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"abstract": "OBJECTIVE\nThe case of a 57-year-old male who experienced acute renal transplant rejection due to subtherapeutic tacrolimus levels as a result of drug interaction with phenobarbital.\n\n\nCONCLUSIONS\nDrug interactions with tacrolimus due to its metabolism through the CYP 450 3A4 enzymatic pathway have led to several reports of altered tacrolimus levels, which can lead to acute rejection in renal transplant recipients. We describe the case of a 57-year-old male initiated on immunosuppressive therapy with tacrolimus in addition to his anticonvulsant medications.\n\n\nCONCLUSIONS\nUpon tacrolimus dose increases, discontinuation of carbamazepine, and minimization of phenobarbital dose, effective tacrolimus trough levels were achieved in our patient. Identification and elimination of such drug-drug interactions is necessary to assure adequate immunosuppression in renal transplant recipients.",
"affiliations": "Montefiore Medical Center, Department of Pharmacy, Bronx, NY 10467, USA.",
"authors": "Siddiqi|Nida|N|;Marfo|Kwaku|K|",
"chemical_list": "D000927:Anticonvulsants; D007166:Immunosuppressive Agents; D016559:Tacrolimus; D010634:Phenobarbital",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190010377804",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "23(6)",
"journal": "Journal of pharmacy practice",
"keywords": null,
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000927:Anticonvulsants; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010634:Phenobarbital; D016559:Tacrolimus",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "585-9",
"pmc": null,
"pmid": "21507867",
"pubdate": "2010-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clinically significant drug-drug interaction between tacrolimus and phenobarbital: the price we pay.",
"title_normalized": "clinically significant drug drug interaction between tacrolimus and phenobarbital the price we pay"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-00414",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PHENOBARBITAL"
},
... |
{
"abstract": "A 49-year-old woman presented to our hospital complaining of abdominal distension and right thigh edema 6 years and 7 months after undergoing total gastrectomy for early gastric cancer in December 2008. The histopathological type of the tumor was poorly differentiated adenocarcinoma. The pathological findings led to a diagnosis of T1aN2M0, Stage II A disease. In August 2015, abdominal CT and MRI revealed para-aortic lymph node swelling, ascites, and a tumor on the right femoral muscles. We performed a needle biopsy of the femoral muscle, and the final diagnosis was intramuscular metastasis from the primary gastric cancer. We initiated chemotherapy using TS-1 plus docetaxel. TS-1(80mg/m2/day)was orally administered for 2 weeks followed by a 1-week drug-free period, and 1 course of docetaxel(40mg/m2)was administered intravenously on day 1. After 2 courses of this regimen, the tumor on the right femoral muscles was reduced in size. However, diarrhea and leukopenia were observed, and the treatment schedule was changed to several other chemotherapy regimens. The patient died of progressive disease 6 months after the diagnosis of muscle metastasis. We report a rare case of late recurrence after curative resection in a patient treated for T1a early gastric cancer.",
"affiliations": "Dept. of Surgery, Suita Municipal Hospital.",
"authors": "Ebisui|Chikara|C|;Hamano|Rie|R|;Nushijima|Yoichiro|Y|;Yanagisawa|Tetsu|T|;Okamura|Shu|S|;Fukuchi|Nariaki|N|;Murata|Kohei|K|;Yokouchi|Hideoki|H|;Kinuta|Masakatsu|M|;Ohishi|Kazuhito|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000230:Adenocarcinoma; D000971:Antineoplastic Combined Chemotherapy Protocols; D017809:Fatal Outcome; D005260:Female; D005269:Femur; D005743:Gastrectomy; D006801:Humans; D008875:Middle Aged; D018482:Muscle, Skeletal; D012008:Recurrence; D013274:Stomach Neoplasms; D013997:Time Factors",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1893-1895",
"pmc": null,
"pmid": "28133167",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of T1a Early Gastric Cancer That Metastasized to the Right Femoral Muscles Six Years and Seven Months after Radical Surgery.",
"title_normalized": "a case of t1a early gastric cancer that metastasized to the right femoral muscles six years and seven months after radical surgery"
} | [
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"companynumb": "JP-ACCORD-048455",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"druga... |
{
"abstract": "We describe a case of lower urinary system symptoms (LUSSs) and acute urinary retention that developed after treatment with a low dose of venlafaxine. A 48-year-old male patient was admitted to our clinic because of difficulty urinating, an intermittent stream, and trickling at the end of urination, together with urinary retention that had started about 45 days ago. The patient had been taking venlafaxine for the previous 6 months. The drug had been prescribed by the psychiatry department for a diagnosis of major depression, and the dose had been increased from 75 mg/day to 150 mg/day 1.5 months earlier. The patients' symptoms were thought to be related to venlafaxine, and the symptoms disappeared completely after venlafaxine was replaced with agomelatine. We concluded that the LUSSs and urinary retention were due to the venlafaxine treatment.",
"affiliations": "Urology Department Atatürk University. oguzdemirdogen@hotmail.com.",
"authors": "Demirdöğen|Şaban Oğuz|ŞO|;Yıldırım Demirdöğen|Esen|E|;Adanur|Şenol|Ş|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D000069470:Venlafaxine Hydrochloride",
"country": "Italy",
"delete": false,
"doi": "10.4081/aiua.2017.2.160",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1124-3562",
"issue": "89(2)",
"journal": "Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica",
"keywords": null,
"medline_ta": "Arch Ital Urol Androl",
"mesh_terms": "D018687:Antidepressive Agents, Second-Generation; D006801:Humans; D008297:Male; D008875:Middle Aged; D016055:Urinary Retention; D000069470:Venlafaxine Hydrochloride",
"nlm_unique_id": "9308247",
"other_id": null,
"pages": "160-161",
"pmc": null,
"pmid": "28679194",
"pubdate": "2017-06-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute urinary retention after venlafaxine use.",
"title_normalized": "acute urinary retention after venlafaxine use"
} | [
{
"companynumb": "TR-MYLANLABS-2017M1082989",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Two patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and rapid onset of high fever, tachycardia and systemic hypotension accompanied by elevated laboratory markers of infection were diagnosed with azathioprine hypersensitivity syndrome only after repeat exposure. Azathioprine hypersensitivity can closely mimic sepsis and/or vasculitis activity and should be considered in AAV, a condition with frequent use of this drug. We discuss the pitfalls in diagnosis and the possible pathophysiologic background.",
"affiliations": "Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.;Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.;Institute for Pathology, Hannover Medical School, Hannover, Germany.;Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.",
"authors": "Greite|Robert|R|;Deutsch|Konstantin|K|;Bräsen|Jan Hinrich|JH|;von Vietinghoff|Sibylle|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ckj/sfy038",
"fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjClinical Kidney Journal2048-85052048-8513Oxford University Press 3074613310.1093/ckj/sfy038sfy038Drug-Induced NephropathiesAzathioprine hypersensitivity syndrome in anti-myeloperoxidase anti-neutrophil cytoplasmic antibody-associated vasculitis Greite Robert 1Deutsch Konstantin 1Bräsen Jan Hinrich 2von Vietinghoff Sibylle 11 Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany2 Institute for Pathology, Hannover Medical School, Hannover, GermanyCorrespondence and offprint requests to: Sibylle von Vietinghoff; E-mail: vonVietinghoff.Sibylle@mh-hannover.deRobert Greite and Konstantin Deutsch authors contributed equally to this work\n\n2 2019 23 5 2018 23 5 2018 12 1 89 91 07 2 2018 2 4 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nTwo patients with anti-neutrophil cytoplasmic antibody–associated vasculitis (AAV) and rapid onset of high fever, tachycardia and systemic hypotension accompanied by elevated laboratory markers of infection were diagnosed with azathioprine hypersensitivity syndrome only after repeat exposure. Azathioprine hypersensitivity can closely mimic sepsis and/or vasculitis activity and should be considered in AAV, a condition with frequent use of this drug. We discuss the pitfalls in diagnosis and the possible pathophysiologic background. \n\nANCA vasculitisazathioprinefeverrelapsesepsis\n==== Body\nBACKGROUND\nInfectious complications of immunosuppressive therapy and vasculitis activity are the main causes of death in patients early after diagnosis of anti-neutrophil cytoplasmic antibody–associated vasculitis (AAV) [1]. Azathioprine is part of the standard maintenance regimen in this condition [2]. We here report two cases where azathioprine hypersensivity syndrome closely mimicked complications of vasculitis leading to intensive care unit (ICU) admissions and significant disease burden.\n\nCase 1\nA 64-year-old man with acute renal failure and known chronic kidney disease (CKD) after partial nephrectomy for renal cell cancer, arterial hypertension, aortic aneurysm and plaque psoriasis was diagnosed with renal anti-myeloperoxidase AAV [Figure 1A, initial Birmingham Vasculitis Activity Score (BVAS) 14]. Therapy with intravenous cyclophosphamide (cumulative dose 6.2 g) stabilized the glomerular filtration rate (GFR) (Figure 1B). His course was complicated by a spinal fracture sustained when jumping from a burning building, necessitating insertion of foreign materials for stabilization. Two weeks after he was started on azathioprine maintenance therapy, he presented in the emergency room (ER) with diarrhoea. He admitted to not regularly taking either azathioprine or corticosteroid. On examination, he was incompletely oriented to time and situation and febrile (38.4°C), with blood pressure of 90/50 mmHg, heart rate 193/min and arrhythmic. A papular, indolent rash was noted on all limbs. Physical examination of the lungs and spinal column was unremarkable; neither meningism nor focal neurological abnormalities were noted. Laboratory values showed an elevated relative neutrophil count (88.7%), C-reactive protein (CRP) and procalcitonin (204 µg/L). Serum creatinine had risen markedly (Figure 1B). The patient was admitted to the ICU for circulatory management and received antibiotic therapy with piperacillin/tazobactam and metronidazole for suspected enteral infection and sepsis plus high-dose steroids for a suspected relapse of vasculitis. He improved rapidly and was transferred to the general ward, where he underwent repeat renal biopsy 4 days later (Figure 1C). Active vasculitis and aggressive tubulointerstitial inflammation were seen. Cyclophosphamide was administered along with five courses of plasma exchange. Renal function improved while receiving monthly intravenous cyclophosphamide and de-escalation of therapy was planned. One day after taking the first dose of azathioprine he was found by his sister in a confused and dishevelled state and admitted to the ER for suspected intoxication. On examination, he was aphasic and disoriented without meningism. Atrial fibrillation with a heart rate up to 180/min was noted, his blood pressure was 147/100 mmHg and his temperature was mildly elevated at 37.8°C. Laboratory results showed no ethanol, elevated CRP, procalcitonin (31.5 µg/L) and an increase in creatinine (Figure 1B). Cerebral computed tomography, magnetic resosnance imaging and electroencephalography yielded no pathologic results. He was admitted to the stroke unit and treated with ampicillin/sulbactam for suspected infection. His rhythm spontaneously converted to normofrequent sinus rhythm and he regained the ability to speak and write over the ensuing 48 h. A diagnosis of azathioprine hypersensitivity syndrome was made. Maintenance immunosuppression was switched to mycophenolate, then rituximab, with limited success. He died 6 months later at home.\n\n\nFIGURE 1 Clinical course and results of renal biopsy. (A–C) Patient 1 received a diagnosis of AAV from a renal biopsy showing necrotizing crescentic glomerulonephritis [(A) Jones haematoxylin and eosin stain, 60× original magnification] and was subsequently treated with cyclophosphamide boli (B). Repeat biopsy at the time of acute clinical presentation yielded persistent vasculitis activity and additionally aggressive tubulointerstitial disease [(C) periodic acid–Schiff stain, 40× and 60× original magnification]. Major elevations of creatinine and CRP were noted at the times of azathioprine exposure and clinical hypersensitivity. (D) Patient 2 similarly responded with CRP and creatinine elevations to azathioprine exposure.\n\nCase 2\nA 49-year-old man diagnosed with rapid progressive glomerulonephritis due to anti-MPO AAV on kidney biopsy (initial BVAS 16) was started on azathioprine for maintenance therapy (100 mg/d) after six courses of intravenous cyclophosphamide (cumulative dose 7 g). His past medical history was significant for excessive leg swelling after insect stings. After 7 days, the patient presented with fever (40.7°C), tachycardia (105/min) and tachypnoea (24/min) in the ER. CRP and procalcitonin (3.6 µg/L) were significantly elevated. Acute renal failure was diagnosed (Figure 1D). Antibiotic treatment with piperacillin-tazobactam and moxifloxacin was started and azathioprine was held for a suspected bacterial infection. Chest X-ray, abdominal ultrasound and echocardiography showed no signs of infection. On Day 2 he developed generalized exanthema. Microbiological testing remained negative and he was discharged 1 week later.\n\nAzathioprine was restarted on Day 17. Approximately 2 h later he was readmitted to the ER with nausea, thoracic wall exanthema, fever (39°C), hypotension (98/52 mmHg), tachycardia (99/min) and tachypnoea (19/min). He was in acute renal failure. CRP and procalcitonin (384 µg/L) were again markedly elevated. The patient was transferred to the ICU and received renal replacement therapy for hyperkalaemia. Microbiological testing was again negative. A diagnosis of azathioprine hypersensitivity was made. After a 5-month follow-up period, he is well with rituximab maintenance therapy and his renal function has returned to baseline (Figure 1D).\n\nDISCUSSION\nIdiosyncratic effects of azathioprine therapy occur independently of dose with an incidence of 1-6.5% [3]. Azathioprine hypersensitivity is independent of hepato- and myelotoxicity, which were absent in our patients and others (Supplementary data, Table S1). Diagnosis is by exclusion of other causes and improvement after drug withdrawal [4].\nTable 1. Clinical constellations that may aid differential diagnosis of vasculitis activity, sepsis and azathioprine hypersensitivity\n\n\tTime of onset (typical)\tClinical signs\tLaboratory values\t\nFever\tAcute renal failure (histology)\tNausea and vomiting\tRash\tAtrial fibrillation\tLeucocytosis\tUrinary sediment\tBacterial cultures\tSerum markers\t\nCRP\tPCT\tANCA\t\nVasculitis activity\tAfter reduction of immunosuppression\t(↑)\tFrequent (crescentic glomerulonephritis) \tRare\tCommon (petechial, vasculitic)\tRare\tRare, usually mild\tRed cell casts, acanthocytes\t−\t↑\t–\t=/↑\t\nSepsis\tDuring induction therapy\t↑\tFrequent (prerenal, acute tubular necrosis)\tInfrequent\tInfrequent\tRare\t↑↑\tUnspecific findings\tFrequently +\t↑↑\t↑\t=/↓\t\nAzathioprine hypersensitivity\tDays after start of azathioprine therapy, within hours after re-exposure\t↑\tFrequent (acute interstitial nephritis)\tCommon\tCommon (neutrophilic dermatitis)\tFrequent\t↑↑\tUnspecific findings\t−\t↑↑\t↑↑\t=/↓\t\nPCT, procalcitonin.\n\n\n\nAzathioprine is initially metabolized into 6-mercaptopurine (6-MP) and methylnitroimidazole. The 6-MP is further metabolized by hypoxanthine phosphoribosyl transferase to 6-thioguanine nucleotides [5]. These nucleotides are responsible for drug action and the dose-dependent side effects. Further metabolism of 6-MP by thiopurine methyltransferase (TPMT) and xanthine oxidase (XO) results in inactive metabolites. Low TPMT activity or XO inhibition are associated with increased toxicity. TPMT polymorphisms can be determined prior to treatment. However, hypersensitivity has been linked to the imidazole side chain rather than TPMT, as 6-MP lacking the imidazole side chain has not yet not caused such reactions [5, 6].\n\nAzathioprine hypersensitivity in AAV is frequently diagnosed only after re-exposure to the drug (Supplementary data, Table S1), also because of overlapping features with both active vasculitis and sepsis, two very common conditions during the first year after diagnosis of vasculitis [1]. Table 1 shows some characteristics that may aid in discriminating these entities. Features that favour hypersensitivity include onset within days of azathioprine administration, marked elevation of laboratory markers of sepsis in the absence of a clinical focus or positive bacterial cultures and stable or declining ANCA titres. However, there is no diagnostic test for azathioprine hypersensitivity. Even renal biopsy may not always determine the diagnosis and indeed, in our first patient, even suggested coexistence of vasculitis activity and hypersensitivity. However, increased awareness of this rare side effect of azathioprine may improve the care of patients with this condition.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n\nSupplementary Material\nSupplementary Table Click here for additional data file.\n==== Refs\nREFERENCES\n1 \nFlossmann O , Berden A , de Groot K \net al\nLong-term patient survival in ANCA-associated vasculitis . Ann Rheum Dis 2011 ; 70 : 488 –494 21109517 \n2 \nJennette JC , Nachman PH. \nANCA glomerulonephritis and vasculitis . Clin J Am Soc Nephrol 2017 ; 12 : 1680 –1691 28842398 \n3 \nde Boer NK , van Bodegraven AA , Jharap B \net al\nDrug insight: pharmacology and toxicity of thiopurine therapy in patients with IBD . Nat Clin Pract Gastroenterol Hepatol 2007 ; 4 : 686 –694 18043678 \n4 \nBidinger JJ , Sky K , Battafarano DF \net al\nThe cutaneous and systemic manifestations of azathioprine hypersensitivity syndrome . J Am Acad Dermatol 2011 ; 65 : 184 –191 21496951 \n5 \nLiu Y-P , Xu H-Q , Li M \net al\nAssociation between thiopurine S-methyltransferase polymorphisms and azathioprine-induced adverse drug reactions in patients with autoimmune diseases: a meta-analysis . PLoS One 2015 ; 10 : e0144234 26633017 \n6 \nGodeau B , Paul M , Autegarden JE \net al\nHypersensitivity to azathioprine mimicking gastroenteritis. Absence of recurrence with 6-mercaptopurine . Gastroenterol Clin Biol 1995 ; 19 : 117 –119 7720971\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2048-8505",
"issue": "12(1)",
"journal": "Clinical kidney journal",
"keywords": "ANCA vasculitis; azathioprine; fever; relapse; sepsis",
"medline_ta": "Clin Kidney J",
"mesh_terms": null,
"nlm_unique_id": "101579321",
"other_id": null,
"pages": "89-91",
"pmc": null,
"pmid": "30746133",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": "18043678;21109517;21496951;26633017;28842398;7720971",
"title": "Azathioprine hypersensitivity syndrome in anti-myeloperoxidase anti-neutrophil cytoplasmic antibody-associated vasculitis.",
"title_normalized": "azathioprine hypersensitivity syndrome in anti myeloperoxidase anti neutrophil cytoplasmic antibody associated vasculitis"
} | [
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"companynumb": "DE-BAYER-2019-119688",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
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"drugadditional": null,
... |
{
"abstract": "HBV reactivation is associated with high mortality rates in hematopoietic stem cell transplantation (HSCT) and prophylactic lamivudine (LMV) treatment is suggested to prevent this phenomenon. However, the duration of LMV treatment in HSCT patients is not fully defined and the time of immune recovery is considered the best parameter for a drug to be safely interrupted. In patients undergoing allogeneic HSCT, the time of immune recovery is not easy to define and may take years after transplantation and prolonged LMV treatments, which can lead to drug-resistant viral strains.\n\n\n\nAn anti-HBc-positive hematological patient who was undergoing prolonged immunosuppression and who experienced HBV reactivation 3 months after the suspension of a prolonged LMV prophylaxis is described. HBV-DNA matching an atypical serological profile characterized by HbsAg negativity and anti-HBs positivity was detected in the patient. The genotypic analysis of the HBV strain identified T127P, F170FL and S204R mutations of HbsAg, which can hinder HBsAg recognition in a diagnostic assay.\n\n\n\nHBV reactivation in the HSCT host can be sustained by HBsAg viral variants with characteristics of altered immunogenicity that cannot be detected by usual laboratory tests. This clinical case description suggests the importance of screening for serum HBV-DNA levels in the diagnosis of HBV reactivation and monitoring HBV-DNA after prophylaxis suspension, particularly in HSCT subjects who have undergone prolonged periods of LMV treatment.",
"affiliations": "Clinical Infectious Disease, Department of Systems Medicine, Tor Vergata University, Rome, Italy.;Clinical Infectious Disease, Department of Systems Medicine, Tor Vergata University, Rome, Italy. maffongelligaetano@gmail.com.;Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy.;Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy.;Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy.;Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy.;Department of Hematology, Stem Cell Transplant Unit, Tor Vergata University, Rome, Italy.;Department of Hematology, Stem Cell Transplant Unit, Tor Vergata University, Rome, Italy.;Department of Hematology, Stem Cell Transplant Unit, Tor Vergata University, Rome, Italy.;Clinical Infectious Disease, Department of Systems Medicine, Tor Vergata University, Rome, Italy.",
"authors": "Cerva|C|C|;Maffongelli|G|G|;Svicher|V|V|;Salpini|R|R|;Colagrossi|L|L|;Battisti|A|A|;Mariotti|B|B|;Cerretti|R|R|;Cudillo|L|L|;Sarmati|L|L|",
