma\t–\t0\t0\t0.03\t0\t2.01\t\t\nVentilator settings\t\t\t\t\t\t\t\t\nModes\tAmbient Air\tPressure control\tPressure control\tPressure control\t\t\tOff on D52\t\nPaO2 (mmHg)\t\t159\t127\t99\t128\t116\t\t\nFiO2\t\t40%\t40%\t40%\t40%\t40%\t\t\nCRRT settings\t\t\t\t\t\t\t\t\nBFR (mL/min)\t\t200\t200\t200\t200\tOff on D40\t\nTotal wastes (mL/h)\t\t2,000\t2,000\t2,000\t1,700\t\t\t\nAnticoagulant\t\tRCA\tHeparin\tHeparin\tHeparin\t\t\nVV-ECMO Settings\t\t\t\t\t\t\t\t\nBFR (L/min)\t\t3.7\t3.75\t3.3\t3.91\t2.58\tOff on D49\t\nECMO FiO2\t\t100%\t50%\t100%\t40%\t21%\t\t\nMedications\t\t\t\t\t\t\t\t\nMethylprednisolone (mg/kg/day)\t\t–\t–\t0.4\t0.4\t0.3\t0.4\t\nTocilizumab 400 mg\t\t\t✓ (D25)\t\t\t✓ (D49)\t\t\nTofacitinib 5 mg BID\t\t✓\t✓\t\t\t\t\t\nBelimumab 400 mg\t\t\t\t\t\t✓ (D49)\t\t\nAN69ST/PEI\t\t✓\t\t✓\t\t\t\t\nCOVID-19, coronavirus disease; ICU, intensive care unit; MV, mechanical ventilation; ECMO, extracorporeal membrane oxygenation; CRRT, continuous renal replacement therapy; AN69ST/PEI, hemofilter with AN69 and polyethyleneimine; BP, arterial blood pressure; VIS, vasoactive inotropic score; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; LDH, lactate dehydrogenase; BUN, blood urea nitrogen; CK, creatinine kinase; CK-MB, creatinine kinase muscle and brain form; CRP; TG, triglyceride; C-reactive protein; IL, interleukin; TNF, tumor necrotizing factor; IFN, interferon; FiO2, fraction of inhaled oxygen; VV-ECMO, veno-venous extracorporeal membrane oxygenation; BPF, blood flow rates.\n\n✓: usage of this device or medications.\n\nOn day 33, he was found to have an elevation of ferritin level and persistent tachycardia. Low dose norepinephrine (0.02 mcg/kg/min) was added. Ferritin levels increased from 1,761.15 to 2,535.39 ng/mL, and IL-6 levels increased from 1,477.59 to 2,535.39 pg/mL. There was persistent viral shedding from sputum with a viral load of 99.65 copies/mL. For suspected recurrence of CRS, another session of CRRT with an AN69ST/PEA hemofilter was performed on day 34, and the IL-6 level decreased to 707 pg/mL on day 35 and 154 pg/mL on day 38. We collected the CRRT effluent to estimate the removal of IL-6 from either CRRT or hemadsorption. The pre-AN69ST/PEI IL-6 level was 715.85 pg/mL, and the level 24 h later was 541.59 pg/mL. A total of 2,369,936 pg of IL-6 was removed, with 483,600 pg (20.4%) removed through the CRRT effluent and 1,886,336 pg (79.6%) removed by hemadsorptions. With adequate urine output and decreased oxygen demand, CRRT was discontinued on day 40.\n\nHe developed another recurrence of CRS on day 45 with an elevation of IL-6 (1,579 pg/mL) and ferritin (2,690 ng/mL) levels. An additional dose of tocilizumab 400 mg and belimumab (B-cell activating factor inhibitor) was administered. ECMO was terminated on day 49, and he was successfully extubated on day 52 (Figures 2B,C). The urine output was 2,000–2,500 mL/day after extubation. The urinalysis findings of dysmorphic RBC, glycosuria, leukocyturia, and RTC resolved. The follow-up diluted Russell viper venom test for lupus anticoagulant level was negative. The sputum RT-PCR revealed persistently positive results for SARS-CoV-2 until day 52. The patient was discharged without oxygen support on day 70 (Figure 1).\n\nFigure 2 Serial Chest radiographs of the patient. (A) The film showing diffuse alveolar process over bilateral lung field, especially right lower lung field just after extracorporeal membrane oxygenator (ECMO setup). (B) The film revealing consolidation over both lungs when first time we tried to wean from ECMO. (C) The film on the day before removing ECMO, demonstrating fibrotic change as lung filed in (B).\n\nDiscussion\n\nCritically ill COVID-19 patients, especially those with multi-organ failure, such as cardiovascular collapse, AKI, CRS, or thromboembolic events, challenge clinicians with a substantial risk of patient mortality (25–27) Thus, treatment for these patients should target multiple derangements induced by COVID-19, including ventilator support and ECMO for refractory hypoxemia, CRRT for AKI and extracorporeal cytokine removal, and biologic agents for cytokine blockade. We used a lung-protective strategy in mechanical ventilation and a CRRT with an AN69ST/PEA hemofilter for uremic toxin removal, volume management, cytokine, and endotoxin removal. VV-ECMO was initiated for oxygenation support. In addition, immunomodulating agents were prescribed to control CRS. We successfully treated a critically ill COVID-19 patient with predicted high mortality. This report also demonstrates a successful experience for managing severe COVID-19 without effective antiviral agents. We also recommend timely implementation of the cytokine-targeted strategy combining CRRT with an AN69ST/PEI hemofilter and tocilizumab for severe COVID-19 with CRS and multi-organ failure.\n\nCRS in COVID-19 originates from a dysregulated immune response to SARS-CoV-2, which is not new to coronary virus infection (6, 28). Treatment for CRS includes removal of the offending pathogen and limiting the propagation of cytokines, in order to limit organ damage. Effective anti-SARS-CoV-2 therapies are not available at this time (29). Mechanical removal of the offending cytokines was reasonable. Methods for cytokine removal include direct hemoperfusion, conventional CRRT, high-dose CRRT, or CRRT with hemofilters with higher cut-off membranes (5). In patients with severe sepsis, CRRT with an AN69ST/PEA hemofilter might be associated with better outcomes. However, the only randomized control trial failed to balance its intervention group and placebo group and showed no benefit (16). However, CRRT with an AN69ST/PEA hemofilter has been shown to have better cytokine removal properties than conventional CRRT (16). This was also evident in our observation.\n\nIn addition to cytokine removal, we also used tocilizumab to neutralize the deleterious effects of IL-6. Recent publications have suggested that tocilizumab might mitigate CRS, although the studies were limited by non-controlled designs or case reports (30, 31) In their reports, the IL-6 level before tocilizumab treatment was 41 ng/L (interquartile range [IQR]: 10–102 ng/L), and elevated to 1,812 ng/L (IQR: 375–2,600 ng/L). Our case had a much higher pre-treatment level (12,049.07 ng/L); further, concurrent CRRT with an AN69ST/PEA hemofilter, the level rapidly reduced to 3,546.53 ng/L, and the second course of CRRT with an AN69ST/PEA hemofilter further reduced the IL-6 level from 2,535.39 ng/L to 139.39 ng/L. A retrospective study, based on data from 85 patients, demonstrated lower mortality rates. However, no IL-6 data were available in this study (32). We propose that there are synergistic benefits from combined CRRT with AN69ST/PEA hemofilter therapy and tocilizumab therapy.\n\nAnother concern about immunomodulation therapy in the absence of effective antiviral therapy is the potential for prolonged viral infection. In our patient, the viral shedding persisted for over 60 days. There is an urgent, but unmet, need for effective antiviral therapy in patients with severe COVID-19 and renal dysfunction. Remdesivir was not be considered universally to be an effective anti-viral agent for SARS-CoV-2; there were negative clinical trials, although the analytic methods may have led to negative trials (33). Of note, remdesivir is not indicated for patients with renal dysfunction (<30 mL/1.73 m2) (4).\n\nVV-ECMO is a reasonable option for refractory ARDS caused by viral pneumonia. Based on the recent meta-analysis, the 90-day mortality rates decreased in the VV-ECMO arm (relative risk [RR] = 0.73 [95% CI 0.58–0.92]; p = 0.008) (34). But bleeding risk was one major complication for ECMO. The current guideline still use VV-ECMO as salvage therapy for severe ARDS with refractory hypoxemia. Advanced age, morbid obesity, and immunocompromised status are relative contra-indications as stated by ESLO guideline. It is not clear whether ECMO would be beneficial in patients with severe ARDS. But good organ support and meticulous prevention and management are keys to success in our patient (35). AKI is a common complication in patients with severe COVID-19 and is associated with worse outcomes (26). Interestingly, renal complications are not limited to AKI; hematuria, proteinuria, or glycosuria also develop with COVID-19 (9). Evidence has shown that hematuria, proteinuria, and glycosuria develop during the critical illness and subside after renal recovery, similar to that observed in our patient (36). We had limited renal biopsy data to explore the underlying pathogenesis of SARS-CoV-2 infections (37), although data from SARS-CoV may give us hints that renal damage from COVID-19 is diverse (38). The increased hematuria and proteinuria are also associated with adverse outcomes (36).\n\nThe plain radiograph is less sensitive than chest CT, but chest radiography is typically the first-line imaging modality ordered for patients with suspected COVID-19. Compared to typical bacteremic pneumonia, the correlation of chest radiography to oxygen demand is poor. In our patient, more consolidation was detected on chest radiography when less O2 demand, shown in Figure 2. The follow-up chest radiograph revealed sequelae of pulmonary fibrosis. It is not useful to predict severity by image evaluation once before diagnosis or during treatment for COVID-19 (39).\n\nThere were some limitations to this case report. As a report of a single case, it is not possible to generalize the experience to the whole patient group with severe COVID-19. However, we are confident that this report would inspire future clinical trials involving the cytokine-targeted therapy, proposed in this study. Second, the patient was treated in an area where there were few critical cases and thus, cannot be generalized to a medical system overwhelmed by the COVID-19 pandemic (2). However, if further clinical trials prove its efficacy, timely cytokine-targeted therapy for critically ill patients with COVID-19 is likely to improve patient outcomes. Third, we did not use antiviral therapy for this patient. Poor renal reserve precluded the patient from remdesivir therapy (4, 29).\n\nIn summary, we demonstrated in this report that timely combined hemoperfusion with cytokine adsorptive capacity and anti-cytokine therapy may successfully treat COVID-19 patients with devastating CRS. For the rapid progression of severe COVID-19 ARDS, cytokine releasing syndrome, acute kidney injury, and multiple organ failure. We would suggest timely initiation of life support and use of multimodality treatment for blockade of cytokine effects (by tocilizumab) and rapid removal of pro-inflammatory cytokines to limit organ damage. This further highlights the importance of implementing cytokine-targeted therapy in severe COVID-19 guided by precise measurement of disease activity.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nTH, Y-CC, C-HW, S-YC, B-LC, and S-CH performed the data collection. TH, Y-CC, C-HW, Y-CY, S-CK, and AT wrote the manuscript. J-TW, C-JY, and S-CC carried out the project administration. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.649583/full#supplementary-material\n\nClick here for additional data file.\n\nAbbreviations\n\nALT alanine aminotransferase\n\nAKI acute kidney injury\n\nAPACHE II Physiologic Assessment and Chronic Health Evaluation II\n\nAST aspartate aminotransferase\n\nRBC red blood cell\n\nRTC renal tubular cells\n\nCBA cytometric bead array\n\nCOVID-19 coronavirus disease\n\nCRP C-reactive protein\n\nCRRT continuous renal replacement therapy\n\nCRS cytokine release syndrome\n\nGFR glomerular filtration rate\n\nICU intensive care unit\n\nIL interleukin\n\nRCA regional citrate anticoagulation\n\nRT-PCR real-time polymerase chain reaction\n\nSARS-CoV-2 severe acute respiratory syndrome coronavirus 2\n\nSOFA sequential organ failure assessment\n\nVIE Vasoactive-Inotropic Equivalent\n\nVV-ECMO veno-venous extracorporeal membrane oxygenation.\n\nFunding. 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J Am Soc Nephrol. (2013) 24 :877–88. 10.1681/ASN.2012070653 23704286\n15. World Health Organization. Laboratory Testing for Coronavirus Disease (COVID-19) in Suspected Human Cases (2020).\n16. Broman ME Hansson F Vincent JL Bodelsson M . Endotoxin and cytokine reducing properties of the oXiris membrane in patients with septic shock: a randomized crossover double-blind study. PLoS One. (2019) 14 :e0220444. 10.1371/journal.pone.0220444 31369593\n17. Rimmele T Kellum JA . Clinical review: blood purification for sepsis. Crit Care. (2011) 15 :205. 10.1186/cc9411 21371356\n18. Schneider AG Journois D Rimmele T . Complications of regional citrate anticoagulation: accumulation or overload? Crit Care. (2017) 21 :281. 10.1186/s13054-017-1880-1 29151020\n19. Chou NK Chen YS Ko WJ Huang SC Chao A Jan GJ . Application of extracorporeal membrane oxygenation in adult burn patients. Artif Organs. (2001) 25 :622–6. 10.1046/j.1525-1594.2001.025008622.x 11531713\n20. Shu CC Wang JY Wu MF Lai HC Chiang BL Yu CJ . Interleukin 23/interleukin 17 axis activated by Mycobacterium avium complex (MAC) is attenuated in patients with MAC-lung disease. Tuberculosis (Edinb). (2018) 110 :7–14. 10.1016/j.tube.2018.03.001 29779777\n21. Fitzgerald JC Weiss SL Maude SL Barrett DM Lacey SF Melenhorst JJ . Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit Care Med. (2017) 45 :e124–e31. 10.1097/CCM.0000000000002053 27632680\n22. Migita K Izumi Y Jiuchi Y Kozuru H Kawahara C Izumi M . Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid A and interleukin-6 during treatment for rheumatoid arthritis. Clin Exp Immunol. (2014) 175 :208–14. 10.1111/cei.12234 24665995\n23. Yao X Ye F Zhang M Cui C Huang B Niu P . In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis. (2020) 71 :732–9. 10.1093/cid/ciaa237 32150618\n24. Chatzidionysiou K Samoli E Sfikakis PP Tektonidou MG . Effect of belimumab treatment on antiphospholipid antibody levels: post-hoc analysis based on two randomised placebo-controlled trials in systemic lupus erythematosus. Ann Rheum Dis. (2020) 79 :304–7. 10.1136/annrheumdis-2019-216367 31712248\n25. Shi S Qin M Cai Y Liu T Shen B Yang F . Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019. Eur Heart J. (2020) 41 :2070–9. 10.1093/eurheartj/ehaa408 32391877\n26. Yang X Yu Y Xu J Shu H Xia J Liu H . Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. (2020) 8 :475–81. 10.1016/S2213-2600(20)30079-5 32105632\n27. Connors JM Levy JH . COVID-19 and its implications for thrombosis and anticoagulation. Blood. (2020) 135 :2033–40. 10.1182/blood.2020006000 32339221\n28. Channappanavar R Perlman S . Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. (2017) 39 :529–39. 10.1007/s00281-017-0629-x 28466096\n29. Cao B Wang Y Wen D Liu W Wang J Fan G . A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. (2020) 382 :1787–99. 10.1056/NEJMoa2001282 32187464\n30. Radbel J Narayanan N Bhatt PJ . Use of tocilizumab for COVID-19-induced cytokine release syndrome: a cautionary case report. Chest. (2020) 158 :e15–e9. 10.1016/j.chest.2020.04.024 32343968\n31. Toniati P Piva S Cattalini M Garrafa E Regola F Castelli F . Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia, Italy. Autoimmun Rev. (2020) 19 :102568. 10.1016/j.autrev.2020.102568 32376398\n32. Capra R De Rossi N Mattioli F Romanelli G Scarpazza C Sormani MP . Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia. Eur J Intern Med. (2020) 76 :31–5. 10.1016/j.ejim.2020.05.009 32405160\n33. McCaw ZR Tian L Vassy JL Ritchie CS Lee CC Kim DH . How to quantify and interpret treatment effects in comparative clinical studies of COVID-19. Ann Intern Med. (2020) 173 :632–7. 10.7326/M20-4044 32634024\n34. Munshi L Walkey A Goligher E Pham T Uleryk EM Fan E . Venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis. Lancet Respir Med. (2019) 7 :163–72. 10.1016/S2213-2600(18)30452-1 30642776\n35. Shekar K Badulak J Peek G Boeken U Dalton HJ Arora L . Extracorporeal Life Support Organization COVID-19 Interim Guidelines: a consensus document from an international group of interdisciplinary extracorporeal membrane oxygenation providers. ASAIO J. (2020) 66 :707–21. 10.1097/MAT.0000000000001193 32604322\n36. Pei G Zhang Z Peng J Liu L Zhang C Yu C . Renal involvement and early prognosis in patients with COVID-19 pneumonia. J Am Soc Nephrol. (2020) 31 :1157–65. 10.1681/ASN.2020030276 32345702\n37. Su H Yang M Wan C Yi LX Tang F Zhu HY . Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int. (2020) 98 :219–27. 10.1016/j.kint.2020.04.003 32327202\n38. Wu VC Huang JW Hsueh PR Yang YF Tsai HB Kan WC . Renal hypouricemia is an ominous sign in patients with severe acute respiratory syndrome. Am J Kidney Dis. (2005) 45 :88–95. 10.1053/j.ajkd.2004.09.031 15696447\n39. Wong HYF Lam HYS Fong AH Leung ST Chin TW Lo CSY . Frequency and distribution of chest radiographic findings in patients positive for COVID-19. Radiology. (2020) 296 :E72–E8. 10.1148/radiol.2020201160 32216717\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-858X",
"issue": "8()",
"journal": "Frontiers in medicine",
"keywords": "COVID-19; continuous renal replacement therapy; cytokine release syndrome; extracorporeal membrane oxygenation; tocilizumab",
"medline_ta": "Front Med (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101648047",
"other_id": null,
"pages": "649583",
"pmc": null,
"pmid": "34164411",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32187464;32216717;32150618;30642776;32339221;3928249;29779777;32251717;23704286;15653384;31712248;32391877;32345226;27632680;32376398;32345702;32366514;32303591;11531713;21371356;31369593;28466096;32220202;32217556;32405160;32327202;32273593;24665995;32604322;15696447;32379918;29151020;8844239;32634024;32343968;32275812;23268665;32105632",
"title": "Successful Treatment of a Critically Ill COVID-19 Patient Using Continuous Renal Replacement Therapy With Enhanced Cytokine Removal and Tocilizumab: A Case Report.",
"title_normalized": "successful treatment of a critically ill covid 19 patient using continuous renal replacement therapy with enhanced cytokine removal and tocilizumab a case report"
} | [
{
"companynumb": "TW-LUPIN PHARMACEUTICALS INC.-2021-19783",
"fulfillexpeditecriteria": "2",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugad... |
{
"abstract": "BACKGROUND\nIndividuals with deep vein thrombosis (DVT) have an increased risk of pulmonary embolism (PE), death, and long-term thrombotic complications.\n\n\nOBJECTIVE\nTo evaluate the efficacy and safety of bemiparin once daily versus enoxaparin twice daily in the treatment of acute DVT, and to establish therapeutic non-inferiority of bemiparin.\n\n\nMETHODS\nThis multicenter, randomized, open-label, active-controlled phase III clinical trial enrolled patients with acute proximal DVT confirmed by complete compression ultrasound (CCUS). Patients received bemiparin once daily or enoxaparin twice daily subcutaneously for 7 days, in combination with warfarin 5 mg/day. Assessment of thrombotic burden was blinded and used CCUS recordings. The primary efficacy endpoint was the percentage of patients with an improvement in thrombotic burden at day 83 (end of follow-up); the secondary efficacy endpoint was the incidence of symptomatic recurrent DVT and PE. Safety endpoints included treatment-emergent adverse events.\n\n\nRESULTS\nThree-hundred and twelve patients were enrolled (~ 62% male; mean age 55.2 years). At least one DVT risk factor was present in 26.1% and 28.7% of the bemiparin and enoxaparin groups, respectively. The proportion of patients who had an improvement in thrombotic burden was similar for bemiparin (78.2%) and enoxaparin [80.8%; difference - 2.66 (97.5% CI - 12.39; ∞)], as was mean change in thrombus score (- 8.8 and - 8.6, respectively). There were no cases of recurrent DVT, and one case of non-fatal symptomatic PE in each treatment group. No major bleeding was reported, and there was no difference in the incidence of non-major bleeding.\n\n\nCONCLUSIONS\nThe efficacy of bemiparin administered once daily is non-inferior to that of enoxaparin administered twice daily with a similar safety profile. CLINICALTRIALS.\nNCT01880216.",
"affiliations": "Regional Clinical Cardiologic Dispensary, Ryazan State Medical University, State Budgetary Institution of the Ryazan Region, Vysokovoltnya, 9, Ryazan, 390026, Russian Federation. suchkov_med@mail.ru.;Laboratorios Farmacéuticos ROVI S.A., Madrid, Spain.;Städtisches Klinikum Dresden-Friedrichstadt, Dresden, Germany.;Berlin-Chemie AG, Menarini Group, Berlin, Germany.;Berlin-Chemie AG, Menarini Group, Berlin, Germany.",
"authors": "Suchkov|Igor A|IA|http://orcid.org/0000-0002-1292-5452;Martinez-Gonzalez|Javier|J|;Schellong|Sebastian M|SM|;Garbade|Toni|T|;Falciani|Michela|M|;|||",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin; D006495:Heparin, Low-Molecular-Weight; D014859:Warfarin; C411345:bemiparin",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40261-017-0600-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1173-2563",
"issue": "38(2)",
"journal": "Clinical drug investigation",
"keywords": null,
"medline_ta": "Clin Drug Investig",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D000925:Anticoagulants; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D017984:Enoxaparin; D005260:Female; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D020246:Venous Thrombosis; D014859:Warfarin",
"nlm_unique_id": "9504817",
"other_id": null,
"pages": "181-189",
"pmc": null,
"pmid": "29214507",
"pubdate": "2018-02",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "10823256;16700847;11228276;24913030;18570617;12574800;15333034;15866245;11991239;16911674;21375522;11177331;20450295;26780736;27688212;24657810;27766049;24970783;16643427;323387;17576867;12484710;23553743;12669122;16445305;10647756;24154729",
"title": "Comparison of Once-Daily Bemiparin with Twice-Daily Enoxaparin for Acute Deep Vein Thrombosis: A Multicenter, Open-Label, Randomized Controlled Trial.",
"title_normalized": "comparison of once daily bemiparin with twice daily enoxaparin for acute deep vein thrombosis a multicenter open label randomized controlled trial"
} | [
{
"companynumb": "RU-CIPLA LTD.-2017RU29845",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENOXAPARIN"
},
"drugadditional": "3",
... |
{
"abstract": "A male patient in his 80s, diagnosed with rectal cancer, underwent transverse colon resection(pT3, pN0, cM0, and pStage Ⅱa, RAS wild-type, BRAF-mutant). However, 19 months later, intraperitoneal metastasis was detected and the patient received 8 courses of mFOLFOX6 plus bevacizumab. Following the observation of an allergic reaction that was attributable to oxaliplatin, the regimen was changed to a total of 7 courses of sLV5FU2 plus bevacizumab. Subsequently, a marked decrease was observed in intraperitoneal metastasis. The patient completed sLV5FU2 plus bevacizumab chemotherapy. At 1 year after the marked decrease, the metastatic recurrence was not exacerbated.",
"affiliations": "Dept. of Surgery, Koyama Memorial Hospital.",
"authors": "Takahashi|Shinji|S|;Hanaka|Junichi|J|;Takahashi|Misaki|M|;Goya|Tomoyuki|T|",
"chemical_list": "D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(7)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D044684:Colon, Transverse; D003110:Colonic Neoplasms; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D009944:Organoplatinum Compounds; D010534:Peritoneal Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1125-1127",
"pmc": null,
"pmid": "32668867",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transverse Colon Cancer with Peritoneal Metastasis Successfully Treated with mFOLFOX6 plus Bevacizumab-A Case Report.",
"title_normalized": "transverse colon cancer with peritoneal metastasis successfully treated with mfolfox6 plus bevacizumab a case report"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-253803",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"dr... |
{
"abstract": "Pain crisis in metastatic disease can be a therapeutic dilemma when differing mechanisms contribute to severe hyperalgesia and neuropathic pain. We discuss clinical presentation and management of excruciating pain from severe lower limb venous outflow obstruction in an opioid tolerant, terminally ill patient with locally invasive and metastatic adenocarcinoma of the cervix. This case illustrates how pain crises at end of life can be successfully managed by using a rational, complementary, multimodal approach. Key points include possible mechanisms of pain from venous outflow obstruction, benefit of hyperbaric subarachnoid bupivacaine, opioid rotation to methadone, and use of ketamine by mouth.",
"affiliations": "Department of Nursing, University of Wisconsin Medical School, Madison, 53792, USA. db.gordon@hosp.wisc.edu",
"authors": "Gordon|Debra B|DB|;Sehgal|Nalini|N|;Schroeder|Mark E|ME|;Cleary|James|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1054/jpai.2002.122948",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-5900",
"issue": "3(3)",
"journal": "The journal of pain",
"keywords": null,
"medline_ta": "J Pain",
"mesh_terms": null,
"nlm_unique_id": "100898657",
"other_id": null,
"pages": "244-8",
"pmc": null,
"pmid": "14622779",
"pubdate": "2002-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of pain crisis at end of life from severe lower extremity venous outflow obstruction with hyperalgesia and allodynia.",
"title_normalized": "treatment of pain crisis at end of life from severe lower extremity venous outflow obstruction with hyperalgesia and allodynia"
} | [
{
"companynumb": "US-SPECGX-T202002183",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LORAZEPAM"
},
"drugadditional": "3",
"dr... |
{
"abstract": "OBJECTIVE\nTo describe spontaneously reported cases of erectile dysfunction (ED) in association with angiotensin II type I blockers (ARB) and other antihypertensive drugs.\n\n\nMETHODS\nAll spontaneously reported cases of ED submitted to the Swedish Medical Products Agency (MPA) between 1990 and 2006, where at least one antihypertensive drug was the suspected agent, were scrutinized. Patient demographics, drug treatment and adverse reactions were recorded. Using the Bayesian Confidence Propagation Neural Network (BCPNN) method, the information component (IC) was calculated.\n\n\nRESULTS\nAmong a total of 225 reports of ED, 59 involved antihypertensive drugs including ARB (9 cases) as suspected agents. A positive IC value was found indicating that ED was reported more often in association with antihypertensive drugs classes, except for angiotensin-converting enzyme inhibitors, compared with all other drugs in the database. Positive dechallenge was reported in 43 cases (72%).\n\n\nCONCLUSIONS\nAll classes of major antihypertensive drugs including ARB were implicated as suspected agents in cases of ED. Few risk factors were identified. The relatively high reporting of ED in association with ARB is in contrast with previous studies, suggesting that ARB have neither a positive nor any effect on ED. This discrepancy suggests that further studies are warrnted on this potential adverse reaction to ARB.",
"affiliations": "Regional Pharmacovigilance Unit, Clinical Pharmacology, Lund University Hospital, Lund, Sweden;",
"authors": "Ekman|Elisabet|E|;Hägg|Staffan|S|;Sundström|Anders|A|;Werkström|Viktoria|V|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/dhps.s8432",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1179-1365",
"issue": "2()",
"journal": "Drug, healthcare and patient safety",
"keywords": "adverse drug reaction; angiotensin II type 1 receptor blockers; antihypertensive drugs; erectile dysfunction; spontaneous reporting",
"medline_ta": "Drug Healthc Patient Saf",
"mesh_terms": null,
"nlm_unique_id": "101544775",
"other_id": null,
"pages": "21-5",
"pmc": null,
"pmid": "21701615",
"pubdate": "2010",
"publication_types": "D016428:Journal Article",
"references": "17091248;18636418;11164180;15073883;9776440;11347725;12874608;17183345;16444456;9696956;18825377;9836664;17151696;11998548;17323599;11206674;16432091;17233791;12389072;12971810;11370797;15819590;12853773",
"title": "Antihypertensive drugs and erectile dysfunction as seen in spontaneous reports, with focus on angiotensin II type 1 receptor blockers.",
"title_normalized": "antihypertensive drugs and erectile dysfunction as seen in spontaneous reports with focus on angiotensin ii type 1 receptor blockers"
} | [
{
"companynumb": "SE-MYLANLABS-2021M1008721",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FELODIPINE"
},
"drugadditional": "1",
... |
{
"abstract": "To perform a retrospective review of the clinical characteristics, microbiological data, and clinical outcomes in patients with granulomatous mastitis (GM) who were treated at our institution with a unique strategy of prolonged antibiotic therapy as the primary treatment modality.\nA retrospective case series was performed on patients (n = 42) with GM seen at the breast specialty clinic of our institution between the years 2004 and 2014. Patients were primarily treated with lipophilic antibiotics, and steroids and surgery were reserved for refractory cases.\nBacteria were identified in 34 samples from 22/42 patients (52.3%). Diphtheroids (presumptive Corynebacterium spp.) were most commonly identified, followed by Corynebacterium spp. and Propionibacterium acnes (now Cutibacterium acnes). Antibiotics were our preferred first-line medical therapy and were used in 33/36 (91.7%) patients. The mean duration of antibiotic therapy was 7.0±4.5 months. Clarithromycin was our antibiotic of choice and was the initial antibiotic used in 15 of the 33 patients (45.5%) treated with antibiotics. Eleven patients required adjunctive therapy with prednisone. The mean duration of steroid therapy was 4.3±2.5 months. Surgery for therapeutic purposes included incision and drainage in seven patients, fine needle aspiration in eight patients, and excision of the fistulous tract in one patient. No patients had large-volume excisions. The average time from the first breast clinic visit to clinical resolution was 8.0±4.6 months.\nGM may be the result of a bacterial process that induces a unique form of inflammatory response. Clinicians should consider special requests to microbiology laboratories to attempt to isolate Corynebacterium spp. in the evaluation of samples sent to the laboratory for analysis. An extended course of a lipophilic antibiotic is a largely unexplored but potentially effective treatment option with low associated morbidity. More research is needed in this area.",
"affiliations": "Department of Medicine, Division of General Internal Medicine, University of Washington, Washington, USA.;Department of Medicine, Division of General Internal Medicine, University of Washington, Washington, USA.;Department of Laboratory Medicine and Pathology, Division of Clinical Microbiology, University of Washington, Washington, USA.;Department of Medicine, Division of General Internal Medicine, Breast Care Program, University of Washington, Washington, USA.",
"authors": "Williams|Meagan S|MS|https://orcid.org/0000-0003-0183-6849;McClintock|Adelaide H|AH|https://orcid.org/0000-0002-6108-5648;Bourassa|Lori|L|https://orcid.org/0000-0001-8903-5274;Laya|Mary B|MB|https://orcid.org/0000-0002-0616-9355",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.4274/ejbh.galenos.2021.2021-3-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "17(3)",
"journal": "European journal of breast health",
"keywords": "Granulomatous mastitis; benign breast disease; breast disease; idiopathic granulomatous mastitis",
"medline_ta": "Eur J Breast Health",
"mesh_terms": null,
"nlm_unique_id": "101709357",
"other_id": null,
"pages": "239-246",
"pmc": null,
"pmid": "34263151",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": "17879688;26179543;25746911;21365412;15730456;30445695;18430482;30479764;25008030;28852671;31273861;22250621;26644764;16297091;18929686;21623925;23663101;15544496;21207047;28739122;31400951;12439810;25759614;24944554;25751209;29381437;24673796;26135858;20013067;15239790;4674439;12745457;27458268;28740959;24090799;26136183",
"title": "Treatment of Granulomatous Mastitis: Is There a Role for Antibiotics?",
"title_normalized": "treatment of granulomatous mastitis is there a role for antibiotics"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-313534",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLARITHROMYCIN"
},
"... |
{
"abstract": "Radiation recall dermatitis (RRD) is an uncommon dermatologic reaction provoked notably by chemotherapy in an area of skin irradiated weeks to years prior. We report a case of RRD with nivolumab in a woman with breast cancer. The patient was diagnosed with invasive ductal carcinoma of the left breast with an isolated spinal metastasis approached in an oligometastatic fashion with neoadjuvant chemotherapy, modified radical mastectomy and adjuvant radiotherapy. Unfortunately, after progression of bony metastases treated with radiotherapy, the patient received nivolumab and subsequently developed a rash corresponding to the adjuvant radiation field. This case highlights the unpredictable nature and characteristic rash of RRD. It is an important differential diagnosis for multidisciplinary teams who also see chemotherapy-induced dermatitis and immune-related adverse events.",
"affiliations": "Department of Surgery, Mount Carmel Health System, Columbus, OH 43081, USA.;Department of Surgery, Mount Carmel Health System, Columbus, OH 43081, USA.;Department of Surgery, Mount Carmel Health System, Columbus, OH 43081, USA.;Department of Hematology, Oncology Zangmeister Cancer Center, Columbus, OH 43219, USA.;Department of Radiation Oncology, Mount Carmel Health System, Columbus, OH 43081, USA.;Department of Radiation Oncology, Mount Carmel Health System, Columbus, OH 43081, USA.",
"authors": "Billena|Cole|C|;Padia|Shilpa|S|;O'Brien|Bridget|B|;Knoble|Jeanna|J|;Gokhale|Abhay|A|;Rajagopalan|Malolan|M|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.2217/imt-2019-0020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1750-743X",
"issue": "12(2)",
"journal": "Immunotherapy",
"keywords": "adverse effects; dermatitis; immunotherapy; nivolumab; radiation recall; radiation recall dermatitis",
"medline_ta": "Immunotherapy",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D005260:Female; D006801:Humans; D000077594:Nivolumab; D011855:Radiodermatitis; D018714:Radiotherapy, Adjuvant",
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"title": "Radiation recall dermatitis after treatment of stage IV breast cancer with nivolumab: a case report.",
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"abstract": "BACKGROUND\nVemurafenib, an inhibitor of mutated B-rapidly accelerated fibrosarcoma, is frequently used in the treatment of melanoma and Erdheim-Chester disease (ECD) patients. Inflammatory adverse effects have been increasingly reported after vemurafenib treatment.\nWe report 6 cases of vemurafenib-associated vasculitis, of whom a personal case of a 75-year-old man with history of ECD who developed purpura and rapidly progressive pauci-immune glomerulonephritis during treatment with vemurafenib.\n\n\nMETHODS\nIn the 5 others cases from the literature, all patients presented skin vasculitis, and with joint involvement in 60% of them. Vemurafenib treatment was stopped (n = 3), continued at reduced doses (n = 1), or continued at the same dose (n = 2).\n\n\nRESULTS\nThree patients (50%) received corticosteroids combined with cyclophosphamide (n = 1), and all achieved remission of vasculitis. One patient experienced vasculitis relapse after vemurafenib therapy was restarted.\n\n\nCONCLUSIONS\nSystemic vasculitis is a rare vemurafenib-associated adverse event that may be life-threatening.",
"affiliations": "APHP, Service de Médecine Interne et Immunologie clinique, Groupe Hospitalier Pitié-Salpêtrière DHU Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie APHP, Service de Dermatologie, Groupe Hospitalier Pitié-Salpêtrière APHP, Service de Néphrologie et Dialyse, Hôpital Tenon APHP, Service d'Anatomopathologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.",