"chemical_list": "D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D019259:Lamivudine",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-017-2672-6",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 267210.1186/s12879-017-2672-6Case ReportHepatitis B reactivation characterized by HBsAg negativity and anti-HbsAg antibodies persistence in haematopoietic stem cell transplanted patient after lamivudine withdrawal Cerva C. carlottacerva@gmail.com 1Maffongelli G. +39 6 20903440maffongelligaetano@gmail.com 1Svicher V. valentina.svicher@uniroma2.it 2Salpini R. rsalpini@yahoo.it 2Colagrossi L. luna_colagrossi@yahoo.it 2Battisti A. battistiarianna@gmail.com 2Mariotti B. benedetta_mariotti@hotmail.it 3Cerretti R. raffaella.cerretti@ptvonline.it 3Cudillo L. cudillo@med.uniroma2.it 3Sarmati L. sarmati@med.uniroma2.it 11 0000 0001 2300 0941grid.6530.0Clinical Infectious Disease, Department of Systems Medicine, Tor Vergata University, Rome, Italy 2 0000 0001 2300 0941grid.6530.0Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy 3 0000 0001 2300 0941grid.6530.0Department of Hematology, Stem Cell Transplant Unit, Tor Vergata University, Rome, Italy 15 8 2017 15 8 2017 2017 17 56626 7 2016 7 8 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nHBV reactivation is associated with high mortality rates in hematopoietic stem cell transplantation (HSCT) and prophylactic lamivudine (LMV) treatment is suggested to prevent this phenomenon. However, the duration of LMV treatment in HSCT patients is not fully defined and the time of immune recovery is considered the best parameter for a drug to be safely interrupted. In patients undergoing allogeneic HSCT, the time of immune recovery is not easy to define and may take years after transplantation and prolonged LMV treatments, which can lead to drug-resistant viral strains.\n\nCase presentation\nAn anti-HBc-positive hematological patient who was undergoing prolonged immunosuppression and who experienced HBV reactivation 3 months after the suspension of a prolonged LMV prophylaxis is described. HBV-DNA matching an atypical serological profile characterized by HbsAg negativity and anti-HBs positivity was detected in the patient. The genotypic analysis of the HBV strain identified T127P, F170FL and S204R mutations of HbsAg, which can hinder HBsAg recognition in a diagnostic assay.\n\nConclusions\nHBV reactivation in the HSCT host can be sustained by HBsAg viral variants with characteristics of altered immunogenicity that cannot be detected by usual laboratory tests. This clinical case description suggests the importance of screening for serum HBV-DNA levels in the diagnosis of HBV reactivation and monitoring HBV-DNA after prophylaxis suspension, particularly in HSCT subjects who have undergone prolonged periods of LMV treatment.\n\nKeywords\nHBV reactivationHbv DNAProphylaxisHepatitis BHematopoietic stem cell transplantationissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nHBV reactivation is a complication of immunosuppressive treatments and is associated with high mortality [1]. Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are considered at major risk for HBV reactivation [1–6], with a mortality rate of up to 40% [3]. A number of national and international guidelines [7–9] have addressed the prophylaxis of HBV reactivation in an immunocompromised host. Nonetheless, several aspects of HBV prevention, such as prophylaxis duration and virological monitoring after prophylaxis suspension, remain poorly defined, particularly in HSCT cases, where HBV reactivation may occur several years after the start of immunosuppressive treatments [10]. Prolonged lamivudine (LMV) prophylaxis is associated with the occurrence of LMV resistance at a rate that increases to 60% in immunocompromised patients [11]. Viral variants, both resistant and sensitive to LMV, can develop in patients under anti-viral treatment and may lead to HBsAg amino acid changes with altered antigenicity, also known as immune escape mutants. The modified HBsAg produced by these viruses is not detectable by current commercial assays.\n\nHere, we report the case of a severely immunocompromised allo-HSCT patient who experienced reactivation of HBV infection a few months after the withdrawal of a very long-term LMV prophylaxis, without the reappearance of HBsAg and with the persistence of high titer anti-HBs antibodies.\n\nCase presentation\nThe patient is a 59-year-old Italian male who received a diagnosis of non-Hodgkin’s lymphoma (NHL) (stage IV) in May 2003. Histological diagnosis indicated a small B-cell lymphoma. From September 2003 to January 2004, he underwent 6 R-CHOP courses (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), which were followed by complete disease remission. In March 2005, the patient experienced an NHL relapse. Therefore, fludarabine treatment (4 courses) was started, and the treatment again resulted in complete remission. In November 2005, he underwent an autologous HSCT. In May 2010, a second relapse of NHL was diagnosed, and a treatment regimen with Rituximab-Bendamustine (R-Bendamustine) was started. After 6 courses of R-Bendamustine, a partial response was obtained. The disease had progressed again by October 2011, and an R-DHAP (rituximab, cisplatin, cytosine arabinoside and dexamethasone) treatment was started. Because of renal toxicity, the R-DHAP was replaced with Alentuzumab, obtaining a partial response. In February 2012, the disease had progressed again. Ofatumumab treatment (9 courses) was initiated with no clinical response. In November 2012, the patient underwent an allo-HSCT by a matched unrelated donor (MUD) as a curative option due to refractory disease. The patient received a reduced intensity condition regimen ([TBF-RIC] consisting of thiotepa, busulfan, and fludarabine plus anti-thymocyte globulin). Graft versus host disease (GvHD) prophylaxis consisted of cyclosporine and methotrexate. The engraftment for neutrophils >500/mmc and platelets >20,000/mmc occurred 20 and 24 days after the allo-HSCT, respectively. The post-transplant course was complicated by Aspergillus pneumonia (day 19 post allo-HSCT), for which the patient underwent prolonged antifungal treatment. In July 2013, the patient had the residual pulmonary nodule surgically removed. In the context of the fungal nodule, a lung adenocarcinoma was histologically present.\n\nAfter allo-HSCT, the patient achieved a stable, complete remission of hematological disease (last follow-up visit in May 2016). At the HBV screening, the patient was identified as positive for anti-HBs, anti-HBc and anti-HBe, and negative for HBV-DNA. The HBV donor serology showed no previous HBV infection (anti-HBc/anti-HBs negative). An HBV DNA test was performed that resulted in a negative outcome. He was not vaccinated for HBV.\n\nTherefore, LMV prophylaxis was started in 2010. The patient continuously received LMV for up to 24 months after the allo-HSCT (January 2015), at which point the prophylaxis was suspended. During the LMV prophylaxis, he remained positive for anti-HBs, anti-HBc and anti-HBe, and HBV-DNA was consistently undetectable. Three months after the suspension of LMV treatment (March 2015), he experienced virological HBV reactivation (serum HBV DNA 42 IU/mL), and no other HBV serological variations were present. Despite HBV reactivation, HBsAg remained negative, and the anti-HBs titers remained consistently high (482 mIU/ml in November 2014, 505 mIU/ml in March 2015, 457 mIU/ml in April 2015, 576 mIU/ml in June 2015 and 542 mIU/ml in July 2015).\n\nA genotypic test (based on the sequencing of HBV reverse transcriptase and HBsAg) was performed during the HBV reactivation diagnosis. The test did not reveal the presence of LMV resistance mutations but showed the presence of three mutations in HbsAg: T127P, F170FL and S204R.\n\nDue to the persistence of quantitative HBV DNA (35 IU/mL), antiviral therapy was started with 245 mg tenofovir. After 2 weeks, the patient underwent a bone density test that documented osteopenia, while the glomerular filtration rate remained stable, although reduced. Tenofovir treatment was interrupted and 0.5 mg entecavir was started. The patient is now in complete hematological remission, and the quantitative HBV DNA is undetectable (see Fig. 1).Fig. 1 Medical History. LNH: non-Hodgkin’s lymphoma; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; FLU: fludarabine treatment; RC: complete remission of disease; Auto HSCT: autologous peripheral blood stem cell transplantation; R: rituximab; RDHAP: rituximab, cisplatin, cytosine arabinoside and dexamethasone; Allo-HSCT: allogenic peripheral blood stem cell transplantation; MUD: matched unrelated donor\n\n\n\n\nConclusions\nThis paper describes the clinical case of an anti-HBc-positive and anti-HBs-positive patient undergoing prolonged immunosuppression who developed HBV reactivation 3 months after the suspension of prolonged (4 years) LMV prophylaxis. At HBV reactivation, the patient showed an atypical serological profile characterized by HBsAg negativity and anti-HBs positivity (with a high antibody titer of 505 mIU/ml). These results corroborate recently published studies showing that a substantial proportion (10% to 80%) of patients who tested positive for anti-HBc and anti-HBs remained HBsAg-negative despite the reuptake of viral replication [12–14]. Overall, our results suggest that this immunological profile is critical in the management of patients who are at risk of HBV reactivation and strongly support the use of serum HBV-DNA (rather than HBsAg) for the diagnosis of HBV reactivation.\n\nHBsAg negativity may be related to the high degree of genetic variability in HBsAg observed in patients who develop immunosuppression-driven HBV reactivation, which may hinder HBsAg recognition by the antibodies used in the diagnostic assay [12, 13]. In particular, a previous study has shown the enrichment of additional N-linked glycosylation sites in the major hydrophilic HBsAg region in patients who remained HbsAg-negative despite HBV reactivation [10]. In vitro studies have shown the ability of these glycosylation sites to hamper or abrogate the recognition and quantification of HBsAg by the currently available diagnostic test. In the current clinical case, the HBsAg mutation S204R was detected. This mutation was localized in the C-terminal transmembrane domain, which is known to play an important role in the modulation of HBsAg secretion and viral particle assembly [15]. The acquisition of a positively-charged amino acid (Arginine [R] at position 204) in this transmembrane domain might alter the HBsAg structure to result in i) HBsAg negativity in the currently available diagnostic test and ii) HBV escape from a high anti-HBs titer. This mutation may also affect the viral particle release, resulting in HBV reactivation that is characterized by a low level of serum HBV DNA, as demonstrated in our clinical case. This concept agrees with a previous study, which showed that the viral clones encoding S204R (lysine [S] substitution with arginine [R] at position 204) and G145R (glycine [G] substitution with arginine [R] at position 145) exhibited an approximately 60% viral secretion defect compared with the wild-type. According to this result, the authors proposed that the basic arginine residues may be important for HBsAg retention within the endoplasmic reticulum [16].\n\nFinally, the genotypic testing also highlighted the presence of two HBV RT mutations (S135Y and I233V) that are potentially involved in resistance to first-generation nucleos(t)ide RT inhibitors [17, 18]. The role of these genetic mutations in facilitating HBV evasion from LMV warrants further investigation.\n\nThis clinical case also demonstrates the challenges of determining the proper duration of prophylaxis. The current guidelines recommend suspending prophylaxis from the immunosuppressive treatments after 12–18 months [19]. However, in the setting of HSCT, the risk of HBV reactivation can persist for several years after transplantation due to the long delays in immune reconstitution. In this context, Hammond et al. [20] showed that the cumulative probability of HBV reactivation increases from 9%, 1 year after transplantation, to 43%, 4 years after transplantation. Thus, the duration of prophylaxis needs to be extended further in the setting of profound immunosuppression to prevent late HBV reactivation episodes. In addition, these findings also highlight the need for markers that can predict the full immune reconstitution against HBV.\n\nIn conclusion, the described case demonstrates that HBV reactivation in the immunocompromised host is a complex phenomenon often sustained by virus strains with virological characteristics that can prevent the recognition of the virus by specific antibodies and by the usual laboratory tests. Therefore, we recommend the careful consideration of the duration of HBV prophylaxis and the subsequent virological monitoring, which should also include the measurement of viral DNA in these patients.\n\nAbbreviations\nHSCTHematopoietic stem cell transplantation\n\nMUDMatched unrelated donor\n\nNHLNon-Hodgkin’s lymphoma\n\nPBSCTPeripheral blood stem cell transplantation\n\nRRituximab\n\nR-CHOPRituximab, cyclophosphamide, doxorubicin, vincristine and prednisone\n\nRDHAPRituximab, cisplatin, cytosine arabinoside and dexamethasone\n\nTBF-RICThiotepa, busulfan, and fludarabine reduced intensity condition regimen\n\nAcknowledgements\nNone.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nCC and MG carried out the case conception and design, and drafted the manuscript. MB and SR participated in the acquisition of data. CR and CL were involved in the clinical management of patients. SR, CL and BA participated in the analysis and interpretation of data. SL, CL, and SV critically revised the manuscript and approved the final version.\n\nAuthors’ information\nSL is a respected consultant in infectious diseases who works in the hematology department and is responsible for the management and prevention of infection during transplant procedures. GM and CC are her young collaborators. VS is a respected researcher who works in the field of virology on chronic viral infections. SR, CL and BA are her young collaborators. CR and CL are medical hematologists who address the management of transplantation patients, MB is their young collaborators.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent for the publication of his clinical details was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare no conflicts of interest related to this manuscript. However, LS has received funds for attending symposia, speaking, grant research support, consultancy and advisory, and board membership from ABBOTT, BRISTOL, GILEAD, MERCK, JANSSEN CILAG, PFIZER, ROCHE, and ViiV HEALTHCARE.\n\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Oketani M Ido A Nakayama N Intractable Hepato-Biliary diseases study Group of Japan. Etiology and prognosis of fulminant hepatitis and late-onset hepatic failure in Japan: summary of the annual nationwide survey between 2004 and 2009 Hepatol Res 2013 43 2 97 105 10.1111/j.1872-034X.2012.01105.x 23409848 \n2. Reactivation of hepatitis B. American Association for the Study of Liver Diseases Emerging Trends Conference; Arlington, Virginia, March 21–22, 2013: American Association for the Study of Liver Diseases; 2013.\n3. Liang R Lau GKK Kwong YL Chemotherapy and bone marrow transplantation for cancer patients who are alsochronic hepatitis B carriers J Clin Oncol 1999 17 394 398 10.1200/JCO.1999.17.1.394 10458258 \n4. Koo YX Tay M Teh YE Risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen negative/hepatitis B core antibody positive patients receiving rituximab-containing combination chemotherapy without routine antiviral prophylaxis Ann Hematol 2011 90 10 1219 1223 10.1007/s00277-011-1241-0 21520001 \n5. Seto WK Chan TS Hwang YY Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study J Clin Oncol 2014 32 33 3736 3743 10.1200/JCO.2014.56.7081 25287829 \n6. Dong HJ Ni LN Sheng GF Song HL Xu JZ Ling Y Risk of hepatitis B virus (HBV) reactivation in non-Hodgkin lymphoma patients receiving rituximab-chemotherapy: a meta-analysis J Clin Virol 2013 57 3 209 214 10.1016/j.jcv.2013.03.010 23562041 \n7. Reddy KR Beavers KL Hammond SP Lim JK Falck-Ytter YT; American Gastroenterological Association Institute. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy Gastroenterology 2015 148 1 215 219 10.1053/j.gastro.2014.10.039 25447850 \n8. Marzano A Angelucci E Andreone P Italian Association for the Study of the liver. Prophylaxis and treatment of hepatitis B in immunocompromised patients Dig Liver Dis 2007 39 5 397 408 10.1016/j.dld.2006.12.017 17382608 \n9. European Association For The Study Of The Liver EASL clinical practice guidelines: management of chronic hepatitis B virus infection J Hepatol 2012 57 1 167 185 10.1016/j.jhep.2012.02.010 22436845 \n10. Schubert A Michel D Mertens T Late HBsAg seroreversion of mutated hepatitis B virus after bone marrow transplantation BMC Infect Dis 2013 13 223 10.1186/1471-2334-13-223 23679074 \n11. Matthews GV Bartholomeusz A Locarnini S Ayres A Sasaduesz J Seaberg E Cooper DA Lewin S Dore GJ Thio CL Characteristics of drug resistant HBV in an international collaborative study of HIV-HBV-infected individuals on extended lamivudine therapy AIDS 2006 20 6 863 870 10.1097/01.aids.0000218550.85081.59 16549970 \n12. Salpini R Colagrossi L Bellocchi MC Hepatitis B surface antigen genetic elements critical for immune escape correlate with hepatitis B virus reactivation upon immunosuppression Hepatology 2015 61 3 823 833 10.1002/hep.27604 25418031 \n13. Colson P Borentain P Coso D Hepatitis B virus reactivation in HBsAg-negative patients is associated with emergence of viral strains with mutated HBsAg and reverse transcriptase Virology 2015 484 354 363 10.1016/j.virol.2015.06.017 26186574 \n14. Seto WK Hepatitis B virus reactivation during immunosuppressive therapy: appropriate risk stratification World J Hepatol 2015 7 6 825 830 10.4254/wjh.v7.i6.825 25937860 \n15. Bruss V Envelopment of the hepatitis B virus nucleocapsid Virus Res 2004 106 2 199 209 10.1016/j.virusres.2004.08.016 15567498 \n16. Sterneck M Kalinina T Günther S Functional analysis of HBV genomes from patients with fulminant hepatitis Hepatology 1998 28 5 1390 1397 10.1002/hep.510280530 9794926 \n17. Tan J Degertekin B Wong SN Husain M Oberhelman K Lok AS Tenofovir monotherapy is effective in hepatitis B patients with antiviral treatment failure to adefovir in the absence of adefovir-resistant mutations J Hepatol 2008 48 3 391 398 10.1016/j.jhep.2007.09.020 18199519 \n18. Schildgen O Sirma H Funk A Variant of hepatitis B virus with primary resistance to adefovir N Engl J Med 2006 354 17 1807 1812 10.1056/NEJMoa051214 16641397 \n19. Hwang JP Lok AS Management of patients with hepatitis B who require immunosuppressive therapy Nat Rev Gastroenterol Hepatol 2014 11 4 209 219 10.1038/nrgastro.2013.216 24247262 \n20. Hammond SP Borchelt AM Ukomadu C Ho VT Baden LR Marty FM Hepatitis B virus reactivation following allogeneic hematopoietic stem cell transplantation Biol Blood Marrow Transplant 2009 15 1049 1059 10.1016/j.bbmt.2009.05.001 19660717\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "17(1)",
"journal": "BMC infectious diseases",
"keywords": "HBV reactivation; Hbv DNA; Hematopoietic stem cell transplantation; Hepatitis B; Prophylaxis",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D019072:Antibiotic Prophylaxis; D018380:Hematopoietic Stem Cell Transplantation; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D006801:Humans; D016867:Immunocompromised Host; D019259:Lamivudine; D008297:Male; D008875:Middle Aged; D014775:Virus Activation",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "566",
"pmc": null,
"pmid": "28806922",
"pubdate": "2017-08-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23409848;23562041;25418031;9794926;25287829;21520001;25447850;10458258;23679074;24247262;17382608;26186574;15567498;22436845;25937860;16641397;19660717;16549970;18199519",
"title": "Hepatitis B reactivation characterized by HBsAg negativity and anti-HbsAg antibodies persistence in haematopoietic stem cell transplanted patient after lamivudine withdrawal.",
"title_normalized": "hepatitis b reactivation characterized by hbsag negativity and anti hbsag antibodies persistence in haematopoietic stem cell transplanted patient after lamivudine withdrawal"
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"abstract": "South Africa is home to more than seven million people living with human immunodeficiency virus (HIV) and a high prevalence of tuberculosis. Human immunodeficiency virus-infected individuals may develop myasthenia gravis (MG), which raises questions regarding their management. An MG database, with 24 years of observational data, was audited for HIV-infected persons. Case reports of MG in HIV-infected persons were reviewed. We identified 17 persons with MG and HIV infection. All had generalized MG with a mean age at onset of 37.8 years. Eleven had acetylcholine receptor antibody-positive MG; one had antibodies against muscle-specific kinase. Six developed MG prior to HIV infection (mean CD4+ 361 cells/mm3); four worsened <6 months of starting antiretrovirals. Eleven developed MG while HIV-infected (mean CD4+ 423 cells/mm3); five presented with mild MG; three in MG crisis requiring rescue therapies (intravenous immune globulin or plasma exchange and/or intravenous cyclophosphamide). Two were diagnosed with HIV infection and MG at the same time. Fifteen required maintenance steroid-sparing immune therapies, predominantly azathioprine, or methotrexate. Plasma HIV viral loads remained below detectable levels on antiretrovirals during immunosuppressant treatment. Over the average follow-up of 6 years, 10 achieved minimal manifestation status, and the remainder improved to mild symptoms. Three cases had tuberculosis before MG, but none developed tuberculosis reactivation on immunosuppressive therapy; one used isoniazid prophylaxis. Herpes zoster reactivation during treatment occurred in one. Conclusions include the following: MG in HIV-infected patients should be managed similarly to individuals without HIV infection; half develop moderate-severe MG; MG symptoms may worsen within 6 months of antiretroviral initiation; safety monitoring must include plasma HIV viral load estimation. Isoniazid prophylaxis may not be indicated in all cases.",
"affiliations": "Neurology, Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa.;Neurology, Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa.",
"authors": "Heckmann|Jeannine M|JM|;Marais|Suzaan|S|",
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"doi": "10.3389/fneur.2020.00775",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295 Frontiers Media S.A. \n\n10.3389/fneur.2020.00775\nNeurology\nPerspective\nManagement Issues in Myasthenia Gravis Patients Living With HIV: A Case Series and Literature Review\nHeckmann Jeannine M. 12* Marais Suzaan 12 1Neurology, Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa\n2Neurology Research Group, UCT Neuroscience Institute, University of Cape Town, Cape Town, South Africa\nEdited by: Nils Erik Gilhus, University of Bergen, Norway\n\nReviewed by: Elena Maria Pennisi, Ospedale San Filippo Neri, Italy; Paolo Emilio Alboini, Casa Sollievo della Sofferenza (IRCCS), Italy\n\n*Correspondence: Jeannine M. Heckmann Jeanine.heckmann@uct.ac.zaThis article was submitted to Neuromuscular Diseases, a section of the journal Frontiers in Neurology\n\n\n21 8 2020 \n2020 \n11 77502 4 2020 24 6 2020 Copyright © 2020 Heckmann and Marais.2020Heckmann and MaraisThis 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.South Africa is home to more than seven million people living with human immunodeficiency virus (HIV) and a high prevalence of tuberculosis. Human immunodeficiency virus–infected individuals may develop myasthenia gravis (MG), which raises questions regarding their management. An MG database, with 24 years of observational data, was audited for HIV-infected persons. Case reports of MG in HIV-infected persons were reviewed. We identified 17 persons with MG and HIV infection. All had generalized MG with a mean age at onset of 37.8 years. Eleven had acetylcholine receptor antibody–positive MG; one had antibodies against muscle-specific kinase. Six developed MG prior to HIV infection (mean CD4+ 361 cells/mm3); four worsened <6 months of starting antiretrovirals. Eleven developed MG while HIV-infected (mean CD4+ 423 cells/mm3); five presented with mild MG; three in MG crisis requiring rescue therapies (intravenous immune globulin or plasma exchange and/or intravenous cyclophosphamide). Two were diagnosed with HIV infection and MG at the same time. Fifteen required maintenance steroid-sparing immune therapies, predominantly azathioprine, or methotrexate. Plasma HIV viral loads remained below detectable levels on antiretrovirals during immunosuppressant treatment. Over the average follow-up of 6 years, 10 achieved minimal manifestation status, and the remainder improved to mild symptoms. Three cases had tuberculosis before MG, but none developed tuberculosis reactivation on immunosuppressive therapy; one used isoniazid prophylaxis. Herpes zoster reactivation during treatment occurred in one. Conclusions include the following: MG in HIV-infected patients should be managed similarly to individuals without HIV infection; half develop moderate–severe MG; MG symptoms may worsen within 6 months of antiretroviral initiation; safety monitoring must include plasma HIV viral load estimation. Isoniazid prophylaxis may not be indicated in all cases.\n\nHIVmyasthenia gravisautoimmuneimmune restorationimmunosuppressive therapyrituximabmethotrexate\n==== Body\nIntroduction\nMyasthenia gravis (MG) has a similar incidence worldwide (1). However, South Africa is also home to more than seven million people living with human immunodeficiency virus (HIV), and therefore the co-occurrence of MG in some persons living with HIV infection is expected. In the early 2000's, South Africa rolled out the largest governmental-sponsored antiretroviral treatment (ART) program globally. Initially, ART triple therapy was provided only to those with CD4+ count of <200 cells/mm3, but since 2016, ART has been available to all with HIV infection regardless of CD4+ count. Present first-line ART comprises efavirenz, tenofovir (TDF), and emtricitabine. South Africa provides treatment to ≈4.4 million HIV-infected people (2).\n\nIn Africa, HIV spreads predominantly through heterosexual transmission, and hepatitis B (HepB) coinfection is rare, but tuberculosis is common (3). As HIV-infected people are at risk of opportunistic infections, and this risk may be increased with comorbid autoimmune diseases requiring immunosuppressive therapies, we audited the results of our HIV-infected patients with MG. We have summarized our results with reported cases to develop empiric management guidelines.\n\nMaterials and Methods\nThe diagnosis of MG was based on clinical criteria of fatigable weakness and responsivity to anticholinesterases, repetitive nerve stimulation (RNS), and/or acetylcholine receptor (AChR)–antibody (ab) testing as previously reported (4, 5). Although routine muscle-specific kinase (MuSK)-ab testing is unavailable, AChR-ab–negative sera were tested for MuSK-abs between 2006 and 2015 (6). Observational data have been collected using standardized forms since 1997. Data captured MG Foundation of America (MGFA) disease outcomes (7), MG composite scores (8), drug dosages, and complications thereof, hospitalization events, and opportunistic infections. The registry (R004/2014) and audit (HREC 611/2013) were approved by the institutional ethics committee.\n\nAlthough screening for HIV was not routinely performed before 2012, since then HIV, HepB, and HepC infection screening occurred prior to starting immunosuppression.\n\nTo review the literature, PubMed was searched for articles published in English (1997–2019) with the terms “HIV” or “AIDS” and “myasthenia gravis” and from manual searching reference lists.\n\nResults\nSeventeen patients were identified in the MG database (n = 844 entries) who were also living with HIV (2003–2019); six were diagnosed with MG and subsequently became HIV-infected; nine were HIV-infected on effective ART [viral load (VL) <20 copies/ml or lower than detectable level (LDL)] prior to developing MG; and two were diagnosed with HIV and MG at the same time (Table 1).\n\nTable 1 Clinical characteristics of patients with concomitant MG and HIV infection.\n\n\tMG-HIV\n (n = 6)\tHIV-MG\n (n = 11)\tCase reports 1998–2019 (n = 13)\t\nSex, female, n (%)\t6 (100)\t8 (73)\t7 (54)\t\nAge at MG symptom onset, mean ±SD, years\t30.8 ± 14.9*\t39.6 ± 8.6*\t38.2 ± 18.6\t\nCD4+ count, mean ±SD, cells/mm3\t361 ± 133#\t423 ± 76#\t428 ± 315\t\nDiagnostic Criteria, n\n(%)\t\t\t\t\n AChR ab+\t6 (100)\t5 (45)\t4 (31)\t\n MuSK ab+\t\t1 (9)\t4\t\n AChR ab−/RNS+\t\t4 (36)\t5 (38)\t\n AChR ab−/RNS−/CHEI+\t\t1 (9)\t0\t\nMGFA Grade Nadir, n\n(%)\t\t\t\t\n 2a/b\t2 (33)\t5 (45)\t9 (69)⋎\t\n 3b\t1 (17)\t3 (27)\t\t\n 4b/5\t3 (50)\t3 (27)\t\t\nConcomitant autoimmune disease\t\t2 (PM/IBM, ATD)\t0\t\nMG treatments, average doses when HIV+\t\t\t\t\n Prednisone (max doses), (n) mg/kg\t0.14 (1)\t0.52 ± 0.3 (10)\t(6)\t\n Azathioprine, mean ±SD (n), mg/kg\t1.2 ± 0.1 (4)##\t2.1 ± 0.3 (5)##\t(2)\t\n Methotrexate, weekly, mean ±SD (n), mg\t\t15.6 (4)\t\t\n Mycophenolate mofetil (n)\t\t2 × 1,250 mg (1)\t(1)\t\n Cyclosporine (n)\t\t2 × 150 mg (1)α\t(1)\t\n Cyclophosphamide pulses, (n)\t\t5 × 250 mg (1)\t\t\n Rituximab cycles (n)\t\t4+2 (1)\t(1)\t\n IVIG/Plasma exchange, n (%)\t\t3β/1χ (4)\t(5/2)\t\nMG crises after MG diagnosis/treatment in HIV+\t0\t1\t1\t\nMinimal manifestation status, n (%)\t4 (80)\t6 (55)\tUK\t\nPatients on continued IS therapy, n (%)\t3 (60)\t10 (91)\tUK\t\nFollow-up since comorbid MG/HIV diagnosis, mean ±SD (n), years\t11.8 ± 5.2**\t3.9 ± 3.1**\t1.2 ± 0.8 (12)\t\nHIV viral load <20 copies on follow-up\t6 (100)\t11 (100)\tUK\t\nMG-HIV refers to the patients with MG who later became infected with HIV; HIV-MG refers to patients living with HIV who later manifested MG. Four HIV-MG cases developed MG ≥45 years. No cases had thymoma-MG.\n\n* Refers to MG diagnosis before the patient became HIV-infected vs. HIV-MG (p = 0.14).\n\n** p = 0.009.\n\n# p = 0.53.\n\n## p = 0.033.\n\nATD, autoimmune thyroid disease; PM/IBM, polymyositis/inclusion body myositis overlap; HIV+, known to be HIV-infected; AChR ab+, acetylcholine receptor ab–positive; MuSK ab+, muscle-specific kinase ab+; AChR ab−, not tested for MusK-abs; CHEI+, responsivity to cholinesterases; IVIg, intravenous immunoglobulin; RNS+, 3-Hz repetitive nerve stimulation >10% decrement; IS, immunosuppressive.\n\nα 3 months before renal dysfunction.\n\nβ Three of the IVIg course were administered at MG diagnosis in crisis (MGFA grade 5).\n\nχ Plasma exchange during MG relapse months after diagnosis (Figure 1). Rituximab cycles: 375 mg/m2 2 weekly × 2, monthly × 2, and then at 6 months.\n\n⋎ MGFA grade 2a/b assigned to descriptions of mild disease. Rituximab cycles: 375 mg/m2 4 weekly × 2, monthly × 2.\n\nCase reports (1998–2019) (9–20).\n\nMG Patients on Immunosuppressant Therapy Becoming Infected With HIV (MG-HIV Group)\nSix women with AChR-ab–positive MG were diagnosed with HIV infection between 1.5 and 40 years after developing MG. Four had thymectomies <3 years of symptom onset. All were receiving immunosuppression at the time of presumed seroconversion: five had reached MGFA minimal manifestation status (MMS), and one had mild symptoms (grade 2A).\n\nThree developed skin rashes, which prompted HIV testing between 1, 2, and 10 years after MG diagnosis. One patient developed a flulike illness 12 years after azathioprine initiation, which was followed by a declining leukocyte count on routine monitoring when HIV infection was confirmed. After stopping azathioprine, the CD4+ count rapidly increased from <100 to >500 cells/mm3. She remained off all immune therapy for 9 years requiring only pyridostigmine for MG symptoms. Antiretroviral treatment was started when the CD4+ count declined to ~200 cells/mm3. Myasthenia gravis symptoms subsequently worsened over several months, and 12 months after ART initiation, a lower dose of azathioprine was reinitiated (CD4+ ~250 cells/mm3), resulting in symptomatic improvement. Another patient developed unexplained weight loss of 20 kg, which prompted HIV testing (CD4+ ~154 cells/mm3). As she was asymptomatic, azathioprine was discontinued, and the CD4+ count recovered to ~650 cells/mm3. Within 6 months, azathioprine was reinitiated, at a lower dose, because of recurring bulbar symptoms. The remaining patient's MG was in remission, and her immunotherapy was being weaned when she tested HIV-positive.\n\nThese patients have been followed up for an average of 11.8 years since their HIV diagnosis. Four remain on azathioprine, although the doses required to control their disease before HIV infection was detected were significantly higher compared to the doses required to control MG after ART was reintroduced (2.6 mg/kg; SD ±0.1 vs. 1.2 ± 0.1; p < 0.0001). Two patients were in MG-MMS and were weaned off azathioprine when testing positive for HIV infection; one has remained in remission for 14 years, but the other developed bulbar symptoms after 10 years and was reinitiated on azathioprine (VL-LDL). The two patients without thymectomies were weaned off prednisone maintaining MMS on maintenance treatment. One patient had pulmonary tuberculosis on two occasions, more than 3 years prior to MG, but was not started on isoniazid prophylaxis when ART was commenced.\n\nPatients Living With HIV Who Subsequently Developed MG (HIV-MG Group)\nEleven HIV-infected people developed MG. Nine were receiving ART [mean, 5 years (SD, ±3.9)] prior to developing MG symptoms, whereas two tested HIV-positive at the time of MG diagnosis. The mean CD4+ count at MG diagnosis was 423 cells/mm3, although three, who had been on effective ART (VL-LDL) had CD4+ counts of <200 cells/mm3 (range, 173–190 cells/mm3).\n\nThree patients presented in MG crisis after 6–12 months of symptoms. Three had a history of tuberculosis 2–11 years before manifesting with MG, but none developed reactivation of tuberculosis on immunosuppressive therapy; isoniazid prophylaxis was used in one case. One individual developed herpes zoster reactivation during MG treatment.\n\nCases Who Were Concurrently Diagnosed With HIV and MG\nA patient was diagnosed with HIV infection (CD4+ ~160 cells/mm3) when admitted in MG crisis following symptoms for 12 months. Acetylcholine receptor antibody testing was negative (MuSK-abs not tested), but with decremental RNS. She required ventilation, but responded rapidly to intravenous immunoglobulin (IVIg) and prednisone (0.8 mg/kg). She was initiated on ART within 1 week and a month later on azathioprine (1.4 mg/kg). At 12 months, she was asymptomatic, and ART was effective (VL-LDL).\n\nAnother case presented with generalized MG (grade 3B), which developed over 4 weeks. Acetylcholine receptor antibody testing was negative (MuSK-abs not tested), but RNS showed a decremental response, and he responded to pyridostigmine. He was found to be infected with HIV (CD4+ ~700 cells/mm3) and HepB (HepC-negative). Antiretroviral treatment and prednisone were initiated, and he improved so rapidly that steroid-sparing therapy was omitted. After 6 months on ART (VL-LDL), he was only mildly symptomatic, and prednisone was successfully weaned over several months.\n\nCases Living With HIV Infection Developing MG\nThe ages of these patients ranged between 28 and 53 years. Five cases had circulating AChR-abs, one had MuSk-abs, and three were AChR-ab–negative (MuSK-abs not tested) but responded to anticholinesterases.\n\nOne case who had been virally suppressed on ART for 5 years developed a detectable VL as a result of an inability to swallow the ART tablets. Three months later, she was diagnosed with MG grade 3B and was initiated on pyridostigmine, increasing prednisone doses (0.9 mg/kg) and azathioprine (1.9 mg/kg). At 12 months, the MG was in MMS, and ART was effective (VL-LDL).\n\nThe drug dosages in newly diagnosed HIV-MG cases were similar to those who were diagnosed with MG and became HIV-infected years later [azathioprine 2.1 vs. 2.6 mg/kg in MG (pre-HIV); p = 0.12]. Four cases were treated with weekly methotrexate (range, 10–20 mg) and one with mycophenolate mofetil 2,500 mg daily for 5 years. The average follow-up since MG diagnosis has been 3.9 years (range, 0.5–10 years). Five achieved persistent MMS, one without treatment, and the other improved to mild MG on maintenance therapy, and therefore none with AChR-abs underwent thymectomy.\n\nSpecial Case Scenarios\nMuSK-MG\nThis woman with severe oculobulbar MG manifesting over 6 months was reported previously (6). She had received effective ART for 4 years. She was admitted in myasthenic crisis (Figure 1) and showed a transient response to pyridostigmine and IVIg. However, she developed steroid-induced psychosis resulting in her refusing plasma exchange. Instead, 5 monthly cyclophosphamide infusions [one-third of 500 mg/mm2 (21)] were administered together with azathioprine and isoniazid prophylaxis. During this time, she had improved slowly, until she relapsed into MG crisis precipitated by pneumonia. She agreed to plasma exchange, which was followed by rituximab infusions (375 mg/mm2) and a steady recovery. She currently remains asymptomatic on azathioprine and ART. Interestingly, within 6 months of starting azathioprine (2.3 mg/kg), her γ-glutamyl transferase (GGT) increased to 3× the upper limit of normal, and isoniazid was discontinued. Subsequently, hepatic transaminases (aspartate transaminase and alanine transaminase) and GGT increased to 4× the upper limit, which normalized after an azathioprine dose reduction (1.1 mg/kg). During the stormy course of MG requiring cyclophosphamide and rituximab infusions, leukocytes remained >3 × 109/L, polymorphs >2 × 109/L, lymphocytes ≥0.7 × 109/L, CD4+ ~222/mm3, and VL-LDL.\n\nFigure 1 HIV-infected patient with MuSK-MG. Black circles and left-sided y axis refers to MG composite score. Open squares and right-sided y axis refers to CD4+ count. ICU, intensive care unit; PEG, percutaneous endoscopic gastrostomy; AZA, azathioprine; IVIg, hyperimmune intravenous globulin; CTX, cyclophosphamide monthly pulses (250 mg); PLEX, plasma exchange; RTX, rituximab infusions (500 mg weekly × 4; and 2 weekly × 2 after 3 months).\n\nMG With HIV Inflammatory Myopathy/Inclusion Body Myositis\nThis middle-aged woman developed proximal weakness over several years since HIV infection was diagnosed and ART initiated. She presented to the neurology service after developing, over 2 years, additional symptoms of fatigable diplopia and bulbar symptoms accompanied by limb fatigability. At presentation, she was receiving effective ART, and serum creatine kinase was raised (1.5× upper limit). Although the serum AChR-abs (and muscle autoimmune panel) were negative, MG was confirmed by a decremental response on RNS and responsivity to intramuscular neostigmine (swallowing and leg strength). A muscle biopsy showed endomysial fibrosis and fiber size variation, but no rimmed vacuoles. Treatment for MG was started viz. pyridostigmine, steroids, and methotrexate. The MGC score improved by 50% over 12 months, but she developed moderate weakness of hand flexors and knee extensors. The prednisone has been weaned, and she remains on methotrexate 20 mg weekly. The working diagnoses include MG, which is at present minimally symptomatic, and HIV-associated inflammatory myopathy overlapping with inclusion body myopathy (22). The current goal is to wean the methotrexate to the lowest dose maintaining control of MG.\n\nDrug–Drug Interactions\nAnother case was diagnosed with AChR-ab–positive MG (grade 2B) after 3 months of symptoms. She had been on effective ART for 4 years (CD4+ 200 cells/mm3; VL-LDL) and had been treated for tuberculosis twice, at least 2 years prior to the diagnosis of HIV and the onset of MG symptoms. Prednisone and methotrexate were started together with isoniazid prophylaxis for 18 months because of associated bronchiectasis. Her CD4+ count remained stable (VL-LDL), but deteriorating bulbar MG symptoms required high-dose prednisone. After 12 months, methotrexate was replaced with cyclosporine, and although the MG responded within 4 months, her kidney function deteriorated (rising urea/creatinine). The ART regimen contained TDF, which was replaced with zidovudine. The cyclosporine dose was initially reduced, but eventually replaced with azathioprine. Although the renal function improved, she developed aplastic anemia. The ART regimen was then altered to include abacavir, nevirapine, and lamivudine, and given that she had achieved MMS, the azathioprine was discontinued. Within weeks, her bulbar symptoms recurred, and she was cautiously started on mycophenolate mofetil (MMF) (500 mg daily) with prednisone. The MMF was increased to 2,500 mg daily. After 15 months, she started improving, and the prednisone dosing could be reduced by 50%. Four years later, she remains in remission on MMF.\n\nLiterature Review\nThirteen case reports were identified and summarized in Table 1 (see legend). One patient had MG-HIV, two were diagnosed with HIV when they presented with mild MG (CD4+ 250–350 cells/mm3), and 10 had HIV-MG. More than 80% had mild–moderate MG symptoms. Only one case presented with MG and a CD4 count of <200 (CD4+ 63 cells/mm3). At least five were on effective ART (VL-LDL) when they developed MG. Five showed mild symptomatic deterioration 3 weeks to 3 months after ART initiation or adjustment (for improved efficacy).\n\nDiscussion\nWe describe a cohort of HIV-infected MG patients, followed for many years, unlike previous cases reports with <2 years follow-up. Several findings need highlighting. Most cases known with HIV infection develop MG with relatively preserved CD4+ counts and/or mild disease at onset. However, HIV-MG may present in crisis and with lower CD4+ counts [ ≤ 222 cells/mm3 in three cases, and (23)].\n\nImmunomodulatory Therapy in HIV-Infected MG Cases\nFour HIV-MG patients required intensive and multiple immune therapies to gain control of their MG despite ART, which included “rescue” therapy with plasma exchanges/IVIg and/or induction therapy with cyclophosphamide or rituximab in addition to maintenance therapies (prednisone and steroid-sparers). Methotrexate is a cost-effective alternative in generalized MG (24), and four HIV-infected people, who were not potentially child-bearing, were managed with methotrexate, and two obtained MG remission status within 6 months.\n\nIn addition to our case, one other reported HIV-infected MuSK-MG patient was treated with rituximab. In both, the protocols comprised 4 weekly, followed shortly after by 2 weekly infusions. Jing et al. (25, 26) and our experience (unpublished) in HIV-uninfected patients have found excellent responses after a single ≈500–600 mg rituximab dose, which may last for 9 to more than 42 months; this regimen should be explored in HIV-infected cases with MG.\n\nIn total, 16 of 17 patients received prednisone and steroid-sparing immunomodulatory therapies. With the exception of one patient who developed a herpes zoster reactivation rash, none developed opportunistic infections during such treatment. It should be noted that all patients receiving ART remained virally suppressed on immunomodulatory therapy. Maintaining effective ART (VL-LDL) while taking immunosuppressive therapies is critically important. New guidelines advise that if the CD4+ count was >200 cells/mm3 before starting immunosuppressive therapies, monitoring of the HIV-VL is the most cost-effective (27). Despite effective ART, MG symptoms may recur years later. It is prudent to then consider additional autoimmune thyroid disease, hormonal-related fluctuations (pregnancy, menopause), and drug–drug interactions. Overall, HIV-infected patients with MG should be managed similarly to HIV-uninfected cases: immunomodulatory therapies should be administered according to the severity of MG.\n\nAlthough it was shown that thymectomy in AChR-ab generalized MG resulted in lower prednisone doses required to improve MG and maintained for 5 years (28), it was not performed here mainly because these patients appeared to improve and maintain MMS with successful weaning of prednisone.\n\nEffects of Level of Immunosuppression and Immune Recovery on MG\nTwo main groups were encountered: MG patients who were well-controlled on immunosuppressive therapy when they became infected with HIV and could subsequently be managed on lower doses of azathioprine compared to pre-HIV dosing (1.3 vs. 2.6 mg/kg; p < 0.0001) and patients who developed MG after HIV acquisition and who required similar doses of immunotherapies to that used in HIV-uninfected populations (29) (2.1 vs. 2.6 mg/kg, respectively; p = 0.12).\n\nAntiretroviral treatment initiation within the first 3 months may be associated with a subclinical “cytokine storm” (30), and recovery of the immune system may take many months as shown by CD4+ count recovery (31). During this period, MG symptoms may deteriorate as was evident from four MG-HIV cases who were weaned off immunosuppressants when diagnosed with HIV, but had to be reinitiated within 6 months of starting ART, albeit with lower doses. A previous report (19) described an HIV-infected man (CD4+ 290 cells/mm3) who developed bulbar MG shortly after the addition of ritonavir to his two-drug ART regimen. The authors suggested that MG occurred as a side effect from ritonavir. At present, in South Africa, it is estimated that there are 200,000 patients on second-line ART (2), which encompasses protease inhibitors (ritonavir). One of our cases received ritonavir without MG deterioration. Our experience with this class has shown few neuromuscular side effects (32). It is more likely that the reported patient (19) worsened due to immune “recalibration” with more effective ART.\n\nIsolated cases presenting with MG at the same time as HIV infection have improved alongside ART with or without a short course of prednisone in addition to anticholinesterases and not requiring long-term immune therapy.\n\nInvestigations Prior to Immunomodulatory Therapy\nCoinfection with HepB/HepC must be excluded. Baseline blood laboratory values should be determined prior to starting or adding immune therapies to the medication list so that drug-induced complications are easily identifiable. If an expected drug-associated side effect occurs, such as raised transaminases with azathioprine, a lower dose may be all that is required to safely continue the drug (33). Prior to rituximab, screening for previous HepB infection (anti-HepB surface-ab− and anti-HepB core-ab–positive, but HepB surface-antigen negative) must be performed because 25–40% of these cases may seroconvert to active HepB after rituximab (34). The WHO estimates that only 10% of HepB-infected people are aware of their infection status (who.int/news-room/fact-sheets/detail/hepatitis-b).\n\nIt is important to screen for active tuberculosis prior to starting immunosuppressive therapy. Among HIV-infected people, cases at particular high risk include those with prior tuberculosis exposure and/or diabetes (35). Screening should include a chest X-ray to exclude active tuberculosis or identify evidence of fibrotic scarring. Human immunodeficiency virus–infected people have 3–20 times higher risk of reactivation of latent tuberculosis compared to the general population (36). In resource-rich areas with low background prevalence of tuberculosis, diagnostic tests, such as the interferon γ release assays (QuantiFERON-TB Gold Plus; T-SPOT test), can be useful to identify infected individuals. However, the results have to be interpreted with caution in areas with high tuberculosis prevalence. These tests may be falsely negative after starting immune therapies (37). False-positive tests may be a response to BCG-vaccinations, environmental exposure to non-tuberculous mycobacteria (35), and in autoimmune diseases (37).\n\nProphylactic Treatment for Tuberculosis During Immunomodulatory Therapy\nWhile some have suggested using prophylactic antifungal and antituberculosis therapies in patients on immunosuppressive therapy (38), we do not follow this practice routinely, although we screen for active tuberculosis by questionnaire and chest radiograph. We recommend that, in tuberculosis-endemic areas, each patient's comorbidities be considered for possible isoniazid preventive therapy. With fibrotic lung lesions, isoniazid preventive therapy for 6–12 months reduced the odds for reactivation of latent tuberculosis by ≈50% (35), but must be given with 25 mg pyridoxine (39).\n\nThe conclusions that can be drawn from these cases include the following: MG in HIV-infected people should be managed similarly to HIV-uninfected individuals; transient worsening of MG may occur weeks to months following ART initiation; monitoring should comprise HIV VLs estimation; and isoniazid prophylaxis is not indicated in all cases.\n\nData Availability Statement\nAll datasets generated for this study are included in the article/supplementary material.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by University of Cape Town Human Research Ethics Committee. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.\n\nAuthor Contributions\nJH performed the case, literature review, and drafted the manuscript. SM edited the manuscript drafts and contributed to the literature review. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThe authors wish to thank Associate Professor S. Dlamini for his assistance with the management of one of the cases.\n\nFunding. JH receives financial support for the South African National Research Foundation.\n==== Refs\nReferences\n1. Mombaur B Lesosky MR Liebenberg L Vreede H Heckmann JM . Incidence of acetylcholine receptor-antibody-positive myasthenia gravis in South Africa\n. Muscle Nerve. 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Vermaak JR Dave JA Levitt N Heckmann JM . Sensory neuropathy and metabolic risk factors in human immune deficiency virus infected South Africans receiving protease inhibitors\n. AIDS Res Ther. (2015 ) 12 :30 . 10.1186/s12981-015-0073-8 26401157 \n33. Heckmann JM Lambson EM Little F Owen EP . Thiopurine methyltransferase (TPMT) heterozygosity and enzyme activity as predictive tests for the development of azathioprine-related adverse events\n. J Neurol Sci. (2005 ) 231 :71 –80\n. 10.1016/j.jns.2005.01.003 15792824 \n34. Riminton DS Hartung HP Reddel SW . Managing the risks of immunosuppression\n. Curr Opin Neurol. (2011 ) 24 :217 –23\n. 10.1097/WCO.0b013e328346d47d 21519254 \n35. Fox GJ Dobler CC Marais BJ Denholm JT . Preventive therapy for latent tuberculosis infection-the promise and the challenges\n. Int J Infect Dis. (2017 ) 56 :68 –76\n. 10.1016/j.ijid.2016.11.006 27872018 \n36. Hasan T Au E Chen S Tong A Wong G . 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"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "11()",