"authors": "Mirouse|Adrien|A|;Savey|Léa|L|;Domont|Fanny|F|;Comarmond|Cloé|C|;Barete|Stéphane|S|;Plaisier|Emmanuelle|E|;Rouvier|Philippe|P|;Cacoub|Patrice|P|;Saadoun|David|D|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2786133210.1097/MD.0000000000004988049883600Research ArticleClinical Case ReportSystemic vasculitis associated with vemurafenib treatment Case report and literature reviewMirouse Adrien MDabSavey Léa MDabDomont Fanny MDabComarmond Cloé MD, PhDabBarete Stéphane MD, PhDcPlaisier Emmanuelle MD, PhDbdRouvier Philippe MD, PhDeCacoub Patrice MD, PhDabSaadoun David MD, PhDab∗Zeron. Pilar Brito a APHP, Service de Médecine Interne et Immunologie clinique, Groupe Hospitalier Pitié-Salpêtrièreb DHU Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curiec APHP, Service de Dermatologie, Groupe Hospitalier Pitié-Salpêtrièred APHP, Service de Néphrologie et Dialyse, Hôpital Tenone APHP, Service d’Anatomopathologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.∗ Correspondence: Dr David Saadoun, Service de Médecine Interne et Immunologie clinique Groupe Hospitalier Pitié-Salpêtrière, 84, boulevard de l’Hôpital, 75013 Paris, France (e-mail: david.saadoun@psl.aphp.fr).11 2016 18 11 2016 95 46 e498813 5 2016 2 9 2016 7 9 2016 Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nVemurafenib, an inhibitor of mutated B-rapidly accelerated fibrosarcoma, is frequently used in the treatment of melanoma and Erdheim–Chester disease (ECD) patients. Inflammatory adverse effects have been increasingly reported after vemurafenib treatment.\n\nPatient concerns and diagnose:\nWe report 6 cases of vemurafenib-associated vasculitis, of whom a personal case of a 75-year-old man with history of ECD who developed purpura and rapidly progressive pauci-immune glomerulonephritis during treatment with vemurafenib.\n\nIntervention:\nIn the 5 others cases from the literature, all patients presented skin vasculitis, and with joint involvement in 60% of them. Vemurafenib treatment was stopped (n = 3), continued at reduced doses (n = 1), or continued at the same dose (n = 2).\n\nOutcomes:\nThree patients (50%) received corticosteroids combined with cyclophosphamide (n = 1), and all achieved remission of vasculitis. One patient experienced vasculitis relapse after vemurafenib therapy was restarted.\n\nLessons:\nSystemic vasculitis is a rare vemurafenib-associated adverse event that may be life-threatening.\n\nKeywords\ncase reporthistiocytosisimmunotherapymelanomavasculitisvemurafenibOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nVemurafenib (PLX4032) is an inhibitor of mutated B-rapidly accelerated fibrosarcoma (BRAF), especially BRAFV600E.[1] Metastatic melanoma patients treated with vemurafenib showed a response rate of 48% and improved survival.[2] Erdheim–Chester disease (ECD) is a rare non-Langherans cell hystiocytosis where BRAFV600E mutation is frequently found.[3,4] ECD patients with BRAFV600E presented good response when treated with vemurafenib.[5,6]\n\nSerious adverse effects (SAEs) were reported in 8% of patients treated with vemurafenib for metastatic melanoma.[2] SAEs were also reported in 94% of ECD or Langherans cell histocytiosis patients treated with vemurafenib.[6] Main side effects included skin (rash, squamous cell carcinoma, hyperkeratosis, alopecia) and gut involvement (nausea, diarrhea), cytopenia, and arthralgia.[2] More recently, inflammatory adverse effects like panniculitis have been reported.[7] Very few cases of vemurafenib-associated vasculitis have been reported.[8–10] Vasculitis may be life-threatening depending on which organ is involved.\n\nHerein, we report a patient with ECD with vemurafenib-associated severe systemic vasculitis. We reviewed the literature and analyzed 5 additional cases of vemurafenib-associated vasculitis.\n\n2 Methods\nThe patient reported was followed in Internal Medicine and Clinical Immunology Department at Pitié-Salpêtrière University Hospital, Paris, France. Demographic, medical history, laboratory, imaging, histology, treatment, and follow-up data were extracted from medical records. Patient gave his informed consent.\n\n2.1 Literature review\nMEDLINE (National Library of Medicine, Bethesda, MD) search was performed until April 2016 using [vemurafenib] or [BRAF inhibitor] and [vasculitis]. Five cases were identified and analyzed.\n\n2.2 Patient\nWe report a 75-year-old man with a 7-year history of ECD admitted in our department. He had a past medical history with arterial hypertension, type 2 diabetes, ST-elevation myocardial infarction (STEMI) without chronic heart failure, and nonalcoholic steatohepatitis. ECD was diagnosed in 2009 on a biopsy sample of perirenal fibrosis, showing foamy CD68+ CD1a− histiocytes. Immunohistochemistry analysis detected the presence of BRAFV600E mutation. Thoracoabdominal computed tomography (CT) scan showed a right pleural effusion, mesenteric panniculitis, right upper femoral metaphysis osteosclerosis, and perirenal fibrosis with hairy kidney sign. Brain magnetic resonance imaging (MRI) showed a left retro-orbital mass. Pegylated interferon α (PEG-IFN) treatment was started in October 2009. Because of disease progression, PEG-IFN was stopped in September 2010 and a recombinant human interleukin (IL)-1 receptor antagonist treatment was initiated. This treatment permitted disease control, but was stopped in September 2013 because of skin adverse effects. Our patient was treated with infliximab from September 2013 to January 2014. This treatment was stopped due to disease progression. A targeted therapy with BRAFV600E inhibitor (vemurafenib) was initiated in January 2014 at 480 mg/d. In September 2014, the dose was reduced to 240 mg/d because of cholestasis. In February 2015, the treatment dose was resumed to 480 mg. This treatment permitted disease control. In February 2016, our patient was admitted to our department for annual disease re-evaluation. Clinical evaluation showed leg edema, infiltrated purpura on the legs, and bilateral lung crackles. Biological explorations found acute kidney injury with serum creatinine level of 225 μmol/l and C-reactive protein (CRP) was elevated at 16 mg/l. Kidney ultrasound showed no renal dilatation. Urine sediment analysis showed microscopic hematuria (47.104 red blood cells/ml). Urine biological explorations found a glomerular proteinuria, with urine protein-to-creatinine ratio of 0.25 g/mmol and albumin-to-creatinine ratio of 0.2 g/mmol. Immune explorations found no complement consumption, no antineutrophil cytoplasmic antibody (ANCA), no cryoglobulins and rheumatoid factor, and no anti-glomerular basement membrane antibody (anti-GBM). Antinuclear antibodies (ANAs) were positive at a 1:320 dilution, with no anti-DNA (ELISA) and no anti-extractable nuclear antigen (ENA). Kidney function worsened in few days to a serum creatinine level of 410 μmol/l. Kidney biopsy sample analysis showed 13 glomeruli with normal permeability (Fig. 1). One glomerulus presented a crescent, compatible with extracapillary proliferative glomerulonephritis. Immufluorescent analysis showed pauci-immune glomerulonephritis (ie, no immunoglobulin deposit, no C1q deposit, no light chains deposit, and some C3 deposits). Thoracoabdominal CT scan and brain MRI findings showed no signs of ECD evolution. We retained the diagnosis of vemurafenib-associated vasculitis with skin and kidney involvement. Vemurafenib was stopped. Our patient was treated with high-dose glucocorticosteroids (methyprednisolone pulse of 1 g/d during 3 days) and cyclophosphamide (0.5 g/m2), monthly during 2 months. Glucocorticosteroids were pursued with prednisone orally at 1 mg/kg/d. The outcome was favorable with quick renal function improvement (Fig. 1).\n\nFigure 1 Vemurafenib-associated pauci-immune glomerulonephritis. A, Kidney biopsy reveals extracapillary crescent (Trichrome stain; original magnification: ×400). B, Course of kidney function (ie, serum creatinine level). We observed a dramatic improvement within days after corticosteroid therapy combined with cyclophosphamide. CSB = corticosteroids bolus, CYC = cyclophosphamide.\n\n2.3 Literature review\nTo our knowledge, there are only 5 additional reported cases of vemurafenib-associated vasculitis (Table 1).[8–11] Apart from our patient, all 5 other patients received vemurafenib as treatment for metastatic melanoma. Median age was 47 (29.8; 58.5) years and sex ratio was 1. Vasculitis appeared 15.5 (9.5; 232.8) days after treatment initiation. Three patients (60%) described arthralgia associated with skin vasculitis. All patients presented biological inflammatory syndrome with elevated CRP. Elevated ANA titers were detected in 3 cases. Vasculitis was biopsy-proven in every case. Vemurafenib treatment was stopped in 3 cases, continued with reduced doses in 1 case, and continued at the same dose in 2 cases (Table 2). Three patients (60%) received steroids as vasculitis treatment. In 1 case, vasculitis relapsed after vemurafenib therapy was restarted. No progressive neoplasm was reported after vasculitis treatment.\n\nTable 1 Demographics, clinical and biological presentations, and histopathology of patients with vemurafenib-associated vasculitis.\n\nTable 2 Vasculitis management and outcomes.\n\n3 Discussion\nSince BRAF inhibitors have entered the field of neoplasm therapy, inflammatory adverse effects have been increasingly reported.[9–15] These adverse effects were mainly skin reactions like panniculitis. Skin vasculitis has already been described in 5 patients treated with vemurafenib.[8–11] Severe systemic vasculitis, including rapidly progressive kidney glomerulonephritis, has never been described to our knowledge.\n\nOther vasculitis-reported cases involved mainly skin and joints. In these cases, vasculitis appeared early after vemurafenib treatment initiation, within the first month. In 1 case, vasculitis appeared 11 weeks after treatment initiation.[8] In our case, serum creatinine level began to increase 20 months after vemurafenib treatment initiation. A delay of more than 1 year of BRAF inhibitor treatment has already been described in a patient who developed panniculitis.[8]\n\nAcute kidney injury has already been described during vemurafenib treatment.[16] However, the diagnosis was an acute immunoallergic interstitial nephritis and there was no evidence of vasculitis.\n\nVemurafenib-associated vasculitis seems to be very rare. Thus, there is no consensus for vasculitis management. For some reported patients, vasculitis regressed only with vemurafenib dose reduction. For other patients, a treatment with steroids has been necessary. In patients treated with vemurafenib for metastatic melanoma, vemurafenib could be continued or restarted after vasculitis management. This is very important for neoplasm control and patient survival. However, restarting vemurafenib treatment may induce vasculitis relapse.[8] In our case, vemurafenib has been stopped because kidney vasculitis might induce kidney failure and require extrarenal replacement therapy. For our patient, vemurafenib benefit might not be superior to the risk of kidney failure.\n\nThe pathogenesis of BRAF inhibitor associated vasculitis is not clear. It has been shown that RAF inhibitors inhibit extracellular signal-regulated kinase (ERK) signaling in cells with mutant BRAF, but unexpectedly enhance signaling in cells with wild-type BRAF.[17] It explains why incidence of some neoplasms, like cutaneous squamous cell carcinomas, is more important in vemurafenib-treated patients. Furthermore, it has been shown that stimulation of neutrophils with lipopolysaccharide (LPS) resulted in the activation of ERK and p38 mitogen-activated protein kinase (MAPK).[18] MAPK pathway activation was associated with neutrophil migration and may explain inflammatory reactions.\n\nIt could be hypothesized that BRAFV600E inhibitors like vemurafenib could paradoxically activate BRAF wild-type and RAS (RAt Sarcoma) pathway in other cells and induce vasculitis or other inflammatory reactions.\n\nIn conclusion, inflammatory disorders associated with BRAF inhibitors are increasingly reported. Vasculitis is a rare vemurafenib-induced adverse event that may be life-threatening. Kidney involvement might lead to kidney failure. Continuing or restarting vemurafenib therapy may induce vasculitis relapse.\n\nAbbreviations: ANAs = antinuclear antibodies, ANCA = antineutrophil cytoplasmic antibody, anti-ENA = antiextractable nuclear antigen, anti-GBM = anti-glomerular basement membrane antibody, CRP = C-reactive protein, CT = computed tomography, ECD = Erdheim–Chester disease, ERK = extracellular signal-regulated kinase, LPS = lipopolysaccharide, MAPK = p38 mitogen-activated protein kinase, MRI = magnetic resonance imaging, PEG-IFN = pegylated interferon α, SAE = serious adverse effect, STEMI = ST-elevation myocardial infarction.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1 Sala E Mologni L Truffa S \nBRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells . Mol Cancer Res MCR \n2008 ; 6 :751 –759 .18458053 \n2 Chapman PB Hauschild A Robert C \nImproved survival with vemurafenib in melanoma with BRAF V600E mutation . N Engl J Med \n2011 ; 364 :2507 –2516 .21639808 \n3 Diamond EL Dagna L Hyman DM \nConsensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease . Blood \n2014 ; 124 :483 –492 .24850756 \n4 Haroche J Charlotte F Arnaud L \nHigh prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses . Blood \n2012 ; 120 :2700 –2703 .22879539 \n5 Haroche J Cohen-Aubart F Emile J-F \nReproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAF(V600E)-mutated Erdheim-Chester disease . J Clin Oncol \n2015 ; 33 :411 –418 .25422482 \n6 Hyman DM Puzanov I Subbiah V \nVemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations . N Engl J Med \n2015 ; 373 :726 –736 .26287849 \n7 Macdonald JB Macdonald B Golitz LE \nCutaneous adverse effects of targeted therapies: part II: Inhibitors of intracellular molecular signaling pathways . J Am Acad Dermatol \n2015 ; 72 :221 –236 .[quiz 237–238] .25592339 \n8 Mössner R Zimmer L Berking C \nErythema nodosum-like lesions during BRAF inhibitor therapy: report on 16 new cases and review of the literature . J Eur Acad Dermatol Venereol \n2015 ; 29 :1797 –1806 .25752368 \n9 Zimmer L Livingstone E Hillen U \nPanniculitis with arthralgia in patients with melanoma treated with selective BRAF inhibitors and its management . Arch Dermatol \n2012 ; 148 :357 –361 .22250191 \n10 Novoa RA Honda K Koon HB \nVasculitis and panniculitis associated with vemurafenib . J Am Acad Dermatol \n2012 ; 67 :e271 –e272 .23158633 \n11 Chaminade A Conte H Jouary T \nBRAF inhibitors-induced panniculitis: a cutaneous side effect mimicking subcutaneous melanoma metastasis . J Eur Acad Dermatol Venereol \n2015 ; 29 :392 –393 .24533578 \n12 Choy B Chou S Anforth R \nPanniculitis in patients treated with BRAF inhibitors: a case series . Am J Dermatopathol \n2014 ; 36 :493 –497 .24879511 \n13 Maldonado-Seral C Berros-Fombella JP Vivanco-Allende B \nVemurafenib-associated neutrophilic panniculitis: an emergent adverse effect of variable severity . Dermatol Online J \n2013 ; 19 :16 .\n14 Kim GH Levy A Compoginis G \nNeutrophilic panniculitis developing after treatment of metastatic melanoma with vemurafenib . J Cutan Pathol \n2013 ; 40 :667 –669 .23581649 \n15 Monfort J-B Pagès C Schneider P \nVemurafenib-induced neutrophilic panniculitis . Melanoma Res \n2012 ; 22 :399 –401 .22828248 \n16 Regnier-Rosencher E Lazareth H Gressier L \nAcute kidney injury in patients with severe rash on vemurafenib treatment for metastatic melanomas . Br J Dermatol \n2013 ; 169 :934 –938 .23909652 \n17 Poulikakos PI Zhang C Bollag G \nRAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF . Nature \n2010 ; 464 :427 –430 .20179705 \n18 Aomatsu K Kato T Fujita H \nToll-like receptor agonists stimulate human neutrophil migration via activation of mitogen-activated protein kinases . Immunology \n2008 ; 123 :171 –180 .17662043\n\n",
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"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D031249:Erdheim-Chester Disease; D006801:Humans; D007211:Indoles; D008297:Male; D013449:Sulfonamides; D056647:Systemic Vasculitis; D000077484:Vemurafenib",
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"title": "Systemic vasculitis associated with vemurafenib treatment: Case report and literature review.",
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"abstract": "BACKGROUND\nDevelopment of de novo malignancy has become a major cause of late mortality in solid organ transplant recipients. Surgery is currently the most important treatment of choice for transplant patients with resectable CRC. However, conventional open surgery represents a great risk to these high-risk patients. They seem to benefit more from laparoscopic surgery, based on the favorable oncological outcome and remarkable short-term advantages of this approach.\nIn this study, we have reported a case of a 50-year-old man who had underwent kidney transplantation for 4 years. He presented with recurrent hematochezia and frequent loose stools for 1 year, and consulted a doctor for recent progressive general malaise and weight loss.\nColonoscopy revealed a near-circumferential mass at the middle rectum about 8 cm from anal verge. Further biopsy confirmed a diagnosis of adenocarcinoma. Following computed tomography demonstrated peripheral lymph node metastasis, but no signs of distant metastasis.\n\n\nMETHODS\nThe patient underwent a laparoscopic assisted low anterior resection with total mesorectal excision for rectal cancer. Concomitantly, a loop transverse colostomy was performed to prevent anastomotic leakage. The surgery was completed within 120 min with a blood loss of 100 mL, and immunosuppressive therapy was not stopped perioperatively. Considering the tumor stage of pT3N1M0, the patient also received adjuvant chemotherapy with a regimen of FOLFOX for 8 cycles.\n\n\nRESULTS\nAnastomotic bleeding occurred in this patient about 4 h after surgery, and a control of hemorrhage per anus was performed timely. The following postoperative course was uneventful without any complications, and graft function stayed well. After 4 months of follow-up period, the patient was in a good condition. No evidences of local recurrence and distant metastasis were found.\n\n\nCONCLUSIONS\nWe have presented a case of successful laparoscopic resection for advanced rectal cancer in a kidney transplant recipient. We believe laparoscopic surgery for CRC in transplant recipients is technically feasible and oncologically safe, which could be a preferred option of surgical procedure in the near future.",
"affiliations": "Department of Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.",
"authors": "Xia|Zenan|Z|;Chen|Weijie|W|;Yao|Ru|R|;Lin|Guole|G|;Qiu|Huizhong|H|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2785886110.1097/MD.0000000000005198051984500Research ArticleClinical Case ReportLaparoscopic assisted low anterior resection for advanced rectal cancer in a kidney transplant recipient A case reportXia Zenan MDaChen Weijie MDaYao Ru MDaLin Guole MDb∗Qiu Huizhong PhDbMelloul. Emmanuel a Department of Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciencesb Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.∗ Correspondence: Guole Lin, MD, Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan 1, Beijing 100730, China (e-mail: guolelin2002@163.com).11 2016 04 11 2016 95 44 e519831 7 2016 16 9 2016 2 10 2016 Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction:\nDevelopment of de novo malignancy has become a major cause of late mortality in solid organ transplant recipients. Surgery is currently the most important treatment of choice for transplant patients with resectable CRC. However, conventional open surgery represents a great risk to these high-risk patients. They seem to benefit more from laparoscopic surgery, based on the favorable oncological outcome and remarkable short-term advantages of this approach.\n\nPatient concerns:\nIn this study, we have reported a case of a 50-year-old man who had underwent kidney transplantation for 4 years. He presented with recurrent hematochezia and frequent loose stools for 1 year, and consulted a doctor for recent progressive general malaise and weight loss.\n\nDiagnoses:\nColonoscopy revealed a near-circumferential mass at the middle rectum about 8 cm from anal verge. Further biopsy confirmed a diagnosis of adenocarcinoma. Following computed tomography demonstrated peripheral lymph node metastasis, but no signs of distant metastasis.\n\nInterventions:\nThe patient underwent a laparoscopic assisted low anterior resection with total mesorectal excision for rectal cancer. Concomitantly, a loop transverse colostomy was performed to prevent anastomotic leakage. The surgery was completed within 120 min with a blood loss of 100 mL, and immunosuppressive therapy was not stopped perioperatively. Considering the tumor stage of pT3N1M0, the patient also received adjuvant chemotherapy with a regimen of FOLFOX for 8 cycles.\n\nOutcomes:\nAnastomotic bleeding occurred in this patient about 4 h after surgery, and a control of hemorrhage per anus was performed timely. The following postoperative course was uneventful without any complications, and graft function stayed well. After 4 months of follow-up period, the patient was in a good condition. No evidences of local recurrence and distant metastasis were found.\n\nConclusion:\nWe have presented a case of successful laparoscopic resection for advanced rectal cancer in a kidney transplant recipient. We believe laparoscopic surgery for CRC in transplant recipients is technically feasible and oncologically safe, which could be a preferred option of surgical procedure in the near future.\n\nKeywords\ncase reportkidney transplantationlaparoscopic surgerylow anterior resectionrectal cancerOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nColorectal cancer (CRC) is one of the most common malignancies and the leading causes of cancer-related death worldwide.[1] Surgery is the cornerstone of curative treatment for patients with resectable CRC. A number of earlier randomized trials and meta-analyses confirmed that laparoscopic surgery for CRC was not inferior to open surgery in terms of survival and recurrence rates, but provides significant short-term advantages, including a shorter hospital stay, reduced analgesic use, faster recovery of intestinal function, and earlier return to activities of daily life.[2,3] Therefore, laparoscopic-assisted surgery has been widely accepted as an alternative to conventional open surgery for CRC.[4]\n\nCurrently, due to the development of minimally invasive techniques, the indications for laparoscopic surgery have gradually expanded to high-risk patients with CRC.[5] Recipients of solid organ transplantation not only have associated problems of chronic immunosuppression and allograft dysfunction, but also suffer from numerous comorbidities, as the primary etiology of their organ failure.[6,7] Conventional surgical treatment for CRC represents a great risk to these high-risk patients, and the benefits of minimal access surgery seem to be shared by them.[8] However, there is still some lack of literature about the evaluation on outcome of laparoscopic surgery for CRC in patients after organ transplantation. Herein, we report a case of a patient who presented with advanced rectal cancer 4 years after kidney transplantation, and underwent laparoscopic assisted low anterior resection.\n\n2 Case report\nA 51-year-old Chinese male had undergone living-donor kidney transplantation for end-stage renal disease (ESRD) due to 8 years of nephrotic syndrome in 2011 at the age of 46 years. His immunosuppression regimen included a combination therapy with tacrolimus 2.5 mg/d, mycophenolate mofetil 1.5 g/d, and prednisolone 10 mg/d. The blood concentration of tacrolimus (FK-506) was monitored regularly at a target level of 4 to 10 ng/mL. No colonoscopy had been performed prior to transplantation, and he did not receive colonoscopic surveillance postoperatively. Renal graft function remained stable in him without any rejection episodes.\n\nFour years after transplantation, the patient presented with recurrent hematochezia (bright red blood per rectum mixed with stools), and a change in bowel habits manifested by frequent loose stools. He did not pay attention to these abnormal conditions until he began to suffer from progressive general malaise and weight loss of 3 kg during the period of 1 month. A colonoscopy was taken subsequently in January 2016, which revealed a near-circumferential mass at the middle rectum about 8 cm from anal verge accompanied by moderate luminal stenosis. The friable lesion proved to be adenocarcinoma by further biopsy. Having made a definite diagnosis, the patient was admitted to our institution in February 2016. He had a previous history of hypertension for 7 years that could be generally controlled by medication, and cigarette smoking for more than 30 years. Regarding his family history, there were no remarkable findings.\n\nOn admission, detailed physical examination revealed a temperature of 36.5°C, pulse of 80 bpm, and blood pressure of 106/60 mm Hg. No special signs were noted except for a healed surgery scar on his right lower abdominal wall. The lower margin of a solid, irregular mass was touched about 6 cm from anal verge through a digital rectal examination. Laboratory tests showed hemoglobin was 133 g/L, fecal occult blood test was positive, serum creatinine was 88 μmol/L, liver function test was normal, and most serum tumor markers (AFP, CEA, CA19-9, and CA72-4) were within the normal range but CA242 was slightly elevated. The following computed tomography (CT) scan demonstrated a soft tissue density mass protruding into the lumen of upper-middle rectum, with the wall thickening and peripheral lymph node metastasis and the transplant kidney was located in the right pelvic cavity (Fig. 1). No evidences of distant metastasis were suggested. FK-506 was 4.7 ng/mL at that time. According to recommendation of interdisciplinary team including urologists, medical physicians, and general surgeons, immunosuppressive therapy with previous regimen was extended perioperatively. Meanwhile, 100 mg of intravenous hydrocortisone was added before anesthesia induction, and turned to a dose of 50 mg/8 h postoperatively for 1 day to prevent acute renal failure caused by the attack of surgery.\n\nFigure 1 Computed tomography scan showed a soft tissue density mass (arrow) protruding into the lumen of rectum (A) and a transplant kidney (arrow) in the right pelvic cavity (B).\n\nWithout any surgery contraindications, a laparoscopic assisted low anterior resection with total mesorectal excision (TME) was performed then. After induction of general anesthesia, the patient was positioned in the lithotomy position. Complete exploration of the abdominal cavity suggested that there was no liver and peritoneal carcinomatosis. The tumor was identified locating at the middle-lower rectum. Specific surgical procedures started with lysis of abdominal adhesions from previous surgery. The sigmoid mesocolon and mesorectum were dissected along the inner side of the ureters by harmonic scalpel, and the vessels and lymphatics were ligated at the root of the superior rectal vessel with Hem-o-lock. The distal rectum was transected intracorporeally 3 cm from the distal margin of tumor with a EC45-A laparoscopic linear stapler (Johnson & Johnson, Cincinnati, OH, USA). After that, a 6 cm left supraumbilical incision was made to remove the proximal rectum, the distal sigmoid colon, and the surrounding tissues of the rectum 10 cm from the proximal margin of tumor. The specimen was obtained for further pathological evaluation (Fig. 2). Reconstruction was performed intracorporeally in the manner of straight end-to-end colorectal anastomosis using a 28 mm transanal circular stapler (COVIDIEN, Mansfield, MA, USA) (Fig. 3). Finally, 2 drainage tubes were placed in the pelvic cavity surrounding the anastomosis site. In order to prevent postoperative anastomotic leakage, a loop transverse colostomy was performed (Fig. 4). The operation was completed successfully within 2 h with a proximate blood loss of 100 mL. Histopathology revealed a well-moderately differentiated adenocarcinoma measuring 4.2 × 5 × 2.3 cm, with invasion through the muscularis propria into pericolorectal tissues (Fig. 5). The resection margins were free of tumor. Among the removed 14 lymph nodes, 3 contained metastatic cancer, indicating the tumor stage of pT3N1M0. Furthermore, immunohistochemistry showed the tumor was negative for MLH-1, MLH-2, MLH-6, and PMS-2.\n\nFigure 2 A tumor measuring 4.2 × 5 cm accompanied with rectum and the surrounding mesorectum were removed. Distance of the tumor from the distal resection margin was 3 cm and from the proximal resection margin was 10 cm.\n\nFigure 3 Laparoscopic assisted resection for rectal cancer. (A) Transection of distal rectum near the graft (arrow). (B) Colorectal anastomosis using a transanal circular stapler.\n\nFigure 4 A loop transverse colostomy was performed to prevent postoperative anastomotic leakage.\n\nFigure 5 Pathology showed a well-moderately differentiated adenocarcinoma with invasion through the muscularis propria into pericolorectal tissues.\n\nApproximately 4 h after surgery, the patient developed archorrhagia (dark red blood and clots per rectum), and the amount of blood loss increased up to 200 mL within 1 h. After exploration per anus, a bleeding wound near the anastomosis was identified and the control of hemorrhage was performed timely. There was no recurrence of archorrhagia ever since. The further postoperative course was uneventful. Graft function stayed well, and serum creatinine levels were always within the normal limits, ranging from 80 to 104 μmol/L. The ostomy was opened on the third postoperative day, and flatus was passed then. The patient went on a liquid diet 4 days after surgery and made a recovery soon. He stayed in hospital for 9 days after surgery, and drainage tubes were removed at discharge.\n\nDuring 4 months of follow-up period, immunosuppressive therapy with tacrolimus 2.5 mg/d, mycophenolate mofetil 1.5 g/d, and prednisolone 10 mg/d continued, no allograft rejection and complications were observed. Considering his tumor stage, he received adjuvant chemotherapy with a regimen of FOLFOX (oxaliplatin/5-fluorouracil/calcium folinate). After 8 cycles of chemotherapy, repeated CT scan indicated no evidences of local recurrence and distant metastasis. To date, the patient was in a good condition.\n\n3 Discussion\nWe have reported the detailed case of a patient after kidney transplantation, in whom laparoscopic surgery for advanced rectal cancer had been performed. Our case demonstrates that laparoscopic assisted surgery for advanced rectal cancer can be tolerated by kidney transplant recipients, and its short as well as long-term outcomes are acceptable and encouraging.\n\nKidney transplantation is a definite treatment for patients with ESRD. As surgical techniques, organ procurement, immunosuppression regimen, and postoperative monitoring have improved, kidney transplant recipients have a higher treatment success rate and a longer life span.[9] However, the development of de novo malignancy has become a major cause of late mortality in these patients.[10]\n\nThe increased risk of CRC after kidney transplantation has been well documented.[10–12] Moreover, compared with the general population, CRC that are diagnosed in kidney transplant patients often display a more aggressive behavior, and the aggressive behavior is characterized by an earlier age of cancer diagnosis,[13] a more advanced cancer stage (American joint committee on cancer stage > II),[14] and a lower 5-year survival.[13,15] Interestingly, a significantly reduced risk of rectal cancer was observed in the transplant recipients when separated from colon cancer,[16,17] and it seems that the elevated risk of CRC was driven by excess of proximal colon cancer.[17] One possible explanation to these results might be that transplant recipients were screened more frequently than the general population primarily through sigmoidoscopy, which did not reach the proximal colon, highlighting the importance of colonoscopy for CRC screening. There have been strong evidences that long-term immunosuppression increases the risk of CRC after kidney transplantation.[11] The use of some specific immunosuppressive agents like azathioprine and calcineurin inhibitor (CNI) including tacrolimus and cyclosporine were also proposed to be associated with higher incidence of post-transplant malignancy.[17,18] The patient in our report developed advanced rectal cancer (pT3N1M0) 4 years after kidney transplantation at an age of 50 years. Based on the general rule, tumors detected within the first 12 months after transplantation are correlated with pre-existed condition. Despite the fact that he had not received colonoscopic surveillance before or at the time of transplantation, we considered the diagnosed rectal cancer as the de novo malignancy. While, long-term exposure to CNI-based triple immunosuppressive agents together with an absence of colonscopic surveillance are speculated to be the 2 major hazard factors for occurrence of rectal cancer in our case.[18]\n\nIt is generally accepted that surgery plays a role in the treatment for CRC after transplantation. Several studies found surgeries exerted a positive effect on survival of transplant patients with CRC.[14,19] Theoretically, these patients were supposed to be more susceptible to perioperative complications. However, Krysa[20] assessed the outcome of 21 kidney transplant recipients undergoing elective colorectal surgery, and suggested the results were favorable, with no transplant rejection, low morbidity and mortality. Wisam[21] also compared postoperative morbidity and oncologic outcome between patients with CRC in chronic immunosuppressive therapy and control groups. No significant difference was observed in wound infection, intra-abdominal abscess, anastomotic leak, urinary tract infection, or pneumonia, but lower in 3- and 5-year overall and disease-free survival. Consistently, several other reports demonstrated standard surgical treatment for CRC could be done safely in transplant recipients as long as the general condition and graft function were allowable.[22,23]\n\nRegarding the relationship between option for timing of surgery and surgical outcomes, Lee[24] found kidney transplant recipients undergoing colorectal resection <1 year of transplant had a higher perioperative mortality rate than those with grafts >1 year, likely due to more emergent surgeries in the early post-transplant period. Emergent colorectal surgery in kidney transplant patients was reported to have a significant risk of anastomotic leak; moreover, the overall major complication rate after emergent surgery was 81%, much higher than 19% of that after elective surgery.[20] Therefore, emergent surgery for CRC in transplant recipients is not recommended considering its worse surgical outcomes.\n\nCompared with conventional open surgery, laparoscopic surgery for rectal cancer possesses comparable oncologic outcomes, and remarkable short-term advantages, particularly, a lower intra-postoperative complication rate.[2,3] Immunosuppression is known to delay wound healing, increase infection risk, and lead to hemorrhage, anemia, as well as renal failure,[25] which may be a bigger problem to open surgery. Therefore, transplant recipients seem to benefit more from the minimal access approach. Alasari[26] evaluated short- and long-term outcomes of minimally invasive (laparoscopic and robotic) colorectal resection in 10 kidney transplant recipients with CRC between May 2007 and August 2012. Having observed a favorable result in operative time (192.5 ± 15 min), blood loss (30 ± 50 mL), and postoperative complication (2/10 minor complications), they proposed minimally invasive colorectal procedures could be considered as safe and feasible alternatives to open colorectal resection in kidney transplant patients. In our report, the patient underwent laparoscopic assisted low anterior resection and prophylactic loop transverse colostomy. We evaluate the outcome of surgery from 3 respects as follows.\n\n3.1 Short-term outcomes\nLaparoscopic resection for CRC in kidney transplant patients is technically feasible. Duration of our surgery was <2 h, and intraoperative blood loss was little. Analgesia pump was not used postoperatively. Except for the anastomotic hemorrhage, no complications occurred including wound or urinary tract infections, pneumonia, anastomotic leakage, and prolonged ileus. Passing flatus began early represented a fast recovery of intestinal function. The favorable outcome in our case provided a powerful support for the advantages of laparoscopic surgery in the treatment of transplant patients with CRC. Most concerns about the use of laparoscopic surgery in CRC focused on technical complexity and longer operative time.[2] However, it was shown that duration of laparoscopic surgery decreased significantly with the number of interventions performed, accompanied with a significant reduction in postoperative morbidity as the surgeon gained more experience.[27] Having performed 148 laparoscopic surgery for CRC in the high-risk elderly patients including 3 kidney and 1 heart transplant recipients from 2010 to 2012 in our institution, we accumulated abundant experience that wound complication was 3.3%, and no case of anastomotic leakage was identified.[28] To prevent anastomotic leakage, temporary diverting ostomy has been recommended for those patients at high risks such as transplant recipients on immunosuppressive therapy,[29] which is our routine method to protect anastomosis. The most common stoma options are the loop transverse colostomy or loop ileostomy. For our patient, his graft was located in the right lower quadrant with severe adhesions from previous surgery around, which may easily get injured during the loop ileostomy. In addition, much more fluid loss after loop ileostomy than loop transverse colostomy leads to a higher incidence of renal insufficiency.[30] For these reasons, loop transverse colostomy seemed to be a better option in this case. Anastomotic bleeding after laparoscopic rectal surgery is not rare. The use of a circular side stapling technique in laparoscopic low anterior resection for rectal cancer proved to be safe and did not increase the risk of anastomotic complications.[31] Possible reason for bleeding in our case was likely to be attributed to the lower location of tumor.[32]\n\n3.2 Long-term oncologic outcome\nLaparoscopic resection for CRC in kidney transplant patients is oncologically safe. Oncologic outcome is usually measured by the extent of resection, disease-free survival and overall survival. Curative extent of resection represents radical tumor removal with negative margins, TME, and a sufficient number of lymph nodes (>12).[33] During our surgery, resection achieved adequate range of intestinal segment and total mesorectum. In addition, 14 lymph nodes were harvested, which fulfilled the standard of radical operation. Similar outcomes could be achieved by Rivas[8] during the laparoscopic resection for colon cancer in transplant patients, as long as the allograft was placed in the contralateral side of the colon resection. As for disease-free survival and overall survival, our patient was alive without recurrence and metastasis after 4 months of follow-up. Further follow-up is needed to evaluate his long-term survival.\n\n3.3 Graft function and immunosuppression modification\nIn this case, 2 trocars were placed away from the incision scar of the transplant surgery and the position of graft. Slightly lower pneumoperitoneum pressure during the surgery was maintained to preserving an adequate allograft function. Immunosuppressive therapy was not stopped perioperatively to avoid danger of rejection, and postoperative serum creatinine levels stayed within the normal limits. In recent years, immunosuppressive medication modification including CNI-free regimens, substitution by mammalian target of rapamycin inhibitors or reduction in dosage of immunosuppression has been utilized as a treatment after cancer diagnosis in some transplant patients.[34,35] It has been speculated that the use of rapamycin, instead of CNI might reduce the recurrence of cancer in transplant patients.[36] In a case of adenocarcinoma in the stage of III B, as in our patient, switching immunosuppression regimen from cyclosporin to rapamycin might be helpful for his survival after surgery.\n\nBased on the favorable oncologic outcome and low operative complications, laparoscopic assisted resection might be a preferred option for transplant patients with CRC. Indeed, decisions regarding surgical approach should also take into consideration of surgeon experience, tumor stage, potential contraindications, and patient expectations.\n\nIn summary, we have reported a case of a patient after kidney transplantation, in whom laparoscopic assisted low anterior resection for advanced rectal cancer had been performed successfully. The de novo rectal cancer was speculated to associate with long-term exposure to CNI-based immunosuppressive agents and an absence of colonscopic surveillance. We believe laparoscopic surgery for CRC in transplant recipients is technically feasible and oncologically safe, which could be a preferred option of surgical procedure in the near future.\n\nAbbreviations: AJCC = American joint committee on cancer, CNI = calcineurin inhibitor, CRC = colorectal cancer, ESRD = end-stage renal disease, mTOR = mammalian target of rapamycin, TME = total mesorectal excision.\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nGL designed this study. GL and HQ were responsible for the diagnosis and laparoscopic surgery. WC and RY collected the clinical data. ZX wrote the first version of the manuscript, and all authors read and approved the final version of the manuscript.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1 Siegel RL Miller KD Jemal A \nCancer statistics, 2016 . CA Cancer J Clin \n2016 ; 66 :7 –30 .26742998 \n2 Morneau M Boulanger J Charlebois P \nLaparoscopic versus open surgery for the treatment of colorectal cancer: a literature review and recommendations from the Comite de l’evolution des pratiques en oncologie . Can J Surg \n2013 ; 56 :297 –310 .24067514 \n3 Wu WX Sun YM Hua YB \nLaparoscopic versus conventional open resection of rectal carcinoma: a clinical comparative study . World J Gastroenterol \n2004 ; 10 :1167 –1170 .15069719 \n4 Jin K Wang J Lan H \nLaparoscopic surgery for colorectal cancer in China: an overview . Int J Clin Exp Med \n2014 ; 7 :4635 –4645 .25663960 \n5 Fujii S Yamamoto S Ito M \nShort-term outcomes of laparoscopic intersphincteric resection from a phase II trial to evaluate laparoscopic surgery for stage 0/I rectal cancer: Japan Society of Laparoscopic Colorectal Surgery Lap RC . Surg Endosc \n2012 ; 26 :3067 –3076 .22580882 \n6 Fisher JS Woodle ES Thistlethwaite JR Jr \nKidney transplantation: graft monitoring and immunosuppression . World J Surg \n2002 ; 26 :185 –193 .11865349 \n7 Wu C Evans I Joseph R \nComorbid conditions in kidney transplantation: association with graft and patient survival . J Am Soc Nephrol \n2005 ; 16 :3437 –3444 .16176999 \n8 Rivas H Martinez JL Delgado S \nLaparoscopic assisted colectomies in kidney transplant recipients with colon cancer . J Laparoendosc Adv Surg Tech A \n2004 ; 14 :201 –204 .15345155 \n9 Gridelli B Remuzzi G \nStrategies for making more organs available for transplantation . N Engl J Med \n2000 ; 343 :404 –410 .10933740 \n10 Asch WS Bia MJ \nOncologic issues and kidney transplantation: a review of frequency, mortality, and screening . Adv Chronic Kidney Dis \n2014 ; 21 :106 –113 .24359993 \n11 Park JM Choi MG Kim SW \nIncreased incidence of colorectal malignancies in renal transplant recipients: a case control study . Am J Transplant \n2010 ; 10 :2043 –2050 .20883538 \n12 Kwon JH Koh SJ Kim JY \nPrevalence of advanced colorectal neoplasm after kidney transplantation: surveillance based on the results of screening colonoscopy . Dig Dis Sci \n2015 ; 60 :1761 –1769 .25577273 \n13 Papaconstantinou HT Sklow B Hanaway MJ \nCharacteristics and survival patterns of solid organ transplant patients developing de Novo colon and rectal cancer . Dis Colon Rectum \n2004 ; 47 :1898 –1903 .15622583 \n14 Lim SM Jung M Shin SJ \nClinical implications from a single-center study of colorectal adenocarcinoma in transplant recipients . Oncology \n2015 ; 88 :195 –200 .25502286 \n15 Kim JY Ju MK Kim MS \nClinical characteristics and treatment outcomes of colorectal cancer in renal transplant recipients in Korea . Yonsei Med J \n2011 ; 52 :454 –462 .21488188 \n16 Stewart T Henderson R Grayson H \nReduced incidence of rectal cancer, compared to gastric and colonic cancer, in a population of 73,076 men and women chronically immunosuppressed . Clin Cancer Res \n1997 ; 3 :51 –55 .9815537 \n17 Safaeian M Robbins HA Berndt SI \nRisk of colorectal cancer after solid organ transplantation in the United States . Am J Transplant \n2016 ; 16 :960 –967 .26731613 \n18 Kato T Kakuta Y Abe T \nThe benefits of cancer screening in kidney transplant recipients: a single-center experience . Cancer Med \n2016 ; 5 :153 –158 .26686199 \n19 Miao Y Everly JJ Gross TG \nDe novo cancers arising in organ transplant recipients are associated with adverse outcomes compared with the general population . Transplantation \n2009 ; 87 :1347 –1359 .19424035 \n20 Krysa J Patel V Taylor J \nOutcome of patients on renal replacement therapy after colorectal surgery . Dis Colon Rectum \n2008 ; 51 :961 –965 .18288538 \n21 Khoury W Lavery IC Kiran RP \nEffects of chronic immunosuppression on long-term oncologic outcomes for colorectal cancer patients undergoing surgery . Ann Surg \n2011 ; 253 :323 –327 .21178764 \n22 Merchea A Abdelsattar ZM Taner T \nOutcomes of colorectal cancer arising in solid organ transplant recipients . J Gastrointest Surg \n2014 ; 18 :599 –604 .24254836 \n23 Zittel TT Mehl CF Reichmann U \nTreatment of advanced rectal cancer in a patient after combined pancreas-kidney transplantation . Langenbeck's Arch Surg \n2004 ; 389 :6 –10 .14574576 \n24 Lee JT Dunn TB Sirany AM \nColorectal surgery after kidney transplantation: characteristics of early vs. late posttransplant interventions . J Gastrointest Surg \n2014 ; 18 :1299 –1305 .24838995 \n25 Takeda A Morozumi K \nCalcineurin inhibitor nephrotoxicity in renal allografts . Nihon Jinzo Gakkai Shi \n2011 ; 53 :610 –614 .21688481 \n26 Alasari S Kim MS Baik SH \nMinimally invasive colorectal resection in kidney transplant recipients: technical tips, short- and long-term outcomes . Int Sch Res Notices \n2014 ; 2014 :254612 .27351016 \n27 Park IJ Choi GS Lim KH \nMultidimensional analysis of the learning curve for laparoscopic resection in rectal cancer . J Gastrointest Surg \n2009 ; 13 :275 –281 .18941844 \n28 Lin GL Qiu HZ Xiao Y \nLaparoscopic and endoscopic minimally invasive surgery for the elderly patients with colorectal . Chin J Laparoscopic Surg (Electron Edn) \n2013 ; 6 :402 –405 .\n29 Huser N Michalski CW Erkan M \nSystematic review and meta-analysis of the role of defunctioning stoma in low rectal cancer surgery . Ann Surg \n2008 ; 248 :52 –60 .18580207 \n30 Klink CD Lioupis K Binnebosel M \nDiversion stoma after colorectal surgery: loop colostomy or ileostomy? \nInt J Colorectal Dis \n2011 ; 26 :431 –436 .21221605 \n31 Oki E Ando K Saeki H \nThe use of a circular side stapling technique in laparoscopic low anterior resection for rectal cancer: experience of 30 serial cases . Int Surg \n2015 ; 100 :979 –983 .25590136 \n32 Ma JJ Ling TL Lu AG \nEndoscopic management for the assessment and treatment of anastomotic bleeding in laparoscopic anterior resection for rectal cancer . Surg Laparosc Endosc Percutan Tech \n2014 ; 24 :465 –469 .24710245 \n33 Shussman N Wexner SD \nCurrent status of laparoscopy for the treatment of rectal cancer . World J Gastroenterol \n2014 ; 20 :15125 –15134 .25386061 \n34 Manuelli M De Luca L Iaria G \nConversion to rapamycin immunosuppression for malignancy after kidney transplantation . Transplant Proc \n2010 ; 42 :1314 –1316 .20534289 \n35 Ajithkumar TV Parkinson CA Butler A \nManagement of solid tumours in organ-transplant recipients . Lancet Oncol \n2007 ; 8 :921 –932 .17913661 \n36 Guba M von Breitenbuch P Steinbauer M \nRapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor . Nat Med \n2002 ; 8 :128 –135 .11821896\n\n",
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"title": "Laparoscopic assisted low anterior resection for advanced rectal cancer in a kidney transplant recipient: A case report.",
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"abstract": "Presentation of a combination of branch retinal artery occlusion (BRAO)/central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO) in systemic lupus erythematosus (SLE) is extremely rare. Herein, we have presented the case of a 29-year-old female with SLE, who simultaneously developed bilateral CRVO and BRAO/CRAO in the absence of antiphospholipid syndrome (APS) as a catastrophic form of clinical flare. A combinatorial diagnosis of CRVO and BRAO/CRAO should be considered during clinical flare-up in a patient with SLE who presents with rapidly progressive visual loss.",
"affiliations": "1 Isfahan Eye Research Center, Department of Ophthalmology, Isfahan University of Medical Sciences, Isfahan, Iran.;2 Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.;1 Isfahan Eye Research Center, Department of Ophthalmology, Isfahan University of Medical Sciences, Isfahan, Iran.",
"authors": "Akhlaghi|M|M|;Abtahi-Naeini|B|B|;Pourazizi|M|M|http://orcid.org/0000-0002-9714-8209",
"chemical_list": "D000925:Anticoagulants; D005938:Glucocorticoids; D007166:Immunosuppressive Agents",
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"issue": "27(6)",
"journal": "Lupus",
"keywords": "Systemic lupus erythematosus; branch retinal artery occlusion; central retinal artery occlusion; central retinal vein occlusion; flare; vision loss",
"medline_ta": "Lupus",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000925:Anticoagulants; D001777:Blood Coagulation; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D015356:Retinal Artery Occlusion; D012170:Retinal Vein Occlusion; D016896:Treatment Outcome; D014786:Vision Disorders; D014785:Vision, Ocular",
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"title": "Acute vision loss in systemic lupus erythematosus: bilateral combined retinal artery and vein occlusion as a catastrophic form of clinical flare.",
"title_normalized": "acute vision loss in systemic lupus erythematosus bilateral combined retinal artery and vein occlusion as a catastrophic form of clinical flare"
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"abstract": "Hydralazine, a vasodilator, is commonly used as an adjunctive treatment for moderate to severe hypertension, heart failure and hypertensive emergencies in pregnancy. Hydralazine-induced lupus was first described in 1953. Clinical presentation ranges from arthralgia, myalgia, petechiae, or rash to single or multiorgan involvement. An occurrence of systemic vasculitis is a rare complication. When presented as the pulmonary-renal syndrome, it could have a rapidly progressive course which can be fatal. Here, we describe a case of hydralazine-associated rapidly progressive glomerulonephritis and pulmonary haemorrhage. We use this case to review the current literature and discuss and highlight the importance of a high degree of clinical acumen, early diagnosis and prompt treatment for better clinical outcomes.",
"affiliations": "Nephrology, Deaconess Health System, Evansville, Indiana, USA.;Internal Medicine, Deaconess Health System, Evansville, Indiana, USA.;Nephrology, Permian Basin Kidney Center, Midland, Texas, USA.;Nephrology, Deaconess Health System, Evansville, Indiana, USA.",
"authors": "Aeddula|Narothama Reddy|NR|;Pathireddy|Samata|S|;Ansari|Asif|A|;Juran|Peter J|PJ|",
"chemical_list": "D005938:Glucocorticoids; D007155:Immunologic Factors; D014665:Vasodilator Agents; D006830:Hydralazine; D000069283:Rituximab; D011239:Prednisolone",
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"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepcasereportsbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2018-22716110.1136/bcr-2018-227161Rare Disease15061523Case ReportHydralazine-associated antineutrophil cytoplasmic antibody vasculitis with pulmonary–renal syndrome Aeddula Narothama Reddy 12Pathireddy Samata 34Ansari Asif 5Juran Peter J 121 Nephrology, Deaconess Health System, Evansville, Indiana, USA2 Medicine, Indiana University School of Medicine, Evansville, Indiana, USA3 Internal Medicine, Deaconess Health System, Evansville, Indiana, USA4 Medicine, Indiana University School of Medicine, Evansville, Indiana, USA5 Nephrology, Permian Basin Kidney Center, Midland, Texas, USACorrespondence to Dr Samata Pathireddy, drspathireddy@gmail.com2018 8 11 2018 8 11 2018 2018 bcr201822716113 10 2018 © BMJ Publishing Group Limited 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2018This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Hydralazine, a vasodilator, is commonly used as an adjunctive treatment for moderate to severe hypertension, heart failure and hypertensive emergencies in pregnancy. Hydralazine-induced lupus was first described in 1953. Clinical presentation ranges from arthralgia, myalgia, petechiae, or rash to single or multiorgan involvement. An occurrence of systemic vasculitis is a rare complication. When presented as the pulmonary–renal syndrome, it could have a rapidly progressive course which can be fatal. Here, we describe a case of hydralazine-associated rapidly progressive glomerulonephritis and pulmonary haemorrhage. We use this case to review the current literature and discuss and highlight the importance of a high degree of clinical acumen, early diagnosis and prompt treatment for better clinical outcomes.\n\ndrug interactionsrenal systemacute renal failurevasculitisspecial-featureunlocked\n==== Body\nBackground\nHydralazine was discovered in the 1950s as a treatment for malaria. It is a direct smooth muscle vasodilator used as an adjunctive treatment for moderate to severe hypertension, heart failure with reduced ejection fraction (ACE inhibitor or angiotensin receptor blocker intolerance) and in hypertensive emergencies in pregnancy.1 Hydralazine is often implicated as a causal factor in drug-induced lupus. Hydralazine-induced antinuclear cytoplasmic antibody (ANCA) vasculitis (AAV) is a rare phenomenon with pulmonary–renal syndrome with the most severe presentation. The pathogenesis of hydralazine-associated AAV is unknown. Theories for the mechanism of hydralazine-associated AAV include,2 (1) hydralazine binding to myeloperoxidase (MPO) leading to neutrophil apoptosis, resulting in the production of multiple autoantibodies; (2) hydralazine-induced reversal of epigenic silencing of MPO and proteinase3 (PR3) leading to increased expression of neutrophil autoantigens and (3) a break in tolerance in slow versus fast acetylators of hydralazine.3 Here, we report a severe complication of hydralazine, presenting as rapidly progressive glomerulonephritis (GN) with pulmonary haemorrhage and discuss the current literature.\n\nCase presentation\nA 65-year-old Caucasian woman with a prior history of bilateral clear cell renal cell carcinoma (2013) treated with bilateral open partial nephrectomies, poorly controlled diabetes mellitus over 30 years, hypertension, obesity with prior gastric bypass surgery, progressive proteinuric chronic kidney disease stage 4, presented to the hospital from home with a 2 day history of shortness of breath and lower extremity swelling and weakness. On presentation, she was afebrile with a blood pressure of 178/88 mm Hg, heart rate of 84 beats/min, pulse oxygenation of 95% on 2 L of O2. The physical was notable for an obese woman with tachypnoea, fine rales and 1+pitting pedal oedema. Initial laboratory workup showed a serum creatinine of 6.1 mg/dL with an estimated glomerular filtration rate of 8 mL/min/1.73 m2(eGFR) (calculated using the four-variable modification of diet in renal disease (MDRD) study equation), blood urea nitrogen of 74 mg/dL, potassium of 3.6 mmol/L, haemoglobin of 7 g/dL, white blood cell count of 6.9 x109/L and platelets of 141 x109/L.A urine analysis showed 300 protein, specific gravity of 1.020, large blood and >100 of red blood cells (RBC)/hpf. Chest X-ray was notable for central vascular congestion. A renal ultrasound showed smaller sized kidneys with no hydronephrosis, calculi, with mild to moderate diffuse parenchymal thinning. Her home medications included atorvastatin, bupropion, aspirin, calcitriol, furosemide, hydralazine, Insulin glargine, levothyroxine, mirtazapine, pantoprazole and metoprolol. She was not a smoker with no history of alcohol use. Denied family history of renal disease.\n\nA review of her outpatient laboratories 3 months prior showed a baseline creatinine of 2.4 mg/dL with corresponding eGFR of 21 mL/min/1.73 m2 (MDRD). Prior urinalysis was positive for 100 of protein with no RBC or blood. Prior serologies including Hepatitis B Ag, Hepatitis C Ab, HIV and antinuclear antibody (ANA) were all negative. Her spot urine protein creatinine ratio was 2.1 g.\n\nInvestigations\nSerological work up, bronchoscopy, CT and renal biopsy.\n\nDifferential diagnosis\nAcute renal failure with pulmonary oedema and uremic haemoptysis.\n\nAcute heart failure.\n\nRespiratory tract infection with prerenal renal failure and or postinfectious GN.\n\nSystemic lupus erythematosus.\n\nCryoglobulinaemic vasculitis.\n\nTreatment\nThe patient admitted and treated with gentle intravenous fluids and a unit of packed red blood cells. Hydralazine was stopped. Serological workup requested given active urine sediment along with a urological evaluation given the history of renal cell carcinoma. Her erythrocyte sedimentation rate was >100. Given the patient’s presentation, laboratory parameters with severe renal failure, urine sediment, high inflammatory markers, GN was high on the differential and pulse intravenous steroids administered while waiting for the final serologies and the renal biopsy. Perinuclear antinuclear cytoplasmic antibody titres were 1:40 (reference range <1:20, ARUP Laboratories, Utah, USA), MPO antibody was positive at 44 AU/mL (reference range 0–19) and serine protease 3 IgG was 5 AU/mL (reference range 0–19). ANA and glomerular basement membrane antibody were negative. Complement 3 was 72 mg/dL (reference range 88–201), Complement 4 was 17 mg/dL (reference range 10–40). Serum protein electrophoresis and Immunofixation electrophoresis were of the normal pattern. A renal biopsy performed.\n\nThe renal biopsy (figure 1) specimen contained 35 glomeruli, 17 of which were globally sclerotic and four were ischaemic. The remaining glomeruli were enlarged and with moderate to severe diffuse and global increase in mesangial matrix and nodule formation. Nine glomeruli had crescents, two of which were cellular, four of which were fibrocellular and three of which were fibrous. Three glomeruli exhibited segmental fibrinoid necrosis. Moderate tubular atrophy and interstitial fibrosis involving 40%–50% of cortical areas with patchy moderate interstitial inflammation by the lymphocytes, plasma cells and monocytes. Severe arteriosclerosis with hyalinosis observed. Immunofluorescence showed weak mesangial staining for IgG, IgA, C3, kappa and lambda, within the spectrum of pauci-immune necrotising crescentic GN. There were low levels of mesangial immune deposits. No definitive immune type electron dense deposits seen.\n\nFigure 1 (A)Glomeruli with a fibrocellular crescent (H&E; original magnification ×400). (B) Glomeruli with a cellular crescent (H&E; original magnification ×400). (C) Glomeruli with segmental fibrinoid necrosis (methenamine-silver stain; original Magnification x400). (D) Glomeruli with nodular sclerosis (H&E; original magnification ×400). (E) Moderate tubular atrophy interstitial fibrosis involving 50% of the cortical area with moderate interstitial inflammation (Masson’s trichrome stain; original Magnification x200).\n\nDiagnosis\nFocal necrotising and crescentic GN, acute and chronic, with low-level immune deposits, superimposed on moderate to severe nodular diabetic glomerulosclerosis with moderate to severe tubular atrophy and interstitial fibrosis.\n\nClinical follow-up\nThe patient was treated with three doses of 1 g pulse intravenous methylprednisolone followed by oral prednisone 60 mg daily. She was started on rituximab infusions weekly (375 mg/m2/week) for 4 weeks. She required regular haemodialysis 5 days into her hospitalisation. On day 10 of her hospitalisation, she went into acute hypoxic respiratory failure with a non-contrast CT scan showing diffuse and extensive bilateral lung parenchymal infiltrates throughout lung fields with lung volume loss and pleural fluid. A bronchoscopy showed diffuse alveolar haemorrhage. She further treated with single volume exchange therapeutic plasmapheresis with fresh frozen plasma for seven sessions.\n\nOutcome and follow-up\nAt the time of writing, the patient remained clinically stable but dependent on haemodialysis therapy for more than 12 months.\n\nDiscussion\nAAV is a well-described clinical entity with an incidence of 10–20 cases per million,4 though very little is known regarding the prevalence of drug-induced vasculitis. Literature is available relating medications to vasculitis as early as the 1940s.2 This theory was supported after the discovery of ANCAs and their target antigens PR3 and MPO in the 1980s, with case series of patients who were ANCA positive and exposed to medications, such as, hydralazine, allopurinol and propylthiouracil, some developed vasculitis.5 6 Exposure to such drugs can provoke an immune reaction that results in the autoantibodies generation and clinical autoimmune disease, including immune complex or pauci-immune GN.2 Evidence of hydralazine-associated vasculitis including rapidly progressive GN dates to the pre-ANCA era.2 Hydralazine-induced vasculitis has an incidence of 5.4% in patients on 100 mg/day to 10.4% with 200 mg/day for >3-years duration, predominantly in patients who are slow acetylators.3 Choi et al7 performed a retrospective examination of drug-associated AAV in 250 MPO-positive AAV patients. In 30 patients with the maximum anti-MPO antibody titers, 10 patients exposed to hydralazine, of whom nine had renal involvement and five showing renal biopsy-proven pauci-immune necrotizing GN. Yokogawa and Vivino,8 in 2009, found 68 hydralazine vasculitis reports. The subjects in the study were predominantly female and had a mean duration of drug exposure of 4.7 years; with a mean dose of 142 mg/day. Renal disease was common on presentation (81%), and patients had further serological evidence of an autoimmune process (96% ANA positive, 26% anti-dsDNA antibody positive and 44% hypocomplementemia), similar to the previous study by Choi et al7. Kumar et al,9 studied 323 cases of AAV of which 12 exposed to hydralazine. Eight out of 12 patients presented with pulmonary infiltrates and one with haemoptysis. Only six patients had a renal biopsy and all of them had pauci-immune crescentic GN. The mean duration of therapy was 22 months with a mean cumulative dose of 146 g. Median age was 70.3 years with all patients being Caucasian with 58.3% female patients. All 12 patients in the study had elevated anti-MPO antibody.\n\nThe identified risk factors that predispose to hydralazine-induced AAV include a cumulative dose of more than 100 g, female gender and thyroid disease.10 Other risk factors identified include the human leucocyte antigen (HLA)-DR4 genotype, slow hepatic acetylation and the null gene for C4.11\n\nWe performed a literature search and in table 1, we reviewed the hydralazine-associated AAV with pulmonary–renal syndrome patients, with only 24 cases reported so far. Seventeen out of 24 patients in the case report survived. Our patient survived, though dependent on the dialysis 12 months after the initial presentation.\n\nTable 1 Hydralazine induced antinuclear cytoplasmic antibody vasculitis-patients with the pulmonary–renal syndrome, treatment and outcomes.\n\nAuthor with reference\tNumber of patients\tPositive \nMPO antibodies\tPulmonary and renal involvement\tTreatment\tOutcome\t\nAlmroth et al20\t17\t12 of 14 tested\t4\tS 4/4 \nCy 2/4 \nAz 1/4, \nP 1/4\tThree out of four \ndied\t\nShort and Lockwood23\t10\t10\t2\tS 2/2 \nCy 1/2\tNot reported\t\nChoi et al7\t10\t10\t5\tS 5/5 \nCy 5/5\tOne out of four died\t\nYokogawa and Vivino8\t2\t2\t1\tS 1/1 \nCy 1/1\tDied\t\nKalra et al24\t1\t1\t1\tS 1/1 \nCy 1/1\tDied\t\nBabar et al19\t2\t1\t1\tS1/1 \nCy 1/1\tDied\t\nMarina et al17\t1\t1\t1\tS 1/1 \nCy 1/1\tDied\t\nAgarwal et al25\t1\t1\t1\tS 1/1 \nCy 1/1\tSurvived\t\nNamas et al26\t1\t1\t1\tS 1/1 \nCy 1/1 \nP 1/1\tSurvived\t\nRasla et al27\t1\t1\t1\tS1/1 \nCy 1/1 \nP 1/1\tSurvived\t\nKumar et al9\t12\t12 of 12\t6\tS 5/6 \nCy 5/6 \nMM 3/6\tFive out of six survived.\t\nAz, azathioprine; Cy, cyclophosphamide; MM, mycophenolate mofetil; P, plasmapheresis; S, steroids.\n\nThe patient in our case had diabetes for more than 30 years. To date, there have been only 10 reported cases of diabetic nephropathy with antineutrophil cytoplasmic antibodies mediated nephritis.12 Of the 10 cases, only three cases showed the pathological evidence of diabetic nephropathy. Approximately 20%–30% of diabetic nephropathy cases also complicated by nondiabetic nephropathy.13 Thus, our case also highlights the need for a higher degree of clinical suspicion in patients with worsening of renal function or abnormal urinalysis that does not concur with the natural course of diabetic nephropathy.\n\nThe mechanisms of hydralazine-associated AAV pathogenesis is not clear. In vivo study data suggests that ANCAs are by themselves pathogenic.14 MPO knockout mice that lack functioning B- and T-lymphocytes, when injected with anti-MPO splenocytes, developed severe necrotizing crescentic GN and haemorrhagic pulmonary capillaritis. It’s hypothesised that hydralazine collects in neutrophils and binds to MPO, this induces neutrophil apoptosis and cytotoxic products which further act as a source of immunogens as apparent by the presence of numerous antibodies that associated with hydralazine-induced AAV.15 The antibodies either alone or by a complex interaction with infectious agents or genetic factors may contribute to the disease. A study done by Magro et al suggested that hydralazine interferes with neutrophil extracellular traps (NETs), which leads to further uptake of previously sequestered antigens.16 Antibodies associated with hydralazine-induced vasculitis include MPO-ANCA, ANA, antihistone antibody, antielastase antibody and antiphospholipid antibody.15 17 Antihistone antibody is commonly seen with drug-induced vasculitis and is absent with ANCA-associated vasculitis.14 The combination of antihistone antibody, MPO and/or PR3 ANCA and absence of anti dsDNA antibody could be used to support the diagnosis of hydralazine-induced vasculitis in the appropriate clinical setting with evidence of pauci-immune GN.18 As the presence of multi-antigenicity is a key finding, multiple serological markers should raise suspicion for drug-induced vasculitis.19 Presence of very high MPO antibody titers is another distinct characteristic of drug-induced pauci-immune GN.7\n\nThe infrequency of drug-induced AAV and overlying features with idiopathic vasculitis is the greater dilemma in early diagnosis.19 The diagnosis relies mainly on constitutional and system-specific symptoms, exhaustive medication history, the total duration of drug therapy, the presence of serological markers and the resolution of symptoms after discontinuation of the offending drug.19 Patients with hydralazine-associated vasculitis characteristically have a more severe course, predominantly due to renal vasculitis and therefore require more aggressive treatment.8 Concomitant occurrence of pulmonary haemorrhage is the most powerful predictor of death,20 21 necessitating early diagnosis and prompt initiation of treatment. For a definitive diagnosis, a renal biopsy is strongly encouraged which also ascertains the severity of disease and aids in prognostication. Apart from a detailed history, laboratory and pathological findings, the Naranjo adverse drug reaction probability scale was used in our case, which specified that the association of hydralazine to pulmonary–renal syndrome was probable.22\n\nCurrently, no guidelines are available and no randomised controlled trials conducted in the treatment of hydralazine and other drug associated AAV. Treatment should individualise to the patient, based on the age, disease severity, co-morbidities and renal function on presentation. In mild cases, discontinuing the offending medication may lead to resolution of AAV. In severe cases, particularly with pulmonary or renal involvement, aggressive management with immunosuppressive regimens are needed for hydralazine and drug-mediated AAV. Corticosteroids with cyclophosphamide or rituximab and therapeutic plasma exchange for the pulmonary haemorrhage and rapidly progressive GN should consider. Immunosuppression should be individualised, preferable with a regimen with fewer side effects and a shorter duration of treatment. It is important to educate the patients about the future drug exposure, with the index drug added to the allergies list in the patient’s medical record. Further studies to better understand the etiopathogenesis of hydralazine-AAV is warranted to invent better markers for diagnosis and treatment.\n\nLearning points\nHydralazine-induced antinuclear cytoplasmic antibody vasculitis and pulmonary–renal syndrome though rare, can be rapidly progressive and fatal.\n\nA thorough clinical and medication history, serologies and pulmonary–renal pathological findings can help in the diagnosis.\n\nTreatment includes stopping the hydralazine, appropriate use of immunosuppressants based on the severity and therapeutic plasmapheresis.\n\nWe would like to thank Dr Dominick Santorielli, MD, Assistant Professor of Pathology and Cell Biology, Columbia University, New York, for the renal biopsy pathology and images.\n\nContributors: NRA, SP, AA and PJJ involved in the planning, conception, acquisition of data and helped with the final drafting of the case report. SP and NRA are the first authors and have equally contributed to the majority of the article.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent: Not required.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Farag M , Mabote T , Shoaib A , et al \nHydralazine and nitrates alone or combined for the management of chronic heart failure: A systematic review . Int J Cardiol \n2015 ;196 :61 –9 . 10.1016/j.ijcard.2015.05.160 26073215 \n2 Hogan JJ , Markowitz GS , Radhakrishnan J \nDrug-induced glomerular disease: immune-mediated injury . Clin J Am Soc Nephrol \n2015 ;10 :1300 –10 . 10.2215/CJN.01910215 26092827 \n3 Pendergraft WF , Niles JL \nTrojan horses: drug culprits associated with antineutrophil cytoplasmic autoantibody (ANCA) vasculitis . Curr Opin Rheumatol \n2014 ;26 :42-9 \n10.1097/BOR.0000000000000014 24276086 \n4 Ntatsaki E , Watts RA , Scott DG \nEpidemiology of ANCA-associated vasculitis . Rheum Dis Clin North Am \n2010 ;36 :447 –61 . 10.1016/j.rdc.2010.04.002 20688243 \n5 Nässberger L , Sjöholm AG , Jonsson H , et al \nAutoantibodies against neutrophil cytoplasm components in systemic lupus erythematosus and in hydralazine-induced lupus . Clin Exp Immunol \n1990 ;81 :380 –3 . 10.1111/j.1365-2249.1990.tb05342.x 2168822 \n6 Dolman KM , Gans RO , Vervaat TJ , et al \nVasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy . Lancet \n1993 ;342 :651 –2 . 10.1016/0140-6736(93)91761-A 8103148 \n7 Choi HK , Merkel PA , Walker AM , et al \nDrug-associated antineutrophil cytoplasmic antibody-positive vasculitis: prevalence among patients with high titers of antimyeloperoxidase antibodies . Arthritis Rheum \n2000 ;43 :405 \n10.1002/1529-0131(200002)43:2<405::AID-ANR22>3.0.CO;2-5 10693882 \n8 Yokogawa N , Vivino FB \nHydralazine-induced autoimmune disease: comparison to idiopathic lupus and ANCA-positive vasculitis . Mod Rheumatol \n2009 ;19 :338 –47 . 10.3109/s10165-009-0168-y 19424772 \n9 Kumar B , Strouse J , Swee M , et al \nHydralazine-associated vasculitis: Overlapping features of drug-induced lupus and vasculitis . Semin Arthritis Rheum \n2018 ;5 :1 \n10.1016/j.semarthrit.2018.01.005 \n10 Lionaki S , Hogan SL , Falk RJ , et al \nAssociation between thyroid disease and its treatment with ANCA small-vessel vasculitis: a case-control study . Nephrol Dial Transplant \n2007 ;22 :3508 –15 . 10.1093/ndt/gfm493 17686815 \n11 McKinnon RA , Nebert DW \nPossible role of cytochromes P450 in lupus erythematosus and related disorders . Lupus \n1994 ;3 :473 –8 . 10.1177/096120339400300608 7704004 \n12 Nishino T , Minami K , Uramatsu T , et al \nAn elderly patient with diabetic nephropathy complicated by ANCA-associated nephritis . Intern Med \n2012 ;51 :1227 –32 . 10.2169/internalmedicine.51.6775 22687795 \n13 Olsen S , Mogensen CE \nHow often is NIDDM complicated with non-diabetic renal disease? An analysis of renal biopsies and the literature . Diabetologia \n1996 ;39 :1638-45 .8960856 \n14 Xiao H , Heeringa P , Hu P , et al \nAntineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice . J Clin Invest \n2002 ;110 :955 –63 . 10.1172/JCI0215918 12370273 \n15 Jiang X , Khursigara G , Rubin RL \nTransformation of lupus-inducing drugs to cytotoxic products by activated neutrophils . Science \n1994 ;266 :810 –3 . 10.1126/science.7973636 7973636 \n16 Magro CM , Momtahen S , Harp J \nThe distinctive histopathology of hydralazine-associated ANCA positive vasculitis: in vivo demonstration of NETosis . Eur J Dermatol \n2017 ;27 :91-92 \n10.1684/ejd.2016.2881 27748260 \n17 Marina VP , Malhotra D , Kaw D \nHydralazine-induced ANCA vasculitis with pulmonary renal syndrome: a rare clinical presentation . Int Urol Nephrol \n2012 ;44 :1907 –9 . 10.1007/s11255-011-9989-7 21590349 \n18 Radić M , Martinović Kaliterna D , Radić J \nDrug-induced vasculitis: a clinical and pathological review . Neth J Med \n2012 ;70 :12-7 .22271809 \n19 Babar F , Posner JN , Obah EA \nHydralazine-induced pauci-immune glomerulonephritis: intriguing case series with misleading diagnoses . J Community Hosp Intern Med Perspect \n2016 ;6 :30632 \n10.3402/jchimp.v6.30632 27124161 \n20 Almroth G , Eneström S , Hed J , et al \nAutoantibodies to leucocyte antigens in hydralazine-associated nephritis . J Intern Med \n1992 ;231 :37 –42 . 10.1111/j.1365-2796.1992.tb00496.x 1310098 \n21 Hogan SL , Nachman PH , Wilkman AS , et al \nPrognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis . J Am Soc Nephrol \n1996 ;7 :23-32 .8808106 \n22 Naranjo CA , Busto U , Sellers EM , et al \nA method for estimating the probability of adverse drug reactions . Clin Pharmacol Ther \n1981 ;30 :239 –45 . 10.1038/clpt.1981.154 7249508 \n23 Short AK , Lockwood CM \nAntigen specificity in hydralazine associated ANCA positive systemic vasculitis . QJM \n1995 ;88 :775-83 .8542262 \n24 Kalra A , Yokogawa N , Raja H , et al \nHydralazine-induced pulmonary-renal syndrome: a case report . Am J Ther \n2012 ;19 :e136-8 \n10.1097/MJT.0b013e3181ed838c 20724911 \n25 Agarwal G , Sultan G , Werner SL , et al \nHydralazine induces myeloperoxidase and proteinase 3 anti-neutrophil cytoplasmic antibody vasculitis and leads to pulmonary renal syndrome . Case Rep Nephrol \n2014 ;2014 :1 –4 . 10.1155/2014/868590 \n26 Namas R , Rubin B , Adwar W , et al \nA challenging twist in pulmonary renal syndrome . Case Rep Rheumatol \n2014 ;2014 :1 –4 . 10.1155/2014/516362 \n27 Rasla S , El Meligy A , Cucu DF \nHydralazine-Induced ANCA Vasculitis in the Setting of Acute Clostridium Difficile Infection . R I Med J \n2016 ;99 :41 –3 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "acute renal failure; drug interactions; renal system; vasculitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D001706:Biopsy; D001797:Blood Protein Electrophoresis; D003937:Diagnosis, Differential; D005260:Female; D005440:Fluid Therapy; D005921:Glomerulonephritis; D005938:Glucocorticoids; D006470:Hemorrhage; D006801:Humans; D006830:Hydralazine; D007155:Immunologic Factors; D007678:Kidney Glomerulus; D008168:Lung; D008171:Lung Diseases; D011239:Prednisolone; D006435:Renal Dialysis; D000069283:Rituximab; D013577:Syndrome; D014665:Vasodilator Agents",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30413463",
"pubdate": "2018-11-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10693882;12370273;1310098;17686815;19424772;20688243;20724911;21590349;2168822;22271809;22687795;24276086;25210633;25525550;26073215;26092827;27124161;27748260;27801920;29519741;7249508;7704004;7973636;8103148;8542262;8808106;8960856",
"title": "Hydralazine-associated antineutrophil cytoplasmic antibody vasculitis with pulmonary-renal syndrome.",
"title_normalized": "hydralazine associated antineutrophil cytoplasmic antibody vasculitis with pulmonary renal syndrome"