"journal": "Frontiers in neurology",
"keywords": "HIV; autoimmune; immune restoration; immunosuppressive therapy; methotrexate; myasthenia gravis; rituximab",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "775",
"pmc": null,
"pmid": "32973647",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "9706730;14600531;23415569;21543153;17720497;29455332;8141507;21819556;25588730;25060190;30692052;10891897;24512313;29790193;16551345;9572258;21339503;31100692;30209157;31865953;21386775;7548525;28121924;20439845;11680327;28789841;19048951;21477422;28283597;27872018;28424453;21519254;15792824;26678433;27105303;26401157;16515244;29568644;12115946",
"title": "Management Issues in Myasthenia Gravis Patients Living With HIV: A Case Series and Literature Review.",
"title_normalized": "management issues in myasthenia gravis patients living with hiv a case series and literature review"
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"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
},
"drugaddition... |
{
"abstract": "Haploidentical hematopoietic SCT (haplo-HSCT) is to be established in patients with acquired severe aplastic anemia (SAA) refractory to immunosuppressive therapy and lacking HLA-matched related or unrelated donors. Graft failure (GF) and GVHD have been major obstacles to HSCT. A total of 17 children and adolescents with SAA underwent haplo-HSCT in our center. The conditioning regimen consisted of BU, fludarabine, CY and anti-thymocyte globulin. All patients received cyclosporine, short-term MTX, mycophenolate mofetil and basiliximab for GVHD prophylaxis. Mesenchymal stem cells derived from unrelated umbilical cord were infused on day 1. Neutrophil engraftment was achieved in all 17 patients in a median time of 16 days (range 9-25 days). The median time of platelet engraftment was 22 days (range 9-95 days) in 16 patients. The cumulative incidence (CI) of II-IV acute GVHD (aGVHD) at day +100 was 30.53±11.12% and III-IV aGVHD occurred in only one patient. The CI of chronic GVHD was 21.25±13.31%. Secondary GF with autologous hematopoiesis recovery occurred in one patient. The OS was 71.60±17.00% at a median follow-up of 362 (36-1321) days. These limited promising data suggest that haplo-HSCT is feasible as a salvage therapy for children and adolescents with refractory SAA who lack matched donors.",
"affiliations": "Department of Hematology, The General Hospital of Air Force PLA, Beijing, China.;Department of Hematology, The General Hospital of Air Force PLA, Beijing, China.;Department of Hematology, The General Hospital of Air Force PLA, Beijing, China.;Department of Hematology, The General Hospital of Air Force PLA, Beijing, China.;Department of Hematology, The General Hospital of Air Force PLA, Beijing, China.",
"authors": "Wang|Z|Z|;Zheng|X|X|;Yan|H|H|;Li|D|D|;Wang|H|H|",
"chemical_list": "D016572:Cyclosporine; D002066:Busulfan",
"country": "England",
"delete": false,
"doi": "10.1038/bmt.2014.187",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "49(12)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D000741:Anemia, Aplastic; D002066:Busulfan; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D036101:Cord Blood Stem Cell Transplantation; D016572:Cyclosporine; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D009504:Neutrophils; D016879:Salvage Therapy; D019172:Transplantation Conditioning; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "1481-5",
"pmc": null,
"pmid": "25133891",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20425804;3049951;17331846;14716336;779871;12476277;17638847;23806238;19734425;16489361;8864434;20851870;16380454;21193055;16338616;14578930;20685256;7581076;15968293;8560574;21963619;20109568;22635243;16778145;10975512",
"title": "Good outcome of haploidentical hematopoietic SCT as a salvage therapy in children and adolescents with acquired severe aplastic anemia.",
"title_normalized": "good outcome of haploidentical hematopoietic sct as a salvage therapy in children and adolescents with acquired severe aplastic anemia"
} | [
{
"companynumb": "CN-PFIZER INC-2015161418",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "A 34-year-old man with refractory acute myelogenous leukemia underwent allogeneic peripheral blood stem cell transplantation (PBSCT) from his HLA-matched sibling. Engraftment was prompt and no acute GVHD developed. However, high fever persisted even after engraftment, and the patient developed headache, diplopia, vertigo and nuchal rigidity on day 20 posttransplant. Cerebrospinal fluid (CSF) showed pleocytosis with no detectable microorganisms. Despite therapy with broad-spectrum antibiotics, antifungal agents and antituberculous drugs, he developed rapid mental deterioration with seizures and died on day 40. Just prior to his death, trichomonads were isolated from both CSF and urine. Scanning electron microscopic examination identified the trichomonad as Trichomonas foetus. At autopsy, trichomonads were detected histopathologically in an area involving meningoencephalitis. To our knowledge, this is the first case of T. foetus meningoencephalitis in a recipient of allogeneic PBSCT and, more importantly, the first human case of T. foetus infection.",
"affiliations": "Keio Bone Marrow Transplant Program, Department of Medicine, Keio University, Tokyo, Japan.",
"authors": "Okamoto|S|S|;Wakui|M|M|;Kobayashi|H|H|;Sato|N|N|;Ishida|A|A|;Tanabe|M|M|;Takeuchi|T|T|;Fukushima|S|S|;Yamada|T|T|;Ikeda|Y|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/sj.bmt.1701032",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "21(1)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000328:Adult; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008590:Meningoencephalitis; D014184:Transplantation, Homologous; D014245:Trichomonas Infections",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "89-91",
"pmc": null,
"pmid": "9486501",
"pubdate": "1998-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Trichomonas foetus meningoencephalitis after allogeneic peripheral blood stem cell transplantation.",
"title_normalized": "trichomonas foetus meningoencephalitis after allogeneic peripheral blood stem cell transplantation"
} | [
{
"companynumb": "JP-PFIZER INC-2018220404",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional": null,
... |
{
"abstract": "This study aimed at providing valid estimates for the risk of clinically relevant seizure aggravation by recommended anti-seizure medications in patients with Genetic Generalized Epilepsy (GGE). To this aim, treatment response, side effects and paradoxical reactions to anti-seizure treatment were retrospectively assessed in a near-population based cohort comprising 471 adult GGE patients. A total of 1046 treatment attempts were analyzed (lamotrigine: 351, valproic acid: 295, levetiracetam: 249, primidone/phenobarbital: 94, zonisamide: 57). Under lamotrigine, seizure aggravation was observed in 15 patients (two patients during levetiracetam, one patient during zonisamide, none during phenobarbital and valproic acid). All but two patients with paradoxical reactions to lamotrigine were diagnosed with juvenile myoclonic epilepsy (JME), otherwise, the clinical and electroencephalographic characteristics of patients with paradoxical reactions did not differ. At treatment start, the estimated risk of a paradoxical reaction to lamotrigine was 7.9 % in JME patients (n = 190). For all GGE patients (incl. JME), the estimated risk of clinically relevant seizure aggravation under treatment with lamotrigine was 3.7 % (1.8 % for zonisamide and 0.8 % for levetiracetam). In conclusion, clinical significant aggravation of seizure frequency is common in lamotrigine-treated JME patients but rare in patients with other GGE subsyndromes or under treatment with other recommended anti-seizure medication.",
"affiliations": "Department of Neurology, Odense University Hospital, Denmark; Department of Clinical Research, University of Southern Denmark, Denmark.;Danish Epilepsy Center, Dianalund, Denmark.;Danish Epilepsy Center, Dianalund, Denmark; Institute of Clinical Medicine, University of Copenhagen, Denmark.;Department of Neurology, Odense University Hospital, Denmark; Department of Clinical Research, University of Southern Denmark, Denmark; OPEN, Open Patient Data Explorative Network, Odense University Hospital, Denmark. Electronic address: cbeier@health.sdu.dk.",
"authors": "Gesche|Joanna|J|;Hjalgrim|Helle|H|;Rubboli|Guido|G|;Beier|Christoph Patrick|CP|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.eplepsyres.2020.106547",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-1211",
"issue": "170()",
"journal": "Epilepsy research",
"keywords": "Juvenile myoclonic epilepsy; Lamotrigine; Myoclonus; Paradoxical reaction",
"medline_ta": "Epilepsy Res",
"mesh_terms": null,
"nlm_unique_id": "8703089",
"other_id": null,
"pages": "106547",
"pmc": null,
"pmid": "33421702",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Risk factors of paradoxical reactions to anti-seizure medication in genetic generalized epilepsy.",
"title_normalized": "risk factors of paradoxical reactions to anti seizure medication in genetic generalized epilepsy"
} | [
{
"companynumb": "DK-NOVARTISPH-NVSC2021DK025659",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",... |
{
"abstract": "BACKGROUND\nNon-medical use of benzodiazepines and Z-drugs is common; however, there is limited information available on the extent of harm related to this in Europe, as well as the relationship between misuse and availability.\n\n\nOBJECTIVE\nTo describe presentations to the emergency department in Europe related to the recreational use of benzodiazepines and Z-drugs and compare regional differences in these presentations with legal drug sales of benzodiazepines and Z-drugs within each country.\n\n\nMETHODS\nEmergency department presentations with recreational misuse of benzodiazepines and Z-drugs were obtained from the Euro-DEN dataset for the period from October 2013 to September 2015; data extracted included demographics, clinical features, reported coused drugs, and outcome data. Sales figures obtained by QuintilesIMS™ (Atlanta, Georgia) were used to compare regional differences in the proportion of benzodiazepines and Z-drugs in the emergency department presentations and legal drug sales across Europe.\n\n\nRESULTS\nOver the 2 years, there were 2119 presentations to the Euro-DEN project associated with recreational use of benzodiazepines and/or Z-drugs (19.3% of all Euro-DEN presentations). Presentations with 25 different benzodiazepines and Z-drugs were registered in all countries, most (1809/2340 registered benzodiazepines and Z-drugs, 77.3%) of which were prescription drugs. In 24.9%, the benzodiazepine was not specified. Where the benzodiazepine/Z-drug was known, the most frequently used benzodiazepines and Z-drugs were respectively clonazepam (29.5% of presentations), diazepam (19.9%), alprazolam (11.7%), and zopiclone (9.4%). The proportions of types of benzodiazepines/Z-drugs related to ED-presentations varied between countries. There was a moderate (Spain, UK, Switzerland) to high (France, Ireland, Norway) positive correlation between ED presentations and sales data (Spearman Row's correlation 0.66-0.80, p < 0.005), with higher correlation in countries with higher ED presentation rates.\n\n\nCONCLUSIONS\nPresentations to the emergency department associated with the non-medical use of benzodiazepines and/or Z-drugs are common, with variation in the benzodiazepines and/or Z-drugs between countries. There was a moderate to high correlation with sales data, with higher correlation in countries with higher ED presentation rates. However, this is not the only explanation for the variation in non-medical use and in the harm associated with the non-medical use of benzodiazepines/Z-drugs.",
"affiliations": "Clinical Toxicology, Guy's and St Thomas' Hospitals NHS Foundation Trust, and King's Health Partners, London, UK. cathelijne.lyphout@uzgent.be.;Emergency Department and Clinical Toxicology Unit, Hospital Universitari Son Espases, Mallorca, Spain.;Denver Health Rocky Mountain Poison & Drug Center, Denver, USA.;Clinical Toxicology, Guy's and St Thomas' Hospitals NHS Foundation Trust, and King's Health Partners, London, UK.;Clinical Toxicology, Guy's and St Thomas' Hospitals NHS Foundation Trust, and King's Health Partners, London, UK.;The National CBRNe Centre of Medicine, Department of Acute Medicine, Medical Division, Oslo University Hospital, Oslo, Norway.;The National CBRNe Centre of Medicine, Department of Acute Medicine, Medical Division, Oslo University Hospital, Oslo, Norway.;European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), Lisbon, Portugal.;Denver Health Rocky Mountain Poison & Drug Center, Denver, USA.;Denver Health Rocky Mountain Poison & Drug Center, Denver, USA.;Clinical Toxicology, Guy's and St Thomas' Hospitals NHS Foundation Trust, and King's Health Partners, London, UK.",
"authors": "Lyphout|C|C|http://orcid.org/0000-0001-8758-7972;Yates|C|C|;Margolin|Z R|ZR|;Dargan|P I|PI|;Dines|A M|AM|;Heyerdahl|F|F|;Hovda|K E|KE|;Giraudon|I|I|;Bucher-Bartelson|B|B|;Green|J L|JL|;|||;Wood|D M|DM|",
"chemical_list": "D053961:Azabicyclo Compounds; D006993:Hypnotics and Sedatives; D010879:Piperazines; C515050:zopiclone; D001569:Benzodiazepines; D000077334:Zolpidem",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-018-2550-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-6970",
"issue": "75(1)",
"journal": "European journal of clinical pharmacology",
"keywords": "Acute toxicity; Benzodiazepine; Emergency department; Euro-DEN; Prescription; Z-drug",
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D053961:Azabicyclo Compounds; D001569:Benzodiazepines; D004636:Emergency Service, Hospital; D005060:Europe; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D063487:Prescription Drug Misuse; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D055815:Young Adult; D000077334:Zolpidem",
"nlm_unique_id": "1256165",
"other_id": null,
"pages": "77-85",
"pmc": null,
"pmid": "30244371",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": "11219371;12369472;12826989;18004131;18174009;18295321;1980692;1981067;22572594;22581465;22673201;22857878;23404347;23770646;24837585;25052878;25061118;25107312;25361166;25587948;26503789;3487931",
"title": "Presentations to the emergency department with non-medical use of benzodiazepines and Z-drugs: profiling and relation to sales data.",
"title_normalized": "presentations to the emergency department with non medical use of benzodiazepines and z drugs profiling and relation to sales data"
} | [
{
"companynumb": "PHHY2019GB092201",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "Allogeneic stem cell transplantation is a treatment option for patients with poor risk CLL. We conducted a retrospective analysis of all CLL patients allografted at our institution, the University Hospital of Cologne, Germany. Data was collected on 40 patients from 2004 to 2012. The mean age was 54, and the majority were male (75 %). On average, the patients were diagnosed 6 years (range 2-12) prior to transplant with an average of 4 years (range 1-8) from time of first-line therapy to transplant. The remission states at the time of transplant were complete remission (CR) (n = 4), stable disease (n = 10), partial remission (n = 20) and progressive disease (n = 6). Only reduced intensity conditioning regimens were employed. The average CD34(+) cell dose was 4.16 × 10(6)/kg. Neutrophil engraftment was seen by day +17 (range 10-23) post-transplant, and 88 % achieved 95-100 % donor chimerism by day 100. Overall survival, progression-free survival and non-relapse mortality at 2 years post-transplant were 65, 52.5 and 27.5 %, respectively. A total of 51 % of patients were found to be minimal residual disease (MRD)-negative at 1 year post-transplant. Our single-centre experience confirms the valuable role of allogeneic stem cell transplantation (allo-SCT) in the treatment of poor risk CLL patients with promising long-term survival and acceptable transplant-related mortality. The advent of newer therapeutic agents should not hinder the consideration of allo-SCT for this patient cohort as it remains the only curative option for these patients.",
"affiliations": "Stem Cell Transplantation Program, Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany, geothy.chakupurakal@uk-koeln.de.",
"authors": "Chakupurakal|G|G|;Leitzke|S|S|;Langerbeins|P|P|;Schiller|J|J|;Schneider|P M|PM|;Holtick|U|U|;Shimabukuro-Vornhagen|A|A|;Theurich|S|S|;Chemnitz|J|J|;Hallek|M|M|;von Bergwelt-Baildon|M|M|;Scheid|C|C|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-015-2449-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "94(10)",
"journal": "Annals of hematology",
"keywords": null,
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D009017:Morbidity; D009026:Mortality; D012189:Retrospective Studies; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1717-25",
"pmc": null,
"pmid": "26259502",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Nonmyeloablative allogeneic stem cell transplantation for chronic lymphocytic leukaemia offers the possibility of disease control with minimal morbidity and mortality--a single institution experience.",
"title_normalized": "nonmyeloablative allogeneic stem cell transplantation for chronic lymphocytic leukaemia offers the possibility of disease control with minimal morbidity and mortality a single institution experience"
} | [
{
"companynumb": "DE-CELGENE-DEU-2015096394",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OFATUMUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Burning mouth syndrome is a chronic pain condition characterized by a burning sensation of the oropharynx. The pathophysiology of burning mouth syndrome includes peripheral and central sensitization. Treatment is generally aimed at symptom reduction. We describe a woman in her seventh decade with burning mouth syndrome that had been refractory to treatment for nearly a decade. Low-dose naltrexone has been reported to provide analgesia in central sensitization states and was successful in reducing pain severity in our patient. We conclude that low-dose naltrexone may be a therapeutic option for patients with burning mouth syndrome who are refractory to conventional therapies.",
"affiliations": "From the Department of Anesthesiology, University of Kansas Medical Center, Kansas City, Kansas.",
"authors": "Neuman|Daniel L|DL|;Chadwick|Andrea L|AL|",
"chemical_list": "D009271:Naltrexone",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000001475",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "15(5)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000698:Analgesia; D002054:Burning Mouth Syndrome; D005260:Female; D006801:Humans; D009271:Naltrexone; D010146:Pain; D059408:Pain Management",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "e01475",
"pmc": null,
"pmid": "33999864",
"pubdate": "2021-05-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8657425;19837031;30248938;27121358;19453963;28536359;25210377;7616460;29487504;25713611;24737367;25992157;24526250;29180911;30189984",
"title": "Utilization of Low-Dose Naltrexone for Burning Mouth Syndrome: A Case Report.",
"title_normalized": "utilization of low dose naltrexone for burning mouth syndrome a case report"
} | [
{
"companynumb": "US-APOTEX-2021AP041794",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ZOLPIDEM TARTRATE"
},
"drugadditional": null,
... |
{
"abstract": "Nocardiosis is a rare infection caused by ubiquitous soil-born, acid-resistant, Gram-positive bacteria that can be life-threatening in immunocompromised patients. Originally usually diagnosed in HIV-positive patients, only few cases have been reported in patients on immunosuppressive therapy for inflammatory bowel disease or rheumatologic disorders. We present a case of a 32-year-old man who was treated with infliximab, prednisolone, and azathioprine for severe terminal ileitis. Although the clinical status improved under triple immunosuppressive therapy, weight loss, weakness, and fatigue persisted. Laboratory studies revealed iron deficiency anemia, hypalbuminemia and raised inflammatory markers. Chest computed tomography scan showed multiple pulmonary nodules and a large cavity in the left upper lobe (segment 3a). Empiric tuberculostatic therapy was introduced for suspected miliary tuberculosis but stopped for lack of clinical improvement and negative tuberculosis tests (interferon-gamma release assay, microscopy, polymerase chain reaction). Finally, the diagnosis of pulmonary nocardiosis with concomitant pulmonary Mycobacterium avium infection was confirmed microbiologically, and the patient was treated with high-dose co-trimoxazole, clarithromycin, ethambutol, and rifampicin for 12 months.This case report underlines the increased risk of severe and rare infections like nocardiosis with combination immunosuppressive therapy and the necessity for thorough diagnostic screening for opportunistic infection. Although long-term antibiotic treatment for nocardiosis is mandatory, the optimal timing to restart immunosuppressive therapy remains ambiguous.",
"affiliations": "Jena University Hospital, Dept. Internal Medicine IV.;Jena University Hospital, Dept. Internal Medicine IV.;Jena University Hospital, Dept. Internal Medicine IV.;Jena University Hospital, Center for Infectious Diseases and Control.;Jena University Hospital, Dept. Internal Medicine IV.",
"authors": "Weber|Marko|M|;Rüddel|Jessica|J|;Bruns|Tony|T|;Pletz|Mathias W|MW|;Stallmach|Andreas|A|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/a-0614-2871",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0044-2771",
"issue": "56(6)",
"journal": "Zeitschrift fur Gastroenterologie",
"keywords": null,
"medline_ta": "Z Gastroenterol",
"mesh_terms": "D000328:Adult; D060085:Coinfection; D003424:Crohn Disease; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D008297:Male; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection; D009615:Nocardia; D009617:Nocardia Infections; D009170:Nontuberculous Mycobacteria; D014391:Tuberculosis, Miliary; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "0033370",
"other_id": null,
"pages": "569-572",
"pmc": null,
"pmid": "29890558",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pulmonary co-infection with nocardia species and nontuberculous mycobacteria mimicking miliary tuberculosis in a patient with Crohn's disease under combined immunosuppressive therapy.",
"title_normalized": "pulmonary co infection with nocardia species and nontuberculous mycobacteria mimicking miliary tuberculosis in a patient with crohn s disease under combined immunosuppressive therapy"
} | [
{
"companynumb": "DE-JNJFOC-20180706545",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "1",
"... |
{