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"abstract": "BACKGROUND\nThe purpose of this retrospective study was to evaluate the survival outcomes of pembrolizumab (PEM) plus enzalutamide (ENZ) versus PEM alone in selected populations of men with previously untreated metastatic castration-resistant prostate cancer (mCRPC) harbouring programmed cell death ligand-1 (PD-L1) staining.\n\n\nMETHODS\nConsecutive men with previously untreated mCRPC harbouring PD-L1 staining who underwent treatment with PEM plus ENZ (PE) or PEM alone (PA) at our medical centre from January 1, 2017, to January 31, 2021, were retrospectively identified. Follow-up was conducted monthly during the first year and then every 1 month thereafter. The primary outcomes of the study were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were the frequency of key adverse events (AEs).\n\n\nRESULTS\nIn total, 302 men were retrospectively reviewed, 96 of whom were deemed to be ineligible per the exclusion criteria, leaving 206 men (PE: n = 100, median age 64 years [range, 43-85] and PA: n = 106, 65 years [range, 45-82]) who were eligible for the study. The median follow-up for both groups was 34 months (range, 2-42). At the final follow-up, the median OS was 25.1 months (95% confidence interval [CI], 22.3-27.6) in the PE group versus 18.3 months (95% CI, 16.5-20.9) in the PA group (hazard ratio [HR] 0.56; 95% CI, 0.39-0.80; p = 0.001). A marked distinction was also observed in the median PFS (6.1 months [95% CI, 4.7-7.8] for PE vs. 4.9 months for PA (95% CI, 3.2-6.4) for PA; HR 0.55, 95% CI, 0.41-0.75; p = 0.001). There were noteworthy differences in the rate of the key AEs between the two groups (72.0% for PE vs. 45.3% for PA, p < 0.001). Noteworthy differences were also detected for fatigue events (7.0% in the PE group vs. 0.9% in the PA group, p = 0.025) and musculoskeletal events (9.0% for PE vs. 0.9% for PA, p = 0.007), but these events tended to be manageable.\n\n\nCONCLUSIONS\nAmong selected populations of men with previously untreated mCRPC harbouring PD-L1 staining, PEM added to ENZ treatment may significantly increase the survival benefits compared with PEM treatment alone regardless of tumor mutation status. The safety profile for PE plus ENZ tends to be manageable.",
"affiliations": "Department of Urinary Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, China.;Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, China.;Department of Orthopaedics, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, China.;Department of Orthopaedics, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, China. yuwg3@mail.sysu.edu.cn.;Department of Neurosurgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, China. xuguix@mail.sysu.edu.cn.",
"authors": "Lin|Huanyi|H|;Liu|Qilong|Q|;Zeng|Xianshang|X|;Yu|Weiguang|W|;Xu|Guixing|G|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D001549:Benzamides; D014408:Biomarkers, Tumor; D009570:Nitriles; D061026:Programmed Cell Death 1 Receptor; D010669:Phenylthiohydantoin; C540278:enzalutamide; C582435:pembrolizumab",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-021-08156-1",
"fulltext": "\n==== Front\nBMC Cancer\nBMC Cancer\nBMC Cancer\n1471-2407\nBioMed Central London\n\n8156\n10.1186/s12885-021-08156-1\nResearch Article\nPembrolizumab with or without enzalutamide in selected populations of men with previously untreated metastatic castration-resistant prostate cancer harbouring programmed cell death ligand-1 staining: a retrospective study\nLin Huanyi linhyi2@mail.sysu.edu.cn\n\n1\nLiu Qilong liuqilong@mail.sysu.edu.cn\n\n2\nZeng Xianshang zxiansh@mail.sysu.edu.cn\n\n3\nYu Weiguang yuwg3@mail.sysu.edu.cn\n\n3\nXu Guixing xuguix@mail.sysu.edu.cn\n\n4\n1 grid.412615.5 Department of Urinary Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China\n2 grid.412615.5 Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China\n3 grid.412615.5 Department of Orthopaedics, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China\n4 grid.412615.5 Department of Neurosurgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China\n13 4 2021\n13 4 2021\n2021\n21 3991 3 2021\n30 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. 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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\nThe purpose of this retrospective study was to evaluate the survival outcomes of pembrolizumab (PEM) plus enzalutamide (ENZ) versus PEM alone in selected populations of men with previously untreated metastatic castration-resistant prostate cancer (mCRPC) harbouring programmed cell death ligand-1 (PD-L1) staining.\n\nMethods\n\nConsecutive men with previously untreated mCRPC harbouring PD-L1 staining who underwent treatment with PEM plus ENZ (PE) or PEM alone (PA) at our medical centre from January 1, 2017, to January 31, 2021, were retrospectively identified. Follow-up was conducted monthly during the first year and then every 1 month thereafter. The primary outcomes of the study were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were the frequency of key adverse events (AEs).\n\nResults\n\nIn total, 302 men were retrospectively reviewed, 96 of whom were deemed to be ineligible per the exclusion criteria, leaving 206 men (PE: n = 100, median age 64 years [range, 43–85] and PA: n = 106, 65 years [range, 45–82]) who were eligible for the study. The median follow-up for both groups was 34 months (range, 2–42). At the final follow-up, the median OS was 25.1 months (95% confidence interval [CI], 22.3–27.6) in the PE group versus 18.3 months (95% CI, 16.5–20.9) in the PA group (hazard ratio [HR] 0.56; 95% CI, 0.39–0.80; p = 0.001). A marked distinction was also observed in the median PFS (6.1 months [95% CI, 4.7–7.8] for PE vs. 4.9 months for PA (95% CI, 3.2–6.4) for PA; HR 0.55, 95% CI, 0.41–0.75; p = 0.001). There were noteworthy differences in the rate of the key AEs between the two groups (72.0% for PE vs. 45.3% for PA, p < 0.001). Noteworthy differences were also detected for fatigue events (7.0% in the PE group vs. 0.9% in the PA group, p = 0.025) and musculoskeletal events (9.0% for PE vs. 0.9% for PA, p = 0.007), but these events tended to be manageable.\n\nConclusions\n\nAmong selected populations of men with previously untreated mCRPC harbouring PD-L1 staining, PEM added to ENZ treatment may significantly increase the survival benefits compared with PEM treatment alone regardless of tumor mutation status. The safety profile for PE plus ENZ tends to be manageable.\n\nKeywords\n\nPembrolizumab\nEnzalutamide\nCastration-resistant\nProstate cancer\nSurvival\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nMetastatic castration-resistant prostate cancer (mCRPC) continues to be a major cause of complications and death among men [1–3]. Management of mCRPC is still controversial [3]. Several therapies have been shown to improve the overall survival (OS) and progression-free survival (PFS) of men with mCRPC [4–6]. Nevertheless, the majority of men eventually die as a consequence of mCRPC within 1–3 years. Combining a programmed cell death protein-1 (PD-1) inhibitor (pembrolizumab [PEM]) with a second-generation androgen receptor (AR) antagonist (enzalutamide [ENZ]) at the time of comprehensive therapy for mCRPC has emerged as an option to potentially prolong the progression of cancer and improve OS [7].\n\nPEM, an IgG4 subclass antibody and a checkpoint inhibitor, binds with high affinity to the cell surface receptor PD-1 [8, 9]. The rationale of an immunological treatment in prostate cancer is shown in Fig. 1. The binding of PEM to PD-1 blocks the inhibitory pathway, triggering a physiological shift to immune reactivity and enhancing the antitumor immune response, and PEM therapy is under development for the management of mCRPC [10, 11]. A recent study [12] showed that one-third of mCRPC biopsies exhibit programmed cell death ligand-1(PD-L1) staining, implying that strategies to enhance CD8+ T cell function and block the inhibitory pathway in the tumor may provide a theoretical basis for the feasibility of mCRPC immunotherapy. Although adding PEM to ENZ treatment has been reported to extend OS for men with mCRPC [13], the activity of PEM monotherapy remains controversial in mCRPC [14]. Immunotherapy with PEM tends to be an ideal treatment option in men with mCRPC, whether as a single agent or in combination with ENZ [9]. Nevertheless, previous pivotal trials [9, 11, 15] with immunotherapy failed to exclude men treated with chemotherapy and/or radiotherapy as well as androgen-deprivation therapy (ADT). Fig. 1 PEM is a humanized monoclonal antibody against PD-1 receptor. The activity of T cells may be restored via the checkpoint blockade using PEM. This binding reactivates the T cell signal induced by the interaction between MHC and TCR by initiating the proliferation of T cells and targeting tumor cells. PEM: pembrolizumab; PD-1: programmed cell death protein-1; MHC: major histocompatibility complex; TCR: T cell receptor\n\nGiven the binding of PEM to PD-1, it is unclear whether to stratify PD-1 staining during the final survival analysis, although previous analyses were powered for the entire population and not the subgroups [16, 17]. Furthermore, with previous trials [18, 19] indicating that 2–12% of mCRPC harbour a hypermutated state, PEM epitomizes a different anticancer option for a subset of mCRPC. Nevertheless, remarkably, only a few men with mCRPC were included in the PEM study [13, 20]; hence, the actual efficacy of PEM, even in a biomarker-selected mCRPC setting, has not been fully assessed. Additionally, a retrospective analysis involving select Chinese men with previously untreated mCRPC harbouring PD-L1 staining is lacking. Herein, we performed a retrospective review to verify whether men with previously untreated mCRPC harbouring PD-L1 staining who underwent treatment with PEM plus ENZ had a greater survival advantage than those who underwent treatment with PEM alone.\n\nMethods\n\nData\n\nConsecutive men with previously untreated mCRPC harbouring PD-L1 staining who received PEM plus ENZ (PE) or PEM alone (PA) from January 1, 2017, to January 31, 2021, and for whom patient characteristics were available were retrospectively identified from the First Affiliated Hospital, Sun Yat-sen University. Eligible patients were men with biopsy-proven adenocarcinoma of the prostate with metastatic prostate adenocarcinoma confirmed by sensitive imaging evidence of disease spread (whole-body magnetic resonance imaging [MRI] allowing the early detection of metastases, technetium-99 bone scans, or positron-emission tomography [PET] with prostate-specific membrane antigen [PSMA]); PD-L1 expression staining (combined positive score [CPS] ≥ 1) as determined by an FDA-approved test; PD-L1 expression was measured using PD-L1 IHC 22C3 pharmDx; microsatellite instable-high status; no prior treatment for mCRPC; at least 3 increasing serum prostate-specific antigen (PSA) values based on the Prostate Cancer Working Group guidelines [21]; an Eastern Cooperative Oncology Group (ECOG) performance status from 0 to 1; and adequate heart, liver and renal function [22]. Key exclusion criteria included unavailable pathologic and laboratory data; prior use of checkpoint inhibitor(s); no evaluable CPS; prior chemotherapy and/or radiotherapy, ADT, or surgery for cancer; interruption of PE or PA, regardless of treatment-induced toxicity or adverse events (AEs); active autoimmune disease; neurologic symptoms or symptomatic central nervous system (CNS) metastasis; cachexy; corticosteroid requirement; cauda equina syndrome; some medical illnesses (i.e., pneumonitis, inflammatory bowel disease, uninhibited hypertension, acute respiratory distress syndrome, septicaemia, or septicopyaemia); surgical emergency (i.e., enterobrosis, lienal rupture); major organ failure (i.e., lung, brain, kidney, and/or heart); uncontrolled intercurrent illness; epilepsy; and neuropathy grade 2 or worse.\n\nStudy design and treatment\n\nA retrospective single-centre review was performed in which eligible men had received at least one dose of the PE or PA regimen for the management of mCRPC harbouring PD-L1 staining. The PE regimen consisted of PEM (200 mg intravenously over 30 min every 3 weeks [13] plus ENZ (160 mg/day) [23]. The PA regimen consisted of 200 mg PEM given intravenously over 30 min every 3 weeks. The regimens for PE and PA were terminated with the occurrence of disease progression, toxic effects, or death. Dose modification was not permitted.\n\nOutcomes and assessments\n\nThe co-primary outcomes were OS, defined as the date of drug treatment to death from any cause, and PFS, defined as the date of drug treatment to either disease progression or death from any cause, whichever occurred first. Symptomatic events involving worsening cancer-related symptoms and/or new cancer-related complications were considered clinical progression [24]. Radiologic progression was defined as equal to or greater than a 20% enlargement in sum diameter of soft-tissue target lesions on a computerized tomography (CT) image, equal to or greater than 2 new bone lesions on a bone scan, or death, whichever came first [24]. Disease evaluation was performed every 3 months according to the Response Evaluation Criteria in Solid Tumors (RECIST, v1.1) [25]. PSA50 was defined as PSA decline of ≥50% from baseline PSA level prior to drug initiation. This follow-up schedule continued until disease progression, uncontrollable drug-related toxic effects, or death. Secondary outcomes were the frequency of key drug-related AEs that were evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.0 [26]. Efficacy data for both cohorts were analysed separately. Men with mCRPC were examined centrally for PD-L1 by immunohistochemistry. Follow-up time was defined as the date of drug treatment to the last follow-up. Follow-up was conducted monthly during the first year and then every 3 months thereafter.\n\nStatistic1al analysis\n\nA χ2 test was used to test for differences between categorical data. Continuous data were compared with Student’s t-test for normally distributed data and the Mann-Whitney U test for non-normally distributed data. Survivorship curves were drawn using the Kaplan-Meier method with a log-rank test. The hazard ratio (HR) was calculated using a Cox proportional hazards model, with age used as a covariate and therapy as the time-dependent factor. The median follow-up was estimated using the reverse Kaplan-Meier method. Two-sided 5% level tests were used, without adjustment for multiplicity. The survival curves were generated by GraphPad Prism 8.0(La Jolla, California, USA). We performed the other statistical analyses using SPSS 26.0 (IBM, Inc., NY, America).\n\nResults\n\nDemographic characteristics\n\nWe identified 302 men with previously untreated mCRPC harbouring PD-L1 staining, of whom 206 were included. Of these men, 100 men underwent PE, and 106 underwent PA, as shown in Fig. 2. Table 1 summarizes the baseline data of men who underwent PE or PA. Baseline data were well balanced between groups. The median age was 64 years (range, 43–85) in the PE group and 65 years (range, 45–82) in the PA group. The median time since diagnosis for both groups was 7 months. PD-L1 CPS was 1–20 in 64.0%, 20–50 in 22.0%, and 50–100 in 14.0% of men undergoing PE versus 1–20 in 63.2%, 20–50 in 21.7%, and 50–100 in 15.1% of men undergoing PA (p = 0.872). Asymptomatic CNS metastasis and no CNS metastasis were 35.0 and 65.0% in the PE group versus 45.3 and 54.7% in the PA group, respectively (p = 0.134). ECOG status was 0 in 38.0% and 1 in 62.0% of men undergoing PE versus 0 in 41.5% and 1 in 58.5% of men undergoing PA (p = 0.608). Additionally, no noteworthy distinctions were observed in terms of age, PSA level, alkaline phosphatase level, albumin, clinical stage at diagnosis, pathological stage at diagnosis, Gleason sum at diagnosis, or the number of metastatic sites. The median follow-up for the study was 34 months (range, 2–42). The median number of treatment cycles was 33 (range, 1–42) for men receiving PE and 34 (range, 1–42) for those who were treated with PA. Fig. 2 Flow diagram exhibiting the methods applied to identify objects to evaluate survival of pembrolizumab plus enzalutamide (PE) versus pembrolizumab alone (PA) in selected men with previously untreated metastatic castration-resistant prostate cancer harbouring programmed cell death ligand-1 staining\n\nTable 1 Characteristics of patients who underwent treatment\n\nVariable\tPE (n = 100)\tPA (n = 106)\tp-value\t\nAge, years\t64 (43–85)\t65 (45–82)\t0.227a\t\nTime since diagnosis, month(s)\t7 (2–15)\t7 (1–17)\t0.361a\t\nPSA levelc, ng/mL\t121 (2–2165)\t126 (4–2110)\t0.183a\t\nAlkaline phosphatase levelc, U/L\t181 (72–1023)\t173 (66–983)\t0.219a\t\nAlbumin g/dl\t3.6 (2.2–3.9)\t3.7 (2.1–4.2)\t0.127a\t\nClinical stage at diagnosis, n (%)\t\t\t0.794b\t\n T1c\t9 (9.0)\t7 (6.6)\t\t\n T2b\t12 (12.0)\t14 (13.2)\t\t\n T2c\t14 (14.0)\t20 (18.8)\t\t\n T3\t20 (20.0)\t21 (19.8)\t\t\n M0\t22 (22.0)\t20 (18.8)\t\t\n M1\t23 (23.0)\t24 (22.6)\t\t\nPathological stage at diagnosis, n (%)\t\t\t0.297b\t\n T2\t22 (22.0)\t20 (18.9)\t\t\n T3\t28 (28.0)\t26 (24.5)\t\t\n N0\t30 (30.0)\t33 (31.1)\t\t\n N1\t20 (20.0)\t27 (25.5)\t\t\nGleason sum at diagnosis, n (%)\t\t\t0.941b\t\n ≤ 6\t23 (23.0)\t24 (22.6)\t\t\n 7\t35 (35.0)\t37 (34.9)\t\t\n ≥ 8\t42 (42.0)\t45 (42.4)\t\t\nPD-L1 expression (CPS cut-off values), n (%)\t\t\t0.872b\t\n 1–20\t64 (64.0)\t67 (63.2)\t\t\n 20–50\t22 (22.0)\t23 (21.7)\t\t\n 50–100\t14 (14.0)\t16 (15.1)\t\t\nmCRPC-related brain metastasis, n (%)\t\t\t0.134b\t\n Asymptomatic CNS metastasis\t35 (35.0)\t48 (45.3)\t\t\n Without CNS metastasis\t65 (65.0)\t58 (54.7)\t\t\nDuration of drug treatment (months)\t16 (1–34)\t17 (2–33)\t0.103a\t\nECOG status, n (%)\t\t\t0.608b\t\n 0d\t38 (38.0)\t44 (41.5)\t\t\n 1e\t62 (62.0)\t62 (58.5)\t\t\nNo. of metastatic sites, n (%)\t\t\t0.597b\t\n 3\t23 (23.0)\t31 (29.2)\t\t\n > 3\t62 (62.0)\t57 (53.8)\t\t\n Unclear\t15 (15.0)\t18 (17.0)\t\t\naIndependent samples t-test; b Mann-Whitney U test; c Calculated one week prior to the start of PE or PA; 0d, Fully active, able to carry on all pre-disease performance without restriction; 1e, Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, i.e., light housework, office work\n\nPE pembrolizumab plus enzalutamide, PA pembrolizumab alone, PSA prostate-specific antigen, CNS central nervous system, PD-L1 programmed cell death ligand-1, CPS combined positive score, mCRPC metastatic castration-resistant prostate cancer, ECOG Eastern Collaborative Oncology Group\n\nFourteen (13.2%) PA-treated men received ENZ prior to death. Figure 3 showed that the best PSA change from baseline in PA-treat men with previously untreated mCRPC harbouring PD-L1 staining. Sixteen men (15.1%) achieved PSA50 after a median of 2 months (range, 1–5) following treatment initiation. Among 16 men, thirteen men had more than 97% PSA decline, and ten men had 100% PSA decline. Figure 4 showed that the best PSA change from baseline in PE-treat men with previously untreated mCRPC harbouring PD-L1 staining. Nineteen men (19.0%) achieved PSA50 after a median of 2 months (range, 1–4) following treatment initiation. Among 19 men, 12 men had 100% PSA decline. The overall response rate was 66% in the PE group versus 56% in the PA group (p < 0.05). Fig. 3 Best PSA change from baseline in PA-treated men with previously untreated metastatic castration-resistant prostate cancer harbouring programmed cell death ligand-1 staining who underwent pembrolizumab alone (n = 106)\n\nFig. 4 Best PSA change from baseline in PE-treated men with previously untreated metastatic castration-resistant prostate cancer harbouring programmed cell death ligand-1 staining who underwent pembrolizumab alone (n = 100)\n\nSurvival analysis\n\nFigures 5 and 6 show the Kaplan-Meier survival curves for the distinctions between the groups in OS and PFS, respectively. At the end of the follow-up, 125 deaths were registered (60.7% [125/206]; 54 men [54%] in the PE group vs. 71 men [67.0%] in the PA group). In the PE group, 38 deaths (38%) were mCRPC-related, and 16 (16%) were not mCRPC-related; in the PA group, 62 deaths (58.5%) were CRPC-related, and 9 (8.5%) were not. The 54 men who died in the PE group had a median age of 78 years (range, 52 to 85), and the 71 men who died in the PA group had a median age of 79 years (range, 55–82). A borderline remarkable difference was found in the median OS between groups (25.1 months [95% CI, 22.3–27.6] for PE vs. 18.3 months [95% CI, 16.5–20.9] for PA). The addition of ENZ to PEM treatment notably improved the median OS versus treatment with PEM alone, and PEM plus ENZ was associated with a noteworthy 44% lower risk of death than PEM alone (HR 0.56, 95% CI, 0.39–0.80; p = 0.001). A remarkable difference of approximately 7 months was detected in the median OS, and the advantage of PE over PA was significant, as the two curves continued to separate until the end of follow-up. Additionally, a marked distinction in the median PFS between groups was noted (6.1 months [95% CI, 4.7–7.8] for PE vs. 4.9 months for PA [95% CI, 3.2–6.4] [HR 0.55, 95% CI, 0.41–0.75; p = 0.001]). Of the 206 men, PE or PA was terminated in 54 (26.2%), mostly due to disease progression (34 of 54 men in the PE group vs. 20 of 54 men in the PA group, p = 0.014). Although more men eventually developed disease progression in the PE group, a noteworthy delay was seen in the time taken for tumors to progress in this group, which may have contributed to the appreciably longer PFS. Fig. 5 Kaplan-Meier curves for overall survival. The median overall survival was 25.1 months (95% confidence interval [CI], 22.3–27.6) for PE and 18.3 months (95% CI, 16.5–20.9) for PA (HR 0.56, 95%CI, 0.39–0.80; p = 0.001). *The hazard ratio was calculated using a Cox proportional hazards model, with the age, time since diagnosis, PSA level, alkaline phosphatase level, clinical stage at diagnosis, pathological stage at diagnosis, Gleason sum at diagnosis, mCRPC-related brain metastasis, ECOG status, and number of metastatic sites used as covariates and therapy as the time-dependent factor\n\nFig. 6 Kaplan-Meier curves for progression-free survival. The median progression-free survival was 6.1 months (95% confidence interval [CI], 4.7–7.8) for PE and 4.9 months (95% CI 3.2–6.4) for PA (HR 0.55, 95%CI, 0.41–0.75; p = 0.001). *The hazard ratio was calculated using a Cox proportional hazards model, with the age, time since diagnosis, PSA level, alkaline phosphatase level, clinical stage at diagnosis, pathological stage at diagnosis, Gleason sum at diagnosis, mCRPC-related brain metastasis, ECOG status, and number of metastatic sites used as covariates and therapy as the time-dependent factor\n\nIn a subset analysis based on PDL1 expression, the median OS in the PE versus PA group was 28.6 months vs. 21.3 months among men with PD-L1 CPS ≥50 (HR 0.62; p = 0.001), 26.6 months vs. 19.4 months among those with a CPS ≥20 (HR 0.43; p = 0.001) and 21.4 months vs. 16.8 months among those with a CPS ≥1 (HR 0.53, p = 0.001). The higher the level of tumor PD-L1 expression indicating the presence of an antitumor immune response, the more likely it will be that the individual will benefit from PE therapy regardless of tumor mutation status.\n\nAdverse events\n\nThe incidence of the key AEs during the first three follow-ups was higher in the PE group than in the PA group. Throughout the follow-up period, cardiovascular events were serious AEs resulting in death. There was no significant difference in cardiovascular events (2 men [1.0%] in the PE group vs. 2 [1.9%] in the PA group, p = 0.953). The most frequently reported AEs were primarily immune-related events, hypothyroidism, hyperthyroidism, fatigue, and musculoskeletal events. Table 2 shows the frequency of the key AEs possibly associated with PE or PA. In the PE group, the frequency of the key AEs was 72.0% (72 AEs in 65 men). In the PA group, the frequency of the key AEs was 45.3% (48 AEs in 55 men). PE-treated men had a higher rate of key AEs than PA-treated men (72.0% vs. 45.3%, p < 0.001). Noteworthy distinctions were observed for fatigue events (7.0% in the PE group vs. 0.9% in the PA group, p = 0.025) and musculoskeletal events (9.0% in the PE group vs. 0.9% in the PA group, p = 0.007), but these events tended to be manageable. There were no noteworthy distinctions between the two cohorts in terms of immune-related events, hypothyroidism, hyperthyroidism, thyroiditis, pneumonitis or interstitial lung disease, vitiligo, colitis, fracture, hypertension, falls, cognitive and memory impairment, or cardiovascular events. Table 2 Key adverse events\n\nVariable, n%\tPE (n = 100)\tPA (n = 106)\tHR (95%)\tp-value\t\nImmune-related event\t21 (21%)\t16 (15.1)\t2.00 (0.21–3.53)\t0.271\t\nHypothyroidism\t11 (11.0)\t8 (7.5)\t4.00 (0.38–2.71)\t0.393\t\nHyperthyroidism\t7 (7.0)\t5 (4.7)\t1.00 (0.12–3.43)\t0.485\t\nThyroiditis\t3 (3.0)\t2 (1.9)\t2.00 (0.37–4.81)\t0.605\t\nPneumonitis or interstitial lung disease\t3 (3.0)\t2 (1.9)\t2.00 (0.74–4.35)\t0.605\t\nVitiligo\t1 (1.0)\t1 (0.9)\t4.00 (0.28–6.54)\t1.000\t\nColitis\t2 (2.0)\t2 (1.9)\t3.00 (0.43–4.22)\t0.953\t\nFatigue (asthenia)\t7 (7.0)\t1 (0.9)\t3.00 (1.79–3.88)\t0.025a\t\nMusculoskeletal eventb\t9 (9.0)\t1 (0.9)\t5.00 (3.65–6.85)\t0.007a\t\nFracturec\t1 (1.0)\t4 (3.8)\t3.00 (0.31–4.76)\t0.196\t\nHypertensiond\t1 (1.0)\t2 (1.9)\t2.00 (0.28–3.41)\t1.000\t\nFall\t2 (2.0)\t1 (0.9)\t2.00 (0.83–3.73)\t0.612\t\nCognitive and memory impairmente\t2 (2.0)\t1 (0.9)\t2.00 (0.14–3.47)\t0.612\t\nCardiovascular event\t2 (1.0)\t2 (1.9)\t3.00 (0.27–4.19)\t0.953\t\naStatistically significant\n\nbincluded musculoskeletal pain, pain in extremity, arthralgia, myalgia, stiffness, muscular weakness, and muscle spasms; c included bone and joint injuries; d included hypertensive retinopathy, increased blood pressure, systolic hypertension, and hypertensive crisis; e included cognitive disorders, amnesia, Alzheimer’s disease, dementia, senile dementia, mental impairment, and vascular dementia\n\nPE pembrolizumab plus enzalutamide, PA pembrolizumab alone, HR Hazard ratio\n\nDiscussion\n\nThe findings from the current retrospective review demonstrated that the addition of PEM to ENZ treatment may be associated with substantially longer PFS times for men with previously untreated mCRPC harbouring PD-L1 staining, prominently longer OS than the use of PEM treatment alone, and a manageable safety profile. The Kaplan-Meier curves for survival among the men in our study suggested an early survival advantage for men undergoing treatment with PEM plus ENZ that continued until the last follow-up, with a remarkable difference of approximately 7 months in median OS, which reached statistical significance regardless of tumor mutation status.\n\nThe results of this retrospective review are consistent with the findings from a phase II single-arm study of 28 men with mCRPC [13], which examined the antitumor effect of PEM added to ENZ treatment in men with mCRPC whose cancer was progressing with ENZ treatment alone. In that study, the median OS for all men was 21.9 months (95% CI, 14.7 to 28.4 months). Their conclusion showed that the PEM plus ENZ regimen is effective in mCRPC, and responses did not require tumor PD-L1 expression. Recently, a multicohort, open-label phase II KEYNOTE-199 study [27] of 258 men with mCRPC assessed the antitumor activity and safety of PEM in three parallel cohorts who had undergone treatment with docetaxel and one or more targeted endocrine therapies. All men received 200 mg PEM every 3 weeks for up to 35 cycles. The study showed that the objective response rate was 5% (95% CI, 2 to 11%) for RECIST-measurable PD-L1-positive men and 3% (95% CI, < 1 to 11%) for RECIST-measurable PD-L1-negative men. The median OS was 9.5 months for RECIST-measurable PD-L1-positive men, 7.9 months for RECIST-measurable PD-L1-negative men, and 14.1 months for men with bone-predominant disease, regardless of PD-L1 expression. Although the mechanisms of response and resistance to docetaxel and ≥ 1 targeted endocrine therapy are still unclear, an explanation as to why a higher median OS (25.1 months) was observed in the present study might be that the earlier the PEM is used, the greater the survival benefit for the men. In previously treated mCRPC, some men have a therapeutic response to PEM [13]. Those who do respond to anti-PD-1/PD-L1 therapy have a distinct, durable response to treatment, suggesting some derive long-term benefit from PEM [27, 28]. The effect of earlier versus later treatment with PEM may have already been felt. Previous studies [13, 27] have found a diminished survival benefit attributable to the lack of effective therapies for mCRPC following the development of resistance to traditional remedies. Furthermore, distinct dissimilarities are observed in the duration of PEM treatment utilised in these studies for men with an initial diagnosis of mCRPC. Variation in PEM treatment duration may contribute to the differences in survival outcomes.\n\nPEM, a highly selective IgG4-kappa humanized monoclonal antibody against the PD-1 receptor, has shown a high response rate in mCRPC with mismatch repair deficiency, regardless of the primary tumor site [29], and was first approved by the FDA on September 4, 2014. The expression of PD-1 is associated with the aggressiveness of mCRPC and results in poor survival [27, 30]. A previous study [11] of 54 consecutive men with progressive, recurrent, or advanced prostate cancer who were treated with 1 to 12 cycles of 200 mg PEM every 3 weeks demonstrated that PEM had modest anticancer activity against mCRPC.\n\nAlthough the efficacy of PEM plus ENZ treatment in prolonging survival is promising, definite differences are observed in the duration of PEM treatment utilized in prior reports [14, 20] for men with an initial diagnosis of mCRPC. PEM is provided until castration resistance and/or disease progression, which may lead to differences in conclusions [27]. The delivery of PEM and ENZ is not synchronized in time, and this may have an effect on clinical decision making [13]. Comparisons of the PEM plus ENZ regimen in the present study with the PEM-based regimen in previous studies in accordance with the duration of therapy have not yet been implemented. Data from studies establishing whether the superiority of contemporaneous administration of PEM and ENZ instead of serial administration need to be explored further.\n\nProstate cancer has inherent characteristics [31]. Its growth and development are highly dependent on androgens [32]. ADT is an effective strategy and is widely used in clinical practice [33]. For men with asymptomatic or symptomatic mCRPC, first-line therapies usually involve ENZ (a targeted AR inhibitor) [31]. ENZ has the ability to bind to the ligand-binding domain of AR and to hinder the translocation of AR to the nucleus and the binding of AR to DNA [34]. Findings from an extended analysis of the phase 3 PREVAIL study [23] assessing ENZ treatment in men with chemotherapy-naive mCRPC showed that the median OS was 35.3 months (95% CI, 32.2-not reached) in the ENZ arm and 31.3 months (95% CI, 28.8–34.2) in the placebo arm. Moreover, the survival benefit conferred by the addition of ENZ to ADT tends to be sustained with extended follow-up, as evidenced by sustained separation of the OS curves. The reported AFFIRM trial [35] in 1199 men with previous docetaxel exposure (2,1 to ENZ or placebo) showed that a significant difference was detected in the median OS (18.4 months for ENZ vs. 13.6 months for placebo).\n\nSeveral key shortcomings should be acknowledged. First, the present retrospective review had inherent weaknesses. Residual confounding variables may lead to overestimation of the survival curve. Second, the identification of disease metastasis was not performed with PSMA PET in all men, and inaccurate imaging may convert the initial diagnosis from metastatic to nonmetastatic disease, eventually leading to the overestimation of the conclusions of the study. Third, the present subjects included were limited to men with previously untreated mCRPC harbouring PD-L1 staining; therefore, generalizability for men with mCRPC is lacking in this study. Fourth, although the AR splice variant 7 may serve as a treatment selection marker [24], detection of the AR splice variant 7 was not performed.\n\nConclusion\n\nThe results described here support the increasing body of evidence indicating that the addition of PEM treatment to ENZ therapy is associated with increased survival benefits in men with previously untreated mCRPC harbouring PD-L1 staining regardless of tumor mutation status. Additionally, the clinical outcomes of long-term maintenance therapy with PEM plus ENZ need further exploration in these men.\n\nAbbreviations\n\nPEM Pembrolizumab\n\nENZ Enzalutamide\n\nmCRPC Metastatic castration-resistant prostate cancer\n\nPD-1 Programmed cell death protein-1\n\nPD-L1 Programmed cell death ligand-1\n\nMHC Major histocompatibility complex\n\nTCR T cell receptor\n\nPE PEM plus ENZ\n\nPA PEM alone\n\nOS Overall survival\n\nPFS Progression-free survival\n\nAEs Adverse events\n\nCI Confidence interval\n\nHR Hazard ratio\n\nADT Androgen-deprivation therapy\n\nMRI Magnetic resonance imaging\n\nPSMA Prostate-specific membrane antigen\n\nCPS Combined positive score\n\nECOG Eastern Collaborative Oncology Group\n\nCNS Central nervous system\n\nCT Computed tomography\n\nBMI Body mass index\n\nRECIST Response Evaluation Criteria in Solid Tumors\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nHL and QL performed the data collection and manuscript writing. XZ performed statistical analysis. WY and GX participated in the study design. All authors have read and approved the final manuscript.\n\nFunding\n\nThis work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nAvailability of data and materials\n\nThe datasets generated during and/or analysed during the current study are not publicly available due to privacy regulations but are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nAll methods were performed in accordance with the relevant guidelines and regulations of the institutional and/or national research committee and the 1964 Helsinki declaration and its later amendments. This study was approved by the Institutional Review Board of the First Affiliated Hospital, Sun Yat-sen University (IRB13–8328), and the Ethics Review Committee of Sun Yat-sen University waived the need for informed consent because there was no active follow-up of study subjects and no data were collected directly from individuals.\n\nConsent for publication\n\nNot applicable.\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\nHuanyi Lin and Qilong Liu contributed equally to this work.\n==== Refs\nReferences\n\n1. Clarke N, Wiechno P, Alekseev B, Sala N, Jones R, Kocak I, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018;19(7):975–86. 10.1016/S1470-2045(18)30365-6.\n2. Conter HJ, Shore ND, Berry WR, Fong PCC, Rodriguez J, Appleman LJ, et al. Pembrolizumab (pembro) plus enzalutamide (enza) in patients (pts) with abiraterone acetate (abi)-pretreated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort C efficacy, safety, and biomarker results. J Clin Oncol. 2020;38(15).\n3. Hoimes CJ, Graff JN, Tagawa ST, Hwang C, Kilari D, Ten Tije AJ, et al. KEYNOTE-199 cohorts (C) 4 and 5: Phase II study of pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(15).\n4. Kyriakopoulos CE, Chen YH, Carducci MA, Liu G, Jarrard DF, Hahn NM, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial. J Clin Oncol. 2018;36(11):1080−+.\n5. Rusthoven CG, Jones BL, Flaig TW, Crawford ED, Koshy M, Sher DJ, et al. Improved Survival With Prostate Radiation in Addition to Androgen Deprivation Therapy for Men With Newly Diagnosed Metastatic Prostate Cancer. J Clin Oncol. 2016;34(24):2835−+.\n6. James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163–77.\n7. Graff JN, Alumkal JJ, Drake CG, Thomas GV, Redmond WL, Farhad M, et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget. 2016;7(33):52810–7. 10.18632/oncotarget.10547.\n8. Arija JAA, Yu EY, Piulats JM, Gravis G, Laguerre B, Oudard S, et al. Pembrolizumab (pembro) plus olaparib in patients (pts) with docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort a update. Ann Oncol. 2020;31:S513–S4. 10.1016/j.annonc.2020.08.880.\n9. Graff JN, Burgents J, Liang LW, Stenzl A. KEYNOTE-641: phase III study of pembrolizumab (pembro) plus enzalutamide for metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2019;30.\n10. Joshua AM, Gurney H, Retz M, Tafreshi A, Fong PCC, Shore ND, et al. Pembrolizumab (pembro) combination therapies in patients with metastatic castration-resistant prostate cancer (mCRPC): Cohorts A-C of the phase Ib/II KEYNOTE-365 study. Ann Oncol. 2020;31:–S1325-S.\n11. Mourey L, Conter HJ, Shore N, Berry WR, Fong PC, Piulats JM, et al. Pembrolizumab (pembro) plus enzalutamide (enza) in patients with abiraterone acetate (abi)-pretreated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort C update. Ann Oncol. 2020;31:S516–S7. 10.1016/j.annonc.2020.08.884.\n12. Haffner MC, Guner G, Taheri D, Netto GJ, Palsgrove DN, Zheng Q, et al. Comprehensive evaluation of programmed death-ligand 1 expression in primary and metastatic prostate Cancer. Am J Pathol. 2018;188(6):1478–85. 10.1016/j.ajpath.2018.02.014.\n13. Graff JN, Beer TM, Alumkal JJ, Slottke RE, Redmond WL, Thomas GV, et al. A phase II single-arm study of pembrolizumab with enzalutamide in men with metastatic castration-resistant prostate cancer progressing on enzalutamide alone. J Immunotherapy Cancer. 2020;8(2).\n14. Petrylak DP, Shore ND, Bennamoun M, Ratta R, Piulats JM, Li B, et al. Pembrolizumab (pembro) or placebo added to docetaxel and prednisone/prednisolone for metastatic castration-resistant prostate cancer (mCRPC) previously treated with next-generation hormonal agents (NHAs): KEYNOTE-921 phase III study. Ann Oncol. 2020;31:S1332–S3. 10.1016/j.annonc.2020.10.453.\n15. Omlin AG, Graff JN, Hoimes CJ, Tagawa ST, Hwang C, Kilari D, et al. KEYNOTE-199 phase II study of pembrolizumab plus enzalutamide for enzalutamide-resistant metastatic castration-resistant prostate cancer (mCRPC): cohorts (C) 4 and 5 update. Ann Oncol. 2020;31:S514–S5. 10.1016/j.annonc.2020.08.882.\n16. Petrylak DP Li B Schloss C Fizazi K KEYNOTE-921: Phase III study of pembrolizumab (pembro) plus docetaxel and prednisone for enzalutamide (enza)- or abiraterone (abi)-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) Ann Oncol 2019 30 351 10.1093/annonc/mdz248.048 30657856\n17. Romano E, Sridhar SS, Kolinsky MP, Gravis G, Mourey L, Piulats JM, et al. Pembrolizumab (pembro) plus docetaxel and prednisone in patients with abiraterone acetate (abi)- or enzalutamide (enza)-pretreated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort B update. Ann Oncol. 2020;31:S512–S3. 10.1016/j.annonc.2020.08.879.\n18. AMM E, Kicinski M, Blank CU, Mandala M, GGV L, Atkinson V, et al. Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2020;6(4):519–27.\n19. Nanda R, Liu MC, Yau C, Shatsky R, Pusztai L, Wallace A, et al. Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial. JAMA Oncol. 2020;6(5):676–84.\n20. Moses MM, Ledet E, Manogue C, Lewis BE, Barata PC, Sartor AO, et al. Pembrolizumab (pembro) in heavily pretreated metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37(7).\n21. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate Cancer clinical trials working group. J Clin Oncol. 2008;26(7):1148–59. 10.1200/JCO.2007.12.4487.\n22. de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, et al. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;20(9):1273–85.\n23. Beer TM, Armstrong AJ, Rathkopf D, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in men with chemotherapy-naive metastatic castration-resistant prostate Cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017;71(2):151–4. 10.1016/j.eururo.2016.07.032.\n24. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028–38. 10.1056/NEJMoa1315815.\n25. Edeline J, Boucher E, Rolland Y, Vauleon E, Pracht M, Perrin C, et al. Comparison of tumor response by response evaluation criteria in solid tumors (RECIST) and modified RECIST in patients treated with sorafenib for hepatocellular carcinoma. Cancer. 2012;118(1):147–56. 10.1002/cncr.26255.\n26. Basch E, Iasonos A, McDonough T, Barz A, Culkin A, Kris MG, et al. Patient versus clinician symptom reporting using the National Cancer Institute common terminology criteria for adverse events: results of a questionnaire-based study. Lancet Oncol. 2006;7(11):903–9. 10.1016/S1470-2045(06)70910-X.\n27. Antonarakis ES, Piulats JM, Gross-Goupil M, Goh J, Ojamaa K, Hoimes CJ, et al. Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J Clin Oncol. 2020;38(5).\n28. Frenel JS, Le Tourneau C, O'Neil B, Ott PA, Piha-Paul SA, Gomez-Roca C, et al. Safety and Efficacy of Pembrolizumab in Advanced, Programmed Death Ligand 1-Positive Cervical Cancer: Results From the Phase Ib KEYNOTE-028 Trial. J Clin Oncol. 2017;35(36):4035−+.\n29. Le DT DJN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13.\n30. Sena LA, Fountain J, Isaacsson Velho P, Lim SJ, Wang H, Nizialek E, et al. Tumor Frameshift mutation proportion predicts response to immunotherapy in mismatch repair-deficient prostate Cancer. Oncologist. 2021;26(2):e270–e8. 10.1002/onco.13601.\n31. Sternberg CN, Fizazi K, Saad F, Shore ND, De Giorgi U, Penson DF, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate Cancer. N Engl J Med. 2020;382(23):2197–206. 10.1056/NEJMoa2003892.\n32. Shore ND, Saad F, Cookson MS, George DJ, Saltzstein DR, Tutrone R, et al. Oral Relugolix for androgen-deprivation therapy in advanced prostate Cancer. N Engl J Med. 2020;382(23):2187–96. 10.1056/NEJMoa2004325.\n33. Shipley WU, Seiferheld W, Lukka HR, Major PP, Heney NM, Grignon DJ, Sartor O, Patel MP, Bahary JP, Zietman AL, Pisansky TM, Zeitzer KL, Lawton CAF, Feng FY, Lovett RD, Balogh AG, Souhami L, Rosenthal SA, Kerlin KJ, Dignam JJ, Pugh SL, Sandler HM, RTOG NRGO. Radiation with or without Antiandrogen therapy in recurrent prostate Cancer. N Engl J Med 2017;376(5):417–428, DOI: 10.1056/NEJMoa1607529.\n34. Teo MY, Rathkopf DE, Kantoff P. Treatment of Advanced Prostate Cancer. In: Klotman ME, editor. Annual Review of Medicine, Vol 70. Annu Rev Med, 2019. p. 479–499, 1, DOI: 10.1146/annurev-med-051517-011947.\n35. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–97. 10.1056/NEJMoa1207506.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "21(1)",
"journal": "BMC cancer",
"keywords": "Castration-resistant; Enzalutamide; Pembrolizumab; Prostate cancer; Survival",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D014408:Biomarkers, Tumor; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D009570:Nitriles; D010669:Phenylthiohydantoin; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor; D064129:Prostatic Neoplasms, Castration-Resistant; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "399",
"pmc": null,
"pmid": "33849473",
"pubdate": "2021-04-13",
"publication_types": "D016428:Journal Article",
"references": "32053137;31774688;29577933;29880291;28146658;26964769;26719232;22894553;31895407;28596308;33215787;29095678;32616555;29384722;31345626;32469183;21713764;32469184;30691365;27429197;27325855;17081915;27477525;18309951",
"title": "Pembrolizumab with or without enzalutamide in selected populations of men with previously untreated metastatic castration-resistant prostate cancer harbouring programmed cell death ligand-1 staining: a retrospective study.",
"title_normalized": "pembrolizumab with or without enzalutamide in selected populations of men with previously untreated metastatic castration resistant prostate cancer harbouring programmed cell death ligand 1 staining a retrospective study"
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"companynumb": "CN-ASTELLAS-2021US014433",
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{
"abstract": "Immune-checkpoint inhibitors (ICIs) are now standard of care for advanced non-small cell lung cancer (NSCLC). Unfortunately, many patients experience immune-related adverse events (irAEs), which are usually mild and reversible, but they require timely management and may be life threatening. No predictive markers of irAEs are available.\n\n\n\nThe neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were evaluated in patients with NSCLC consecutively treated with ICIs. Prespecified cutoff values of NLR and PLR were used and related to outcome and onset of irAEs. A control group of patients with advanced NSCLC not receiving ICIs was included.\n\n\n\nThe study included 184 patients: 26 (14.1%) received pembrolizumab upfront, and 142 (77%) received ICIs (pembrolizumab, nivolumab or atezolizumab) after one or more lines of chemotherapy. The median number of ICIs cycles was six (range, 1-61). The median progression-free survival and overall survival were 4.8 (95% CI, 3.4-6.3) and 20.6 (95% CI, 14.7-26.5) months, respectively. Sixty patients (32.6%) developed irAEs, mainly grade 1-2 (65.0%), causing ICI interruption in 46 cases (25.0%). Low NLR and low PLR at baseline were significantly associated with the development of irAEs (odds ratio [OR], 2.2; p = .018 and OR, 2.8; p = .003, respectively). Multivariate analyses confirmed PLR as independent predictive marker of irAEs (OR, 2.3; p = .020).\n\n\n\nNLR and PLR may predict the appearance of irAEs in non-oncogene-addicted aNSCLC, although this conclusion warrants prospective validation.\n\n\n\nThis study was designed to investigate the role of blood biomarkers in predicting the occurrence of immune-related adverse events (irAEs) in patients with advanced non-small cell lung cancer receiving immunotherapy. The results of the study suggest a potential predictive role of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as markers for irAE development in this category of patients. These data provide rationale for an easy and feasible application to be validated in clinical practice.",
"affiliations": "Medical Oncology 2, Veneto Institute of Oncology IOV, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy.;Department of Oncology, San Bortolo General Hospital, Azienda Unità Locale Socio Sanitaria (AULSS) 8, Vicenza, Italy.;Medical Oncology 2, Veneto Institute of Oncology IOV, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy.;Medical Oncology 2, Veneto Institute of Oncology IOV, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy.;Clinical Trials and Biostatistics, Veneto Institute of Oncology IOV, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy.;Medical Oncology 2, Veneto Institute of Oncology IOV, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy.;Medical Oncology 2, Veneto Institute of Oncology IOV, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy.;Department of Oncology, San Bortolo General Hospital, Azienda Unità Locale Socio Sanitaria (AULSS) 8, Vicenza, Italy.;Medical Oncology 2, Veneto Institute of Oncology IOV, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy pierfranco.conte@unipd.it laura.bonanno@iov.veneto.it.;Medical Oncology 2, Veneto Institute of Oncology IOV, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy pierfranco.conte@unipd.it laura.bonanno@iov.veneto.it.",
"authors": "Pavan|Alberto|A|;Calvetti|Lorenzo|L|;Dal Maso|Alessandro|A|;Attili|Ilaria|I|;Del Bianco|Paola|P|;Pasello|Giulia|G|;Guarneri|Valentina|V|;Aprile|Giuseppe|G|;Conte|PierFranco|P|;Bonanno|Laura|L|0000-0001-5218-4970",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C000594389:atezolizumab; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2018-0563",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "24(8)",
"journal": "The oncologist",
"keywords": "Immune‐related adverse events; Immunotherapy; Lung cancer; Neutrophil‐to‐lymphocyte ratio; Platelet‐to‐lymphocyte ratio; Predictive markers",
"medline_ta": "Oncologist",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; D002289:Carcinoma, Non-Small-Cell Lung; D016903:Drug Monitoring; D064420:Drug-Related Side Effects and Adverse Reactions; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D000077594:Nivolumab; D010976:Platelet Count; D061026:Programmed Cell Death 1 Receptor; D000077982:Progression-Free Survival; D012189:Retrospective Studies; D018570:Risk Assessment",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "1128-1136",
"pmc": null,
"pmid": "31015312",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": "15122199;23876227;23890059;26028407;26125452;26222619;26412456;26446948;26715621;26765102;27025911;27029035;27510892;27718847;28285682;28412137;28612596;28838390;28881921;28950287;28975219;29045560;29065983;29327044;29430978;29442281;29442540;29567557;29606147;29643991;29658856;29672849;29863955;29880896",
"title": "Peripheral Blood Markers Identify Risk of Immune-Related Toxicity in Advanced Non-Small Cell Lung Cancer Treated with Immune-Checkpoint Inhibitors.",
"title_normalized": "peripheral blood markers identify risk of immune related toxicity in advanced non small cell lung cancer treated with immune checkpoint inhibitors"
} | [
{
"companynumb": "IT-ROCHE-2338678",
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"activesubstancename": "PEMBROLIZUMAB"
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{
"abstract": "Cyclophosphamide (CYC) is used in clinical practice off-label for the induction of remission in childhood polyarteritis nodosa (PAN). Mycophenolate mofetil (MMF) might offer a less toxic alternative. This study was undertaken to explore the relative effectiveness of CYC and MMF treatment in a randomized controlled trial (RCT).\n\n\n\nThis was an international, open-label, Bayesian RCT to investigate the relative effectiveness of CYC and MMF for remission induction in childhood PAN. Eleven patients with newly diagnosed childhood PAN were randomized (1:1) to receive MMF or intravenous CYC; all patients received the same glucocorticoid regimen. The primary end point was remission within 6 months while compliant with glucocorticoid taper. Bayesian distributions for remission rates were established a priori for MMF and CYC by experienced clinicians and updated to posterior distributions on trial completion.\n\n\n\nBaseline disease activity and features were similar between the 2 treatment groups. The primary end point was met in 4 of 6 patients (67%) in the MMF group and 4 of 5 patients (80%) in the CYC group. Time to remission was shorter in the MMF group compared to the CYC group (median 7.1 weeks versus 17.6 weeks). No relapses occurred in either group within 18 months. Two serious infections were found to be likely linked to MMF treatment. Physical and psychosocial quality-of-life scores were superior in the MMF group compared to the CYC group at 6 months and 18 months. Combining the prior expert opinion with results from the present study provided posterior estimates of remission of 71% for MMF (90% credibility interval [90% CrI] 51, 83) and 75% for CYC (90% CrI 57, 86).\n\n\n\nThe present results, taken together with prior opinion, indicate that rates of remission induction in childhood PAN are similar with MMF treatment and CYC treatment, and MMF treatment might be associated with better health-related quality of life than CYC treatment.",
"affiliations": "University College London Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.;University of Liverpool, Liverpool, UK.;University of Liverpool, Liverpool, UK.;St. Joan de Déu Hospital, Barcelona, Spain.;St. Joan de Déu Hospital, Barcelona, Spain.;Alder Hey Children's NHS Foundation Trust, Liverpool, UK.;Alder Hey Children's NHS Foundation Trust, Liverpool, UK.;Alder Hey Children's NHS Foundation Trust, Liverpool, UK.;Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.;Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.;University of Liverpool, Liverpool, UK.;Royal Manchester Children's Hospital, Manchester, UK.;Hacettepe University, Ankara, Turkey.;Hacettepe University, Ankara, Turkey.;Bangor University, Bangor, UK.;Bangor University, Bangor, UK.;General University Hospital in Prague and Charles University, Prague, Czech Republic.;Lancaster University, Lancaster, UK.;Lancaster University, Lancaster, UK.;University of Cambridge, Cambridge, UK.;Instituto Giannina Gaslini, IRCCS, UOSID Centro Trial, Genoa, Italy.;University of Liverpool, Liverpool, UK.;University College London Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.",
"authors": "Brogan|Paul A|PA|0000-0001-6178-6893;Arch|Barbara|B|;Hickey|Helen|H|;Anton|Jordi|J|0000-0002-8792-4219;Iglesias|Este|E|;Baildam|Eileen|E|;Mahmood|Kamran|K|;Cleary|Gavin|G|;Moraitis|Elena|E|;Papadopoulou|Charalampia|C|;Beresford|Michael W|MW|;Riley|Phil|P|;Demir|Selcan|S|;Ozen|Seza|S|0000-0003-2883-7868;Culeddu|Giovanna|G|;Hughes|Dyfrig A|DA|;Dolezalova|Pavla|P|;Hampson|Lisa V|LV|;Whitehead|John|J|;Jayne|David|D|;Ruperto|Nicola|N|;Tudur-Smith|Catrin|C|;Eleftheriou|Despina|D|",
"chemical_list": "D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.1002/art.41730",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2326-5191",
"issue": "73(9)",
"journal": "Arthritis & rheumatology (Hoboken, N.J.)",
"keywords": null,
"medline_ta": "Arthritis Rheumatol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D009173:Mycophenolic Acid; D010488:Polyarteritis Nodosa; D012074:Remission Induction; D016896:Treatment Outcome",
"nlm_unique_id": "101623795",
"other_id": null,
"pages": "1673-1682",
"pmc": null,
"pmid": "33760371",
"pubdate": "2021-09",
"publication_types": "D000073843:Equivalence Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Mycophenolate Mofetil Versus Cyclophosphamide for Remission Induction in Childhood Polyarteritis Nodosa: An Open-Label, Randomized, Bayesian Noninferiority Trial.",
"title_normalized": "mycophenolate mofetil versus cyclophosphamide for remission induction in childhood polyarteritis nodosa an open label randomized bayesian noninferiority trial"
} | [
{
"companynumb": "NVSC2021GB174991",
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{
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "1",
... |
{
"abstract": "DOK7 congenital myasthenic syndrome (DOK7-CMS) generally presents early in life and is treated with salbutamol or ephedrine. This report describes an atypical case of a 39-year-old woman who presented with proximal upper limb weakness in the third trimester of pregnancy and was initially diagnosed with seronegative myasthenia gravis. Dramatic clinical worsening under pyridostigmine and further inefficacy of steroids, intravenous human immunoglobulin (IVIG) and plasma exchange (PLEX) led to the presumptive diagnosis of a CMS. Initially, a slow-channel CMS was regarded as more probable due to prominent finger extension weakness. Accordingly, fluoxetine was started and a lengthy improvement was seen. Clinical deterioration occurred after fluoxetine withdrawal, when a c.1124_1127dup homozygous mutation was detected in DOK7 gene. Afterwards, salbutamol was started and the patient became asymptomatic. This case highlights the importance of considering CMS before an adult-onset myasthenic syndrome and suggests a benefit from fluoxetine not previously reported in DOK7-CMS.",
"affiliations": "Department of Neurology, Hospital Prof. Doutor Fernando Fonseca, EPE, IC 19, 2720-276 Amadora, Portugal. Electronic address: marianagsantos2010@gmail.com.;Department of Neurology, Hospital Prof. Doutor Fernando Fonseca, EPE, IC 19, 2720-276 Amadora, Portugal.;Department of Neurology, Hospital Prof. Doutor Fernando Fonseca, EPE, IC 19, 2720-276 Amadora, Portugal.;Neuromuscular Disorders' Clinic, Hospital Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Rua da Junqueira, 126, 1349-019 Lisbon, Portugal.;CGC Genetics/Centro de Genética Clínica - Laboratory of Clinical Genomics, Rua Sá da Bandeira, 706 - 1°, 4000-432 Porto, Portugal.;CGC Genetics/Centro de Genética Clínica - Laboratory of Clinical Genomics, Rua Sá da Bandeira, 706 - 1°, 4000-432 Porto, Portugal.;Department of Neurology, Hospital Prof. Doutor Fernando Fonseca, EPE, IC 19, 2720-276 Amadora, Portugal.;Department of Neurology, Hospital Prof. Doutor Fernando Fonseca, EPE, IC 19, 2720-276 Amadora, Portugal.",
"authors": "Santos|Mariana|M|;Cruz|Simão|S|;Peres|João|J|;Santos|Luís|L|;Tavares|Purificação|P|;Basto|Jorge Pinto|JP|;Salgado|Vasco|V|;Valverde|Ana Herrero|AH|",
"chemical_list": "C511692:DOK7 protein, human; D009124:Muscle Proteins; D005473:Fluoxetine",
"country": "England",
"delete": false,
"doi": "10.1016/j.nmd.2017.12.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8966",
"issue": "28(3)",
"journal": "Neuromuscular disorders : NMD",
"keywords": "Congenital myasthenic syndrome; DOK7; Fluoxetine; Pregnancy",
"medline_ta": "Neuromuscul Disord",
"mesh_terms": "D000328:Adult; D005260:Female; D005473:Fluoxetine; D006801:Humans; D009124:Muscle Proteins; D018908:Muscle Weakness; D020294:Myasthenic Syndromes, Congenital; D011247:Pregnancy; D016896:Treatment Outcome",
"nlm_unique_id": "9111470",
"other_id": null,
"pages": "278-282",
"pmc": null,
"pmid": "29395672",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "DOK7 myasthenic syndrome with subacute adult onset during pregnancy and partial response to fluoxetine.",
"title_normalized": "dok7 myasthenic syndrome with subacute adult onset during pregnancy and partial response to fluoxetine"
} | [
{
"companynumb": "PT-MYLANLABS-2018M1022319",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PYRIDOSTIGMINE"
},
"drugadditional": "1",
... |
{
"abstract": "Allogeneic hematopoietic stem cell transplantation (alloSCT) is currently the only curative treatment modality for myelodysplastic syndromes (MDS). The treatment paradigm for MDS has changed in recent years with the introduction of hypomethylating agents (HMAs). The present retrospective multicenter study was designed to assess the effects of pre-transplant HMA on transplant outcome and determine which patients would benefit most from this therapy. A total of 109 patients who received alloSCT at one of five institutions between 2007 and 2010 were enrolled in this study regardless of pre-transplant HMA therapy. 81 of the 109 patients enrolled were treated with HMA prior to alloSCT. 28 patients received alloSCT without HMA bridging. The distributions of WHO classification groups and IPSS scores were similar between the two groups (P = 0.752 and P = 0.265, respectively). Pre-transplant HMA did not affect OS (P = 0.244), and there were no differences in response to HMA therapy within the HMA-treated group. The cumulative incidence of NRM was not significantly different between the two groups (P = 0.500). However, for patients with a high blast count (>5 % of bone marrow at the time of diagnosis), pre-transplant HMA therapy had a NRM benefit (83.3 vs. 48.6 %, P = 0.014).",
"affiliations": "Severance Hospital, Yonsei University College of Medicine, 250 Seongsan-ro, Seodaemun-gu, Seoul, 120-752, Korea.",
"authors": "Kim|Yundeok|Y|;Kim|In-Ho|IH|;Kim|Hyeong Joon|HJ|;Park|Silvia|S|;Lee|Kyoo-Hyung|KH|;Kim|Soo Jeong|SJ|;Lee|Jung-Hee|JH|;Kim|Dae-Young|DY|;Yoon|Sung-Soo|SS|;Kim|Yeo-Keoung|YK|;Jang|Jun Ho|JH|;Park|Seon Yang|SY|;Ahn|Jae-Sook|JS|;Cheong|Chul Won|CW|;Lee|Je-Hwan|JH|;Cheong|June-Won|JW|;|||",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-014-1549-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "99(5)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D004248:DNA (Cytosine-5-)-Methyltransferases; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D011300:Preoperative Care; D012189:Retrospective Studies; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "635-43",
"pmc": null,
"pmid": "24648120",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "21239814;12495905;12149198;17124062;17315156;17382251;6198660;11877264;19543327;10547344;9489648;20451404;12011120;7683356;8704196;12200358;6996481;16532500;19857589;23113470;10694545;6194100;16609072;9338076;6156004;19151791;8329721;11069027;17038533;15703418",
"title": "Multicenter study evaluating the impact of hypomethylating agents as bridging therapy to hematopoietic stem cell transplantation in myelodysplastic syndromes.",
"title_normalized": "multicenter study evaluating the impact of hypomethylating agents as bridging therapy to hematopoietic stem cell transplantation in myelodysplastic syndromes"
} | [
{
"companynumb": "KR-CELGENEUS-286-50794-14080829",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,... |
{
"abstract": "The judiciousness of the use of clozapine in patients with schizophrenia in clinical practice is brought to an even sharper focus when it has to be used in combination with other agents that cause myelosuppression, for example, chemotherapy and radiation treatment. There are a few references till date illustrating the combination of clozapine and chemotherapy and/or radiation therapy. To the best of our knowledge, such a case has not been reported from India. We report the case of a 39-year-old gentleman with a diagnosis of schizophrenia, remaining psychiatrically stable on clozapine, who underwent combination treatment of chemotherapy and radiotherapy for the treatment of cancer of the tongue in a tertiary care oncology centre in India.",
"affiliations": "Psychiatric Unit and Department of Palliative Care, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, India.;Department of Medical Oncology, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, India.;Department of Radiation Oncology, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, India.;Department of Head and Neck Surgical Oncology, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, India.",
"authors": "Deodhar|Jayita K|JK|;Prabhash|Kumar|K|;Agarwal|Jai P|JP|;Chaturvedi|Pankaj|P|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0019-5545.130507",
"fulltext": "\n==== Front\nIndian J PsychiatryIndian J PsychiatryIJPsyIndian Journal of Psychiatry0019-55451998-3794Medknow Publications & Media Pvt Ltd India IJPsy-56-19110.4103/0019-5545.130507Case ReportClozapine and cancer treatment: Adding to the experience and evidence Deodhar Jayita K. Prabhash Kumar 1Agarwal Jai P. 2Chaturvedi Pankaj 3Psychiatric Unit and Department of Palliative Care, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, India1 Department of Medical Oncology, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, India2 Department of Radiation Oncology, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, India3 Department of Head and Neck Surgical Oncology, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, IndiaAddress for correspondence: Dr. Jayita K. Deodhar, Psychiatric Unit and Department of Palliative Care, Psychiatric Unit, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, India. E-mail: jukd2000@yahoo.co.ukApr-Jun 2014 56 2 191 193 Copyright: © Indian Journal of Psychiatry2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The judiciousness of the use of clozapine in patients with schizophrenia in clinical practice is brought to an even sharper focus when it has to be used in combination with other agents that cause myelosuppression, for example, chemotherapy and radiation treatment. There are a few references till date illustrating the combination of clozapine and chemotherapy and/or radiation therapy. To the best of our knowledge, such a case has not been reported from India. We report the case of a 39-year-old gentleman with a diagnosis of schizophrenia, remaining psychiatrically stable on clozapine, who underwent combination treatment of chemotherapy and radiotherapy for the treatment of cancer of the tongue in a tertiary care oncology centre in India.\n\nCancerchemotherapyclozapineradiation therapy\n==== Body\nINTRODUCTION\nThe importance of the judicious use of clozapine in patients with schizophrenia in clinical practice is brought to an even sharper focus when it has to be used in combination with other agents that cause myelosuppression, for example, chemotherapy and radiation treatment. Chemotherapy can cause can cause marked bone marrow suppression, leading to neutropenia and thrombocytopenia. Radiation therapy can have acute effects on the bone marrow too. The use of clozapine with other agents, which cause leukopenia is a formal contraindication. Clozapine has to be usually discontinued if the white blood cell count drops below 3000 per cubic millimetre. Discontinuation of clozapine, however, may lead to a risk of relapse in those patients with schizophrenia who have been well controlled with this medication. This gives rise to a therapeutic tight spot and the effective management of both schizophrenia and cancer requires an intensive liaison between the oncology and the psychiatry teams responsible for care of the patient. There are a few references till date illustrating the combination of clozapine and chemotherapy and/or radiation therapy.[123] To the best of our knowledge, such a case has not been reported from India. We report the case of a 39-year-old gentleman with a diagnosis of schizophrenia, remaining psychiatrically stable on clozapine, who underwent combination treatment of chemotherapy and radiotherapy for the treatment of cancer of the tongue, in a tertiary care oncology centre in India.\n\nCASE REPORT\nA 39-year-old gentleman was being treated for paranoid schizophrenia since the onset of positive psychotic symptomatology in 1996 and had been on clozapine for 7 years prior to his presentation in our cancer hospital, in the dose of 300 mg (in daily divided doses). He was also on a combination of trifluoperazine 2.5 mg and trihexyphenidyl 1 mg 3 times a day. Though he did have occasional auditory hallucinations, overall he remained psychiatrically stable. He did not report any distressing side-effects of the medications except for excess salivation. He was diagnosed with cancer of the tongue T4N2bM0 moderately differentiated squamous carcinoma in August 2009. Detailed investigations showed that the tumor was borderline inoperable, which led to institution of platinum- and taxane-based neoadjuvant chemotherapy, each chemotherapy cycle lasting for 3 weeks.\n\nAs a formal nationally co-ordinated clozapine monitoring protocol in India is not present, previous annual complete blood count reports were lacking. However, there was no history suggestive of infection and the complete blood count done in the hospital prior to starting chemotherapy was essentially within normal limits (white blood cell count 10,400 per cubic millimetre (mm) and neutrophils 8,160 per cubic mm, hemoglobin of 13.3 g/dl, platelets 387,000 per cubic mm). The dose of clozapine was reduced by the institute-based liaison psychiatrist to 250 mg in daily divided doses before chemotherapy started in an attempt to reduce the hypersalivation, which was helpful and did not lead to any exacerbation of psychotic symptoms. A decision to continue on clozapine in this dose was taken following a detailed discussion between the liaison psychiatrist with patient and his brother, discussing the benefits and risks associated, with regular monitoring schedules fixed for mental state examination, complete blood counts and medications. Though the white blood cell count monitoring was advised 17 days following the start of the first cycle of chemotherapy, it was decided that it be done earlier than that, in view of the concurrent treatments.\n\nA complete blood count done on the 10th day in a private laboratory following start of first chemotherapy cycle revealed a drop in the white blood cell count to 2300 per cubic mm, neutrophils were 79%, platelet count of 250, 000 per cubic mm and hemoglobin of 10.3 g/dl. The patient developed high grade fever and mucositis, for which he was assessed on the 11th day and daily subsequently for the next week by the medical oncologist. The white blood cell count repeated on the 12th day, this time in the hospital laboratory, revealed a further drop to 1000 per cubic mm. Patient was started on antibiotics and granulocyte colony stimulating factor, following which the white blood cell counts improved on the 17th day to 8910 per cubic mm. As the platelet count was low, patient received platelet transfusion.\n\nIn the course of these events in these 8 days from 10th to 17th day following start of chemotherapy, the liaison psychiatrist after discussing with patient and his brother had earlier reduced the dose of clozapine to 200 mg daily in divided doses on the 5th day, considering the possible synergistic effect of the drug, as reported in literature[4] and a watch was kept on the mental state. But further discussion between the psychiatrist and the consultant medical oncologist and also between the former and the patient with his brother, led to the decision of maintaining patient in the same dose of clozapine, keeping in view the patient's psychiatrically stable condition and to prevent rebound psychosis leading from any further reduction, as this neutropenia seemed to be related to the chemotherapy.\n\nBy the 18th day, which was originally suggested as the day for monitoring post first chemotherapy cycle, when the complete blood count was repeated, the white blood cell count was 10,800 per cubic mm and neutrophil count 7680 per cubic mm, (essentially within normal limits), but still a low haemoglobin of 10.3 g/dl and a manual platelet count of 100,000 per cubic mm.\n\nThe pre-planned second cycle of chemotherapy was delayed by just 6 days following completion of the first cycle and a third cycle was added at the scheduled time after imaging and reassessment by the multidisciplinary Head and Neck Joint Clinic of the hospital. Growth factors were started on day 6 of each of these cycles as a preventive measure, in view of the experience of the first cycle. The white blood cell and neutrophil counts remained within normal limits after the second cycle but dropped to 2400 per cubic mm and 570 per cubic mm respectively after the third cycle. These stabilized to normal limits within the next 2 weeks. The dose of clozapine that the patient was on remained unchanged [Figure 1].\n\nFigure 1 White blood cell count during cancer treatment course. 1 CT – First chemotherapy cycle; 2 CT – Second chemotherapy cycle; 3 CT – Third chemotherapy cycle; Wk – Week; D – Day; Pall RT – Palliative radiation therapy; MT – Metronomic therapy\n\nAt this stage, a further reassessment by the head and neck oncology group advised radiation therapy with a palliative intent in view of progressive disease. The psychiatry team liaised with the consultant radiation oncologist prior to scheduling of radiotherapy sessions, with continuation of weekly monitoring protocols for mental state examination and complete blood counts. The patient underwent palliative external radiotherapy to face and neck to a dose of 50 Gy in 20 fractions, which led to partial relief in pain and swallowing. During this period, his mental state remained stable and white blood cell counts were maintained within normal limits, continuing so during the 2 months following completion of radiation treatment. To palliate further, metronomic therapy was then advised, which the patient underwent, with regular psychiatric review and weekly complete blood counts over the next 2 months. There was no resurgence of psychotic symptoms. Unfortunately, he had a rapid progression of disease and developed local infection. The white blood cell count increased to 13,600 per cubic mm and later to15,600 per cubic mm. He passed away 2 weeks later, nearly 8 months following his initial diagnosis.\n\nDISCUSSION\nThe sequence of events described above underlies the importance of frequent monitoring of white blood cell counts when clozapine and cancer treatments are concomitantly administered. The normal white blood cell count prior to the onset of chemotherapy and subsequent drop following it, with improvements after the chemotherapy cycles, were maintained during and after radiation treatment. This makes the possibility of a synergistic effect less likely in this particular case, and no persistent neutropenia is noted, unlike in other cases reported in the literature.[5]\n\nIn previously reported cases, clozapine replaced by haloperidol[67] and olanzapine[8] following neutropenia led to a psychotic relapse, which necessitated reintroduction of clozapine. Considering this evidence, the continuation of clozapine despite the steep drop in the total white blood cell and the absolute neutrophil count following the first chemotherapy cycle, though a difficult decision to make, was aided by extensive discussion and shared decision making between the liaison psychiatrist and medical oncologist, and also with the patient and his brother, who was the primary caregiver. This step was followed during radiation therapy too. The proactive use of colony stimulating factor in the subsequent chemotherapy cycles proved useful, as reported in the literature.[7]\n\nCONCLUSION\nIt is possible to continue clozapine in a patient with chronic schizophrenia undergoing chemoradiation for cancer with close supervision and collaboration with oncology clinicians. As the evidence in this topic is limited and controlled trials would not be possible, it is important to share the experience and add to the existing literature to facilitate an informed decision making by the clinicians in managing dually vulnerable patients with comorbid schizophrenia and cancer.\n\nSource of Support: Nil\n\nConflict of Interest: None declared\n==== Refs\nREFERENCES\n1 Goulet K Grignon S Case report: Clozapine given in the context of chemotherapy for lung cancer Psychooncology 2008 17 512 6 17847125 \n2 Wesson ML Finnegan DM Clark PI Continuing clozapine despite neutropenia Br J Psychiatry 1996 168 217 20 8837913 \n3 Taylor D Paton C Kapur S Clozapine and chemotherapy Maudsley Prescribing guidelines 2009 10th ed London Informa Health Care 74 \n4 Avnon M Stolerman I Clozapine, cancer and schizophrenia Am J Psychiatry 1993 150 1562 3 8379568 \n5 Rosenstock J Clozapine therapy during cancer treatment Am J Psychiatry 2004 16 175 14702271 \n6 Hundertmark J Campbell P Reintroduction of clozapine after diagnosis of lymphoma Br J Psychiatry 2001 178 576 11388983 \n7 Frieri T Barzega G Bada A Villari V Maintaining clozapine treatment during chemotherapy for non-Hodgkin's lymphoma Prog Neuropsychopharmacol Biol Psychiatry 2008 32 1611 2 18606485 \n8 Rosenberg I Mekinulov B Cohen LJ Galynker I Restarting clozapine treatment during ablation chemotherapy and stem cell transplant for Hodgkin's lymphoma Am J Psychiatry 2007 164 1438 9 17728433\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0019-5545",
"issue": "56(2)",
"journal": "Indian journal of psychiatry",
"keywords": "Cancer; chemotherapy; clozapine; radiation therapy",
"medline_ta": "Indian J Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "0013255",
"other_id": null,
"pages": "191-3",
"pmc": null,
"pmid": "24891711",
"pubdate": "2014-04",
"publication_types": "D016428:Journal Article",
"references": "8837913;11388983;8379568;17728433;18606485;17847125;14702271",
"title": "Clozapine and cancer treatment: Adding to the experience and evidence.",
"title_normalized": "clozapine and cancer treatment adding to the experience and evidence"
} | [
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"companynumb": "PHHY2014IN160148",
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{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nMaternal D alloimmunization detected in early gestation requires aggressive intervention to prevent severe fetal anemia. An intrauterine transfusion (IUT) is indicated to prevent fetal death once severe fetal anemia has been detected, but is not without risk. Protocols combining therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIG) have been described, but they usually bridge to IUT.\n\n\nMETHODS\nWe describe a 27-year-old G4, P0-1-2-0 Caucasian female with a history of ruptured ectopic pregnancy presented at 12 weeks' gestation with a very high anti-D titer (2048). TPE was performed on that week and twice more in the following week, with a fourth final exchange during Week 14. A loading dose of IVIG (2 g/kg) was administered over 2 days after the third TPE and then 1 g/kg per week until Week 28 (total, 14 doses).\n\n\nRESULTS\nThe antibody titer decreased to 256 by the beginning of 15 weeks' gestation and remained stable at that level for the remainder of the pregnancy. Doppler ultrasonographic measurements of the fetal middle cerebral artery peak flow velocity performed throughout gestation showed no evidence of fetal anemia. A healthy male infant was delivered at 37 weeks' gestation with mild immune-mediated hemolysis. The infant underwent successful treatment with an IVIG dose of 750 mg/kg and a red blood cell exchange.\n\n\nCONCLUSIONS\nOur unique TPE-IVIG protocol was successful at preventing the onset of severe fetal anemia in a patient with high titer anti-D. Since IUT may be fatal, our approach offers a safer and less-invasive treatment regime that can adequately sustain a fetus until term.",
"affiliations": "Division of Transfusion Medicine, Department of Pathology, North Shore University Hospital and Hofstra North Shore-LIJ School of Medicine, Manhasset, New York.",