"abstract": "BACKGROUND\nRare sites of metastases, atypical symptoms and paraneoplastic syndromes are often neglected or misinterpreted, especially when they represent early symptoms of an underlying malignant disease. Hence, an interdisciplinary approach to these patients is essential to avoid tumor progression and metastatic spread in order to provide curative treatment options to the patients. We here report the case of a young woman presenting with visual loss which led to diagnosis of a thymic carcinoma.\n\n\nMETHODS\nA 28-year old white woman presented with subacute loss of vision in the last trimester of her first pregnancy which was first interpreted as an exacerbation of a pre-existing dermatomyositis and treated with steroids. After failure of steroid therapy choroidal metastases from an undifferentiated thymic carcinoma were diagnosed. This also shed a new light on the dermatomyositis the patient had been suffering from for seven years possibly representing a paraneoplastic syndrome from the tumor. Despite aggressive chemotherapy, the patient died from progressive disease eight years after first onset of dermatomyositis and 14 months after initial diagnosis of the thymic carcinoma.\n\n\nCONCLUSIONS\nChoroidal metastases from a thymic carcinoma have never been reported before but should be included into the differential diagnosis of choroidal masses.",
"affiliations": "Medizinische Universitaetsklinik Tuebingen, Innere Medizin II fuer Onkologie, Haematologie, Immunologie, Rheumatologie und Pulmologie, Otfried Mueller Str. 10, D-72076, Tuebingen, Germany. sebastian.haen@med.uni-tuebingen.de.;Pathologisches Institut, Universitaetsmedizin Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167, Mannheim, Germany. philipp.stroebel@med.uni-goettingen.de.;Pathologisches Institut, Universitaetsmedizin Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167, Mannheim, Germany. alexander.marx@umm.de.;Departement fuer Augenheilkunde, Universitaetsklinikum Tuebingen, Schleichstr. 12, D-72076, Tuebingen, Germany. daniela.suesskind@med.uni-tuebingen.de.;Institut fuer Pathologie, Abteilung fuer Allgemeine Pathologie und Pathologische Anatomie, Universitaetsklinikum Tuebingen, Liebermeisterstr. 8, D-72076, Tuebingen, Germany. falko.fend@med.uni-tuebingen.de.;Radioonkologische Klinik, Universitaetsklinikum Tuebingen, Hoppe-Seyler-Str. 3, D-72076, Tuebingen, Germany. reichmann@strahlentherapie-fn.de.;Medizinische Universitaetsklinik Tuebingen, Innere Medizin II fuer Onkologie, Haematologie, Immunologie, Rheumatologie und Pulmologie, Otfried Mueller Str. 10, D-72076, Tuebingen, Germany. hans-georg.kopp@med.uni-tuebingen.de.;Medizinische Universitaetsklinik Tuebingen, Innere Medizin II fuer Onkologie, Haematologie, Immunologie, Rheumatologie und Pulmologie, Otfried Mueller Str. 10, D-72076, Tuebingen, Germany. lothar.kanz@med.uni-tuebingen.de.;Medizinische Universitaetsklinik Tuebingen, Innere Medizin II fuer Onkologie, Haematologie, Immunologie, Rheumatologie und Pulmologie, Otfried Mueller Str. 10, D-72076, Tuebingen, Germany. frank.mayer@med.uni-tuebingen.de.",
"authors": "Haen|Sebastian P|SP|;Stroebel|Philipp|P|;Marx|Alexander|A|;Suesskind|Daniela|D|;Fend|Falko|F|;Reichmann|Ursula|U|;Kopp|Hans-Georg|HG|;Kanz|Lothar|L|;Mayer|Frank|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12885-015-1968-4",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 26675671196810.1186/s12885-015-1968-4Case ReportChoroidal metastases from thymic carcinoma during pregnancy: Case Report Haen Sebastian P. sebastian.haen@med.uni-tuebingen.de 12Stroebel Philipp philipp.stroebel@med.uni-goettingen.de 34Marx Alexander alexander.marx@umm.de 3Suesskind Daniela daniela.suesskind@med.uni-tuebingen.de 5Fend Falko falko.fend@med.uni-tuebingen.de 6Reichmann Ursula reichmann@strahlentherapie-fn.de 7Kopp Hans-Georg hans-georg.kopp@med.uni-tuebingen.de 1Kanz Lothar lothar.kanz@med.uni-tuebingen.de 1Mayer Frank frank.mayer@med.uni-tuebingen.de 11 Medizinische Universitaetsklinik Tuebingen, Innere Medizin II fuer Onkologie, Haematologie, Immunologie, Rheumatologie und Pulmologie, Otfried Mueller Str. 10, D-72076 Tuebingen, Germany 2 Interfakultaeres Institut fuer Zellbiologie, Abteilung Immunologie, Auf der Morgenstelle 15, D-72076 Tuebingen, Germany 3 Pathologisches Institut, Universitaetsmedizin Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany 4 Institut fuer Pathologie, Universitaetsmedizin Goettingen, Robert-Koch-Str. 40, D-37075 Goettingen, Germany 5 Departement fuer Augenheilkunde, Universitaetsklinikum Tuebingen, Schleichstr. 12, D-72076 Tuebingen, Germany 6 Institut fuer Pathologie, Abteilung fuer Allgemeine Pathologie und Pathologische Anatomie, Universitaetsklinikum Tuebingen, Liebermeisterstr. 8, D-72076 Tuebingen, Germany 7 Radioonkologische Klinik, Universitaetsklinikum Tuebingen, Hoppe-Seyler-Str. 3, D-72076 Tuebingen, Germany 16 12 2015 16 12 2015 2015 15 97220 4 2015 1 12 2015 © Haen et al. 2015Open 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\nRare sites of metastases, atypical symptoms and paraneoplastic syndromes are often neglected or misinterpreted, especially when they represent early symptoms of an underlying malignant disease. Hence, an interdisciplinary approach to these patients is essential to avoid tumor progression and metastatic spread in order to provide curative treatment options to the patients. We here report the case of a young woman presenting with visual loss which led to diagnosis of a thymic carcinoma.\n\nCase presentation\nA 28-year old white woman presented with subacute loss of vision in the last trimester of her first pregnancy which was first interpreted as an exacerbation of a pre-existing dermatomyositis and treated with steroids. After failure of steroid therapy choroidal metastases from an undifferentiated thymic carcinoma were diagnosed. This also shed a new light on the dermatomyositis the patient had been suffering from for seven years possibly representing a paraneoplastic syndrome from the tumor. Despite aggressive chemotherapy, the patient died from progressive disease eight years after first onset of dermatomyositis and 14 months after initial diagnosis of the thymic carcinoma.\n\nConclusions\nChoroidal metastases from a thymic carcinoma have never been reported before but should be included into the differential diagnosis of choroidal masses.\n\nKeywords\nThymic carcinomaUveal metastasisDermatomyositisissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nPrimary thymic carcinomas are rare tumors accounting for 7-25 % of all neoplasms of the thymus [1]. They are distinguished from the more frequent thymomas based on their different morphology and biology [2, 3]. Due to frequent invasion of pericardium or pleural space and metastatic spread, their prognosis is generally poor [4] with median survival times for patients with irresectable disease of 13 months [5]. Thymic carcinomas differ from thymomas also with respect to associated paraneoplastic autoimmune diseases. Thymomas are frequently associated with characteristic autoimmune phenomena like myasthenia gravis or pure red cell aplasia, which normally do not occur in thymic carcinomas. However, sporadic cases of polymyositis or hypercalcemia have been encountered in the latter [6–8].\n\nChoroidal metastases are exceedingly rare. They can occasionally cause symptoms leading to the primary diagnosis of other tumors like lung and breast cancers, as well as melanoma [9, 10]. However, in most patients the underlying diseases are already diagnosed, and choroidal metastases represent late symptoms of the disease [10].\n\nWith the permission of the kin of the patient, we here report a case in which the presentation with visual loss resulted in the diagnosis of a thymic carcinoma which had not been found during earlier examinations.\n\nCase presentation\nA 28-year old white woman presented with distinct deterioration of visual acuity during the last trimester of her first pregnancy. Her vision decreased to 20/40 in the left and 20/400 in the right eye. In the beginning, the visual loss occurred intermittently, but worsened over time. In addition, the patient complained about flickering. During the worst episodes she could only see contours with a vague discrimination of light. Simultaneously, symptoms of a dermatomyositis, which had been diagnosed and successfully treated several years earlier, reappeared. At that time, the diagnosis of dermatomyositis had been confirmed by skin biopsy. An extensive workup to rule out an underlying malignancy had then not revealed any suspicious results. However, a CT scan had not been performed. The patient subsequently had received several immunosuppressive treatments including azathioprine, methotrexate and adalimumab, as well as immunoglobulins and steroids resulting in a long-lasting remission of the dermatomyositis.\n\nThe decrease in visual acuity occurred isochronal with another exacerbation of skin symptoms and was therefore initially interpreted as a manifestation of the reappearing dermatomyositis and treated with steroids since also initial ophthalmologic workup did not reveal pathological results. After failure of immunosuppressive therapy, repeated ophthalmologic examination revealed an amelanotic choroidal mass at the posterior pole including the peripapillary region and a second choroidal lesion superior to the optic disc in the right eye. Also, in the left eye another amelanotic choroidal tumor situated predominantly nasal superior to the optic disc was detected. In both eyes, an inferior exsudative retinal detachment was seen (Fig. 1a and b). Finally, a large tumor mass in the mediastinum, pleural thickening and pulmonary nodules as well as a mediastinal lymphadenopathy were detected in MRI scans. CT scans were not performed because of the actual pregnancy. After delivery of a healthy boy at the 37th + 2 week of pregnancy through Caesarean section, a lung and pleural biopsy was performed by lateral thoracotomy and the patient was referred to our center for further treatment.Fig. 1 Diagnostic evaluation. a and b Composite color fundus photographs of both eyes showing the amelanotic choroidal lesions (arrows) at the posterior pole of the right eye (a) and predominantly nasal superior to the optic disc in the left eye (b). c and d Radiographic imaging. CT scan of the chest (c). Note the large mediastinal mass with pleural spreading. MRI scan of the orbits (d). The arrow marks the choroidal lesion. e and f Histological appearance of the undifferentiated thymic carcinoma (400-fold magnification). The H&E stain (e) shows compact nests of undifferentiated epithelial cells with narrow cytoplasm without evidence of keratinization, large vesicular nuclei and high mitotic rate, separated by broad collagen bands (immunostaining for CD5). The tumor cells show a strong expression of CD5 (f) characteristic for an undifferentiated thymic carcinoma\n\n\n\nThe clinical examination showed a 28-year old woman in proper general condition. Her skin was reddish and thickened with distinct flaking. The examination of the heart, lungs and abdomen did not reveal any pathologic results. Decreased visual acuity was noted in both eyes. Additionally, the patient complained about paraesthesia with tickling in both feet. Other neurological symptoms were not detectable.\n\nLaboratory testing revealed a slightly increased creatine kinase (193 U/l, normal up to 170 U/l), an elevated C-reactive protein (2.77 mg/dl, normal up to 0.5 mg/dl), anemia with haemoglobin of 9.8 g/dl, elevated uric acid levels of 6.5 mg/dl (reference range 2.4 to 5.7 mg/dl) and a significantly increased lactate dehydrogenase of 959 U/l (normal up to 250 U/l) as well as thrombocytosis of 789 G/μl (normal up to 450 G/μl).\n\nWhole body CT and MRI scans showed metastases to the choroids, pleura and regional lymph nodes (Fig. 1b and c). The lung biopsy revealed a poorly differentiated carcinoma with strong expression of cytokeratins 5/6, CD5 and CD117 and absence of neuroendocrine markers (CD56; chromogranin, synaptophysin), a constellation highly specific for thymic carcinomas (Fig. 1e and f). A lymphoepithelioma-like thymic carcinoma was ruled out by negative EBV in situ hybridization. In addition, a thymic carcinoma with t (15;19) translocation was likewise ruled out by specific real-time polymerase chain reaction (RT-PCR), which failed to demonstrate a BRD4-NUT gene fusion product. Thus a final diagnosis of an undifferentiated thymic carcinoma was established. The tumor at initial diagnosis presented in stage IVb (T4, N2 (hilar lymph nodes), M1b (pleura, lung, choroid)) [11, 12].\n\nThymic carcinomas are often moderately differentiated squamous cell carcinomas histologically resembling the appearance of squamous cell carcinomas elsewhere in the body, e.g. the lung [13, 14]. In our patient, one potential differential diagnosis was the lymphocyte poor EBV-associated lymphoepithelioma-like carcinoma, an aggressive tumor with a poor prognosis [15, 16]. However, EBV association was ruled out by in situ hybridisation. Another differential diagnosis in young adults with a rapidly progressive carcinoma is the so-called thymic carcinoma with t (15; 19) translocation, which is associated with a fatal prognosis, including rapid local invasion and systemic dissemination [17–20]. In our case, this diagnosis could also be ruled out, since the BRD4-NUT fusion gene transcript resulting from this chromosomal translocation could not be detected. Hence, a final diagnosis of a high grade, poorly differentiated thymic carcinoma was established by exclusion of other possible subtypes of primary thymic carcinomas.\n\nClassical metastatic spread patterns of thymic carcinoma comprise regional anterior perithymic, deep intrathoracic and cervical lymph nodes, as well as the pleura, the pericardium and the lung [12]. Extrathoracic organ metastases mainly affect the liver and the kidney, but may also involve the bones [4, 21–24]. Also one case of orbit metastases from a neuroendocrine thymic carcinoma was reported [25].\n\nTo our knowledge, our patient represents the first case of choroidal metastases from thymic carcinoma. Although choroidal metastases are generally rare (e.g. about 5-10 % in breast and lung carcinoma patients, respectively [26, 27]), the choroid represents the most common ocular site for metastatic disease (up to 88 % of secondary ocular tumors) which is due to hematogenenous dissemination into abundant choroidal vasculature [9, 28, 29]. The most common primary tumors presenting with choroidal metastases are breast (40-53 %) [9, 26, 30–32] and lung carcinoma (20-29 %) [9, 30, 33] but may also include tumors (2-4 % each) from the gastrointestinal tract, the kidney, the prostate and the skin [9, 30, 34–39], as well as carcinoid tumors of different localisation including one reported case of a thymic carcinoid [40]. Evidence for choroidal metastases from other tumors has emerged in recents years. These observations are mainly limited to single case reports and comprise metastases from malignancies of the thyroid [29, 41–45], the urogenital tract [46–49], the pancreas [50, 51], salivary glands [52, 53], and the chorion [54], as well as sarcomas [55, 56].\n\nIn our patient, fractioned radiation therapy of the orbits with a cumulative dose of 30 Gy (10 × 3 Gy) using opposite, coplanar and coaxial fields in an isocentric adjustment with 6 MV photons was performed and resulted in regression of the choroidal metastases and an improvement of visual acuity from 20/400 to 20/40 in the right eye and from 20/40 to 20/16 in the left eye resulting in reconstitution of reading ability. Afterwards, chemotherapy with Cisplatin (75 mg/m2) and Paclitaxel (175 mg/m2) was initiated as a t (15; 19)-positive carcinoma was still assumed at that time. Due to the rapid clinical response, this treatment was continued for a total of six cycles after receiving the final pathology report. After four cycles, a good partial response was observed in CT scan. However, progressive disease was evident in the staging after six cycles. The regime was then changed to a modified PAC-scheme (Carboplatin AUC5 instead of cisplatin because of a suspected paclitaxel-induced peripheral polyneuropathy CTC grade 1, Doxorubicin 50 mg/m2 and Cyclophosphamide 500 mg/m2). Nevertheless, the tumor progressed further, and the patient died of progressive disease in respiratory insufficiency eight years after first manifestation of the dermatomyositis and fourteen months after primary diagnosis. The median overall survival of patients with undifferentiated thymic carcinoma has been reported to be about six months [57].\n\nRetrospectively, the pre-existing dermatomyositis might have represented the first symptom of an at that time clinically occult tumor. The association between the epithelial thymic carcinoma and the dermatomyositis in this case could not be totally proven but such an association has been reported in some cases of thymomas [58], but appears to be extremely rare in thymic carcinomas with only two reports in the literature [59, 60].\n\nConclusions\nOur case demonstrates that thymic carcinomas should be included into the differential diagnosis in cases with choroidal metastases and with dermatomyositis and no detectable tumor, especially in young adults. To our knowledge, this is the first case of a thymic carcinoma with highly aggressive and fatal course and atypical clinical presentation with choroidal metastases.\n\nConsent\nWritten informed consent was obtained from the patient’s relatives for publication of this case report and the accompanying images. A copy of the written informed consent is available for review by the Editor-in-Chief upon request.\n\nAbbreviations\nBRDbromodomain-containing protein\n\nCDcluster of differentiation\n\nCTcomputed tomography\n\nEBVepstein barr virus\n\nHEhematoxylin eosin\n\nMRImagnetic resonance imaging\n\nMVmegavolt\n\nNUTnuclear protein in testis\n\nPACplatinum adriamycin cyclophosphamide\n\nRT-PCRreal-time polymerase chain reaction\n\nCompeting interests\n\nThe authors declare that they have no competing interests to disclose.\n\nAuthors’ contributions\n\nSPH: Acquisition of data, analysis and interpretation of data, corresponding author, drafting and critical revision of the article. PS: Acquisition of data, analysis and interpretation of data, critical revision of the article. AM: Acquisition of data, analysis and interpretation of data, critical revision of the article. DS: Acquisition of data, analysis and interpretation of data, critical revision of the article. FF: Acquisition of data, analysis and interpretation of data, critical revision of the article. UR: Acquisition of data, analysis and interpretation of data, critical revision of the article. HGK: Acquisition of data, analysis and interpretation of data, critical revision of the article. LK: Acquisition of data, analysis and interpretation of data, supervision of the study, critical revision of the article. FM: Conception and design, acquisition of data, analysis and interpretation of data, supervision of the study, critical revision of the article. All authors read and approved the submitted version of the article.\n\nAcknowledgements\nSebastian P. Haen is supported by the Deutsche José Carreras Leukemia Foundation (Grant-No. DJS 08/04). The authors wish to thank Lynne Yakes for editorial assistance.\n\nFunding\nSebastian P. Haen was supported by the Deutsche José Carreras Leukemia Foundation (Grant-No. DJS 08/04).\n==== Refs\nReferences\n1. 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Bilgin AB Apaydin KC Unal M Ilhan HD Turkoglu EB Aydin N A case report of bilateral choroidal metastases of epithelial carcinoma of pancreas Arq Bras Oftalmol 2014 77 259 60 10.5935/0004-2749.20140065 25410180 \n52. Shields JA Carvalho C Shields CL Singh AD Wagner D Bilateral choroidal metastasis from adenoid cystic carcinoma of the submandibular gland Retina 2000 20 406 7 10.1097/00006982-200004000-00018 10950424 \n53. Walls G Napier S Stewart D Visual impairment due to bilateral multifocal choroidal metastasis of parotid adenocarcinoma: a case report Front Oncol 2014 4 136 10.3389/fonc.2014.00136 24926438 \n54. Hazan A Katz MS Leder H Blace N Szlechter M Choroidal metastases of choriocarcinoma Retin Cases Brief Rep 2014 8 95 6 10.1097/ICB.0000000000000012 25372318 \n55. Krema H McGowan H Tanzer H Simpson R Laperriere N Unusual orange-colored choroidal metastases J Ophthalmic Vis Res 2013 8 53 7 23825713 \n56. Cristina NG Francisco ED Vanesa RG Fernando CG Luis CM Emiliano HG Choroidal metastasis from primary bone leiomyosarcoma Int Ophthalmol 2015 35 721 5 10.1007/s10792-015-0096-0 26109142 \n57. Lin JT Wei-Shu W Yen CC Liu JH Chen PM Chiou TJ Stage IV thymic carcinoma: a study of 20 patients Am J Med Sci 2005 330 172 5 10.1097/00000441-200510000-00004 16234609 \n58. Ago T Nakamura M Iwata I Murai H Okuma K Tsuru T Dermatomyositis associated with invasive thymoma Intern Med 1999 38 155 9 10.2169/internalmedicine.38.155 10225672 \n59. Fong PH Wee A Chan HL Tan YO Primary thymic carcinoma and its association with dermatomyositis and pure red cell aplasia Int J Dermatol 1992 31 426 8 10.1111/j.1365-4362.1992.tb02675.x 1512098 \n60. Takahashi F Tsuta K Nagaoka T Miyamoto H Saito Y Amano H Successful resection of dermatomyositis associated with thymic carcinoma: report of a case Surg Today 2008 38 245 8 10.1007/s00595-007-3601-x 18306999\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "15()",
"journal": "BMC cancer",
"keywords": null,
"medline_ta": "BMC Cancer",
"mesh_terms": "D000328:Adult; D002830:Choroid Neoplasms; D003882:Dermatomyositis; D005260:Female; D006801:Humans; D010257:Paraneoplastic Syndromes; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D013945:Thymoma; D013953:Thymus Neoplasms; D014786:Vision Disorders",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "972",
"pmc": null,
"pmid": "26675671",
"pubdate": "2015-12-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23082768;12796605;14991904;19506156;26179536;10225672;8944040;23988200;18514123;2065283;23538460;16234609;8374886;2040007;25114878;23730117;24744926;21435886;25396317;25771814;12208262;2985993;22425924;15531474;26109142;1991250;25460493;24767240;25153655;19347264;1512098;2835144;12549639;9850173;25410180;9261313;15296905;25794021;8008351;12888048;24449136;23969474;8467458;10950424;4412321;25372318;8302083;18306999;24926438;25431734;15283186;8044305;18314613;25827542;23133771;25872533;8814741;9924304;23825713",
"title": "Choroidal metastases from thymic carcinoma during pregnancy: Case Report.",
"title_normalized": "choroidal metastases from thymic carcinoma during pregnancy case report"
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"abstract": "High-dose (HD) chemotherapy with melphalan and autologous blood stem cell transplantation (ABSCT) for treatment of symptomatic multiple myeloma (MM) on an outpatient basis has been well established in the USA and Canada, whereas in Germany and Western Europe an inpatient setting is the current standard. We report on a German single-centre program to offer the procedure on an outpatient basis to selected patients.\n\n\n\nMajor requirements included: patients had to have family and/or other caregivers, had to be able to reach the hospital within 45 min and have an ECOG performance score of 0-1. Patients with severe co-morbidities were not included.\n\n\n\nFrom September 2012 until April 2016, 21 patients with MM stage IIIA were enrolled. All engrafted within the expected time range (median 14 days), and no severe adverse events occurred. 14 patients (67%) had an episode of neutropenic fever and blood cultures were positive in 4 patients (19%). Although rather liberal criteria for hospital admission were applied, 14 patients (67%) were treated entirely on an outpatient basis.\n\n\n\nHD chemotherapy and ABSCT on an outpatient basis is safe and feasible if it is conducted in an elaborate surveillance program. The feedback from patients was very positive, thus encouraging further expansion of the program.",
"affiliations": "Department of Medicine V, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.;Department of Medicine V, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.;Institute of Medical Biometry und Informatics, Heidelberg University, Marsilius Arkaden 130.3, 69120, Heidelberg, Germany.;Department of Medicine V, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.;Department of Medicine V, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.;Department of Medicine V, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.;Department of Medicine V, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.;Department of Medicine V, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.;Department of Medicine V, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.;Department of Medicine V, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.;Department of Medicine V, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. patrick.wuchter@medma.uni-heidelberg.de.",