"authors": "Bellone|Michael|M|;Boctor|Fouad N|FN|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "United States",
"delete": false,
"doi": "10.1111/trf.12633",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1132",
"issue": "54(8)",
"journal": "Transfusion",
"keywords": null,
"medline_ta": "Transfusion",
"mesh_terms": "D000328:Adult; D000743:Anemia, Hemolytic; D001783:Blood Flow Velocity; D001805:Blood Transfusion, Intrauterine; D005260:Female; D005315:Fetal Diseases; D005865:Gestational Age; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007231:Infant, Newborn; D008297:Male; D020768:Middle Cerebral Artery; D010951:Plasma Exchange; D011247:Pregnancy; D011248:Pregnancy Complications; D012203:Rh Isoimmunization; D017585:Ultrasonography, Doppler, Transcranial",
"nlm_unique_id": "0417360",
"other_id": null,
"pages": "2118-21",
"pmc": null,
"pmid": "24673470",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Therapeutic plasma exchange and intravenous immunoglobulin as primary therapy for D alloimmunization in pregnancy precludes the need for intrauterine transfusion.",
"title_normalized": "therapeutic plasma exchange and intravenous immunoglobulin as primary therapy for d alloimmunization in pregnancy precludes the need for intrauterine transfusion"
} | [
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"companynumb": "US-SHIRE-US201845909",
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"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
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"abstract": "OBJECTIVE\nNon-immune complex (IC)-mediated renal thrombotic microangiopathy (TMA) has been reported in patients with systemic lupus erythematosus (SLE), but most studies included patients with both renal TMA and IC-mediated lupus nephritis (LN). In this study, the clinicopathological features and outcomes of renal injury characterised by only renal TMA were retrospectively analyzed.\n\n\nMETHODS\nPatients with glomerular and/or vascular TMA in the absence of subendothelial or epithelial immune deposits were screened from 2,332 biopsied of SLE patients. The TMA lesions were divided into glomerular, vascular or both. Acute tubular-interstitial injury was semi-quantitatively analyzed. The podocyte foot process effacement (FPE) was measured by electronic microscopy.\n\n\nRESULTS\nTwo hundred fifty-seven (11.0%) renal biopsies revealed TMA, among which 237 biopsies showed TMA coexisting with LN, and 20 (0.9%) biopsies had only renal TMA without or with only mesangial immune deposits. All patients manifested with acute kidney injury and haematological disorders. Among them, 11 (55%) required renal replacement therapy, 12 (60%) had nephrotic syndrome and 13 (65.0%) showed microvascular haemolytic anaemia with thrombocytopenia. Seventeen (85%) biopsies revealed both glomerular TMA and vascular TMA, two had only glomerular TMA and one had vascular TMA. Eight (40%) had no glomerular immune deposits and 12 (60%) showed only mesangial immune deposits. The acute tubulointerstitial injury in patients requiring dialysis was more severe than those not needing dialysis ((43.6 ± 24.9) % vs. (21.7 ± 20.1) %, p = 0.047). FPE of podocytes was positively correlated with proteinuria (r2 = 0.347, p = 0.006). All patients received high-dose methylprednisolone pulse therapy. Four patients received plasma exchange. The renal function of 11 patients requiring dialysis initially recovered after 16.0 (interquartile range [IQR] 9.0, 30.0) days of treatment. During the follow-up of 58.0 (IQR 36.0, 92.3) months, remission was achieved in 19 (95%) patients; only one patient had no response. No patient died or progressed to end-stage renal disease; six patients (30%) relapsed.\n\n\nCONCLUSIONS\nRenal TMA, usually accompanying severe renal injury, was not uncommon in SLE patients with renal disease and should be distinguished from immune complex-mediated severe classes of LN. Early intensive immunosuppressive treatment may be associated with a good long-term renal outcome. Key Points • Most previous reports of renal TMA in SLE patients were associated with severe types of immune complex-mediated lupus nephritis; • Renal TMA with glomerular pauci-immune or only mesangial immune deposits was found in SLE patients and clinically presented with severe acute renal injury but good renal outcome; • Renal TMA should be considered as a unique type of SLE-associated renal injury.",
"affiliations": "National Clinical Research Center of Kidney Diseases, Jinling Clinical Medical College of Nanjing Medical University, No. 305, Zhongshan East Road, Nanjing, 210002, Jiangsu, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Jinling Clinical Medical College of Nanjing Medical University, No. 305, Zhongshan East Road, Nanjing, 210002, Jiangsu, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Jinling Clinical Medical College of Nanjing Medical University, No. 305, Zhongshan East Road, Nanjing, 210002, Jiangsu, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Jinling Clinical Medical College of Nanjing Medical University, No. 305, Zhongshan East Road, Nanjing, 210002, Jiangsu, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Jinling Clinical Medical College of Nanjing Medical University, No. 305, Zhongshan East Road, Nanjing, 210002, Jiangsu, China.;National Clinical Research Center of Kidney Diseases, Jinling Clinical Medical College of Nanjing Medical University, No. 305, Zhongshan East Road, Nanjing, 210002, Jiangsu, China. huwx@vip.163.com.",
"authors": "Chen|Wencui|W|;Liang|Shaoshan|S|;Zuo|Ke|K|;Yang|Liu|L|;Zeng|Caihong|C|;Hu|Weixin|W|http://orcid.org/0000-0002-6263-6149",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-021-05627-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "40(7)",
"journal": "Clinical rheumatology",
"keywords": "Clinicopathological features; Lupus nephritis; Outcome; Systemic lupus erythematosus; Thrombotic microangiopathy",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D006801:Humans; D007668:Kidney; D008180:Lupus Erythematosus, Systemic; D008181:Lupus Nephritis; D006435:Renal Dialysis; D012189:Retrospective Studies; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "2735-2743",
"pmc": null,
"pmid": "33543375",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": "9153540;22890468",
"title": "Clinicopathological features and outcomes of SLE patients with renal injury characterised by thrombotic microangiopathy.",
"title_normalized": "clinicopathological features and outcomes of sle patients with renal injury characterised by thrombotic microangiopathy"
} | [
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"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-317348",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
... |
{
"abstract": "Liver injury due to coronavirus disease 2019 (COVID-19) is being increasingly recognized. Abnormal liver chemistry tests of varying severities occur in a majority of patients. However, there is a dearth of accompanying liver histologic studies in these patients.\n\n\n\nThe current report details the clinical courses of 2 patients having severe COVID-19 hepatitis. Liver biopsies were analyzed under light microscopy, portions of liver tissue were hybridized with a target probe to the severe acute respiratory syndrome coronavirus-2 S gene, and small sections from formalin-fixed paraffin-embedded liver tissue were processed for electron microscopy.\n\n\n\nThe liver histology of both cases showed a mixed inflammatory infiltrate with prominent bile duct damage, endotheliitis, and many apoptotic bodies. In situ hybridization and electron microscopy suggest the intrahepatic presence of severe acute respiratory syndrome coronavirus-2, the findings of which may indicate the possibility of direct cell injury.\n\n\n\nOn the basis of the abundant apoptosis and severe cholangiocyte injury, these histopathologic changes suggest a direct cytopathic injury. Furthermore, some of the histopathologic changes may resemble acute cellular rejection occurring after liver transplantation. These 2 cases demonstrate that severe COVID-19 hepatitis can occur even in the absence of significant involvement of other organs.",
"affiliations": "Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: mariaisabel.fiel@mountsinai.org.;Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.;Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.;Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.;Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.;Department of Pathology and Division of Gastroenterology, State University of New York, Stony Brook Medical Center, Stony Brook, New York.;Department of Pathology and Division of Gastroenterology, State University of New York, Stony Brook Medical Center, Stony Brook, New York.;Division of Liver Diseases and Recanati-Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York.;Division of Liver Diseases and Recanati-Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York.;Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.;Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.;Division of Liver Diseases and Recanati-Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York.",
"authors": "Fiel|M Isabel|MI|;El Jamal|Siraj M|SM|;Paniz-Mondolfi|Alberto|A|;Gordon|Ronald E|RE|;Reidy|Jason|J|;Bandovic|Jela|J|;Advani|Rashmi|R|;Kilaru|Saikiran|S|;Pourmand|Kamron|K|;Ward|Stephen|S|;Thung|Swan N|SN|;Schiano|Thomas|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jcmgh.2020.09.015",
"fulltext": "\n==== Front\nCell Mol Gastroenterol Hepatol\nCell Mol Gastroenterol Hepatol\nCellular and Molecular Gastroenterology and Hepatology\n2352-345X\nElsevier\n\nS2352-345X(20)30158-2\n10.1016/j.jcmgh.2020.09.015\nOriginal Research\nFindings of Hepatic Severe Acute Respiratory Syndrome Coronavirus-2 Infection\nFiel M. Isabel mariaisabel.fiel@mountsinai.org\n1∗\nEl Jamal Siraj M. 1\nPaniz-Mondolfi Alberto 1\nGordon Ronald E. 1\nReidy Jason 1\nBandovic Jela 2\nAdvani Rashmi 2\nKilaru Saikiran 3\nPourmand Kamron 3\nWard Stephen 1\nThung Swan N. 1\nSchiano Thomas 3\n1 Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York\n2 Department of Pathology and Division of Gastroenterology, State University of New York, Stony Brook Medical Center, Stony Brook, New York\n3 Division of Liver Diseases and Recanati-Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York\n∗ Correspondence Address correspondence to: M. Isabel Fiel, MD, MS, Annenberg 15th Floor, Mount Sinai Hospital, New York, New York 10029. fax: (212) 828-4188. mariaisabel.fiel@mountsinai.org\n2021\n28 9 2020\n11 3 763770\n15 7 2020\n23 9 2020\n© 2020 The Authors\n2020\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nBackground & Aims\n\nLiver injury due to coronavirus disease 2019 (COVID-19) is being increasingly recognized. Abnormal liver chemistry tests of varying severities occur in a majority of patients. However, there is a dearth of accompanying liver histologic studies in these patients.\n\nMethods\n\nThe current report details the clinical courses of 2 patients having severe COVID-19 hepatitis. Liver biopsies were analyzed under light microscopy, portions of liver tissue were hybridized with a target probe to the severe acute respiratory syndrome coronavirus-2 S gene, and small sections from formalin-fixed paraffin-embedded liver tissue were processed for electron microscopy.\n\nResults\n\nThe liver histology of both cases showed a mixed inflammatory infiltrate with prominent bile duct damage, endotheliitis, and many apoptotic bodies. In situ hybridization and electron microscopy suggest the intrahepatic presence of severe acute respiratory syndrome coronavirus-2, the findings of which may indicate the possibility of direct cell injury.\n\nConclusions\n\nOn the basis of the abundant apoptosis and severe cholangiocyte injury, these histopathologic changes suggest a direct cytopathic injury. Furthermore, some of the histopathologic changes may resemble acute cellular rejection occurring after liver transplantation. These 2 cases demonstrate that severe COVID-19 hepatitis can occur even in the absence of significant involvement of other organs.\n\nKeywords\n\nCOVID-19\nNon-hepatotropic Virus\nHepatitis\nLiver Biopsy\nSARS-CoV-2\nLiver Injury\nAbbreviations used in this paper\n\nACE2, angiotensin-converting enzyme receptors\nACR, acute cellular rejection\nCOVID-19, coronavirus disease 2019\nDILI, drug-induced liver injury\nEM, electron microscopy\nHCV, hepatitis C virus\nLT, liver transplantation\nNAFLD, nonalcoholic fatty liver disease\nPCR, polymerase chain reaction\nSARS-CoV-2, severe acute respiratory syndrome coronavirus-2\n==== Body\nSummary\n\nLiver injury from COVID-19 infection is increasingly being identified, with a dearth of corresponding liver biopsy data to date. The unique liver histology of 2 patients who both recovered with severe COVID-19 hepatitis is presented. Liver involvement may be the only manifestation of COVID-19 infection.\n\nCoronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2), is a global pandemic of unprecedented proportions.1 During the months of March and April 2020, New York City became the epicenter of the COVID-19 pandemic, and Mount Sinai Hospital was one of the major hospitals in the region that took care of several thousand COVID-19 patients. In the midst of the pandemic, ongoing liver transplantation (LT) and referrals of patients with severe liver disease continued unabated.2\n\nInitial reports focused on COVID-19 as mainly involving the lungs and being the main cause of morbidity and mortality.3 However, neurologic, cardiac, renal, hepatobiliary, and gastrointestinal tract involvements are increasingly being recognized.3 The reported incidence of liver injury in patients with COVID-19 ranges from 14% to 53%.4, 5, 6 Those studies are mainly based on abnormal liver enzyme elevations in the absence of tissue examination. In one study, a significant number of cases were noted to have elevation of liver enzymes occurring at approximately the tenth day of hospitalization and associated with lopinavir/ritonavir treatment.7 The authors also found that prolonged hospital stays were associated with abnormal liver enzymes noted at the time of initial admission.7 Risk factors included underlying chronic liver disease such as viral hepatitis and nonalcoholic fatty liver disease (NAFLD).4 In a study involving 252 COVID-19 patients, the investigators found that patients having NAFLD had a significantly higher risk of disease progression, a higher likelihood of developing abnormal liver tests during hospitalization, and longer viral shedding times as compared with patients without NAFLD.6\n\nIn a previous study of postmortem examinations, liver histology showed lobular lymphocytic inflammation and centrilobular sinusoidal dilatation, with only a few cases showing parenchymal necrosis.8 Furthermore, in another autopsy study of a 51-year-old man, microvesicular steatosis and mild lobular and portal inflammation were noted.9 At the present time, no detailed histologic, immunohistochemical, and ultrastructural findings have been reported in the literature regarding infection of the liver by COVID-19. Herein we report 2 patients who presented with high aminotransferases and underwent liver biopsy that showed acute hepatitis. A detailed histologic analysis along with in situ hybridization and electron microscopy (EM) were performed on liver tissue to suggest direct hepatic involvement by the novel coronavirus SARS-CoV-2.\n\nClinical Histories\n\nCase 1\n\nThe patient is a 63-year-old man who underwent LT in 2017 for hepatitis C (HCV) and alcohol-related liver disease. He received a genotype 1b HCV (+) donor with a pre-perfusion liver biopsy showing no underlying fibrosis and mild portal inflammation. He underwent antiviral therapy with sofosbuvir/ledipasvir starting 3 months after LT and achieved a sustained virologic response. He had developed dialysis-dependent chronic renal failure related to calcineurin inhibitor nephrotoxicity, hypertension, and insulin-dependent diabetes mellitus but always had normal liver chemistry tests and never previously had an episode of acute cellular rejection (ACR). The patient was stable for 2 years after LT until he suffered a stroke in January 2020. Laboratory tests on discharge from the transplant center after his stroke were normal with aspartate aminotransferase 12 U/L, alanine aminotransferase 14 U/L, alkaline phosphatase 68 U/L, and normal serum bilirubin. The tacrolimus dose was stable with a level of 4–6 ng/mL. He was discharged to a rehabilitation facility on regular doses of his medications, which included aminosalicylic acid 81 mg, atorvastatin, calcium acetate, dorzolamide drops, famotidine, insulin, labetalol, nifedipine, ropinirole, sodium bicarbonate, tacrolimus 2 mg twice a day, and tamsulosin. While residing at the rehabilitation facility, the patient developed constitutional symptoms and was found to be COVID-19 (+) via nasopharyngeal swab testing and referred to a local hospital where the liver enzymes were noted to be abnormal (Table 1). The patient was started on N-acetyl cysteine and acyclovir empirically; however, follow-up laboratory tests showed rising liver enzymes.Table 1 Liver Enzyme Values of Case 1 and Case 2\n\n\tAST, U/L (1–35)\tALT, U/L (1–45)\tAlk Phos, U/L (38–126)\tT bili, mg/dL (0.1–1.2)\tD-dimer, μg/mL (0–0.5)\tFerritin, ng/mL (30–400)\tProcalcitonin, ng/mL (<0.49)\tCRP, mg/L (0–5)\t\nCase 1\t\t\t\t\t\t\t\t\t\n HD 1\t1083\t1035\t824\t1.1\t\t\t\t\t\n HD 2\t2074\t1761\t907\t3.1\t\t\t\t\t\n HD 3\t1691\t1578\t915\t3.9\t1.84\t4677\t5.24\t24.5\t\n HD 6\t769\t994\t1363\t7.1\t1.38\t2863\t3.57\t11.3\t\n HD 9\t541\t776\t1568\t9.3\t0.77\t2520\t1.16\t7.0\t\nCase 2\t\t\t\t\t\t\t\t\t\n HD 1\t2786\t2909\t210\t13.8\t\t827\t0.35\t8.4\t\n HD 8\t1700\t1856\t132\t20.6\t1290\t1558\t0.26\t0.7\t\n HD 15\t591\t650\t184\t31.5\t172\t\t\t0.9\t\n HD 18\t506\t616\t241\t33.5\t0.27\t224\t0.28\t0.7\t\n HD 24\t200\t221\t166\t10.7\t\t\t\t\t\nAlk Phos, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; HD, hospital day; T bili, total bilirubin.\n\nHe was transferred to Mount Sinai Hospital for further management. Reverse transcription polymerase chain reaction (PCR) on a repeat nasopharyngeal swab specimen confirmed SARS-CoV-2 infection, and the tacrolimus dose was increased to 3 mg twice a day in the setting of a trough level of 3.0 ng/mL. On presentation, the aminotransferases and alkaline phosphatase levels were elevated, as was the total serum bilirubin. Doppler ultrasonography showed no vascular or biliary abnormalities. The following additional lab results were obtained: undetectable PCR for herpes simplex 1 and 2, HCV, hepatitis B virus, Epstein-Barr virus, and cytomegalovirus, undetectable antibody to hepatitis E, and undetectable immunoglobulin M for hepatitis A virus. The triglyceride level was 483 mg/dL (0–150). Inflammatory markers were significantly elevated (Table 1) including lactate dehydrogenase of 702 U/L (reference range, 100–220). The platelet count was 132 × 103, and the white blood cell count was 3.9 × 103. The patient’s clinical and serologic features supported the diagnosis of COVID-19 infection.\n\nA liver biopsy was performed 9 days after the initial presentation and on hospital day 6. The histologic changes are highlighted in Figure 1. The majority of the portal tracts uniformly showed a mixed inflammatory infiltrate with a few eosinophils, prominent bile duct damage, and endotheliitis (Figure 1a). The lobule showed disarray with many apoptotic bodies, foci of necrosis, and abundant mitotic figures (Figure 1b). Focal central venulitis was noted. C4d immunostain was positive in a few endothelial cells lining the portal and central venules. CD61 immunostain to determine the presence of fibrin thrombi was negative. In rare portal tracts, severe bile duct damage with cholangiocytes undergoing apoptosis was seen (Figure 1c). A diagnosis of ACR and concomitant severe acute hepatitis was rendered.Figure 1 Liver biopsy findings of case 1. (a) Portal tract showing mixed inflammatory infiltrate consisting of lymphocytes, blast-like cells, and eosinophils, along with mild endotheliitis and severe bile duct damage. Bile duct is barely unrecognizable, and in its place are apoptotic cholangiocytes (arrowheads). Open arrowhead indicates accompanying hepatic arteriole. H&E, original magnification ×40. Black stars indicate a damaged bile duct. (b) Lobule shows disarray with many hepatocytes undergoing apoptosis in various stages (black arrowheads), while there is also concomitant increased mitotic activity (white arrows). H&E, original magnification ×40. (c) A few portal tracts are devoid of inflammation. Because of paucity of inflammation in this particular portal tract, one can visualize the cholangiocytes undergoing apoptosis (arrow). H&E, original magnification ×40. (d) RNA localization of COV-S protein using RNAScope showing dot-like particles (black arrow) in cytoplasm of an infected endothelial cell.\n\nSlides for RNAScope for SARS-CoV-2 spike protein showed positive staining in rare cells and were seen as cytoplasmic dotted signals. In the absence of double immunostaining, the type of cells with positive staining could not be identified with certainty (Figure 1d). Throughout the entire 3.2-cm length of the liver biopsy, only 8 such cells were found to be positive. No cells were positive for the SARS-CoV-2 spike protein anti-sense strand probe, indicating that no active replication could be detected.\n\nEM revealed the presence of viral-like particles displaying a double membrane electron-dense periphery with characteristic outward projecting processes consistent with a peplomer-like arrangement and measuring 100 nm on average, consistent with members of the Coronaviridae family10, 11, 12 (Figure 2a). The virions were mostly located within intracytoplasmic vesicles in close proximity to the endoplasmic reticulum. After the biopsy, the tacrolimus level was optimized to achieve a trough level of approximately 10. Infectious diseases department was consulted and recommended that the patient did not warrant medical treatment for COVID-19 infection because he was oxygenating normally and had a normal chest x-ray. Under observation, the patient’s liver chemistry tests slowly down trended, as did all of the inflammatory markers (Table 1) until discharge.Figure 2 Electron microscopy photos of case 1 and case 2. (a) EM showing presence of viral-like particles (encircled) displaying a double membrane electron-dense periphery with characteristic outward projecting processes consistent with a peplomer-like arrangement and measuring 100 nm on average. (b) Viral-like particles (encircled) measuring approximately 100 nm on average, with noticeable surface (peplomeric) projections appearing to be within sinusoidal endothelial cells.\n\nCase 2\n\nThe patient is a 36-year-old previously healthy woman who presented to a local hospital with 6 days of progressive nausea, vomiting, and scleral icterus. She also had anorexia, myalgias, and fevers 1 week before her presentation, taking approximately 1.5 g acetaminophen and no other prescription or over-the-counter medications. Initial laboratory tests at presentation on April 6, 2020 showed markedly elevated aminotransferases, total serum bilirubin, and a mildly elevated alkaline phosphatase (Table 1). The international normalized ratio was 1.3. Additional serologic markers included antinuclear antibodies + 1:160, liver-kidney microsomal antibody negative, anti-smooth muscle antibody negative, cytomegalovirus immunoglobulin M negative, Epstein-Barr virus PCR negative, herpes simplex virus (–), human immunodeficiency virus (–), and negative acute serologies for hepatitis A virus, hepatitis B virus, and HCV. Serologic tests are outlined in Table 1. She had normal magnetic resonance imaging of the liver; a nasopharyngeal swab was (+) for COVID-19. The patient was started on an infusion of N-acetyl cysteine, and a liver biopsy was performed on hospital day 7. She was thereafter transferred to Mount Sinai Hospital.\n\nReview of the liver biopsy (Figure 3) showed severe acute hepatitis with marked lobular disarray characterized by inflammatory infiltrates, many acidophilic bodies, ballooned hepatocytes, scattered ceroid-laden macrophages, Kupffer cell hyperplasia, and activated sinusoidal lining cells. Portal areas showed mild to moderate mixed inflammation composed of lymphocytes, few plasma cells, scattered eosinophils and neutrophils, accompanied by mild interface hepatitis and mild ductular reaction (Figure 3a and b). Centrilobular hepatocyte necrosis with dropout and focal confluent necrosis were seen. Mild endotheliitis was noted, and most of the interlobular bile ducts were severely damaged. The severe damage was characterized by cholangiocytes having eosinophilic cytoplasm and densely pyknotic nuclei indicative of apoptosis (Figure 3c). CD61 immunostaining showed granular positive staining along the sinusoidal endothelial lining and in some of the terminal hepatic venules, indicative of the presence of non-occlusive fibrin thrombi (Figure 3d).Figure 3 Liver biopsy findings of case 2. (a) Portal tract with mixed inflammation, including eosinophils, activated lymphocytes, and rare plasma cells. Bile ducts are severely damaged (arrowheads), with some cholangiocytes undergoing acidophilic change and apoptosis. Detached necrotic cholangiocytes are seen in the lumen (bottom right). H&E, original magnification ×40. (b) High power view of lobule showing scattered hepatocytes undergoing apoptosis (arrowheads), with rest of the lobule showing ballooning degeneration of hepatocytes and foci of necroinflammation. H&E, original magnification ×40. (c) Portal tract containing dense mixed inflammatory infiltrate with bile duct showing cholangiocytes undergoing acidophilic change (arrowheads). H&E, original magnification ×40. (d) Immunostain for CD61 shows granular lace-like pattern of staining decorating the endothelial lining of the sinusoids as well as terminal hepatic venule (arrowhead). Original magnification ×40. (e) In situ hybridization showing hepatocyte with intracytoplasmic granular staining for COV-Spike protein (arrow). Original magnification ×40.\n\nSimilar to what was seen in case 1, RNAScope for SARS-CoV-2 spike protein was positive in rare cells (Figure 3e). A total of 6 positive cells throughout the biopsy length of 3.8 cm were identified; no cells were positive for viral replication by spike protein anti-sense strand probe. Transmission electron microscopy showed viral-like particles measuring approximately 100 nm on average, with noticeable surface (peplomeric) projections. Ultrastructurally, these virions appeared to be within sinusoidal endothelial cells10, 11, 12 (Figure 2b).\n\nThe patient was deemed not to require treatment for COVID-19 because she was oxygenating well and had no radiographic evidence of pneumonia. She was also found to have thyroid-stimulating hormone of .008 and was diagnosed with thyroiditis, which has recently been reported in COVID-19 infection,13 and she was started on cholestyramine and ursodiol. She had repeat negative PCR testing for SARS CoV-2 on hospital days 15, 18, and 24 at Mount Sinai. Because she was feeling much better she was discharged, with lactate dehydrogenase of 209 and D-dimer <0.27. Laboratory testing 1 week later showed an ongoing decrease in her liver enzymes, although the bilirubin was still elevated to 10.7 mg/dL with an indirect fraction of 7.8 mg/dL.\n\nDiscussion\n\nThe cases presented in the current report had markedly elevated liver enzymes at presentation, with both fitting the clinical course timeline as well as the histologic features of severe COVID-19 hepatitis. RNA localization of SARS-CoV-2 S protein using in situ hybridization and EM findings suggest that SARS-CoV-2 may have played a major role in the liver damage incurred by these 2 patients. Despite the initial presentation of severe liver damage, both patients recovered from COVID-19 hepatitis.\n\nCurrently, it is known that the development of abnormal liver chemistry tests and various forms of liver injury may result from COVID-19,14 with the majority of cases having mildly elevated liver enzymes.4 In a series of 99 COVID-19 patients, only 1 case presented with severe liver injury with markedly elevated liver enzymes, whereas 43 of 99 showed mild alanine aminotransferase and aspartate aminotransferase elevations (in 28% and 35%, respectively).15 In patients with significantly increased liver enzymes, there were longer hospital stays, and most patients were taking medications such as lopinavir/ritonavir, with the latter raising the possibility of drug-induced liver injury (DILI).7 A recent review concluded that significantly elevated aminotransferases are only found in severe cases of COVID-19.16 However, to date there are only case reports or small case series detailing the liver histologic findings found in patients with COVID-19 infection.4 Microvesicular steatosis and the presence of mild lymphocytic inflammation in the lobules and rarely in portal tracts are the main findings reported.4 Furthermore, there is a dearth of reported liver biopsies in COVID-19 infection of solid organ recipients.17 Aside from one post-LT pediatric case wherein a liver biopsy was performed several days after LT, no other cases have been reported.18\n\nLiver biopsies from both patients in this study showed prominent mitoses of hepatocytes along with acidophilic bodies, ballooning degeneration, and mild inflammation. Histology also showed mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage. Although these features are seen in acute T-cell–mediated rejection, which might conceivably explain the portal tract findings in patient 1, patient 2 did not have LT and yet showed a similar histology. Lagana et al18 reported the presence of increased mitotic activity and the presence of numerous apoptotic bodies in their post-LT case. A case series from the SARS epidemic in 2003 described the histology of 3 patients. These patients all had elevated liver enzymes in the 300–400 range, and liver histology showed prominent mitoses.19 The authors surmised that the prominent mitoses were likely due to a hyperproliferative state and cell cycle arrest. They further described ballooning degeneration and mild to moderate lobular inflammation. The authors ascribed these findings to what was previously reported in avian coronavirus and transmissible gastroenteritis coronavirus infections in which the coronavirus had exerted extensive cytopathic effect through the induction of apoptosis of host cells by activation of caspase.19, 20, 21 The 2 cases presented here appear to have similar cytopathic effect from SARS-CoV-2 due to the increased number of apoptotic bodies noted on both liver biopsies.\n\nThe proposed mechanism of liver injury from SARS-CoV-2 includes severe inflammatory responses and direct cytotoxicity due to active viral replication with angiotensin-converting enzyme receptors (ACE2) being abundant in the liver, particularly in cholangiocytes and endothelial cells.22 It has been shown that SARS-CoV-2 interacts with host receptors in liver cells. Gene expression of ACE2 transmembrane serine protease 2 (TMPRSS2) and paired basic amino acid cleaving enzyme (FURIN) has been shown. All 3 receptors are abundant in cholangiocytes and hepatocytes as well as in endothelial cells. Because these 3 receptors are present in various liver cells, SARS-CoV-2 may cause direct injury via a cytopathic effect, either by lysis and/or by inducing necrosis and apoptosis.22, 23, 24 Therefore, the ballooning degeneration and apoptosis as well as the striking bile duct damage may possibly be due to direct viral injury, with in situ hybridization and EM demonstrating viral particles within the liver. Previous case reports have failed to demonstrate the detection of intrahepatic viral particles. SARS-CoV-2 can also infect the gastrointestinal tract because of the abundant ACE2 receptors present.24,25 Therefore, the possibility that SARS-CoV-2 may enter the liver via the portal vein (portal venous viremia) can also be entertained.23 Varga et al26 have shown SARS-CoV-2 can directly infect endothelial cells across vascular beds of different organs, although not specifically in the liver. Widespread endothelial cell dysfunction in heart, kidney, lung, and small intestine resulted in apoptosis and prominent endotheliitis of submucosal vessels.26 Another mechanism believed to be the underlying cause of liver injury is ischemic changes in those with severe COVID-19 and DILI.4,27,28 In addition to the direct damage, translocation, and DILI, immune-mediated liver injury is another mechanism to consider. This is especially important in light of the increased inflammatory markers noted on serologic testing.16 Although SARS-CoV-2 virus is a new virus and our understanding of its tissue and cellular localization and replication is very limited, the sparse distribution of the virus as seen in the liver in the 2 current cases is not surprising because of the comparable sporadic and occasional cellular distribution described with the first SARS-CoV coronavirus in the early and mid-2000s.29,30 Despite the fact that we could not prove that the virus is replicating within the liver tissue because we did not see positive signals for the anti-sense strand of the S gene of the virus, we could not rule out such a possibility because the viral particles are sparsely distributed, and there is a limited amount of liver tissue in these core needle biopsies.\n\nThe clinical picture of the 2 patients is that of a spontaneously resolving COVID-19 infection with the markedly elevated liver tests and inflammatory markers decreasing concurrently. Although the patients did not have severe pulmonary, cardiac, or neurologic manifestations of COVID-19 infection that warranted treatment, significant liver chemistry abnormalities developed that correlated with the histologic liver damage noted. Neither patient had known underlying intrinsic liver disease, but if they did in light of the severe histologic liver damage noted, it is possible that they might have developed acute-on-chronic liver failure due to COVID-19.14,31\n\nSome of the histologic findings seen in Case 1 are also typically seen in ACR, such as mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage. In addition, there was histologic evidence of acute hepatitis, likely because of COVID-19, ie, COVID-19 hepatitis. Lagana et al18 showed similar findings in their case that occurred 7 days after transplantation. Although it is possible that this patient had both mild ACR and concurrent COVID-19 hepatitis, it is more likely that the histologic features are due to COVID-19 because the magnitude of the aminotransferase elevation is not typical of mild ACR, and the substantive decline in liver tests with only a minimal increase in tacrolimus dose is not typical of ACR.\n\nAlthough both of the reported post-LT cases may be episodes of ACR that were triggered by COVID-19, as can occur with other viral infections,32 it is more likely that these histologic features are all related to COVID-19 infection because case 2 in the current report had very similar features. The endotheliitis demonstrated in these 2 patients appears similar to that reported in other organs.26,33 The histology thus suggests both a direct viral cytopathic effect and an immunologic liver injury involving cholangiocytes, hepatocytes, and liver sinusoidal endothelial cells. The significant bile duct damage and apoptosis of cholangiocytes are very prominent in these cases. In the absence of intrinsic liver disease, resolution of the direct cytopathologic injury may occur with clearance of SARS-CoV-2, yet it will remain to be seen whether the immunologic component of the liver injury will as well. Thus, close follow-up of such patients is warranted.\n\nIn conclusion, the current report details the liver histologic findings of acute COVID-19 infection in 2 patients, which are supported by the use of in situ hybridization and EM studies. Apoptosis, especially of cholangiocytes, abundant mitoses, mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage are typical. This histology suggests a direct cytopathic viral injury most notably in sinusoidal endothelial cells and other liver cells, with concurrent immunologic features. Such histologic changes can resemble ACR, so LT physicians must consider this possibility in post-LT patients with COVID-19 infection. These cases also demonstrate that patients can have severe liver injury in the absence of significant involvement of other organs by COVID-19.\n\nMaterials and Methods\n\nHistopathology\n\nTransjugular needle liver biopsy was performed for patient 1, and a percutaneous liver biopsy was performed for patient 2. Core biopsy specimens were immediately placed in formalin and fixed for a minimum of 3 hours. Routine tissue processing through graded alcohols was performed. Thereafter, the liver biopsy tissues were embedded in paraffin (FFPE). Three 4-μm-thick sections were cut for H&E stain to assess different levels and one 4-μm section for Masson trichrome stain. H&E and trichrome-stained slides were analyzed by routine light microscopy. Adequacy of the specimen was determined including the linear length of tissue and the number of complete portal tracts. Morphologic evaluation was performed under light microscopy. Histopathologic features analyzed included degree of portal and lobular inflammation, parenchymal damage including apoptosis, presence of fibrosis, bile duct injury, and endothelial damage.