"authors": "Lisenko|Katharina|K|;Sauer|Sandra|S|;Bruckner|Thomas|T|;Egerer|Gerlinde|G|;Goldschmidt|Hartmut|H|;Hillengass|Jens|J|;Schmier|Johann W|JW|;Shah|Sofia|S|;Witzens-Harig|Mathias|M|;Ho|Anthony D|AD|;Wuchter|Patrick|P|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan",
"country": "England",
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"doi": "10.1186/s12885-017-3137-4",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 313710.1186/s12885-017-3137-4Research ArticleHigh-dose chemotherapy and autologous stem cell transplantation of patients with multiple myeloma in an outpatient setting Lisenko Katharina katharina.lisenko@med.uni-heidelberg.de 1Sauer Sandra sandra.sauer@med.uni-heidelberg.de 1Bruckner Thomas bruckner@imbi.uni-heidelberg.de 2Egerer Gerlinde gerlinde.egerer@med.uni-heidelberg.de 1Goldschmidt Hartmut hartmut.goldschmidt@med.uni-heidelberg.de 13Hillengass Jens jens.hillengass@med.uni-heidelberg.de 1Schmier Johann W. johann.schmier@med.uni-heidelberg.de 1Shah Sofia sofia.shah@med.uni-heidelberg.de 1Witzens-Harig Mathias mathias.witzens-harig@med.uni-heidelberg.de 1Ho Anthony D. anthony_dick.ho@urz.uni-heidelberg.de 1Wuchter Patrick +49 621 3706807patrick.wuchter@medma.uni-heidelberg.de 141 0000 0001 2190 4373grid.7700.0Department of Medicine V, Heidelberg University, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany 2 0000 0001 2190 4373grid.7700.0Institute of Medical Biometry und Informatics, Heidelberg University, Marsilius Arkaden 130.3, 69120 Heidelberg, Germany 3 0000 0001 0328 4908grid.5253.1National Center for Tumor Diseases Heidelberg (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany 4 0000 0001 2190 4373grid.7700.0Institute of Transfusion Medicine and Immunology, German Red Cross Blood Service Baden-Württemberg—Hessen, Medical Faculty Mannheim, Heidelberg University, Friedrich-Ebert-Straße 107, 68167 Mannheim, Germany 22 2 2017 22 2 2017 2017 17 15118 7 2016 15 2 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nHigh-dose (HD) chemotherapy with melphalan and autologous blood stem cell transplantation (ABSCT) for treatment of symptomatic multiple myeloma (MM) on an outpatient basis has been well established in the USA and Canada, whereas in Germany and Western Europe an inpatient setting is the current standard. We report on a German single-centre program to offer the procedure on an outpatient basis to selected patients.\n\nMethods\nMajor requirements included: patients had to have family and/or other caregivers, had to be able to reach the hospital within 45 min and have an ECOG performance score of 0–1. Patients with severe co-morbidities were not included.\n\nResults\nFrom September 2012 until April 2016, 21 patients with MM stage IIIA were enrolled. All engrafted within the expected time range (median 14 days), and no severe adverse events occurred. 14 patients (67%) had an episode of neutropenic fever and blood cultures were positive in 4 patients (19%). Although rather liberal criteria for hospital admission were applied, 14 patients (67%) were treated entirely on an outpatient basis.\n\nConclusions\nHD chemotherapy and ABSCT on an outpatient basis is safe and feasible if it is conducted in an elaborate surveillance program. The feedback from patients was very positive, thus encouraging further expansion of the program.\n\nKeywords\nMultiple myelomaAutologous blood stem cell transplantationHigh-dose chemotherapyOutpatient settingOutpatient supportive careissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nHigh-dose (HD) chemotherapy and autologous blood stem cell transplantation (ABSCT) is a standard of care in transplant eligible patients with multiple myeloma (MM) and a variety of malignant diseases [1–4]. Initially established as a single ABSCT in newly diagnosed MM, subsequent trials have shown the benefit of a tandem ABSCT in overall survival, particularly in those patients who do not reach at least a very good partial remission after the first autograft [5–8]. Moreover, HD chemotherapy and ABSCT is also an effective treatment option for relapse MM patients [9–11].\n\nMM patients undergoing HD chemotherapy and ABSCT have traditionally been admitted to the hospital for several weeks. With the increasing ABSCT experience of the transplanting centres, the patients’ wish for a shorter stay in the hospital, increasing number of nosocomial infections and growing economic pressure, particularly in view of increasing absolute numbers of ABSCTs in Europe during the last decade [12], there is a clear trend towards outpatient treatment. The experience from performing HD chemotherapy and ABSCT in an outpatient setting in the late 1990s has indicated a high degree of safety, feasibility, cost saving and patient satisfaction [13–16]. Although it has been well established in the United States of America [17–19] and Canada [20, 21], only single reports on outpatient HD chemotherapy and ABSCT in Europe are available [22, 23]. To the best of our knowledge, the outpatient treatment option has not been established as a routine in a transplant centre in Germany so far.\n\nSince 2012, we have performed HD chemotherapy and ABSCT on an outpatient basis in individually selected MM patients within an elaborated program. Currently, this outpatient ABSCT program is being extended to a higher case number, and up to 2 patients undergo this treatment in parallel at a time. This report summarizes our experience of 21 ABSCTs performed on an outpatient basis. The aim of this retrospective study is to demonstrate our approach and analyse the safety and efficacy of the program.\n\nMethods\nStudy design and data collection\nA retrospective single-centre analysis of MM patients (n = 21) who underwent HD melphalan chemotherapy and ABSCT as an outpatient between September 2012 and February 2016 at our University Hospital outpatient clinic was performed. Clinical parameters (gender, age, Eastern Cooperative Oncology Group (ECOG) score), disease stage at first diagnosis according to Salmon and Durie, type of monoclonal protein, modality of induction and mobilization therapy, peripheral blood stem cell (PBSC) collection result, remission status pre and post ABSCT, transplanted CD34+ cell number, haematological reconstitution data, toxicities and supportive interventions were assessed retrospectively.\n\nTo identify potential factors predicting the need for inpatient admission and illustrate the possible differences in toxicities and haematological reconstitution, patients were retrospectively grouped according to the necessity of hospital admission (hereafter referred to as “outpatients” and “temporary inpatients”). Retrospective data analysis was approved by the Ethics Committee of the Medical Faculty, Heidelberg University. Patients’ informed written consent was obtained.\n\nInclusion and exclusion criteria and safety issues\nThe following inclusion criteria were defined: general transplantation eligibility, age 18–70 years, ECOG performance status 0–1, implanted port catheter system or excellent peripheral vein conditions, availability of an accompanying care-taking person, availability by cell phone, transport distance from home or hotel to the outpatient clinic of ≤45 min, patient’s compliance with the given instructions and patient’s informed consent.\n\nThe exclusion criteria were defined as follows: light-chain amyloidosis, detection of antibodies to human leukocyte antigens (HLA) and/or insufficient platelet increase after platelet transfusion, insurmountable language barrier, medical complications during induction or mobilization therapy and severe comorbidities like cardiac or renal insufficiency.\n\nThere was an intention to treat all of the patients on an outpatient basis in our outpatient clinic. If indicated, a hospital admission could be arranged instantly, and patients could contact a haematologist by phone at any time. All of the patients received a detailed information brochure regarding the prevention of infection, body care, oral hygiene, diet and physical activity during aplasia.\n\nHD chemotherapy and ABSCT\nIndication and eligibility for HD melphalan and ABSCT were determined by the treating physician. All of the patients received HD melphalan (100 mg/m2, day -3 and day -2, 1 h infusion) as the conditioning regimen. The melphalan dosage was reduced by 50% due to comorbidities in one patient with refractory myeloma who had already undergone three previous courses of HD melphalan chemotherapy and ABCST. A minimum of 2.0 × 106 CD34+ cells/kg patient’s body weight was re-infused in all cases on day 0 using standard supportive therapy (500 mg acetaminophen p.o., 2 mg clemastine intravenous (i.v.), and 10 mg dihydrocodeine p.o.). No growth factors were used post-transplantation.\n\nMonitoring and Supportive Care\nMonitoring\nDuring patient monitoring visits, clinical examination, vital signs assessment (blood pressure, heart rate, body temperature, weight) and laboratory testing (blood count, electrolytes, creatinine, liver values, coagulation status and C-reactive protein) were performed daily, including weekends. All visits as well as any treatment took place in the outpatient clinic in a specified area and with staff previously introduced to the patients in order to avoid any stay in the waiting area to reduce the risk of infection. Daily visits were continued until recovery of leucocytes >1.0 × 109/L, neutrophils >0.5 × 109/L and platelets >50 × 109/L in the absence of any signs of infection.\n\nAntiemetic prophylaxis\nCompared to an antiemetic prophylaxis given in the inpatient setting [24], an intensified oral supportive medication for preventing chemotherapy-induced nausea and vomiting was administered: dexamethasone 2 to 4 mg day -3 and dexamethasone 1 to 2 mg day -2 to day -1, granisetron 2 mg days -3 to day +4, aprepitant 125 mg day -3, aprepitant 80 mg day -2 to day +2. Dimenhydrinate and/or metoclopramide p.o. were prescribed to the patients as home medication, if required. Moreover, pantoprazole 40 mg p.o. was administered once daily.\n\nHydration and prophylaxis of stomatitis\nFor all patients, 1 to 2 L of 0.9% saline solution and, depending on the serum potassium level, 10–30 mval potassium chloride were administered by i.v. daily. To prevent stomatitis, patients were strongly recommended to rinse the mouth with Caphosol® (calcium-phosphate solution) at least once per hour during their stay at the outpatient clinic and at home.\n\nNon-steroidal anti-rheumatics were avoided due to unintended fever suppression, but opioid analgesics were used for pain management, e.g. in case of stomatitis.\n\nAntiviral and antibiotic prophylaxis and treatment\nPatients received daily ciprofloxacin 2×500 mg per os (p.o.) until haematological reconstitution and aciclovir 2×400 mg p.o. for 6 months after ABSCT. In case of fever (>38.3 °C), an empirical antibiotic treatment with 1 g ertapenem i.v. per 24 h was initiated. Blood cultures were obtained and further diagnostic tests including imaging techniques were performed if necessary. At the discretion of the treating physician, the empirical i.v. antibiotic therapy was initiated in some cases at subfebrile temperatures when C-reactive protein (CRP) elevation was observed. In case of persisting fever >72 h, antibiotic therapy was substituted by i.v. 3x piperacillin 4 g/tazobactam 0.5 g per 24 h, and the patient was admitted to the hospital. Intravenous antibiotic therapy was continued until the fifth day without fever or haematological reconstitution.\n\nCriteria for inpatient admission and discharge\nRounds were conducted daily, and the patient’s clinical status was evaluated by the treating physician. In alignment with previously published policies of other centres [15], we pursued a rather liberal strategy for hospitalization of outpatients, primarily based on clinical parameters. Patients were admitted to the hospital in case of fever persisting for more than 72 h. Further criteria for inpatient admission were ECOG score >2, pneumonia, sepsis, uncontrolled pain, diarrhoea and an indication for parenteral nutrition in case of grade 3 stomatitis or nausea and vomiting. A discharge from hospital and further treatment again as an outpatient was possible, depending on the patient’s clinical status.\n\nAssessment of haematological reconstitution and remission status\nAfter ABSCT, blood count was performed on a daily basis until platelet and leucocyte/neutrophil engraftment. Platelet engraftment was defined as the first of 3 consecutive days on which platelets reached 20 × 109/L without platelet transfusion. Because the platelet count did not fall below 20 × 109/L or a platelet transfusion was necessary in some patients, we also assessed days until platelets ≥50 × 109/L as a second variable for platelet engraftment. Leucocyte engraftment was defined by a leucocyte count of ≥1.0 × 109/L. Days with leucocytes <1.0 × 109/L were recorded as days in aplasia. Neutrophil recovery was defined as the first of 3 days on which neutrophils reached 0.5 × 109/L. The remission status was assessed according to international uniform response criteria for MM [25].\n\nAssessment of patient satisfaction\nPatients’ satisfaction was assessed using a structured questionnaire after hematologic reconstitution when daily monitoring at the outpatient clinic was discontinued. The patients were asked to give marks ranging from 1 (very good) to 6 (unsatisfactory) for the medical care provided by physicians and nurses and for the treatment at the outpatient clinic as a whole. They were also asked to determine whether they would, if indicated, undergo further HD chemotherapy and ABSCT in the outpatient setting again.\n\nStatistical Analysis\nDescriptive statistics and comparison between groups were performed using R studio 7.6. Data are given as absolute numbers and percentage and, if not otherwise stated, the median and range. For the comparison of categorical variables, Fisher’s Exact test in case of 2 × 2 contingency tables or its Freeman-Halton extension in case of 2 × >2 contingency tables was used. To identify differences among groups in case of continuous variables, a Wilcoxon-Mann-Whitney test was performed. Leucocyte, neutrophil and platelet recovery over time was calculated and plotted using Kaplan-Meier survival analysis. To calculate the differences between the engraftment curves, a log-rank test was used. A P-value <0.05 was considered statistically significant.\n\nResults\nPatients’ characteristics\nOverall, 21 MM patients were identified as candidates for an outpatient treatment, and HD chemotherapy and ABSCT was initiated in our outpatient clinic. In 14 cases (67%), therapy was performed completely on an outpatient basis. In 7 patients (33%), hospital admission and at least temporary inpatient treatment were indicated. Patients were grouped according to the necessity of hospital admission (“outpatients” vs. “temporary inpatients”).\n\nMore than twice as many male than female patients (n = 15 vs. n = 6) were intended to be treated on an outpatient basis. ECOG performance status prior to HD chemotherapy and ABSCT was 0 in 20 (95%) and 1 in 1 (5%) patients. All patients had an available accompanying person throughout the treatment period, except for one patient who suddenly and unexpectedly no longer had a care-giving family member available. Almost all of the patients (n = 19, 90%) had a central port catheter system. The majority of the patients had received bortezomib, doxorubicin, dexamethasone (PAD) or bortezomib, cyclophosphamide, dexamethasone (VCD) as induction therapy. Virtually all of the patients (n = 20, 95%) had received cyclophosphamide, doxorubicin, dexamethasone (CAD) for stem cell mobilization. A median PBSC stem cell collection result of 9.7 (range 7.4–24.8) and 13.7 (range 9.1–23.0) CD34+ cells x106/kg was noted in out- and inpatients, respectively. Further details are shown in Table 1. No significant differences were found in the patients’ characteristics between outpatient and temporary inpatient cases.Table 1 Patients’ characteristics\n\nParameters\tOverall cohort\tOutpatient treatment\tHospital admission\t\nP-value\t\nPatient number, n\t21\t14\t7\t/\t\nGender, n (%)\t\t\t\t0.61\t\n Male\t15 (71)\t9 (64)\t6 (86)\t\t\n Female\t6 (29)\t5 (36)\t1 (14)\t\t\nECOG, n (%)\t\t\t\t\t\n 0–1\t21 (100)\t14 (100)\t7 (100)\t1.00\t\nSocial conditions, n (%)\tbesser\t\t\t0.33\t\n Accompanying person available\t20 (95)\t14 (100)\t6 (86)\t\t\n Single\t1 (5)\t0 (0)\t1 (14)\t\t\nImplanted port catheter, n (%)\t\t\t\t0.53\t\n yes\t19 (90)\t12 (86)\t7 (100)\t\t\n no\t2 (10)\t2 (14)\t0 (0)\t\t\nDiagnosis of MM\t\t\t\t\t\n Age at first diagnosis, years\t58 (43–67)\t57 (43–67)\t59 (47–66)\t0.85\t\nStage at first diagnosis III, n (%)\t\t\t\t1.00\t\n A\t21 (100)\t14 (100)\t7 (100)\t\t\n B\t0 (0)\t0 (0)\t0 (0)\t\t\nHeavy chain type, n (%)\t\t\t\t0.34\t\n IgG\t11 (52)\t9 (64)\t2 (29)\t\t\n IgA\t9 (43)\t5 (36)\t4 (57)\t\t\n Light chain only\t1 (5)\t0 (0)\t1 (14)\t0.33\t\nLight chain type, n (%)\t\t\t\t1.00\t\n κ\t13 (62)\t9 (64)\t4 (57)\t\t\n λ\t8 (38)\t5 (36)\t3 (43)\t\t\nInduction therapy, n (%)\t\t\t\t0.61\t\n PAD\t10 (48)\t5 (36)\t5 (71)\t\t\n VAD\t2 (10)\t2 (14)\t0 (0)\t\t\n VCD\t8 (38)\t6 (43)\t2 (29)\t\t\n Other\t1 (5)\t1 (7)\t0 (0)\t\t\nMobilization therapy, n (%)\t\t\t\t1.00\t\n 1xCAD\t20 (95)\t13 (93)\t7 (100)\t\t\n Other\t1 (5)\t1 (7)\t0 (0)\t\t\nPBSC collection\t\n Age at PBSC collection, years\t59 (44–67)\t57 (44–67)\t59 (47–67)\t0.79\t\n Collected CD34+ cells × 106/kg\t11.8 (7.4–24.8)\t9.7 (7.4–24.8)\t13.7 (9.1–23.0)\t0.20\t\n\nCAD cyclophosphamide, doxorubicin, dexamethasone, ECOG Eastern Cooperative Oncology Group, MM multiple myeloma, PAD bortezomib, doxorubicin, dexamethasone, PBSC peripheral blood stem cells, VAD vincristine, doxorubicin, dexamethasone, VCD bortezomib, cyclophosphamide, dexamethasone. Unless otherwise indicated, data are given as medians (range)\n\n\n\n\nHD chemotherapy and ABSCT\nThe majority of patients received HD chemotherapy and ABSCT as a first-line treatment (n = 15, 71%). 6 patients (29%) received an autologous transplant as part of a salvage therapy regimen. 3 patients underwent a second course of HD chemotherapy and ABSCT in an outpatient setting as consolidation therapy or in case of relapse after 3–28 months. The median age at ABSCT was 59 (51–70) and 62 (51–67) years in out- and inpatients, respectively. All of the patients received HD melphalan. In one case, the melphalan dosage was reduced to 50% as an individual decision in a heavily pretreated patient, as described above. The remission status is summarized in Table 2.Table 2 HD chemotherapy and transplant characteristics\n\nParameters\tOverall cohort\t\nABSCT number, n\t21\t\nAge at ABSCT, years\t59 (51–70)\t\nTherapy line, n (%)\t\n First line therapy\t15 (71)\t\n Salvage therapy\t6 (29)\t\nRemission prior HD/ABSCT, (%)\t\n CR\t0 (0)\t\n nCR\t5 (24)\t\n VGPR\t6 (29)\t\n PR\t8 (38)\t\n MR\t0 (0)\t\n SD\t1 (5)\t\n PD\t1 (5)\t\nHD chemotherapy\t\n HD melphalan n, (%)\t20 (95)\t\n Dose modification, n (%)\t1 (5)\t\nABSCT\t\n Transplanted CD34+ cells × 106/kg\t3.3 (2.1–6.5)\t\n PBSC storage duration, months\t2 (0–144)\t\nRemission post HD and ABSCT\t\n CR\t2 (10)\t\n nCR\t8 (38)\t\n VGPR\t3 (14)\t\n PR\t7 (33)\t\n MR\t0 (0)\t\n SD\t1 (5)\t\n PD\t0 (0)\t\n\nABSCTautologous blood stem cell transplantation, (n)CR (near) complete remission, HD high dose, MR minimal response, PBSC peripheral blood stem cells, PD progressive disease, PR partial remission, SD stable disease, VGPR very good partial remission. Unless otherwise indicated, data are given as medians (range)\n\n\n\n\nPost-ABSCT treatment, toxicities and supportive care\nThe overall cumulative treatment duration for 21 patients was 444 days, of which 391 days (88%) were spent on an outpatient basis and 53 days (12%) on an inpatient basis. On average, the treatment duration was 21 (range 18–25) and 22 (range 19–31) days for out- and temporary inpatients, respectively. No significant differences in treatment duration were found between the patient cohorts (P = 0.38). Overall, 7 patients had an indication for temporary hospital admission. 4 patients were admitted to the hospital because of neutropenic fever persisting more than 72 h (patient no. 5, 7, 18, 21). In 2 further cases, hospital admission was indicated due to grade III stomatitis (patient no. 1 and 16). In one case, inpatient monitoring was initiated due to a local inflammation of the port catheter implantation site (patient no. 13). Patients who were temporarily admitted to the hospital spent a median of 15 (range 8–19) days as outpatients and 5 (range 2–18) days as inpatients. The sequence of days spent as an out- and inpatient during HD chemotherapy and ABSCT for each patient is indicated in Fig. 1. In 3 cases, patients were discharged from the hospital after haematological reconstitution without need for further outpatient treatment.Fig. 1 Out- and inpatient stay. Days as out- and inpatient are indicated for each patient. The numerical sequence of the patients (patient number 1 to 21) corresponds to the chronology of the performed ABSCTs\n\n\n\n\nAll patients presented with stomatitis, though to various degrees. Remarkably, only mild grade I stomatitis was observed in the majority of patients (n = 17, 81%), and as few as 2 and 2 patients developed grade II and III stomatitis, respectively. Grade III mucositis was defined as a reason for hospital admission.\n\nRed cell and platelet transfusion was performed on 6 patients (29%) and 15 patients (71%) overall, respectively, without significant differences found between the two patient cohorts.\n\nInfectious complications\nNeutropenic fever was observed in 14 patients (67%). In 4 patients, prolonged neutropenic fever longer than 72 h was a reason for hospital admission. 3 patients with neutropenic fever >72 h had only low increase of temperature and were in a good overall condition, so a hospital admission was not initiated (patient no. 2, 15, 19). All of the patients who developed neutropenic fever were treated with i.v. antibiotics (mainly ertapenem 1 mg/d i.v.). In 4 outpatients and 1 inpatient, i.v. antibiotic treatment was initiated due to subfebrile temperatures and CRP elevation.