\n\nIn Situ Hybridization\n\nSections at 3 μm in thickness were taken from FFPE for RNA in situ hybridization using the RNAscope HPV kit (Advanced Cell Diagnostics, Inc, Hayward, CA) according to the manufacturer’s instructions on a Leica Bond III automated stainer (Leica Biosystems, Buffalo Grove, IL). Tissue sections were hybridized separately with a target probe to the SARS-CoV-2 S gene encoding the spike protein (catalogue #848561) to detect viral proteins within the cells to indicate infected cells and SARS-CoV-2 antisense strand of the S gene (catalogue #845701) to detect active viral replication within the cells. Positive controls for the SARS-CoV-2 S and antisense strand of the genes were prepared in-house from SARS-CoV-2-infected Vero cell lines (cell lines gift from Dr Florian Krammer, Icahn School of Medicine at Mount Sinai, New York, NY). To assess for the RNA integrity, probes for the endogenous housekeeping gene UBC (catalogue #RS7760) were used. The preamplifier, amplifier, and horseradish peroxidase–labeled probes were then hybridized sequentially, followed by color development with DAB. Specific staining signals were identified as brown, punctate dots present in the cytoplasm and/or nucleus.\n\nTransmission Electron Microscopy\n\nThe tissue processed for EM was received in paraffin blocks. Designated portions of the specimen were dissected out with a single edge razor blade and placed into xylene overnight to dissolve the paraffin. The tissue was then brought to water through decreasing concentrations of ethanol and then fixed with 3% glutaraldehyde in a 0.2 sodium cacodylate buffer at pH 7.4.The specimen was then post-fixed with 1% osmium tetroxide tissues and embedded in Epon 812. One micrometer plastic sections were cut and stained with methyl blue and azure II for light microscopic orientation and to select smaller representative areas. Ultrathin 60-nm sections were collected into 200 mesh copper grids and stained with lanthanum and lead citrate. Sections were examined in a Hitachi 7650 (Tokyo, Japan) transmission electron microscope at 80 kV.\n\nAll authors had access to the study data and reviewed and approved the final manuscript.\n\nCRediT Authorship Contributions\n\nMaria Isabel Fiel, MD (Conceptualization: Lead; Data curation: Lead; Methodology: Equal; Writing – original draft: Lead)\n\nSiraj M. El Jamal, MD (Methodology: Supporting; Writing – original draft: Supporting)\n\nAlberto Paniz-Mondolfi, MD (Methodology: Supporting; Writing – original draft: Supporting)\n\nRonald E. Gordon, PhD (Methodology: Supporting; Writing – original draft: Supporting)\n\nJason Reidy, PhD (Methodology: Supporting)\n\nJela Bandovic, MD (Methodology: Supporting; Visualization: Supporting)\n\nRashmi Advani, MD (Data curation: Supporting)\n\nSaikiran Kilaru, MD (Data curation: Supporting)\n\nKamron Pourmand, MD (Data curation: Supporting)\n\nStephen Ward, MD, PhD (Formal analysis: Supporting)\n\nSwan N. Thung, MD (Formal analysis: Supporting)\n\nThomas D. Schiano, MD (Conceptualization: Equal; Formal analysis: Equal; Writing – original draft: Equal)\n\nConflicts of interest The authors disclose no conflicts.\n==== Refs\nReferences\n\n1 World Health Organization Coronavirus disease 2019 (COVID-19) situation report-99 2020 World Health Organization Geneva, Switzerland\n2 Hygiene NDoHaM. COVID-19 data Available from: https://www1.nyc.gov/site/doh/covid/covid-19-data.page 2020\n3 Wu Z. McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention JAMA 323 2020 1239 1242 32091533\n4 Sun J. Aghemo A. Forner A. Valenti L. COVID-19 and liver disease Liver Int 2020\n5 Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. Liu L. Shan H. Lei C.L. Hui D.S.C. Du B. Li L.J. Zeng G. Yuen K.Y. Chen R.C. Tang C.L. Wang T. Chen P.Y. Xiang J. Li S.Y. Wang J.L. Liang Z.J. Peng Y.X. Wei L. Liu Y. Hu Y.H. Peng P. Wang J.M. Liu J.Y. Chen Z. Li G. Zheng Z.J. Qiu S.Q. Luo J. Ye C.J. Zhu S.Y. Zhong N.S. Clinical characteristics of coronavirus disease 2019 in China N Engl J Med 382 2020 1708 1720 32109013\n6 Ji D. Qin E. Xu J. Zhang D. Cheng G. Wang Y. Lau G. Non-alcoholic fatty liver diseases in patients with COVID-19: a retrospective study J Hepatol 73 2020 451 453 32278005\n7 Fan Z. Chen L. Li J. Cheng X. Jingmao Y. Tian C. Zhang Y. Huang S. Liu Z. Cheng J. Clinical features of COVID-19-related liver damage Clin Gastroenterol Hepatol 18 2020 1561 1566 32283325\n8 Tian S. Xiong Y. Liu H. Niu L. Guo J. Liao M. Xiao S.Y. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies Mod Pathol 33 2020 1007 1014 32291399\n9 Xu Z. Shi L. Wang Y. Zhang J. Huang L. Zhang C. Liu S. Zhao P. Liu H. Zhu L. Tai Y. Bai C. Gao T. Song J. Xia P. Dong J. Zhao J. Wang F.S. Pathological findings of COVID-19 associated with acute respiratory distress syndrome Lancet Respir Med 8 2020 420 422 32085846\n10 ML PEaM Electron microscopy in viral diagnosis 1988 CRC Press Boca de Raton, FL\n11 Oshiro L.S. Schieble J.H. Lennette E.H. Electron microscopic studies of coronavirus J Gen Virol 12 1971 161 168 4107843\n12 Paniz-Mondolfi A. Bryce C. Grimes Z. Gordon R.E. Reidy J. Lednicky J. Sordillo E.M. Fowkes M. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) J Med Virol 2020\n13 Brancatella A. Ricci D. Viola N. Sgrò D. Santini F. Latrofa F. Subacute thyroiditis after SARS-CoV-2 infection J Clin Endocrinol Metab 105 2020 dgaa276 32436948\n14 Targher G. Mantovani A. Byrne C.D. Wang X.B. Yan H.D. Sun Q.F. Pan K.H. Zheng K.I. Chen Y.P. Eslam M. George J. Zheng M.H. Risk of severe illness from COVID-19 in patients with metabolic dysfunction-associated fatty liver disease and increased fibrosis scores Gut 2020\n15 Chen N. Zhou M. Dong X. Qu J. Gong F. Han Y. Qiu Y. Wang J. Liu Y. Wei Y. Xia J. Yu T. Zhang X. Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Lancet 395 2020 507 513 32007143\n16 Zippi M. Fiorino S. Occhigrossi G. Hong W. Hypertransaminasemia in the course of infection with SARS-CoV-2: incidence and pathogenetic hypothesis World J Clin Cases 8 2020 1385 1390 32368531\n17 Pereira M.R. Mohan S. Cohen D.J. Husain S.A. Dube G.K. Ratner L.E. Arcasoy S. Aversa M.M. Benvenuto L.J. Dadhani D. Kapur S. Dove L.M. Brown R.S. Rosenblatt R.E. Samstein B. Uriel N. Farr M.A. Satlin M. Small C.B. Walsh T. Kodiyanplakkal R.P. Miko B.A. Aaron J.G. Tsapepas D.S. Emond J.C. Verna E.C. COVID-19 in solid organ transplant recipients: initial report from the US epicenter Am J Transplant 2020\n18 Lagana S.M. De Michele S. Lee M.J. Emond J.C. Griesemer A.D. Tulin-Silver S.A. Verna E.C. Martinez M. Lefkowitch J.H. COVID-19 associated hepatitis complicating recent living donor liver transplantation Arch Pathol Lab Med 2020\n19 Chau T.N. Lee K.C. Yao H. Tsang T.Y. Chow T.C. Yeung Y.C. Choi K.W. Tso Y.K. Lau T. Lai S.T. Lai C.L. SARS-associated viral hepatitis caused by a novel coronavirus: report of three cases Hepatology 39 2004 302 310 14767982\n20 Liu C. Kokuho T. Kubota T. Watanabe S. Inumaru S. Yokomizo Y. Onodera T. A serodiagnostic ELISA using recombinant antigen of swine transmissible gastroenteritis virus nucleoprotein J Vet Med Sci 63 2001 1253 1256 11767065\n21 Eléouët J.F. Druesne N. Chilmonczyk S. Monge D. Dorson M. Delmas B. Comparative study of in-situ cell death induced by the viruses of viral haemorrhagic septicaemia (VHS) and infectious pancreatic necrosis (IPN) in rainbow trout J Comp Pathol 124 2001 300 307 11437506\n22 Bourgonje A.R. Abdulle A.E. Timens W. Hillebrands J.L. Navis G.J. Gordijn S.J. Bolling M.C. Dijkstra G. Voors A.A. Osterhaus A. van der Voort P.H.J. Mulder D.J. van Goor H. Angiotensin-converting enzyme-2 (ACE2), SARS-CoV-2 and pathophysiology of coronavirus disease 2019 (COVID-19) J Pathol 2020\n23 Pirola C.J. Sookoian S. COVID-19 and ACE2 in the liver and gastrointestinal tract: putative biological explanations of sexual dimorphism Gastroenterology 2020\n24 Wong S.H. Lui R.N. Sung J.J. Covid-19 and the digestive system J Gastroenterol Hepatol 2020\n25 Xiao F. Tang M. Zheng X. Liu Y. Li X. Shan H. Evidence for gastrointestinal infection of SARS-CoV-2 Gastroenterology 158 2020 1831 1833.e3 32142773\n26 Varga Z. Flammer A.J. Steiger P. Haberecker M. Andermatt R. Zinkernagel A.S. Mehra M.R. Schuepbach R.A. Ruschitzka F. Moch H. Endothelial cell infection and endotheliitis in COVID-19 Lancet 395 2020 1417 1418 32325026\n27 Xu L. Liu J. Lu M. Yang D. Zheng X. Liver injury during highly pathogenic human coronavirus infections Liver Int 40 2020 998 1004 32170806\n28 Li J. Fan J.G. Characteristics and mechanism of liver injury in 2019 coronavirus disease J Clin Transl Hepatol 8 2020 13 17 32274341\n29 Ding Y. He L. Zhang Q. Huang Z. Che X. Hou J. Wang H. Shen H. Qiu L. Li Z. Geng J. Cai J. Han H. Li X. Kang W. Weng D. Liang P. Jiang S. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways J Pathol 203 2004 622 630 15141376\n30 To K.F. Lo A.W. Exploring the pathogenesis of severe acute respiratory syndrome (SARS): the tissue distribution of the coronavirus (SARS-CoV) and its putative receptor, angiotensin-converting enzyme 2 (ACE2) J Pathol 203 2004 740 743 15221932\n31 Boettler T. Newsome P.N. Mondelli M.U. Maticic M. Cordero E. Cornberg M. Berg T. Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper JHEP Rep 2 2020 100113 32289115\n32 Cakaloglu Y. Devlin J. O'Grady J. Sutherland S. Portmann B.C. Heaton N. Tan K.C. Williams R. Importance of concomitant viral infection during late acute liver allograft rejection Transplantation 59 1995 40 45 7839426\n33 Magro C. Mulvey J.J. Berlin D. Nuovo G. Salvatore S. Harp J. Baxter-Stoltzfus A. Laurence J. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases Transl Res 2020\n\n",
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"journal": "Cellular and molecular gastroenterology and hepatology",
"keywords": "COVID-19; Hepatitis; Liver Biopsy; Liver Injury; Non-hepatotropic Virus; SARS-CoV-2",
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"title": "Findings of Hepatic Severe Acute Respiratory Syndrome Coronavirus-2 Infection.",
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"abstract": "The long-term survival of relapsed/refractory (R/R) adult T-cell acute lymphoblastic leukemia (T-ALL) is quite poor, and early T-cell precursor (ETP) ALL has recently been described as a high-risk T-ALL subgroup. However, the optimal therapeutic approach to R/R adult T-ALL remains poorly established.\nAt present, cytoreductive therapy followed by allogeneic stem cell transplantation (allo-SCT) is considered to be the most clinically relevant and curative modality for R/R T-ALL. Above all, achieving minimal residual disease (MRD) is a key factor for successful allo-SCT and maintaining long-term remission for R/R patients. As a salvage regimen, nelarabine is the only therapy that was specifically approved for use in patients with R/R T-ALL. A combination of conventional chemotherapeutic agents and novel agents, such as venetoclax, can be used as alternatives for cytoreduction and bridging to transplantation. Relevant literatures published in the last 30 years were searched from PubMed to review the topic of T-ALL, and allo-SCT.\nAn effective salvage regimen, to achieve negative MRD, followed by allo-SCT is currently the best way to improve the clinical outcomes of adult R/R T-ALL. Moreover, posttransplant therapies, such as prophylactic or preemptive donor leukocyte infusion and hypomethylating agents, need to be considered as sequential therapy.",
"affiliations": "Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea.;Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea.;Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea.;Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea.;Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea.;Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea.",
"authors": "Baek|Dong Won|DW|;Lee|Jung Min|JM|;Kim|Juhyung|J|;Cho|Hee Jeong|HJ|;Moon|Joon Ho|JH|;Sohn|Sang Kyun|SK|",
"chemical_list": null,
"country": "England",
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"doi": "10.1080/17474086.2021.1960817",
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"issue": "14(8)",
"journal": "Expert review of hematology",
"keywords": "Acute lymphoblastic leukemia; T-cell; post-transplant therapy; relapsed/refractory; stem cell transplantation",
"medline_ta": "Expert Rev Hematol",
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"pages": "765-775",
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"pubdate": "2021-08",
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"title": "Therapeutic strategies, including allogeneic stem cell transplantation, to overcome relapsed/refractory adult T-cell acute lymphoblastic leukemia.",
"title_normalized": "therapeutic strategies including allogeneic stem cell transplantation to overcome relapsed refractory adult t cell acute lymphoblastic leukemia"
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"abstract": "Steroid-induced ocular hypertension (OHTN) after penetrating keratoplasty (PKP) may cause irreversible damage to the optic nerve and graft failure. The purpose of this study is to report the first case of a post PKP patient with poorly controlled IOP, successfully treated with Kahook Dual Blade (KDB) goniotomy in both eyes.\nThe patient was a 62-year old male with prior PKP in both eyes for lattice corneal degeneration. After an uncomplicated phacoemulsification in the left eye, his IOP increased to 32 mmHg on maximum tolerated IOP lowering therapy, including oral acetazolamide. This patient was dependent on scleral contact lenses for his irregular astigmatism post PKP to achieve his best-corrected visual acuity. Thus, we needed to consider a conjunctival sparing procedure and decided to proceed with performing a KDB goniotomy in the left eye. At 29 months follow up the visual acuity (VA) remained at 20/20 and IOP 13 mmHg on dorzolamide/timolol combination drop. A year following, his right eye also required KDB goniotomy combined with cataract surgery to treat his cataract and elevated IOP of 28 mm Hg. At 18 months post KDB goniotomy, the right eye VA was 20/50 and IOP 13 mmHg on dorzolamide/timolol combination drop.\nThis case demonstrates KDB goniotomy may be a good surgical alternative for post PKP steroid-induced OHTN or glaucoma, especially in patients requiring scleral contact lens for their visual rehabilitation.",
"affiliations": "Department of Ophthalmology, University of Colorado School of Medicine, 1675 Aurora Ct, F731, Aurora, CO, 80045, United States.;Department of Ophthalmology, University of Colorado School of Medicine, 1675 Aurora Ct, F731, Aurora, CO, 80045, United States.;Department of Ophthalmology, University of Colorado School of Medicine, 1675 Aurora Ct, F731, Aurora, CO, 80045, United States.",
"authors": "Epstein|Rebecca|R|;Taravella|Michael|M|;Pantcheva|Mina B|MB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2020.100826",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(19)30077-5\n10.1016/j.ajoc.2020.100826\n100826\nCase Report\nKahook Dual Blade goniotomy in post penetrating keratoplasty steroid-induced ocular hypertension\nEpstein Rebecca Taravella Michael Pantcheva Mina B. mina.pantcheva@ucdenver.edu∗ Department of Ophthalmology, University of Colorado School of Medicine, 1675 Aurora Ct, F731, Aurora, CO, 80045, United States\n∗ Corresponding author. mina.pantcheva@ucdenver.edu\n09 7 2020 \n9 2020 \n09 7 2020 \n19 10082615 2 2019 17 6 2020 6 7 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nSteroid-induced ocular hypertension (OHTN) after penetrating keratoplasty (PKP) may cause irreversible damage to the optic nerve and graft failure. The purpose of this study is to report the first case of a post PKP patient with poorly controlled IOP, successfully treated with Kahook Dual Blade (KDB) goniotomy in both eyes.\n\nObservations\nThe patient was a 62-year old male with prior PKP in both eyes for lattice corneal degeneration. After an uncomplicated phacoemulsification in the left eye, his IOP increased to 32 mmHg on maximum tolerated IOP lowering therapy, including oral acetazolamide. This patient was dependent on scleral contact lenses for his irregular astigmatism post PKP to achieve his best-corrected visual acuity. Thus, we needed to consider a conjunctival sparing procedure and decided to proceed with performing a KDB goniotomy in the left eye. At 29 months follow up the visual acuity (VA) remained at 20/20 and IOP 13 mmHg on dorzolamide/timolol combination drop. A year following, his right eye also required KDB goniotomy combined with cataract surgery to treat his cataract and elevated IOP of 28 mm Hg. At 18 months post KDB goniotomy, the right eye VA was 20/50 and IOP 13 mmHg on dorzolamide/timolol combination drop.\n\nConclusions\nThis case demonstrates KDB goniotomy may be a good surgical alternative for post PKP steroid-induced OHTN or glaucoma, especially in patients requiring scleral contact lens for their visual rehabilitation.\n\nKeywords\nPenetrating keratoplastySteroid-induced ocular hypertensionKahook dual bladeGoniotomy\n==== Body\n1 Introduction\nOcular hypertension (OHTN) is a common complication following corneal transplantation surgery and can contribute to the development of glaucoma. Additionally, the accelerated chronic endothelial cell loss following penetrating keratoplasty (PKP) in eyes with poorly controlled intraocular pressure (IOP) may result in graft failure.1 Thus, elevated IOP is a common cause of vision loss in post PKP patients.2 Many studies have tried to determine the incidence of OHTN or glaucoma following penetrating keratoplasty (PKP).3,4 The mechanism for intraocular pressure (IOP) elevation following PKP is thought to be multifactorial and includes the need for chronic topical steroid use, synechial angle closure, anatomical distortion of the angle, collapse of the trabecular meshwork, and postoperative inflammation.5 Medical therapy remains the key for management of post PKP OHTN and glaucoma. Medically refractory cases are traditionally treated with trabeculectomy, cyclodestructive procedures, or glaucoma drainage devices.6, 7, 8 These surgical techniques effectively lower the IOP but carry a high-risk of complications, including hypotony, blebitis, tube exposure, endothelial cell loss, and graft failure.9, 10, 11 Novel minimally invasive glaucoma procedures have become commercially available in recent years. They offer an improved safety profile and faster postoperative recovery due to smaller incisions and quicker operative times.12 Little is known about the efficacy of these devices in the IOP management in post PKP patients. The Kahook dual blade (New World Medical Inc., Rancho Cucamonga, California, USA) was launched in the United States in 2015 and was designed to achieve near complete removal of TM with minimal, if any, surrounding tissue damage. This is in contrast to other ab interno trabeculectomy techniques (Gonioscopy-Assisted Transluminal Trabeculotomy (GATT), Trabectome, and traditional trabeculotomy), where residual TM leaflets remain post-procedure.13 There is no data on the efficacy of KDB goniotomy in post PKP patients with steroid-induced OHTN or glaucoma. We report a case of a patient with post PKP steroid-induced OHTN successfully treated with KDB goniotomy.\n\n2 Case report\nA 62 year-old male with a history of bilateral PKP for lattice corneal dystrophy presented with elevated IOP after undergoing uncomplicated cataract surgery in his left eye. He had a known history of steroid-induced OHTN with well-controlled IOP on topical beta-blocker daily prior to his cataract phacoemulsification. He was referred to the glaucoma clinic with IOP of 32 mmHg OS on maximum topical IOP lowering therapy. A slit lamp exam revealed clear PKP in both eyes with arcuate cuts in left cornea. The anterior chamber was deep and quiet in the right eye and deep with trace cell in the left eye given his recent cataract surgery. The left eye had posterior chamber intraocular lens and the right eye had a mild to moderate nuclear sclerotic cataract. He had open angles bilaterally with no synechiae and 2+ pigment in the trabecular meshwork. The optic nerve exam showed cup-to-disc ratio of 0.4 in both eyes and normal appearance of both maculas. Previous Humphrey 24-2 visual fields demonstrated nonspecific scattered depressions in both eyes. His optic nerve optical coherence tomographies (OCT) had low signal strengths, but were within normal limits. Oral acetazolamide extended release twice daily was added but his IOP remained uncontrolled at 28 mmHg OS. The patient had irregular astigmatism following his corneal transplants and was dependent on scleral contact lenses to achieve his best-corrected visual acuity. Therefore a procedure that required a conjunctival bleb was deemed high risk for failure, complications and a poor choice for his visual rehabilitation. The decision was made to proceed with a KDB goniotomy in the left eye given that his IOP remained elevated with maximum IOP lowering therapy, including oral carbonic anhydrase inhibitor for four weeks prior to surgery. The KDB goniotomy was performed according to a standard protocol as described by Sieck et al.14 A paracentesis was made and viscoelastic was injected into the anterior chamber. A 2.4 mm clear corneal incision was made avoiding the donor tissue. The patient's head was rotated 30–45° away from the surgeon and the microscope was tilted 30–45° toward the surgeon. A gonioprism was placed on the cornea and the KDB was introduced and advanced along Schlemm's canal in the nasal quadrant. Approximately 3–4 clock hours of TM was excised. Viscoelastic was irrigated and aspirated out of the anterior chamber, and the clear corneal wound was hydrated.\n\nOn postoperative day 1, the vision in the left eye was 20/300 without correction, 20/60 through pinhole. The intraocular pressure was 7 mmHg, a microhyphema was noted and the patient was told to stop all IOP lowering medications and to start a regimen of pilocarpine 1%, moxifloxacin, and prednisolone acetate 4 times daily in his left eye. The pilocarpine use was part of standard post goniotomy regimen to prevent formation of peripheral anterior synechiae and potential failure of the procedure. At 1 week the IOP was 11 mmHg and the moxifloxacin was discontinued. The patient continued a weekly taper of the prednisolone and pilocarpine. At 1 month, his IOP was 8 mmHg in the left eye. His prednisolone acetate was changed to loteprednol 3 times daily, and the pilocarpine was discontinued. Six months postoperatively, his visual acuity was 20/25-2 with his scleral contact lens in place and IOP remained at 10 mmHg off all IOP lowering medications. A gradual IOP elevation to 21 mmHg was noted over time and at 15 months dorzolamide-timolol topical combination drop was started twice daily to assure further IOP control. At his most recent visit, 29 months after the KDB goniotomy, his best corrected visual acuity was 20/20-1 and his IOP was 13 mmHg on dorzolamide-timolol and loteprednol 0.5% twice daily.\n\nEleven months following his glaucoma procedure in the left eye, his right eye had IOP elevation to 28 mmHg refractory to maximum topical IOP lowering therapy and required an oral carbonic anhydrase inhibitor. The decision was made to proceed with KDB goniotomy combined with cataract phacoemulsification in the right eye. On postoperative day 1, the VA in the right eye was 20/300 without correction and 20/100 through pinhole with IOP of 17 mmHg with microhyphema. At six months postoperatively his right eye had best corrected visual acuity of 20/25 + 1 with a scleral contact lens and IOP 14 mmHg on dorzolamide-timolol twice daily. The most recent exam was 18 months after the surgical intervention in the right eye and his IOP remains well controlled at 13 mm Hg on dorzolamide-timolol and loteprednol twice daily. His vision has decreased to 20/50 in the right eye due to lattice degeneration recurrence in the corneal graft. He continues to have a healthy cup-to-disc ratio and stable visual fields and retinal nerve fiber thickness.\n\n3 Discussion\nThere are many potential complications that can occur in post PKP patients with steroid-induced OHTN or glaucoma being one of the more serious and vision threatening problems. If not well controlled the elevation in IOP can also lead to graft failure. Consequently, it is imperative to have good IOP control following PKP and to monitor these patients closely for optic nerve damage to prevent future vision loss.\n\nThe mechanism for developing glaucoma is believed to be multifactorial; however, the prolonged use of topical steroids after PKP is thought to be a significant cause of IOP elevation.5 In patients with keratoconus, Pramanik et al. estimated the incidence of steroid-induced glaucoma to be 3.6% (4/112 eyes).15 Erdurmus et al. found the incidence of steroid-induced OHTN or glaucoma to be 73% in 100 patients with keratoconus who underwent PKP.16 Medical management and laser trabeculoplasty17 are common initial nonsurgical treatment options for post PKP steroid-induced OHTN or glaucoma. If IOP remains poorly controlled despite maximum tolerated medical therapy and laser trabeculoplasty, surgical intervention must be considered. Traditionally, medically refractory cases are treated with trabeculectomy, cyclodestructive procedures, or glaucoma drainage devices.6, 7, 8 There is a greater risk of graft failure with these surgical procedures. In filtering procedures, the risk of endothelial cell loss is due to the use of antimetabolites and their toxicity.18 With glaucoma drainage devices the cause of endothelial cell loss is due to the tube's proximity to the graft.19 Some recent studies suggest that this risk of cell loss could be minimized with ciliary sulcus tube placement.20 Minimally invasive glaucoma surgeries could potentially provide a safer surgical option in these patients if they can be shown to be effective. A recent case report by Nazarali et al. demonstrated the efficacy of gonioscopy-assisted transluminal trabeculotomy (GATT) in a post PKP patient with steroid-induced glaucoma.21\n\nIn this report the KDB goniotomy effectively reduced the high IOP present in both eyes of our patient after failed maximum tolerated medical therapy. Importantly, he was able to continue to use scleral contact lenses after the procedure to achieve his best-corrected visual acuity. The effect of the KDB goniotomy was sustained for more than 2 years postoperatively in the left eye, and 1.5 years postoperatively in the right eye. He required the addition of combination dorzolamide-timolol in the left eye at 15 months and was kept on this medication in the right eye after his KDB goniotomy.,\n\nComplications with the KDB goniotomy are typically mild. The most common complications that have been reported include IOP spike and hyphema due to blood reflux from Schlemm's canal which have an approximately 6% and 40% occurrence respectively.22,23\n\n4 Conclusions\nWe report the first case of post PKP steroid-induced OHTN effectively treated with KDB goniotomy. This procedure may be especially beneficial for patients needing to continue their contact lens wear to achieve best-corrected vision. The risk for endothelial cell loss is expected to be less as there is no device left behind in the angle and no antimetabolite use. Further prospective studies of larger patient populations are needed to elucidate the role of KDB goniotomy in post PKP patients.\n\nPatient consent\nThe patient provided written consent for his case to be published.\n\nFunding\nThis work was supported in part by a Challenge Grant to the Department of Ophthalmology from 10.13039/100001818Research to Prevent Blindness.\n\nAuthorship\nAll authors meet the current ICMJE criteria for authorship.\n\nDeclaration of competing interest\nThe authors have no financial conflicts of interest to disclose.\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgments\nNone.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajoc.2020.100826.\n==== Refs\nReferences\n1 Reinhard T. Bohringer D. Sundmacher R. Accelerated chronic endothelial cell loss after penetrating keratoplasty in glaucoma eyes J Glaucoma 10 6 2001 Dec 446 451 11740213 \n2 Sharma A. Sharma S. Pandav S.S. Mohan K. Post penetrating keratoplasty glaucoma: cumulative effect of quantifiable risk factors Indian J Ophthalmol 62 5 2014 May 590 595 24881607 \n3 Karadag O. Kugu S. Erdogan G. Kandemir B. Eraslan Ozdil S. Dogan O.K. Incidence of and risk factors for increased intraocular pressure after penetrating keratoplasty Cornea 29 3 2010 278 282 20118781 \n4 Sekhar G.C. Vyas P. Nagarajan R. Mandal A. Gupta S. Post-penetrating keratoplasty glaucoma J Ophthalmol 41 1993 181 184 \n5 Ayyala R.S. Penetrating keratoplasty and glaucoma Surv Ophthalmol 45 2 2000 91 105 11033036 \n6 Sherwood M.B. Smith M.F. Driebe W.T. Jr. Drainage tube implants in the treatment of glaucoma following penetrating keratoplasty Ophthalmic Surg 24 1993 185 189 8483569 \n7 Tandon A, Espandar L, Cupp D, Ho S, Johnson V, Ayyala RS. Surgical management for postkeratoplasty glaucoma: a meta-analysis. J Glaucoma 23(7):424-429.\n8 Gilvarry A.M. Kirkness C.M. Steele A.D. The management of post-keratoplasty glaucoma by trabeculectomy Eye 3 pt 6 1989 713 718 2630351 \n9 Arroyave C. Scott I. Fantes F. Feuer W. Murray T. Corneal graft survival and intraocular pressure control after penetrating keratoplasty and glaucoma drainage device implantation Ophthalmology 108 2001 1978 1985 11713065 \n10 Kusakabe A, Okumura N, Mori K, et al. Effect of trabeculectomy on corneal endothelial loss in cases of after penetrating-keratoplasty glaucoma. Cornea 36(3):317-321.\n11 Ficker L.A. Kirness C.M. Steele A.D. Intraocular surgery following penetrating keratoplasty: the risks and advantages Eye 4 1990 693 697 2282943 \n12 Saheb H. Ahmed I.L. Micro-invasive glaucoma surgery: current prespectives and future directions Curr Opin Ophthalmol 23 2 2012 Mar 96 104 22249233 \n13 Seibold L.K. Soohoo J.R. Ammar D.A. Kahook M.Y. Preclinical investigation of ab interno trabeculectomy using a novel dual-blade device Am J Ophthalmol 155 3 2013 524 529 23218696 \n14 Sieck E.G. Seibold L.K. Outcomes of Kahook Dual Blade goniotomy with and without phacoemulsification and cataract extraction Ophthalmol Glaucoma 1 2018 75 81 \n15 Pramanik S. Musch D.C. Sutphin J.E. Extended long-term outcomes of penetrating keratoplasty for keratoconus Ophthalmology 113 2006 1633 1638 16828503 \n16 Erdurmus M. Cohen E.J. Yildiz E.H. Steroid-induced intraocular pressure elevation or glaucoma after penetrating keratoplasty in patients with keratoconus or Fuchs dystrophy Cornea 28 2009 759 764 19574912 \n17 Nakakura S. Imamura H. Nakamura T. Selective laser trabeculoplasty for glaucoma after penetrating keratoplasty Optom Vis Sci 86 4 2009 Apr e404 e406 19258912 \n18 Dreyer E.B. Chatuvedi N. Zurakowski D. Effect of mitomycin C and fluorouracil-supplemented trabeculectomies on the anterior segment Arch Ophthalmol 113 1995 578 580 7748126 \n19 Topouzis F. Coleman A.L. Choplin N. Follow-up of the original cohort with the Ahmed glaucoma valve implant Am J Ophthalmol 128 1999 198 204 10458176 \n20 Rumelt S. Rehany U. Implantation of glaucoma drainage implant tube into the ciliary sulcus in patients with corneal transplants Arch Ophthalmol 116 5 1998 May 685 687 9596513 \n21 Nazarali S. Cote S.L. Gooi P. Gonioscopy-assisted transluminal trabeculotomy (GATT) in postpenetrating keratoplasty steroid induced glaucoma: a case report J Glaucoma 27 2018 e162 e164 30059406 \n22 SooHoo J.R. Seibold L.K. Kahook M.K. Ab interno trabeculectomy in the adult patient Middle East Afr J Ophthalmol 22 1 2015 25 29 25624670 \n23 Mansouri K.M. Intraocular pressure reduction after use of a novel goniotomy blade combined with phacoemulsification Data Presented as a Poster at the 7th World Glaucoma Congress, June 21-July 1 2017 (Helsinki, Finland)\n\n",
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"journal": "American journal of ophthalmology case reports",
"keywords": "Goniotomy; Kahook dual blade; Penetrating keratoplasty; Steroid-induced ocular hypertension",
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"title": "Kahook Dual Blade goniotomy in post penetrating keratoplasty steroid-induced ocular hypertension.",
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"abstract": "Myeloid sarcoma is a tumor mass of immature myeloid or granulocytic cells that affects extramedullary anatomic sites, including uncommonly the oral cavity. A 24-year-old female was referred for evaluation of a fast growing painful gingival swelling lasting 2 weeks, associated with fever, fatigue, and cervical lymphadenopathy. Intraoral examination showed a bluish swelling on the right posterior lower gingiva exhibiting necrotic surface. Incisional biopsy of the gingival lesion displayed diffuse infiltration of undifferentiated tumor cells with granulocytic appearance, strongly immunopositive for CD99, myeloperoxidase and Ki-67 (60%), and negative for CD20, CD3, CD34 and TdT. Blood tests presented a severe pancytopenia, and genetic analysis confirmed the diagnosis of acute promyelocytic leukemia. The final diagnosis was of oral myeloid sarcoma associated with acute promyelocytic leukemia with t(15;17). The patient was submitted to chemotherapy but died of the disease one month later. The clinicopathologic and immunohistochemical features of the present case are compared with the 89 cases of oral myeloid sarcoma previously reported in the English-language literature. Key words:Myeloid sarcoma, chloroma, granulocytic sarcoma, gingiva, oral, acute promyelocytic leukemia, acute myeloid leukemia.",
"affiliations": "DDS, PhD, Oral Pathology, Department of Oral Diagnosis and Pathology, School of Dentistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.;DDS, MSc, Oral Pathology, Department of Oral Diagnosis and Pathology, School of Dentistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.;DDS, PhD , Oral Medicine, Department of Oral Diagnosis and Pathology, School of Dentistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.;DDS, PhD , Oral Medicine, Department of Oral Diagnosis and Pathology, School of Dentistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.;DDS, PhD, Oral Pathology, Department of Oral Diagnosis and Pathology, School of Dentistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.;DDS, PhD, Oral Pathology, Department of Oral Diagnosis and Pathology, School of Dentistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.;DDS, PhD, Oral Pathology, Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (FOP-UNICAMP), Piracicaba, Brazil.;DDS, PhD, Oral Pathology, Department of Oral Diagnosis and Pathology, School of Dentistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.",
"authors": "de Andrade|Bruno-Augusto-Benevenuto|BA|;Farneze|Renan-de Barros|RB|;Agostini|Michelle|M|;Cortezzi|Ellen-Brilhante|EB|;Abrahão|Aline-Corrêa|AC|;Cabral|Marcia-Grillo|MG|;Rumayor|Alicia|A|;Romañach|Mário-José|MJ|",
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"fulltext": "\n==== Front\nJ Clin Exp DentJ Clin Exp DentMedicina Oral S.L.Journal of Clinical and Experimental Dentistry1989-5488Medicina Oral S.L. 5393510.4317/jced.53935Case ReportOral Medicine and PathologyMyeloid sarcoma of the oral cavity: A case report and review \nof 89 cases from the literature de Andrade Bruno-Augusto-Benevenuto 1Farneze Renan-de Barros 2Agostini Michelle 3Cortezzi Ellen-Brilhante 3Abrahão Aline-Corrêa 1Cabral Marcia-Grillo 1Rumayor Alicia 4Romañach Mário-José 11 DDS, PhD, Oral Pathology, Department of Oral Diagnosis and Pathology, School of Dentistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil2 DDS, MSc, Oral Pathology, Department of Oral Diagnosis and Pathology, School of Dentistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil3 DDS, PhD , Oral Medicine, Department of Oral Diagnosis and Pathology, School of Dentistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil4 DDS, PhD, Oral Pathology, Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (FOP-UNICAMP), Piracicaba, Brazil Department of Oral Diagnosis and Pathology\nSchool of Dentistry, Federal University of Rio de Janeiro (UFRJ)\nAv. Professor Rodolpho Paulo Rocco, 325, 1º andar \nRio de Janeiro, Brazil 21941- 913\n, E-mail: brunoabandrade@Conflict of interest statement:The authors declare that they have no conflict of interest.\n\n1 9 2017 9 2017 9 9 e1167 e1171 12 7 2017 11 4 2017 Copyright: © 2017 Medicina Oral S.L.2017This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Myeloid sarcoma is a tumor mass of immature myeloid or granulocytic cells that affects extramedullary anatomic sites, including uncommonly the oral cavity. A 24-year-old female was referred for evaluation of a fast growing painful gingival swelling lasting 2 weeks, associated with fever, fatigue, and cervical lymphadenopathy. Intraoral examination showed a bluish swelling on the right posterior lower gingiva exhibiting necrotic surface. Incisional biopsy of the gingival lesion displayed diffuse infiltration of undifferentiated tumor cells with granulocytic appearance, strongly immunopositive for CD99, myeloperoxidase and Ki-67 (60%), and negative for CD20, CD3, CD34 and TdT. Blood tests presented a severe pancytopenia, and genetic analysis confirmed the diagnosis of acute promyelocytic leukemia. The final diagnosis was of oral myeloid sarcoma associated with acute promyelocytic leukemia with t(15;17). The patient was submitted to chemotherapy but died of the disease one month later. The clinicopathologic and immunohistochemical features of the present case are compared with the 89 cases of oral myeloid sarcoma previously reported in the English-language literature.\n\n\n\n Key words:Myeloid sarcoma, chloroma, granulocytic sarcoma, gingiva, oral, acute promyelocytic leukemia, acute myeloid leukemia.\n==== Body\nIntroduction\nMyeloid sarcoma (MS), also known as granulocytic sarcoma or chloroma, is a tumor mass of immature myeloid cells that usually occurs in an extramedullary site or bone of male patients in the sixth decade of life (1). MS has been associated with acute myeloid leukemias (AML) or other myeloproliferative disorders (2-3). Treatment and prognosis of MS depends on the hematological status and clinical presentation (4).\n\nThe microscopical features of MS include the presence of immature myeloblasts within a dense inflammatory background, which are better identified after careful histological and immunohistochemical evaluation (4-5). Some markers are useful to confirm an immature myeloid phenotype of tumor cells, such as myeloperoxidase (MPO), CD68, CD117, CD34, and CD99 (6).\n\nOral involvement by MS is uncommon. To the best of our knowledge, only 89 cases of oral MS have been published in the English-language literature so far, and only four of them were associated with acute promyelocytic leukemia (1-15). Herein, we report an additional case of oral MS in a 24-year-old female with acute promyelocytic leukemia, including a review of the literature.\n\nCase Report\nA 24-year-old female was referred by a general dentist for evaluation of a fast growing gingival swelling that had been present for 2 weeks. The patient reported a 3-weeks history of fever and fatigue. Physical examination revealed cervical lymphadenopathy, and intraoral examination showed discrete areas of clotted blood within the gingival sulcus of some teeth, and a 3 cm painful brownish swelling with necrotic and bleeding surface localized in the right posterior lower gingiva (Fig. 1). Radiographic examination of the mandible showed no bone involvement (Fig. 2). Under the presumptive clinical diagnosis of lymphoma/leukemia, a blood study was requested and the patient was submitted to an incisional biopsy.\n\nFigure 1 Clinical features of oral myeloid sarcoma. (A) Intraoral examination showing pale oral mucosa, blood accumulation within the gingival sulcus of various teeth, and a normal colored swelling on the buccal posterior lower gingiva of the right side. (B) Brownish swelling with ulceration on the lingual aspect of the right posterior lower gingiva exhibiting also necrotic and bleeding surface.\n\n\n\nFigure 2 Panoramic radiography exhibiting absence of bone involvement.\n\n\n\nThe gingival specimen showed a diffuse connective tissue infiltration by poorly differentiated blast-like cells intermingled with chronic inflammatory infiltrate. Tumor cells were large, round to oval, with mild to moderately basophilic cytoplasm containing granules, and round to folded nuclei with fine chromatin. Occasional mitotic figures were found (Fig. 3). By immunohistochemis-try, tumor cells were intensely positive for myeloperoxidase (dilution 1:5000, polyclonal, Dako, Carpinteria, CA, USA) and CD99 (dilution 1:100, clone 12e7, Dako, Carpinteria, CA, USA), and negative for CD20 (dilution 1:1000, clone L26, Dako, Carpinteria, CA, USA), CD3 (dilution 1:500, polyclonal, Dako, Carpinteria, CA, USA), CD34 (dilution 1:50, clone QBEnd10, Dako, Carpinteria, CA, USA), and TdT (dilution 1:50, polyclonal, Dako, Carpinteria, CA, USA). Ki-67 (dilution 1:100, clone MIB-1, Dako, Carpinteria, CA, USA) labeling was high, with 60% of tumor cells positive (Fig. 3). Blood findings showed pancytopenia (0.7 x109/L leucocytes, 31 x 109/L platelets, hemoglobin 6.3 g/dl, and hematocrit 18.6%) and the specific chromosomal translocation t(15;17) revealed by genetic analysis confirmed the diagnosis of acute promyelocytic leukemia with recurrent genetic abnormality. The final diagnosis of the oral lesion was myeloid sarcoma associated with acute promyelocytic leukemia with t(15;17). The patient was then referred to a hematology-oncology service, and submitted to chemotherapy including all trans retinoic acid (ATRA), idarubicin, and cytarabine. Unfortunately, the patient died one month later after severe hemorrhagic episodes.\n\nFigure 3 Histopathological and immunohistochemical features of oral myeloid sarcoma. (A) Diffuse infiltration of the gingival connective tissue by sheets of poorly differentiated hematopoietic cells, exhibiting dense nuclei, and basophilic cytoplasm within a background of capillary proliferation and abundant erythrocyte extravasation (HE, 100X). (B) The infiltrate is composed mostly of myelocytes promyelocytes, and myeloblasts. The cells are large in size and round to oval in shape, and the cytoplasm was mild to moderately basophilic (HE, 400X). Tumor cells showed a strong positivity for (C) myeloperoxidase, and (D) Ki-67 (Immunoperoxidase, 400X). \n\n\n\nDiscussion\nMyeloid sarcoma (MS) is an extramedullary solid tumor composed of myeloblasts or immature cells of granulocytic lineage and erythroid precursors (2,3). First described by Burns and King in 1811, MS is also referred as “chloroma” due its green colored appearance when exposed to air, by the presence of myeloperoxidase in the tumor cells (1). Since the greenish color is not a consistent clinical finding and considering a proved granulocytic origin, the terms granulocytic sarcoma or myeloid sarcoma are preferably adopted by most authors (1-3).\n\nMS is mainly found in the bone and soft tissues, but it may affect virtually any site of the body such as the skin, lymph nodes, orbit and eye, oral cavity, bronchi, pericardium, peritoneum, gastrointestinal tract, kidney, reproductive organs, breast, and bladder (1-4). Considering the 89 cases of oral MS previously published in the English literature, the average age of the patients is 45 years (ranging from 1 to 89 years), with slight predilection for females (1,2:1). The mandible is the most common affected site (28 cases), followed by maxilla (20 cases), gingiva (13 cases), and palate (seven cases) (1-15). MS affected multiple intraoral anatomical sites in eight cases, six of them with concomitant involvement of maxilla and mandible (5,7,8,11,13-15). The most common clinical feature of oral MS is a painful swelling or nodule with reddish to brownish-colored ulcerated surface. From all cases reviewed from the literature, only five exhibited evident greenish coloration (1,2,4,10,12). The clinical differential diagnosis is wide, ranging from lymphoma, squamous cell carcinoma and sarcomas to benign reactive or inflammatory lesions. The diagnosis of oral MS is usually based on histopathological and immunohistochemical analysis, and a history of symptoms associated with hematological diseases that might be absent (7-9). In the present case, the patient was a 24-years-old female patient, who was diagnosed concomitantly with a subtype of acute myeloid leukemia. The clinical appearance of the present case was consistent with a malignant tumor, showing an ulcerated and painful brownish-colored swelling in the lingual aspect of the lower posterior gingiva with no bone involvement. The identification of pale-appearing mucosae and areas of coagulated blood within the gingival sulcus led us to suspect of a leukemia, which was confirmed after blood test and genetic analyses.\n\nMicroscopically, oral MS exhibits variable numbers of primitive, poorly differentiated cells with granular cytoplasm, round to oval nuclei with well-defined membrane and prominent nucleoli, intermingled with reactive inflammatory infiltrate. The tumor cells show different stages of myeloid differentiation, including the eosinophilic myelocytes and blastic cells with minimal granulocytic differentiation (9). The microscopical differential diagnosis of oral MS includes diffuse large B-cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, and poorly-differentiated squamous cell carcinoma (7). The histopathological diagnosis can be difficult, especially in cases of prominent reactive inflammatory infiltrate background and limited correlation with clinical features. Immunohistochemical analysis is necessary to prove the granulocytic origin of tumor cells (6), which are usually positive for myeloperoxidase (MPO) and CD99, important markers for the diagnosis of myeloid sarcoma (9). In the present case, the identification of the granulocytic appearance of the tumor cells was difficult on hematoxylin and eosin-stained slides, and the immunohistochemical positivity for myeloperoxidase in a cytoplasmic pattern and for CD99 in a membrane pattern was essential to achieve the final diagnosis.\n\nMS may precede, coexist with, or follow a presentation of acute myeloid leukemia (AML), but might also result from an acute blastic transformation of myelodysplastic syndromes or myeloproliferative neoplasms (6). In fact, the diagnosis of MS is currently considered synonym of AML, and the same chemotherapeutic regimens are used (6). Acute promyelocytic leukaemia (APL; also previously known as AML-M3) accounts for around 8% of all AML cases, occurring mainly in early adulthood. APL is characterized by the predominance of abnormal promyelocytes in the bone marrow and identification of a specific chromosomal translocation t(15;17)(q24.1;q21.1) resulting in a fusion transcript between the genes promyelocytic (PML on chromosome 15) and retinoic acid receptor alpha (RARA on chromosome 17). The most common diseases associated with oral MS are AML (43 cases), followed by myelodysplastic syndrome (11 cases), and chronic myeloid leukemia (seven cases), nevertheless 14 patients with oral MS did not present nor developed associated leukemia or myelodysplastic neoplasms (1-15).\n\nApproximately 90% of patients with APL have shown complete remission of disease after the advent of ATRA and anthracycline-based therapeutic regimens (7). However, the rate of early induction death is still high in patients with APL, and one of the most common causes is hemorrhage, as observed in the present case. Only four out of 89 cases of oral MS reported in the English literature were associated with APL (3), and one died of the disease, as the present case. From all oral MS cases reported in the literature, 53 patients died of disease, 16 had no evidence of disease, and 11 were alive with disease (1-15).\n\nIn summary, oral MS is uncommon, with clinical and microscopical features that may mimic inflammatory lesions or other malignant tumors. Careful morphological and immunohistochemical analyses, correlating with clinical data are necessary to establish the diagnosis of oral MS. Clinicians and oral pathologists should consider MS when evaluating gingival swellings and ulcerations in patients with clinical findings suggestive of hematological abnormalities.\n==== Refs\n1 Wiernik PH Serpick AA Granulocytic sarcoma (chloroma) Blood 1970 35 361 9 4908654 \n2 Neiman RS Barcos M Berard C Bonner H Mann R Rydell RE Granulocytic sarcoma: a clinicopathologic study of 61 biopsied cases Cancer 1981 48 1426 37 7023656 \n3 Welch P Grossi C Carroll A Dunham W Royal S Wilson E Granulocytic sarcoma with an indolent course and destructive skeletal disease. Tumor characterization with immunologic markers, electron microscopy, cytochemistry, and cytogenetic studies Cancer 1986 57 1005 10 2417685 \n4 Rodriguez JC Arranz JS Forcelledo MF Isolated granulocytic sarcoma: report of a case in the oral cavity J Oral Maxillofac Surg 1990 48 748 52 2193130 \n5 Ritter JH Goldstein NS Argenyi Z Wick MR Granulocytic sarcoma: an immunohistologic comparison with peripheral T-cell lymphoma in paraffin sections J Cutan Pathol 1994 21 207 16 7962823 \n6 Colella G Tirelli A Capone R Rubini C Guastafierro S Myeloid sarcoma occurring in the maxillary gingiva: a case without leukemic manifestations Int J Hematol 2005 81 138 41 15765782 \n7 Xie Z Zhang F Song E Ge W Zhu F Hu J Intraoral granulocytic sarcoma presenting as multiple maxillary and mandibular masses: a case report and literature review Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007 103 e44 8 17428693 \n8 Srinivasan B Ethunandan M Anand R Hussein K Ilankovan V Granulocytic sarcoma of the lips: report of an unusual case Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008 105 e34 6 18155599 \n9 Papamanthos MK Kolokotronis AE Skulakis HE Fericean AM Zorba MT Matiakis AT Acute myeloid leukaemia diagnosed by intra-oral myeloid sarcoma. A case report Head Neck Pathol 2010 4 132 5 20512638 \n10 Qiu YT Yang C Zhang XH Primary granulocytic sarcoma of the mandibular condyle presenting with the characteristic green color J Oral Maxillofac Surg 2010 68 2575 79 20561729 \n11 da Silva-Santos PS Silva BS Coracin FL Yamamoto FP Pinto-Junior DD Magalhães MG Granulocytic sarcoma of the oral cavity in a chronic myeloid leukemia patient: an unusual presentation Med Oral Patol Oral Cir Bucal 2010 15 e350 2 19767700 \n12 Seema S Jay GR Devi CS Aadithya BU Niharika S Granulocytic sarcoma of the oral cavity Indian J Cancer 2011 48 378 80 21921350 \n13 Moshref M Lotfi A Mashhadi-Abbas F Kargahi N Granulocytic sarcoma (chloroma) presenting as multiple sites in oral cavity: report of a case Iran J Cancer Prev 2014 7 53 7 25250149 \n14 Sharma A Singh HP Gupta AA Garg P Moon NJ Chavan R Granulocytic sarcoma in non-leukaemic child involving maxillary sinus with long term follow up: A rare case report Ann Maxillofac Surg 2014 4 90 5 24987607 \n15 Kumar P Singh H Khurana N Urs AB Augustine J Tomar R Diagnostic challenges with intraoral myeloid sarcoma: report of two cases & review of world literature Exp Oncol 2017 39 78 85 28361861\n\n",
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"title": "Myeloid sarcoma of the oral cavity: A case report and review of 89 cases from the literature.",
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"abstract": "This is a retrospective analysis to assess the safety and efficacy of abiraterone acetate (AA) in metastatic castrate-resistant prostate cancer (mCRPC) patients treated at tertiary care institute.\nThe clinical records of mCRPC patients treated with AA at our tertiary care institute between July 2013 and December 2015 were reviewed. The treatment efficacy, toxicities, and its determinants were analyzed.\nA total of 59 mCRPC patients treated with AA were reviewed, of whom 37 were chemo-naive and 22 had received prior chemotherapy (postchemo). The median follow-up duration was 10.0/15.0 months for chemo-naïve/postchemotherapy patients. 43.2%/36.36% of chemo-naive/postchemo patients had visceral metastases. The median overall survival (OS) and progression-free survival (PFS) were 15/7.8 months and 10/5.3 months for chemo-naive/postchemo patients, respectively. Median time to best prostate-specific antigen response was 3.4 months. Abiraterone was relatively well tolerated with no grade 4 toxicity or treatment-related death. We found the presence of previous taxene use and baseline symptoms to be significantly determinant of OS with abiraterone.\nThe present study reported the efficacy of abiraterone in both chemo-naïve and postchemo patients of mCRPC outside clinical trial setting. We found lower OS and PFS with abiraterone as compared to that reported in the clinical trial setting in both chemo-naïve and postchemo patients, and particularly in those patients with the visceral disease, and further clinical trial for abiraterone in this subgroup of patients is warranted.",
"affiliations": "Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharastra, India.;Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharastra, India.;Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharastra, India.;Department of Radiology, Tata Memorial Hospital, Mumbai, Maharastra, India.;Department of Nuclear Medicine, Tata Memorial Hospital, Mumbai, Maharastra, India.;Department of Radiology, Tata Memorial Hospital, Mumbai, Maharastra, India.;Centre for Cancer Epidemiology, TATA Memorial Centre, Mumbai, Maharastra, India.;Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharastra, India.",
"authors": "Joshi|Amit|A|;Shrirangwar|Sameer|S|;Noronha|Vanita|V|;Sable|Nilesh|N|;Agarwal|Archi|A|;Popat|Palak|P|;Bhattacharjee|Atanu|A|;Prabhash|Kumar|K|",
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"fulltext": "\n==== Front\nSouth Asian J CancerSouth Asian J CancerSAJCSouth Asian Journal of Cancer2278-330X2278-4306Wolters Kluwer - Medknow India SAJC-9-2310.4103/sajc.sajc_433_18ORIGINAL ARTICLE: Genitourinary CancersA tertiary care audit of using abiraterone acetate in patients of metastatic castrate-resistant prostate cancer Joshi Amit Shrirangwar Sameer Noronha Vanita Sable Nilesh 1Agarwal Archi 2Popat Palak 1Bhattacharjee Atanu 3Prabhash Kumar Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharastra, India1 Department of Radiology, Tata Memorial Hospital, Mumbai, Maharastra, India2 Department of Nuclear Medicine, Tata Memorial Hospital, Mumbai, Maharastra, India3 Centre for Cancer Epidemiology, TATA Memorial Centre, Mumbai, Maharastra, IndiaCorrespondence to: Dr. Kumar Prabhash, E-mail: kprabhash1@gmail.comJan-Mar 2020 9 1 23 26 Copyright: © 2019 The South Asian Journal of Cancer2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Introduction:\nThis is a retrospective analysis to assess the safety and efficacy of abiraterone acetate (AA) in metastatic castrate-resistant prostate cancer (mCRPC) patients treated at tertiary care institute.\n\nMaterials and Methods:\nThe clinical records of mCRPC patients treated with AA at our tertiary care institute between July 2013 and December 2015 were reviewed. The treatment efficacy, toxicities, and its determinants were analyzed.\n\nResults:\nA total of 59 mCRPC patients treated with AA were reviewed, of whom 37 were chemo-naive and 22 had received prior chemotherapy (postchemo). The median follow-up duration was 10.0/15.0 months for chemo-naïve/postchemotherapy patients. 43.2%/36.36% of chemo-naive/postchemo patients had visceral metastases. The median overall survival (OS) and progression-free survival (PFS) were 15/7.8 months and 10/5.3 months for chemo-naive/postchemo patients, respectively. Median time to best prostate-specific antigen response was 3.4 months. Abiraterone was relatively well tolerated with no grade 4 toxicity or treatment-related death. We found the presence of previous taxene use and baseline symptoms to be significantly determinant of OS with abiraterone.\n\nConclusion:\nThe present study reported the efficacy of abiraterone in both chemo-naïve and postchemo patients of mCRPC outside clinical trial setting. We found lower OS and PFS with abiraterone as compared to that reported in the clinical trial setting in both chemo-naïve and postchemo patients, and particularly in those patients with the visceral disease, and further clinical trial for abiraterone in this subgroup of patients is warranted.\n\nAbirateronechemo-naive/postchemometastatic castrate-resistant prostate cancernontrial settingvisceral disease\n==== Body\nIntroduction\nAndrogen deprivation therapy (ADT) is the initial treatment of choice for men with metastatic prostate cancer for the past several years.[1] Although ADT is palliative, it can normalize serum levels of prostate-specific antigen (PSA) in over 90% of patients and can produce objective tumor responses in 80%–90%. This antitumor activity can improve quality of life by reducing bone pain as well as the rates of complications (e.g., pathologic fracture, spinal cord compression, and ureteral obstruction).[23] The duration of response to ADT for patients with metastatic disease is highly variable, and most patients eventually progressed to metastatic castrate resistant prostate cancer (mCRPC), although such patients may remain responsive to additional therapies directed against androgenic stimulation of the prostate cancer.\n\nA unique molecular alteration in castration-resistant prostate cancer is the up-regulation of androgen biosynthesis enzymes, leading to an increase in intratumoral androgen concentrations.[456] Other alterations include overexpression of androgen receptors, and androgen receptor mutations leading to androgen-receptor binding by additional ligands that would not stimulate the wild-type receptor.[78] This has led to the development of drugs which act by inhibition of the enzymes responsible for androgen production, as well as those which inhibit the androgen receptor. Abiraterone acetate (AA), a prodrug of abiraterone, is a selective inhibitor of androgen biosynthesis that potently blocks cytochrome P450 c17, a critical enzyme in testosterone synthesis, thereby blocking androgen synthesis by the adrenal glands and testes and within the prostate tumor. Two randomized phase III trial COU-AA-301 and 302 have demonstrated the efficacy of AA in patients of castrate-resistant prostate cancer in both postdocetaxel and chemo-naïve patients. We report the clinical outcome of metastatic castration-resistant prostate cancer patients treated with AA in real-life clinical practice at our institute.\n\nMaterials and Methods\nStudy design and outcome measures\nThis is a retrospective analytical study for determining the outcomes of AA in mCRPC. The data regarding demographics, previous treatment, tumor details, toxicities, response, progression, and survival of patients receiving abiraterone was obtained from the electronic medical record. This study was approved by the institutional review board of the author's institution.\n\nThe definition of clinical, biochemical, and radiological progressive disease was according to the Prostate Cancer Clinical Trials Working Group-2 criteria.[9] PSA response was defined as ≥50% decline in PSA level from baseline on treatment. Overall survival (OS) and progression-free survival (PFS) were defined as the time from the first dose of AA to death, and to the first event of clinical, radiographic or PSA progression or death, in both chemotherapy naive and postdocetaxel group, respectively. The covariates of interest were explored for OS and PFS.\n\nStudy population\nThe present study included mCRPC patients both chemotherapy naïve and those who are progressed on one or multiple lines of therapy and started on AA between July 2013 and December 2015. Patients were treated with 1000 mg AA once daily in combination with 5 mg prednisone twice a day until disease progression, death or unacceptable toxicity. Clinical and biochemical follow-up with serum PSA, blood counts, liver, renal profile, and imaging when indicated were regularly undertaken during the treatment period.\n\nStatistical analysis\nR studio version 3.4.2 was used for analysis. Proportions and frequencies are mentioned for categorical variables while median with interquartile range is used for continuous variables. Patients who had not expired at last follow-up are censored during the estimation of OS by the Kaplan–Meier method. Factors affecting PFS and OS are identified by COX regression analysis.\n\nResults\nCharacteristics of patients’ cohort\nA total of 59 patients were reviewed, of whom 37 were chemo-naïve and 22 were postchemotherapy. Table 1 summarizes the characteristics of the patient cohort. The median follow-up duration was 10 months (2.7, 29.6) and 15 months (3.6, 48.1) for chemo-naïve and postchemotherapy group, respectively. The mean age of the study cohort was 67 years. Comorbidities such as diabetes mellitus, hypertension, and ischemic heart disease were present in 17 (28.8%), 30 (50.8%), and 10 (16.9%) of patients, respectively. Median baseline PSA and Gleason score was 132.5 and 8, respectively. A total of 9 out of 59 patients were diagnosed with localized disease at the time of initial presentation and underwent definitive surgery[4] or radical radiotherapy.[5] These patients also received ADT when they developed metastatic disease. A total of 19 out of 59 (32.2%) patients opted for medical castration and rest of the patient underwent surgical orchidectomy for ADT. At the time of starting AA, visceral disease (lymph node and visceral organ metastases) was present in 16 (43.2%) chemo-naïve and 8 (36.36%) postchemo patients. About 85% of patients were symptomatic for disease, and 14 out of 59 patients received ketoconazole before initiation of AA.\n\nTable 1 Patient’s characteristics and treatment details\n\nParameters\tChemo-naive (n=37)\tPostchemotherapy (n=22)\t\nAge, median (range)\t68 (49-84)\t66 (55-75)\t\nECOG, n (%)\t\t\t\n 0-1\t26 (70.2)\t19 (86.3)\t\n 2\t8 (21.6)\t3 (13.6)\t\n 3\t1 (2.7)\t0\t\n 4\t2 (5.4)\t0\t\nGleason score at baseline, n (%)\t\t\t\n <8\t28 (75.6)\t9 (40.9)\t\n >8\t8 (21.6)\t13 (59.0)\t\n Unknown\t1 (2.7)\t0\t\nMedian PSA\t137\t129\t\nSymptomatic for disease at the time of starting abiraterone, n (%)\t30 (81)\t20 (90)\t\nDisease location, n (%)\t\t\t\n Bone only\t21 (56.7)\t14 (63.6)\t\n Viscera\t16 (43.2)\t8 (36.36)\t\nComorbidities, n (%)\t\t\t\n Diabetes mellitus\t8 (21.6)\t9 (40.9)\t\n Hypertension\t21 (56.7)\t9 (40.9)\t\n IHD\t10 (16.9)\t0\t\nPrevious cytotoxic regimen, n (%)\t\t\t\n 1\t0\t19 (86.36)\t\n 2\t0\t3 (13.6)\t\nADT, n (%)\t\t\t\n Surgical\t22 (59.4)\t18 (81.8)\t\n Medical\t15 (40.5)\t4 (18.1)\t\nPSA response with abiraterone, n (%)\t15 (39.4)\t4 (18.1)\t\nReasons of discontinuation of abiraterone, n (%)\t\t\t\n Disease progression\t36 (97.2)\t19 (86.3)\t\n Treatment-related complication\t1 (2.7)\t2 (9.0)\t\n Patient’s decision\t0\t1 (4.5)\t\nPSA=Prostate specific antigen, ADT=Androgen deprivation therapy, ECOG=Eastern Cooperative Oncology Group, IHD=Ischemic heart disease\n\nClinical efficacy\nProstate-specific antigen response\nThe proportion of patients with best PSA response is 4 (18.1%) in postchemo groups and 15 (39.4%) in chemo-naïve group [Table 1]. Median time to best PSA response was 3.4 months, with 3/38 chemo-naïve, and 0/22 postchemo patients were still under treatment at the time of the last follow-up. Disease progression was the major reason of treatment discontinuation.\n\nOverall survival and progression-free survival\nThe median OS and progression-free survival for the complete cohort were 11.9 (95% confidence interval [CI]: 10, 17) months and 6.7 (95% CI: 5.5, 9.9) months, respectively. The patients with visceral disease had numerically inferior OS (9.7 vs. 12.8 months) and inferior PFS (5.8 vs. 8.7 months) than those without visceral disease, which was not statistically significant (P value 0.088 and 0.25). The median OS and PFS was 15 months (95% CI: 11.4, 28.1) and 7.8 months (95% CI: 3.9–16.5) for chemo-naïve group and 10 months (95% CI: 7.4, 12.5) and 5.3 (95% CI: 4.3, 9.6) months for postchemo group, respectively [Table 2].\n\nTable 2 Overall survival and progression-free survival\n\n\tParameter\tNumber of patients\tEvent\tMedian\t95% LCL\t95% UCL\t\nOverall study population\tPFS\t59\t56\t6.7\t5.5\t9.9\t\nOS\t59\t48\t11.9\t10\t17\t\nVisceral disease (n=24)\tPFS\t24\t23\t5.8\t4.5\t7.8\t\nWithout visceral disease (n=35)\t35\t33\t8.7\t5.3\t12.8\t\nVisceral disease (n=24)\tOS\t24\t21\t9.7\t7.4\t17.4\t\nWithout visceral disease (n=35)\t35\t27\t12.8\t11.3\t30.1\t\nChemo-naïve (n=37)\tPFS\t37\t34\t7.8\t3.9\t16.5\t\nPostchemotherapy (n=22)\t22\t22\t5.3\t4.3\t9.6\t\nChemo-naïve (n=37)\tOS\t37\t28\t15\t11.4\t28.1\t\nPostchemotherapy (n=22)\t22\t20\t10\t7.4\t15.5\t\nPFS=Progression-free survival, OS=Overall survival, LCL=Lower confidence limit, UCL=Upper confidence limit\n\nAdverse events\nTable 3 shows the treatment-related toxicities in patients treated with AA. We found the following common adverse events (all grades). Nausea 12 (20.3%), hypertension 11 (18.6%), fatigue 11 (18.6%), liver function abnormality 10 (16.9%), vomiting 7 (11.8%), hypokalemia 6 (10.1%), fluid retention 5 (8.4%), thrombocytopenia 3 (5.0%), and cardiac toxicity 2 (3.3%). Two patients required dose modifications due to thrombocytopenia and transaminitis each. Only three patients stopped abiraterone due to toxicity; the reason for it was fluid retention and cardiac toxicity. There was no grade 4 toxicity or treatment-related death among them.\n\nTable 3 Adverse events during treatment\n\nToxicity\tGrade I (%)\tGrade II (%)\tGrade III (%)\tGrade IV (%)\t\nThrombocytopenia\t2 (3.3)\t0\t1 (1.6)\t0\t\nFatigue\t3 (5.0)\t6 (10.1)\t2 (3.3)\t0\t\nTransaminitis\t6 (10.1)\t0\t1 (1.69)\t0\t\nHyperbilirubinemia\t3 (5)\t0\t0\t0\t\nHypokalemia\t5 (8.4)\t1 (1.69)\t0\t0\t\nNausea\t12 (20.3)\t0\t0\t0\t\nFluid retention\t4 (6.77)\t0\t1 (1.69)\t0\t\nCardiac disorder\t0\t0\t2 (3.3)\t0\t\nVomiting\t6 (10.1)\t0\t1 (1.69)\t0\t\nUnivariate analysis\nIn univariate analysis, the presence of the previous taxene used or not was the significant determinant of both OS and PFS with Abiraterone [Table 4] with the P = 0.004 and 0.005, respectively. The presence of low Gleason score (hazard ratio [HR] 0.53, 95% CI: 0.33–0.85, P = 0.0086) was determinant of best PSA response. HR observed with other covariates such as initial PSA, performance status, stage at diagnosis, and baseline PSA are detailed in Table 4.\n\nTable 4 Univariate Cox proportional hazard analysis on overall survival and progression-free survival\n\nParameter\tOS\tPFS\t\n\t\t\nHR\tP\tHR\tP\t\nInitial PSA\t1.00\t0.29\t1.00\t0.53\t\nECOG PS\t1.22\t0.29\t1.20\t0.38\t\nStage at diagnosis\t0.91\t0.83\t1.12\t0.74\t\nBaseline PSA before starting of abiraterone\t1.00\t0.19\t1.00\t0.17\t\nGleason score\t1.16\t0.29\t1.18\t0.24\t\nPrevious taxene (yes or no)\t2.42\t0.004\t2.24\t0.005\t\nBaseline symptoms\t3.32\t0.014\t1.90\t0.084\t\nSite of metastasis (visceral or others)\t1.65\t0.088\t1.377\t0.25\t\nPFS=Progression-free survival, OS=Overall survival, PSA=Prostate specific antigen, ECOG PS=Eastern Cooperative Oncology Group performance status, HR=Hazard ratio\n\nDiscussion\nIn a Phase 3, multicenter, randomized, placebo-controlled study by de Bono et al.,[10] AA 1000 mg daily with prednisolone 5 mg BD has been shown to improves survival in patients with metastatic castration-resistant prostate cancer who have failed one or two prior chemotherapy regimens, one of which contained docetaxel. In addition, in a study done by Ryan et al.,[11] AA with prednisolone has been shown to improve survival in chemotherapy naïve patient also. Till date, no data is available for the use of AA in Indian patients. Hence, we have planned for retrospective analysis of patients receiving AA in mCRPC from July 2013 to December 2015 at our tertiary care institute.\n\nIn this study, we reported the efficacy and toxicity of abiraterone in patients of mCRPC from an unselected patient population in a nontrial setting. The inclusion of all abiraterone treated patients at our institute during a defined period serves to provide a representative picture of the efficacy of abiraterone in real-world setting.\n\nIn our study, unexpectedly, the median PFS and OS of chemo-naïve patients were remarkably much shorter than that reported in COU-AA-302 study.[11] In contradiction to above in post chemo group we found the tolerability and PFS with abiraterone similar to what reported in COU-AA-301 study, however OS was found to be inferior similar to chemo naive group.[10] The reasons for this difference may be explained by relatively high tumor burden (which is supported by a higher median baseline PSA level) in our patient cohort, unselected patient population in contrast to clinical trial, nonaffordability for further lines of therapy and small sample size. In addition, many of our patients received (14 out of 59) prior ketokonazole, (patient group that was excluded in both COU-AA-301 and COU-AA-302 study, due to the potential overlapping mechanism of action) which has been shown to be associated with inferior outcome with Abiraterone. In a study by Kim et al.[12] on sequential use of the androgen synthesis inhibitors ketoconazole and AA in castration-resistant prostate cancer demonstrated modest clinical efficacy with abiraterone inpatients previously treated with ketoconazole [Table 5]. Besides this, our study cohort included 85% of symptomatic patients when compared with COU-AA-302 study in which only asymptomatic or mildly symptomatic patients were included.\n\nTable 5 Clinical outcome in the present study and the abiraterone acetate pivotal trials\n\nSurvival outcome\tPresent study (Chemo-naïve)\tCOU-AA-302 study\tPresent study (postchemotherapy)\tCOU-AA-301 study\t\nMedian OS, months\t15.06\t34.7\t10.06\t15.8\t\nMedian PFS, months\t7.86\t16.5\t5.36\t5.6\t\nPSA response, %\t39.4\t62\t18.1\t29\t\nPFS=Progression-free survival, OS=Overall survival, PSA=Prostate specific antigen\n\nIn our cohort, abiraterone effectively achieved a PSA response (≥50% PSA decline) in 15 (39.4%) chemotherapy-naive patients and 4 (18.1%) postdocetaxel patients. All biochemical responses were achieved within a median of 7 months of treatment. We found that achievement of the best PSA response after abiraterone is a favorable prognostic factor which is in consistency with prior studies.[1011]\n\nWhile the efficacy of abiraterone in with visceral metastases or symptomatic disease is not clear, our study suggests that patients with high tumor burden, visceral metastases may have inferior outcome with abiraterone in terms of PFS and OS. In contrast, as seen in the subgroup analysis in the TAX 327 study the presence of symptomatic or visceral metastasis did not confer inferior clinical outcome to docetaxel-based chemotherapy.[13] With the lack of randomized trial specifically addressing this issue, the practice of using abiraterone in this particular subgroup should be further evaluated.\n\nLimitations of the present study include the usual shortcomings of retrospective study such as under-reporting of adverse events, incompleteness of data collection and selection bias. However, these limitations should not affect the ability to calculate the survival outcome of abiraterone.\n\nConclusion\nThe present study reported the efficacy abiraterone in both chemo-naïve and postchemo patients of mCRPC outside clinical trial setting. We found lower OS and PFS with abiraterone as compared to that reported in the clinical trial setting in both chemo-naïve and postchemo patients, and particularly in those patients with visceral disease, and further clinical trial for abiraterone in this subgroup of patients is warranted.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Hellerstedt BA Pienta KJ The current state of hormonal therapy for prostate cancer CA Cancer J Clin 2002 52 154 79 12018929 \n2 Loblaw DA Virgo KS Nam R Somerfield MR Ben-Josef E Mendelson DS Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology Practice Guideline J Clin Oncol 2007 25 1596 605 17404365 \n3 Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer Eur Urol 2014 65 467 79 24321502 \n4 Holzbeierlein J Lal P LaTulippe E Smith A Satagopan J Zhang L Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance Am J Pathol 2004 164 217 27 14695335 \n5 Stanbrough M Bubley GJ Ross K Golub TR Rubin MA Penning TM Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer Cancer Res 2006 66 2815 25 16510604 \n6 Montgomery RB Mostaghel EA Vessella R Hess DL Kalhorn TF Higano CS Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth Cancer Res 2008 68 4447 54 18519708 \n7 Scher HI Sawyers CL Biology of progressive, castration-resistant prostate cancer: Directed therapies targeting the androgen-receptor signaling axis J Clin Oncol 2005 23 8253 61 16278481 \n8 Attard G Cooper CS de Bono JS Steroid hormone receptors in prostate cancer: A hard habit to break? Cancer Cell 2009 16 458 62 19962664 \n9 Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin Oncol 2008 26 1148 59 18309951 \n10 de Bono JS Logothetis CJ Molina A Fizazi K North S Chu L Abiraterone and increased survival in metastatic prostate cancer N Engl J Med 2011 364 1995 2005 21612468 \n11 Ryan CJ Smith MR de Bono JS Molina A Logothetis CJ de Souza P Abiraterone in metastatic prostate cancer without previous chemotherapy N Engl J Med 2013 368 138 48 23228172 \n12 Kim W Zhang L Wilton JH Fetterly G Mohler JL Weinberg V Sequential use of the androgen synthesis inhibitors ketoconazole and abiraterone acetate in castration-resistant prostate cancer and the predictive value of circulating androgens Clin Cancer Res 2014 20 6269 76 25336698 \n13 Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer N Engl J Med 2004 351 1502 12 15470213\n\n",
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"issue": "9(1)",
"journal": "South Asian journal of cancer",
"keywords": "Abiraterone; chemo-naive/postchemo; metastatic castrate-resistant prostate cancer; nontrial setting; visceral disease",
"medline_ta": "South Asian J Cancer",
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"title": "A tertiary care audit of using abiraterone acetate in patients of metastatic castrate-resistant prostate cancer.",
"title_normalized": "a tertiary care audit of using abiraterone acetate in patients of metastatic castrate resistant prostate cancer"
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... |
{
"abstract": "Ecthyma gangrenosum is a rare cutaneous infection that occurs classically in immunocompromised patients with Pseudomonas aeruginosa bacteremia and is associated with a high mortality rate. Causative pathogens may exhibit various antibiotic evasion mechanisms, and thus, treatment may be challenging. We present a case of ecthyma gangrenosum in association with an implantable port in which cultures confirmed ten unique strains of Pseudomonas aeruginosa, highlighting the ability of this pathogen to form biofilms, rapidly mutate and ultimately evade antibiotic therapy. Dermatologists play a key role in the prompt diagnosis of this life-threatening condition, and a thorough understanding of pathogenic mechanisms is critical in selecting an efficacious treatment regimen.",
"affiliations": "Department of Dermatology, Medstar Georgetown University Hospital/Medstar Washington Hospital Center, Washington, DC, USA.;Department of Dermatology, Medstar Georgetown University Hospital/Medstar Washington Hospital Center, Washington, DC, USA.;Division of Dermatology, Children's National Hospital, Washington, DC, USA.",
"authors": "Russomanno|Kristen|K|https://orcid.org/0000-0003-1257-6405;Cardis|Michael|M|https://orcid.org/0000-0003-4547-101X;Kirkorian|Anna Yasmine|AY|https://orcid.org/0000-0002-4449-1572",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14496",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "38(2)",
"journal": "Pediatric dermatology",
"keywords": "\nPseudomonas aeruginosa\n; antibiotic resistance; ecthyma; ecthyma gangrenosum; pseudomonas infections",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D018441:Biofilms; D004352:Drug Resistance, Microbial; D004473:Ecthyma; D006801:Humans; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "458-460",
"pmc": null,
"pmid": "33389781",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Ecthyma gangrenosum: The critical role of biofilms and other mechanisms of antibiotic resistance and implications for management.",
"title_normalized": "ecthyma gangrenosum the critical role of biofilms and other mechanisms of antibiotic resistance and implications for management"
} | [
{
"companynumb": "US-PFIZER INC-202101335700",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AVIBACTAM SODIUM\\CEFTAZIDIME"
},
"drugaddit... |
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