\n\nIn 4 patients, the peripheral blood cultures were positive. In one patient (no. 10), Streptococcus mitis was detected in peripheral blood culture. An i.v. antibiotic therapy with ertapenem was initiated in this patient on an outpatient basis because the criteria for hospital admission were not fulfilled. In 2 patients, peripheral blood cultures were positive for Staphylococcus aureus (patient no. 1) and Staphylococcus hominis (patient no. 16), respectively, and a port catheter explantation was performed in these patients due to a suspicion of a port catheter infection. Moreover, Escherichia coli was detected in peripheral blood cultures; in this case, inpatient treatment was initiated (patient no. 18). In no case any multi-resistant bacteria were detected. In one patient (no. 7), a port catheter explantation was performed due to persisting fever without any evidence of germs in peripheral or central blood cultures. One patient developed slight diarrhoea, and in one patient, a urinary tract infection was documented. No pulmonary infections and severe adverse events (SAE) were observed. Table 3 gives an overview of the post-ABSCT treatment, toxicities and supportive care provided.Table 3 Post-ABSCT treatment, toxicities and supportive care\n\nParameters\tOverall cohort\tOutpatient treatment\tHospital admission\t\nP-value\t\nABSCT number, n\t21\t14\t7\t/\t\nTreatment duration\t\n Overall, days\t21 (18–31)\t21 (18–25)\t22 (19–31)\t0.38\t\n Days as outpatient\t19 (8–25)\t21 (18–25)\t15 (8–19)\t<0.01\t\n Days as inpatient\t0 (0–18)\t/\t5 (2–18)\t<0.01\t\nReason for hospital admission, n (%)\t\t\t\t/\t\n Neutropenic fever ≥72 h\t4 (19)\t/\t4 (57)\t\t\n Grade III stomatitis\t2 (10)\t/\t2 (29)\t\t\n Other\t1 (5)\t/\t1 (14)\t\t\nToxicities\t\n Stomatitis, n (%)\t\n I\t17 (81)\t13 (93)\t4 (57)\t\t\n II\t2 (10)\t1 (7)\t1 (14)\t\t\n III\t2 (10)\t0 (0)\t2 (29)\t\t\n Neutropenic fever\t\n n, (%)\t14 (67)\t8 (57)\t6 (86)\t0.34\t\n No. of days with fever\t3 (1–10)\t2 (1–7)\t4 (2–10)\t0.14\t\n Diarrhoea, n (%)\t1 (5)\t1 (7)\t0 (0)\t1.00\t\n Pulmonary infection, n (%)\t0 (0)\t0 (0)\t0 (0)\t1.00\t\n Urinary tract infection, n (%)\t1 (5)\t0 (0)\t1 (14)\t0.33\t\n Positive blood cultures, n (%)\t\n Peripheral\t4 (19)\t1 (7)\t3 (43)\t0.09\t\n Central\t0 (0)\t0 (0)\t0 (0)\t1.00\t\n Port catheter infection, n (%)\t\n Suspicion of\t3 (14)\t0 (0)\t3 (43)\t0.03\t\n Proven\t0 (0)\t0 (0)\t0 (0)\t1.00\t\n Port catheter explantation\t3 (14)\t0 (0)\t3 (43)\t0.03\t\n SAE, n (%)\t0 (0)\t0 (0)\t0 (0)\t1.00\t\nSupport/Intervention\t\n Red cell transfusion, n (%)\t6 (29)\t3 (21)\t3 (43)\t0.35\t\n Platelet transfusion, n (%)\t15 (71)\t9 (64)\t6 (86)\t0.61\t\n i.v. antibiotics\t\n In case of neutropenic fever, n (%)\t14 (67)\t8 (57)\t6 (86)\t0.34\t\n At subfebrile temperature, n (%)\t5 (24)\t4 (29)\t1 (14)\t0.62\t\n Overall, days\t7 (4–14)\t7 (4–10)\t8 (4–14)\t0.61\t\n Days as outpatient\t6 (1–10)\t7 (4–10)\t1 (0–6)\t/\t\n Days as inpatient\t5 (2–14)\t/\t5 (2–14)\t/\t\n\nABSCT autologous blood stem cell transplantation, i.v. intravenous, no. number, SAE severe adverse event. Unless otherwise indicated, data are given as medians (range)\n\n\n\n\nHematopoietic reconstitution\nThe time in aplasia was 11 (range 8–15) and 9 (range 7–11) days in out- and inpatients (P = 0.11), respectively. The median time to reach leucocytes ≥1.0 × 109/L after ABSCT was 15 (range 13–20) and 13 (11–16) days for out- and inpatients, respectively. In addition, 14 (range 13–20) and 14 (12–16) days for out- and inpatients were required to reach neutrophil recovery ≥0.5 × 109/L. No significant differences in leucocyte and neutrophil reconstitution were observed between both groups (P = 0.11 and P = 0.23, respectively). A statistical comparison between the groups in terms of neutrophil recovery was limited by a lack of available neutrophil recovery data.\n\nBecause the majority of patients (n = 15, 71%) received a platelet transfusion, platelet recovery ≥20 × 109/L could not be evaluated sufficiently. The median number of days to reach platelets ≥50 × 109/L after ABSCT was 14 (range 11–22) in outpatients and 14 (range 11–25) in temporary inpatients. No significant differences in platelet recovery ≥50 × 109/L were observed between both patient cohorts (P = 0.97). The hematopoietic reconstitution data after ABSCT are summarized in Table 4. Similar results were observed when leucocyte, neutrophil and platelet reconstitution was analysed as a function of time, using both Kaplan-Meier analysis and log-rank test for curve comparison. No significant differences were found with regard to leucocytes recovery ≥1.0 × 109/L (P = 0.14), neutrophil recovery ≥0.5 × 109/L (P = 0.33) and platelet recovery ≥50 × 109/L (P = 0.59) between the patient cohorts.Table 4 Hematopoietic reconstitution\n\nParameters\tOverall cohort\tOutpatient treatment\tHospital admission\t\nP-value\t\nDays to L <1.0 × 109/L\t4 (2–5)\t4 (3–5)\t4 (2–5)\t0.83\t\nDays to L ≥1.0 × 109/L\t14 (11–20)\t15 (13–20)\t13 (11–16)\t0.11\t\nDays in aplasia\t10 (7–15)\t11 (8–15)\t9 (7–11)\t0.11\t\nDays to N ≥0.5 × 109/L\t14 (12–20)\t14 (13–20)\t14 (12–16)\t0.23\t\nPlatelets ≥20 × 109/L\t\n Platelet transfusion, n (%)\t15 (71)\t9 (64)\t6 (86)\t0.61\t\n Analysed ABSCTs, n (%)\t6 (29)\t5 (36)\t1 (14)\t/\t\nDays to platelets ≥20 × 109/L\t10 (9–16)\t10 (9–11)\t16\t/\t\nPlatelets ≥50 × 109/L\t\n Days to platelets ≥50 × 109/L\t14 (11–25)\t14 (11–22)\t14 (11–25)\t0.97\t\n\nABSCT autologous blood stem cell transplantation, L leucocytes, NA not available, N neutrophils. Unless otherwise indicated, data are given as medians (range)\n\n\n\n\nPatients’ satisfaction\nAccording to the ratings given by the patients in the questionnaire, the level of satisfaction was high: on a scale from 1 (excellent) to 6 (insufficient), physicians got a rating of 1.1, nurses of 1.2 and the treatment as a whole got a rating of 1.3 (mean values, n = 20). All of the patients agreed, if indicated, to undergo further HD chemotherapy and ABSCT in an outpatient setting again. In 3 cases, patients had indeed two consecutive autologous transplants within the program (#6/#18, #8/#10 and #9/#12).\n\nDiscussion\nIn Europe, HD melphalan chemotherapy followed by ABSCT is performed almost always on an inpatient basis, and only scattered reports on outpatient HD chemotherapy exist [23]. In contrast, in the USA and Canada, outpatient HD chemotherapy and ABSCT in MM and lymphoma patients has been well established for decades [19] and is performed with a high degree of safety [16–18, 26], cost savings [14, 15, 20] and patient satisfaction [13]. As one of the first centres in Europe, we established an outpatient ABSCT program at our institution in 2012. Based on our inpatient HD melphalan chemotherapy and ABSCT treatment protocol, we developed a comprehensive treatment plan for an outpatient setting. Patients were carefully selected and criteria have been developed for hospital admission. Comprehensive patient education about how to behave during aplasia at home took place. Moreover, daily rounds of the outpatients, including vital parameter monitoring, and laboratory tests were performed. The outpatient ABSCT program also included the advanced management of side effects exceeding the standard inpatient care, including a triple anti-emetic regimen, strong recommendation to rinse the mouth with Caphosol® at least once an hour and administration of daily i.v. fluids. Furthermore, with regard to Kim et al., who showed that sequential prophylaxis with oral fluoroquinolone followed by i.v. ertapenem may effectively prevent episodes of bacteremia and hospitalizations in neutropenic MM outpatient ABSCT recipients [27], an empirical i.v. antibiotic therapy was initiated at subfebrile body temperatures when CRP elevation was detected.\n\nBetween 2012 and 2016, 21 MM patients underwent HD chemotherapy and ABSCT on an outpatient basis. No SAEs were observed. In our patient cohort, confirmed post-transplant infections were documented in 5 of the 21 patients (24%, positive blood cultures in 4 patients and 1 positive urine culture in 1 patient). This is comparable to the results of Paul et al., who reported an infection rate of 22% (18 of 82 patients) in an initial brief in-hospital stay of MM patients group receiving HD melphalan and ABSCT [17], and to Graff et al., who described an infection rate of 19% (19 of 95 patients) in MM and lymphoma patients undergoing this therapy as outpatients [18]. Less than 10% of patients (2 of 21) developed grade 3 stomatitis. No grade 4 or 5 stomatitis cases were observed. In contrast, Jagannath et al. reported a stomatitis grade ≥3 in 31% of 118 MM patients undergoing outpatient HD chemotherapy and ABSCT [15]. We attribute the low mucositis rate in our patient cohort to regular Caphosol® mouth rinse. Neutropenic fever was observed in two-thirds of the cases. However, the median fever duration was relatively short (2 and 4 days for outpatients and those who required a hospital admission, respectively), and the majority of patients with neutropenic fever (8 of 14) were not admitted for inpatient stay. The neutropenic fever rate is comparable to those observed by Jagannath et al. (50% of 118 outpatient MM auto-transplants [15]) and Leger et al. (56% of 60 outpatient ABSCTs in relapse follicular lymphoma [21]). Moreover, the observed neutropenic fever rate was relatively low compared to in-house historical patient cohorts undergoing HD chemotherapy and ABSCT, with rates of approximately 80% [28, 29]. Although Meisenberg et al. and Paul et al. reported a pulmonary infection rate of 4% (of 27 patients [16]) and 5% (of 82 MM patients [17]) in outpatient auto-transplantation cases, respectively, no pulmonary infections were documented in our patient cohort.\n\nThe rate of positive blood cultures in our patient cohort (19%, 4 of 21 patients) is in line with the observation of Graff et al. (10%, 9 of 95 MM and lymphoma ABSCT receiving outpatients [18]) and Paul et al. (16%, 13 of 82 MM patients with an initial in-hospital stay post ABSCT [17]). Moreover, Graff et al. reported 1 central venous line infection among 95 MM/lymphoma patients treated on an outpatient basis (4%) [18]. In our patient group, port explantation was performed in 3 cases (14%) due to a clinical suspicion of port infection upon persisting fever, but without definitive prove of infection by bacterial culture. 90% (19 of 21) of transplanted patients received i.v. antibiotics. Compared to Jagannath et al. who reported a use of i.v. antibiotics in 78% (of 118 MM patients) transplanted in an outpatient setting [15] the higher relative number of patients with i.v. antibiotics in our group can be attributed to an early intervention strategy with initiation of ertapenem infusion at subfebrile temperatures and elevated CRP levels.\n\nGraff et al. observed a neutrophil ≥0.5 × 109/L recovery and platelet ≥20 × 109/L after a median of 10 and 19 days, respectively, in a cohort of MM and lymphoma patients undergoing outpatient ABSCT. We observed neutrophil ≥0.5 × 109/L recovery and platelet recovery after a median of 14 days in both groups, which is almost identical with study data of two historical in-house patient cohorts undergoing HD chemotherapy and ASCT at our institution, with the time to leukocyte increase ≥1 × 109/L and time to platelet increase ≥50 × 109/L being a median of 14 days [28, 29]. Pack red cell and platelet transfusion was necessary in 6 (29%) and 15 (71%) patients. This corresponds to the findings of Jagannath et al. (57% and 97%) [15].\n\nOn average, the median treatment duration was 21 and 22 days for outpatients and those who were intermittently admitted to the hospital, respectively. This is in line with the treatment duration of a completely in-hospital-treated MM patient undergoing HD chemotherapy and ABSCT at our institution [29]. Hospital admission was indicated in one-third (7 of 21) of the auto-transplanted MM patients in our cohort. In a comparable MM patient group described by Jagannath et al., 21% of the 118 outpatient transplant procedures required hospital admission [15]. However, in a cohort of 82 MM patients who had an initial brief hospital stay and were followed as outpatients, as described by Paul et al., 67% required hospital re-admission [17]. In our MM patient group, patients who were admitted to the hospital had a relatively short median inpatient treatment of 5 days, and the necessity of hospital admission did not lead to prolonged overall treatment duration. Thus, the temporary inpatient treatment-duration in our cohort was even shorter compared to the cohort of outpatient ABSCTs performed in patients with different hematologic malignancies reported by McDiarmid et al. (median total length of stay 21 d, median inpatient 7 d and median outpatient 14 d) [30].\n\nOverall, approximately 90% (391 days) of the overall cumulative treatment days for 21 patients were spent on an outpatient basis and 10% (53 days) on an inpatient basis. With increasing numbers of outpatient ABSCTs at our centre, the relatively short inpatient stay will represent a significant cost saving option. The magnitude of this effect depends on a number of factors, including reimbursement for in-/outpatient ABSCT, occupancy rate of hospital beds, staff availability etc., and should be addressed in detail in future studies.\n\nLimitations of the presented data result from the relatively small number of outpatients. In addition, this patient cohort was carefully selected and represented only about 5% of all transplanted myeloma-patients at our center during that time period. It therefore represents a pilot-study aiming to proof the feasibility and to describe the necessary preconditions.\n\nAccording to the results of the structured questionnaire, the patient’s satisfaction with outpatient medical care provided by physicians and nurses as well as their treatment in the outpatient clinic as a whole was very high. In addition, all of the patients indicated willingness to undergo further HD chemotherapy and ABSCT within the outpatient program again, if indicated. This was actually the case in three patients. Further continuation and expansion of the program is intended.\n\nConclusions\nCarefully selected MM patients undergoing HD chemotherapy and ABSCT can successfully be treated on an outpatient basis with low morbidity and infectious complications and very high patient satisfaction. Although dependent on a number of variables, including the individual compensation agreement with the health-insurance providers, such an approach may also have a significant economic impact on the performing transplant centre.\n\nAbbreviations\n(n)CR(Near) complete remission\n\nABSCTAutologous blood stem cell transplantation\n\nCADCyclophosphamide, doxorubicin, dexamethasone\n\nCRPC-reactive protein\n\nECOGEastern Cooperative Oncology Group\n\nHDHigh-dose\n\nHLAHuman leukocyte antigen\n\ni.v.Intravenous\n\nLLeucocytes\n\nMMMultiple myeloma\n\nMRMinimal response\n\nNNeutrophils\n\nNANot available\n\np.o.Per os\n\nPADBortezomib, doxorubicin, dexamethasone\n\nPBSCPeripheral blood stem cell\n\nPDProgressive disease\n\nPRPartial remission\n\nSAESevere adverse events\n\nSDStable disease\n\nVADVincristine, doxorubicin, dexamethasone\n\nVCDBortezomib, cyclophosphamide, dexamethasone\n\nVGPRVery good partial remission\n\nAcknowledgements\nNone.\n\nFunding\nNone.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article.\n\nAuthors’ contributions\nContributions: PW and KL conceptualized the study, acquired, analysed and interpreted the data and wrote the manuscript. KL and TB performed biostatistics. SSa, GE, HG, JH, JS, SS, MWH and ADH were involved in patient enrolment, clinical decision making, helped design the study and contributed data for patient characteristics and/or transplantation parameters. All authors revised and approved the submitted manuscript.\n\nCompeting interests\nThe first author and all co-authors confirm that there are no potential conflicts of interest to disclose, except the following:\n\nGerlinde Egerer: Honoraria and membership on Advisory Boards of MSD, Gilead GE. Honoraria from MSD, Pfizer, Teva, Pharmamar.\n\nHartmut Goldschmidt: Advisory Board: Janssen, Celgene, Novartis, Onyx, Millennium, BMS. Speakers Bureau: Celgene, Janssen, Novartis, Chugai, Onyx, Millennium. Research support: Celgene, Janssen, Chugai, Novartis, BMS, Millennium.\n\nJens Hillengass: Amgen-Consultant. Advisory Board: Janssen, Celgene, Novartis, BMS. Speakers honoraria: Janssen, Celegene, Amgen\n\nMathias Witzens-Harig: Consultancy for Celgene and honorarium from Roche.\n\nAnthony D. Ho: Consultancy, honoraria and membership on Advisory Boards of Genzyme/Sanofi-Aventis.\n\nPatrick Wuchter: Honoraria and membership on Advisory Boards of Sanofi-Aventis. Membership on Advisory Boards and Travel Grants from Hexal AG.\n\nConsent for publication\nNot applicable.\n\nEthics approval and consent to participate\nRetrospective data analysis was approved by the Ethics Committee of the Medical Faculty, Heidelberg University. Patients’ informed written consent was obtained.\n==== Refs\nReferences\n1. Cornell RF Kassim AA Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity Bone Marrow Transplant 2016 51 4 479 491 10.1038/bmt.2015.307 26726946 \n2. Engelhardt M Terpos E Kleber M European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma Haematologica 2014 99 2 232 242 10.3324/haematol.2013.099358 24497560 \n3. Hubel K de la Rubia J Azar N Corradini P Current status of haematopoietic autologous stem cell transplantation in lymphoid malignancies: a European perspective Eur J Haematol 2015 94 1 12 22 10.1111/ejh.12362 24797118 \n4. Passweg JR Baldomero H Bader P Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually Bone Marrow Transplant 2016 51 6 786 792 10.1038/bmt.2016.20 26901709 \n5. Regelink JC van Roessel CH van Galen KP Long-term follow-up of tandem autologous stem-cell transplantation in multiple myeloma J Clin Oncol Off J Am Soc Clin Oncol 2010 28 35 e741 743 10.1200/JCO.2010.31.5515 \n6. Attal M Harousseau JL Facon T Single versus double autologous stem-cell transplantation for multiple myeloma N Engl J Med 2003 349 26 2495 2502 10.1056/NEJMoa032290 14695409 \n7. Child JA Morgan GJ Davies FE High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma N Engl J Med 2003 348 19 1875 1883 10.1056/NEJMoa022340 12736280 \n8. Attal M Harousseau JL Stoppa AM A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome N Engl J Med 1996 335 2 91 97 10.1056/NEJM199607113350204 8649495 \n9. Auner HW Szydlo R Rone A Salvage autologous stem cell transplantation for multiple myeloma relapsing or progressing after up-front autologous transplantation Leuk Lymphoma 2013 54 10 2200 2204 10.3109/10428194.2013.773998 23387937 \n10. Michaelis LC Saad A Zhong X Salvage second hematopoietic cell transplantation in myeloma Biol Blood Marrow Transplantation 2013 19 5 760 766 10.1016/j.bbmt.2013.01.004 \n11. Lemieux E Hulin C Caillot D Autologous stem cell transplantation: an effective salvage therapy in multiple myeloma Biol Blood Marrow Transplantation 2013 19 3 445 449 10.1016/j.bbmt.2012.11.013 \n12. Passweg JR Baldomero H Bader P Hematopoietic SCT in Europe 2013: recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants Bone Marrow Transplant 2015 50 4 476 482 10.1038/bmt.2014.312 25642761 \n13. Schulmeister L Quiett K Mayer K Quality of life, quality of care, and patient satisfaction: perceptions of patients undergoing outpatient autologous stem cell transplantation Oncol Nurs Forum 2005 32 1 57 67 10.1188/05.ONF.57-67 15660144 \n14. Meisenberg BR Ferran K Hollenbach K Reduced charges and costs associated with outpatient autologous stem cell transplantation Bone Marrow Transplant 1998 21 9 927 932 10.1038/sj.bmt.1701191 9613786 \n15. Jagannath S Vesole DH Zhang M Feasibility and cost-effectiveness of outpatient autotransplants in multiple myeloma Bone Marrow Transplant 1997 20 6 445 450 10.1038/sj.bmt.1700900 9313876 \n16. Meisenberg BR Miller WE McMillan R Outpatient high-dose chemotherapy with autologous stem-cell rescue for hematologic and nonhematologic malignancies J Clin Oncol 1997 15 1 11 17 8996119 \n17. Paul TM Liu SV Chong EA Outpatient autologous stem cell transplantation for patients with myeloma Clin Lymphoma Myeloma Leuk 2015 15 9 536 540 10.1016/j.clml.2015.05.006 26141214 \n18. Graff TM Singavi AK Schmidt W Safety of outpatient autologous hematopoietic cell transplantation for multiple myeloma and lymphoma Bone Marrow Transplant 2015 50 7 947 953 10.1038/bmt.2015.46 25867651 \n19. Research CfIBaMT. CIBMTR Center Survey Report. In, 2015. https://www.cibmtr.org/referencecenter/slidesreports/documents/cibmtr_center_survey_report.pdf. Accessed 19 Feb 2017. \n20. Holbro A Ahmad I Cohen S Safety and cost-effectiveness of outpatient autologous stem cell transplantation in patients with multiple myeloma Biol Blood Marrow Transplant 2013 19 4 547 551 10.1016/j.bbmt.2012.12.006 23253556 \n21. Leger C Sabloff M McDiarmid S Outpatient autologous hematopoietic stem cell transplantation for patients with relapsed follicular lymphoma Ann Hematol 2006 85 10 723 729 10.1007/s00277-006-0149-6 16832675 \n22. Morabito F Martino M Stelitano C Feasibility of a mixed inpatient-outpatient model of peripheral blood stem cell transplantation for multiple myeloma Haematologica 2002 87 11 1192 1199 12414350 \n23. Devizzi L Guidetti A Tarella C High-dose yttrium-90-ibritumomab tiuxetan with tandem stem-cell reinfusion: an outpatient preparative regimen for autologous hematopoietic cell transplantation J Clin Oncol 2008 26 32 5175 5182 10.1200/JCO.2008.16.8294 18854569 \n24. Schmitt T Goldschmidt H Neben K Aprepitant, granisetron, and dexamethasone for prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan in autologous transplantation for multiple myeloma: results of a randomized, placebo-controlled phase III trial J Clin Oncol 2014 32 30 3413 3420 10.1200/JCO.2013.55.0095 25225424 \n25. Durie BG Harousseau JL Miguel JS International uniform response criteria for multiple myeloma Leukemia 2006 20 9 1467 1473 10.1038/sj.leu.2404284 16855634 \n26. Stiff P Mumby P Miler L Autologous hematopoietic stem cell transplants that utilize total body irradiation can safely be carried out entirely on an outpatient basis Bone Marrow Transplant 2006 38 11 757 764 10.1038/sj.bmt.1705525 17057729 \n27. Kim JH Goulston C Zangari M Impact of a change in antibacterial prophylaxis on bacteremia and hospitalization rates following outpatient autologous peripheral blood stem cell transplantation for multiple myeloma Transpl Infect Dis 2014 16 3 421 429 10.1111/tid.12225 24797543 \n28. Wuchter P Ran D Bruckner T Poor mobilization of hematopoietic stem cells-definitions, incidence, risk factors, and impact on outcome of autologous transplantation Biol Blood Marrow Transplant 2010 16 4 490 499 10.1016/j.bbmt.2009.11.012 19925876 \n29. Harter C Schulze B Goldschmidt H Piperacillin/tazobactam vs ceftazidime in the treatment of neutropenic fever in patients with acute leukemia or following autologous peripheral blood stem cell transplantation: a prospective randomized trial Bone Marrow Transplant 2006 37 4 373 379 10.1038/sj.bmt.1705256 16400334 \n30. McDiarmid S Hutton B Atkins H Performing allogeneic and autologous hematopoietic SCT in the outpatient setting: effects on infectious complications and early transplant outcomes Bone Marrow Transplant 2010 45 7 1220 1226 10.1038/bmt.2009.330 19946343\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "17(1)",
"journal": "BMC cancer",
"keywords": "Autologous blood stem cell transplantation; High-dose chemotherapy; Multiple myeloma; Outpatient setting; Outpatient supportive care",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating; D003131:Combined Modality Therapy; D005260:Female; D005858:Germany; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D009367:Neoplasm Staging; D012189:Retrospective Studies; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "151",
"pmc": null,
"pmid": "28228122",
"pubdate": "2017-02-22",
"publication_types": "D016428:Journal Article",
"references": "23298856;19946343;21060027;24497560;26901709;18854569;26726946;8996119;23186983;26141214;9613786;15660144;12736280;17057729;12414350;16400334;25225424;23387937;25867651;24797118;23253556;25642761;24797543;16832675;14695409;16855634;8649495;9313876;19925876",
"title": "High-dose chemotherapy and autologous stem cell transplantation of patients with multiple myeloma in an outpatient setting.",
"title_normalized": "high dose chemotherapy and autologous stem cell transplantation of patients with multiple myeloma in an outpatient setting"
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"fulfillexpeditecriteria": "1",
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"abstract": "A 72-year-old man with stage IV hypopharyngeal cancer, who had been treated for three months with combination chemotherapy, was referred to our cardiology department for evaluation of transient palpitation. Combination therapy with cetuximab, cisplatin, and 5-fluorouracil per cycle had been administered intravenously for five cycles every three weeks for three months. After the admission due to slight palpitation and severe hypomagnesemia (Mg = 0.6 mmol/L), monitor ECG showed supraventricular tachycardia (SVT), which was incessantly sustained and ceased every few minutes. 12-lead ECG obtained during tachycardia demonstrated long RP' narrow QRS tachycardia. SVT was initially considered to be related to severe hypomagnesemia. However, it still occurred even after normalization of serum magnesium level. As the SVT was refractory to landiolol and verapamil, catheter ablation was performed a few days after the admission, revealing non-reentrant focal atrial tachycardia (AT) originating from the posterolateral region of the right atrium. Homogenization of the origin of the AT was then performed with radiofrequency, resulting in complete suppression of the AT. In the present case, the patient receiving the combination therapy of cetuximab, cisplatin, and 5-FU developed focal atrial tachycardia after chemotherapy, which was successfully treated with the radiofrequency catheter ablation.",
"affiliations": "Department of Cardiology, Gifu University, Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan. mourinho384@yahoo.co.jp.;Department of Cardiology, Gifu Seiryu Hospital, 3-25 Kawabe, Gifu, 501-1151, Japan.",
"authors": "Sahashi|Yuki|Y|0000-0003-2260-4166;Nawa|Takahide|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12012-021-09648-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-7905",
"issue": "21(6)",
"journal": "Cardiovascular toxicology",
"keywords": "5-fluorouracil; Arrhythmia; Atrial tachycardia; Cetuximab; Cisplatin",
"medline_ta": "Cardiovasc Toxicol",
"mesh_terms": null,
"nlm_unique_id": "101135818",
"other_id": null,
"pages": "494-497",
"pmc": null,
"pmid": "33830451",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incessant Atrial Tachycardia Following Combination Chemotherapy with Cetuximab, Cisplatin and 5-Fluorouracil for Hypopharyngeal Cancer.",
"title_normalized": "incessant atrial tachycardia following combination chemotherapy with cetuximab cisplatin and 5 fluorouracil for hypopharyngeal cancer"
} | [
{
"companynumb": "JP-MICRO LABS LIMITED-ML2021-01588",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
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"abstract": "OBJECTIVE\nTo obtain safety and effectiveness data on a combined anti-HIV drug, Epzicom (abacavir 600 mg/lamivudine 300 mg), a post-marketing surveillance on Epzicom that was required by the Japanese regulatory authority was conducted between January 2005 and December 2010.\n\n\nMETHODS\nA joint survey (HIV-related drug [HRD] survey) has been conducted involving manufacturers of drugs for treatment of HIV infection in Japan. Safety and effectiveness data from total 624 cases (1107.3 person-years) registered to the HRD surveys and received Epzicom were obtained. Adverse drug reactions (ADRs) were defined as adverse events (AE) of which association with Epzicom could not be 'ruled out'.\n\n\nRESULTS\nIt was found that the incidence of ADR was 32.4% (202/624 cases) on the case basis. In addition, the frequently reported ADR included hyperlipidaemia (59 cases), hypertriglyceridaemia (21 cases), blood bilirubin increased (19 cases), gamma-glutamyltransferase increase (14 cases), blood triglyceride increase (14 cases) and rash (14 cases). Serious AEs were seen in 19 patients (30 events), including one death (no evident association with Epzicom). There were four cases (0.6%) of survey-defined 'hypersensitivity', and the incidence was 0.9% (4/445) among abacavir naïve patients; none of which was reported as serious. No case of myocardial infarction was reported. One pregnant case who delivered a normal baby by caesarean section was reported to have experienced aggravation of anaemia and nausea.\n\n\nCONCLUSIONS\nThe post-marketing surveillance indicated that the incidence of both ischaemic heart disease and hypersensitivity associated with Epzicom was considerably low, suggesting that this drug can be safely used in the Japanese population.",
"affiliations": "ViiV Healthcare K.K., Tokyo, 151-8566, Japan.",
"authors": "Kurita|Tomoko|T|;Kitaichi|Tomomi|T|;Nagao|Takako|T|;Miura|Toshiyuki|T|;Kitazono|Yoshifumi|Y|",
"chemical_list": "D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D004338:Drug Combinations; C492871:abacavir, lamivudine drug combination; D019259:Lamivudine",
"country": "England",
"delete": false,
"doi": "10.1002/pds.3588",
"fulltext": "\n==== Front\nPharmacoepidemiol Drug SafPharmacoepidemiol Drug SafpdsPharmacoepidemiology and Drug Safety1053-85691099-1557Blackwell Publishing Ltd Oxford, UK 10.1002/pds.3588Original ReportsSafety analysis of Epzicom® (lamivudine/abacavir sulfate) in post-marketing surveillance in Japan† Kurita Tomoko 1Kitaichi Tomomi 1Nagao Takako 1Miura Toshiyuki 12*Kitazono Yoshifumi 11 ViiV Healthcare K.K.Tokyo, 151-8566, Japan2 Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki UniversityNagasaki City, Nagasaki Prefecture, Japan*Correspondence to: T. Miura, ViiV Healthcare K.K. GSK Building, 4-6-15 Sendagaya, Shibuya-ku, Tokyo, 151-8566. E-mail: toshiyuki.2.miura@viivhealthcare.com† The data presented in this study was officially reported to the Japanese regulatory authority (Phamaceuticals and Medical Devices Agency, PMDA) and is available at the following website: http://www.info.pmda.go.jp/saishinsa/P201200044/16627200_22100AMX00411_A100_1.pdf.\n\n4 2014 03 3 2014 23 4 372 381 29 4 2013 04 12 2013 16 1 2014 © 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.2014This 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.Purpose\nTo obtain safety and effectiveness data on a combined anti-HIV drug, Epzicom (abacavir 600 mg/lamivudine 300 mg), a post-marketing surveillance on Epzicom that was required by the Japanese regulatory authority was conducted between January 2005 and December 2010.\n\nMethods\nA joint survey (HIV-related drug [HRD] survey) has been conducted involving manufacturers of drugs for treatment of HIV infection in Japan. Safety and effectiveness data from total 624 cases (1107.3 person-years) registered to the HRD surveys and received Epzicom were obtained. Adverse drug reactions (ADRs) were defined as adverse events (AE) of which association with Epzicom could not be ‘ruled out’.\n\nResults\nIt was found that the incidence of ADR was 32.4% (202/624 cases) on the case basis. In addition, the frequently reported ADR included hyperlipidaemia (59 cases), hypertriglyceridaemia (21 cases), blood bilirubin increased (19 cases), gamma-glutamyltransferase increase (14 cases), blood triglyceride increase (14 cases) and rash (14 cases). Serious AEs were seen in 19 patients (30 events), including one death (no evident association with Epzicom). There were four cases (0.6%) of survey-defined ‘hypersensitivity’, and the incidence was 0.9% (4/445) among abacavir naïve patients; none of which was reported as serious. No case of myocardial infarction was reported. One pregnant case who delivered a normal baby by caesarean section was reported to have experienced aggravation of anaemia and nausea.\n\nConclusions\nThe post-marketing surveillance indicated that the incidence of both ischaemic heart disease and hypersensitivity associated with Epzicom was considerably low, suggesting that this drug can be safely used in the Japanese population.\n\nabacavirlamivudinehuman immunodeficiency virushypersensitivitymyocardial infarctionJapanpharmacoepidemiology\n==== Body\nINTRODUCTION\nIn recent years, prognosis of human immunodeficiency virus type 1 (HIV-1) infection has been markedly improved by combinational antiretroviral therapy (cART). It is no exaggeration to say that adherence to cART is the most important critical factor to determine success/failure of this therapy. The cART regimen recommended for initial treatment includes two nucleoside reverse transcriptase inhibitors (NRTIs) as the backbone, in combination with a single non-NRTI (NNRTI) or a protease inhibitor or an integrase inhibitor.1–4\n\nEpizicom is a fixed-dose combination tablet developed by GlaxoSmithKline, containing 300 mg of lamivudine and 600 mg of abacavir, for the purpose of improving adherence to drug intake and enabling once-daily oral administration of the backbone (one tablet/dose). The combination of abacavir +lamivudine has been used in many overseas clinical studies to show its effectiveness against HIV infection,5–10 and it is listed as a favourable NRTI backbone combination in international and local HIV treatment guidelines as of 2012.2–4 Because this combined drug was approved in the USA in August 2004 and in Europe in December 2004, it has been approved in more than 40 countries by March 2011. In Japan, it was marketed in January 2005. The application for approval of Epzicom in Japan was subjected to preferential review as anti-HIV drug, and its review by the regulatory authority was made quickly on the basis of overseas data. Its components abacavir (Ziagen®) and lamivudine (Epivir®) have been marketed in Japan since 1999 and 1997, respectively. Thus, there had already been much clinical experience as to the safety and efficacy of long-term use of the components of Epzicom in Japan by the time of submission. However, no domestic clinical data on the combined form were available before approval of the product. Thus, the approval for this product in Japan was made with a condition that the marketing authorization holder collects information on clinical use of this product within the framework of post-marketing surveillance. In response to this special requirement, post-marketing data on clinical use of Epzicom were collected from 624 cases managed at 27 domestic facilities between January 2005 and December 2010. We here report safety and effectiveness data on this product obtained from the post-marketing surveillance. The safety data presented here is based on those officially reported to the Japanese regulatory authority (Pharmaceuticals and Medical Devices Agency [PMDA]) on 22 March 2011.\n\nMETHODS\nSubjects\nIn Japan, anti-HIV drugs are designated orphan drugs (medicines used for rare diseases). Because the number of HIV + people is small in Japan and anti-HIV drugs are commonly used with other drugs for treatment of HIV infection (anti-HIV drugs, drugs for treatment of opportunistic infection and so on), a joint survey (HIV-related drug [HRD] surveys) has been conducted, involving manufacturers and distributors of drugs for treatment of HIV infection. The survey has been conducted at registered sites, designed to collect safety and effectiveness information on antiretrovirals marketed in Japan. It was designed to enrol all of the patients receiving antiretrovirals in principle; however, the decisions of the enrollment were made by contractor physicians; a common survey form has been filled out by the contractor physicians and recollected in each year. The management of the survey has been delegated to Nihon Ultmarc Inc. (currently CMIC-PMS Co., Ltd.). The post-marketing survey on Epzicom covered all Epzicom-treated patients registered to the HRD survey between January 2005 and March 2009 (final follow-up in December 2010). Note that the safety data presented here are based on those officially reported to the PMDA on 22 March 2011 after the completion of mandatory post-marketing surveillance for this drug. In addition, a survey on safety of Epzicom use during pregnancy was conducted if such cases were experienced.\n\nObserved items for safety analysis\nInformation was collected as to the reason (disease name) for use of the product; gender; age; race; history of anti-HIV drug treatment; complications upon registration (including renal dysfunction, hepatic dysfunction, and haemophilia); concomitant drugs; CDC disease stage11 situations of product use (dosing method, dose level, dosing period); situation of concomitant drug use; presence/absence of adverse events (AEs) developing after the start of Epzicom treatment; and name of AEs and their date of onset, course, intervention and seriousness (events causing death, disabilities, hospitalization, semi-serious outcome, congenital anomalies, etc., listed in Item 253 of the Pharmaceutical Affairs Law Enforcement Rules were deemed as serious). The causal relationship of each AE to the product was rated on a five-category scale ‘definitely associated’, ‘associated’, ‘not ruled out’, ‘unknown’ or ‘ruled out’. The AEs except ‘ruled out’ were defined as ‘adverse drug reactions (ADR)’ in the present analysis. Terminology of AEs in this report strictly follows MedDRA version 13.1. In addition, the following were investigated as topics of special focus: (1) hypersensitivity reaction (criteria for hypersensitivity given in Table 1); (2) association with pre-existing hepatic dysfunction; and (3) Epzicom use in pregnant women.\n\nTable 1 Criteria for hypersensitivity†\n\nCategory A\tHypersensitivity/anaphylactic symptoms/allergic reactions/drug allergy\t\nCategory B\tCases meeting the following two or more items:\t\n\t• Rash\t\n\t• Fever\t\n\t• Gastrointestinal symptoms (nausea, vomiting, diarrhoea and abdominal pain)\t\n\t• Constitutional symptoms (coma, fatigue, malaise, myalgia and abnormal chest radiographs [infiltration is mainly noted and may be localized in some cases])\t\nExclusion criteria\t• A patient in whom other causes are highly probable despite the presence of hypersensitivity-like symptoms\t\n\t• A patient without recurrence after readministration of abacavir\t\n\t• A patient with disappearance of symptoms during treatment with abacavir\t\n\t• A patient who does not meet the criteria for category B despite suspected hypersensitivity to abacavir\t\n† Patients who meet the criteria for category A or B but not the exclusion criteria are determined to have hypersensitivity to abacavir.\n\nEffectiveness analysis\nTo investigate effectiveness of the drug, surrogate markers (plasma HIV-RNA copy number and CD4 +T-cell count) were measured before and after starting Epzicom treatment; however, this analysis was limited to the patients who had never received prior antiretroviral treatment.\n\nStatistical analysis\nBackground variables of patients were subjected to stratified analysis and so on, using chi-square test or Fisher's exact test, and p < 0.05 (two-tailed) was regarded statistically significant. For multivariate analysis, logistic regression analysis was performed with stepwise selection. All of the statistical analyses were conducted using SAS Ver 9.13.\n\nRESULTS\nBackground characteristics of the surveyed patients\nThe survey form was recollected from all of the 624 patients treated with Epzicom among the patients registered to this survey from nationwide 27 facilities participating in the joint HRD survey. Analysis of safety was conducted on 1107.3 person-years, and 126 of 624 were lost during the observed period. Table 2 summarizes the background characteristics of the patients. Of the 624 patients surveyed, 94.4% (589 cases) were Japanese, with the percentage of men being 92.8% (579 cases). Age ranged from 10 to 81 years, with the percentage of adults (15 ≤ and ≤ 64 years) being 96.0% (599 cases) and the percentage of elderly patients (over 65 years) being 3.7% (23 cases). The reason for use of this product was HIV infection in all cases, with the mean daily dose level being one tablet in all cases. The number of anti-HIV drugs concomitantly used was one in 45.5% (284 cases) and two in 42.1% (263 cases). Thus, all cases were treated with two or more drugs, including Epzicom, implying that all patients were treated with three or more anti-HIV agents. The percentage of patients without a history of other anti-HIV drug therapy before the start of Epzicom therapy (treatment-naïve) was 34.1% (213/624).\n\nTable 2 Characteristics of the subjects\n\n\t\tSafety analysis population\t\nPatient factor\t\tPatients (N)\tProportion (%)\t\nTotal\t624\t100.0\t\nReason for use\tHIV infection\t624\t100.0\t\nSex\tMale\t579\t92.8\t\n\tFemale\t45\t7.2\t\nAge†\t15–64 years\t599\t96.0\t\n\t65–81 years\t23\t3.7\t\nEthnic groups\tJapanese\t589\t94.4\t\n\tOthers\t35\t5.6\t\nHistory of treatment with antiretrovirals\tAbsent\t213\t34.1\t\n\tPresent\t411\t65.9\t\nHistory of allergy\tAbsent\t322\t51.6\t\n\tPresent\t210\t33.7\t\n\tUnknown\t92\t14.7\t\nComplications\tAbsent\t158\t25.3\t\n\tPresent\t466\t74.7\t\nRenal impairment\tAbsent\t586\t93.9\t\n\tPresent\t38\t6.1\t\nHepatic disorder\tAbsent\t461\t73.9\t\n\tPresent\t163\t26.1\t\nHaemophilia\tAbsent\t584\t93.6\t\n\tPresent\t40\t6.4\t\nConcomitant use of non anti-HIV drugs\tAbsent\t0\t0.0\t\n\tPresent\t624\t100.0\t\nNumber of concomitant anti-HIV drugs‡\tNone\t0\t0.0\t\n\t1 drug\t284\t45.5\t\n\t2 drugs\t263\t42.1\t\n\t3 drugs\t62\t9.9\t\n\t≥4 drugs\t15\t2.4\t\nCDC classification\tA\t240\t38.5\t\n\tB\t34\t5.4\t\n\tC\t121\t19.4\t\n\tUnknown\t228\t36.5\t\nTotal duration of treatment (days)\t2–180\t623\t99.8\t\n\t181–365\t529\t84.8\t\n\t366–730\t444\t71.2\t\n\t731–1517\t234\t37.5\t\n† Two pts were <15 years old.\n\n‡ Total numbers throughout the observed periods.\n\nData on adverse drug reactions\nIn this survey, ADRs were defined as AEs whose causal relationship to the product could not be ‘ruled out’. As shown in Table 3, 202 of the 624 patients showed a total of 325 ADRs, with the incidence being 32.4% (202/624). In addition, ADRs whose causal relationship to the product was rated as ‘definitely associated’ or ‘associated’ were seen in 58 patients (9.0%, 101 events). In analysis of the incidence of ADR by MedDRA system organ class, the incidence was the highest with ‘metabolism and nutrition disorders’ (13.9%, 87/624 patients), followed by ‘investigations (laboratory abnormality)’ (10.3%, 64/624), ‘gastrointestinal disorders’ (4.3%, 27/624), ‘skin and subcutaneous tissue disorders’ (4.0%, 25/624), ‘hepatobiliary disorders’ (3.7%, 23/624), ‘psychiatric disorders’ (1.3%, 8/624) and ‘nervous system disorders’ (1.3%, 8/624). Regarding the names of ADR, the expressions used by the reporting physicians were converted into MedDRA preferred terms, thereby separately processing the ADRs of different expressions used by reporting physicians even if they looked similar (e.g. abnormal hepatic function vs liver disorder, and rash vs drug eruption). When analysed in this way, the number of reported cases was the largest with hyperlipidaemia (59 cases), followed by hypertriglyceridaemia (21 cases), blood bilirubin increased (19 cases), gamma-glutamyltransferase increase (14 cases), blood triglyceride increase (14 cases), rash (14 cases), hyperuricaemia (eight cases), hyperbilirubinaemia (eight cases), blood uric acid increase (eight cases), hepatic dysfunction (seven cases), liver disorder (seven cases), nausea (seven cases), drug eruption (five cases), hypertension (five cases), diabetes mellitus (five cases), diarrhoea (five cases) and so on. Serious AEs were reported on 19 patients (30 events), including two cases each of pancreatitis acute, fever, liver disorder and drug eruption, and one case each of other serious AEs. Of these serious AEs, two events seen in two patients were reported as ‘associated’ with Epzicom (hepatic dysfunction and immune reconstitution inflammatory syndrome). There was one fatal case (pancytopenia), and the causal relationship to Epzicom was reported as ‘not ruled out’; this patient had syphilis, esophageal candidiasis and HIV encephalopathy as underlying diseases, and presented with bone marrow suppression under Valgancyclovir and AZT/3TC prior to starting Epzicom.\n\nTable 3 Adverse drug reactions observed during the treatment with Epzicom† (325 events in 202 subjects)\n\nAdverse drug reaction\tCases (%)\t\nBlood and lymphatic system disorders\t4 (0.64)\t\nIron deficiency anaemia\t1\t\nNormochromic normocytic anaemia\t1\t\nPancytopenia\t1\t\nHaemorrhagic diathesis\t1\t\nCardiac disorders\t3 (0.48)\t\nAtrioventricular block complete\t1\t\nAtrioventricular block first degree\t1\t\nCardiac failure\t1\t\nEndocrine disorders\t1 (0.16)\t\nHyperthyroidism\t1\t\nGastrointestinal disorders\t27 (4.33)\t\nAbdominal discomfort\t2\t\nAbdominal pain\t1\t\nAbdominal pain upper\t2\t\nAscites\t1\t\nConstipation\t1\t\nDiarrhoea\t5\t\nGastritis\t2\t\nGingivitis\t1\t\nNausea\t7\t\nPancreatitis acute\t2\t\nReflux oesophagitis\t2\t\nVomiting\t1\t\nAbdominal symptom\t1\t\nGeneral disorders and administration site conditions\t7 (1.12)\t\nAsthenia\t1\t\nMalaise\t3\t\nPyrexia\t3\t\nHepatobiliary disorders\t23 (3.69)\t\nCholelithiasis\t1\t\nHepatic function abnormal\t7\t\nHepatitis fulminant\t1\t\nHyperbilirubinaemia\t8\t\nJaundice\t1\t\nLiver disorder\t7\t\nImmune system disorders\t1 (0.16)\t\nImmune reconstitution symdrome\t1\t\nInfections and infestations\t6 (0.96)\t\nHepatitis C\t2\t\nHerpes zoster\t3\t\nInfluenza\t1\t\nAtypical mycobacterial infection\t1\t\nInjury, poisoning, and procedural complications\t2 (0.32)\t\nSpinal compression fracture\t1\t\nLumbar vertebral fracture\t1\t\nInvestigations\t65 (10.42)\t\nAlanine aminotransferase increased\t2\t\nAspartate aminotransferase increased\t2\t\nBlood bilirubin increased\t19\t\nBlood cholesterol increased\t3\t\nBlood creatine phosphokinase increased\t1\t\nBlood creatinine increased\t1\t\nBlood glucose increased\t1\t\nBlood lactate dehydrogenase increased\t1\t\nBlood triglycerides increased\t14\t\nBlood uric acid increased\t8\t\nGamma-glutamyltransferase increased\t14\t\nGlucose urine present\t1\t\nBlood urine present\t1\t\nHaemoglobin decreased\t1\t\nLiver function test abnormal\t3\t\nLow density lipoprotein increased\t1\t\nPlatelet count decreased\t4\t\nLymphocyte count increased\t1\t\nNeutrophil count decreased\t1\t\nWhite blood cell count decreased\t1\t\nBlood alkaline phosphatase increased\t4\t\nMetabolism and nutrition disorders\t87 (13.94)\t\nDiabetes mellitus\t5\t\nGlucose tolerance impaired\t1\t\nGout\t1\t\nHypercalcaemia\t1\t\nHypercholesterolaemia\t3\t\nHypertriglycaeridaemia\t21\t\nHyperuricaemia\t8\t\nMetabolic disorder\t1\t\nHyperphosphatasaemia\t1\t\nDecreased appetite\t1\t\nHyperlipidaemia\t59\t\nMusculoskeletal and connective tissue disorders\t3 (0.48)\t\nMyalgia\t1\t\nOsteonecrosis\t1\t\nOsteoporosis\t1\t\nNeoplasms benign, malignant, and unspecified (including cysts and polyps)\t2 (0.32)\t\nKaposi's sarcoma\t1\t\nCastleman's disease\t1\t\nMetastatic gastric cancer\t1\t\nNervous system disorders\t8 (1.28)\t\nCerebral infarction\t1\t\nDisturbance in attention\t1\t\nDizziness\t2\t\nDysgeusia\t1\t\nHeadache\t2\t\nTremor\t1\t\nPsychiatric disorders\t8 (1.28)\t\nDepressed mood\t1\t\nDepression\t3\t\nInitial insomnia\t1\t\nInsomnia\t3\t\nAbnormal behaviour\t1\t\nRenal and urinary disorders\t5 (0.8)\t\nCalculus urinary\t1\t\nNephrolithiasis\t1\t\nRenal impairment\t3\t\nRespiratory, thoracic, and mediastinal disorders\t2 (0.32)\t\nCough\t1\t\nDyspnoea\t1\t\nSkin and subcutaneous tissue disorders\t25 (4.01)\t\nDermatitis\t1\t\nDrug eruption\t5\t\nErythema nodosum\t1\t\nPruritus\t2\t\nRash\t14\t\nRash generalized\t1\t\nSeborrhoeic dermatitis\t1\t\nFacial wasting\t1\t\nVascular disorders\t5 (0.80)\t\nHypertension\t5\t\n† The terms are based on MedDRA version 13.1.\n\nTwo cases of children received Epzicom (aged less than 15 years); however, no ADRs were reported.\n\nIschaemic heart diseases\nAlthough the association of abacavir with myocardial infarction (MI) was previously reported,12 no ischaemic heart disease (IHD) associated with abacavir sulfate (ABC) administration (including MI and angina pectoris) was reported (one MI and one angina pectoris case were reported as ABC non-related AE). In the post-marketing surveillance of Ziagen (abacavir sulfate 300 mg) conducted from September 1999 to September 2009 (enrollment of the last patients was March 2008), none of the 643 patients (1345.7 person-years) developed IHD including MI (unpublished data, submitted elsewhere). In the present surveys, no case of IHDs including MI was reported either. Note that 180 of the 624 had been involved in Ziagen post-marketing surveillance as well; therefore, when combining data from two surveys, no case of IHD was reported in total 1087 patients (2452.99 person-years).\n\nAdverse drug reactions by background characteristics of the subjects\nThe influence of the background characteristics of the patients on ADR was analysed. The analysis revealed statistically significant differences in the incidence of ADR depending on history of anti-HIV drug therapy, history of allergy, other complications and the number of anti-HIV drugs concomitantly used (Table 4), and all of which were significant with multivariate analysis (Table 5). Although effect of pre-existing hepatic dysfunction was one of the topics of special focus because ABC is eliminated primarily by hepatic metabolism, no association was observed between pre-existing hepatic dysfunction and the incidence of ADR (Table 4).\n\nTable 4 The frequency of adverse drug reactions according to the characteristics of the subjects\n\nFactors\tNo. of patients\tWith ADRs\tNo. of ADR events\tIncidence of ADR (%)\tχ‡ or Fisher's exact test (based on cases)\t\nOverall\t624\t202\t325\t32.4\t–\t\nSex\tMale\t579\t191\t311\t33.0\tNS\t\n\tFemale\t45\t11\t14\t24.4\t\nAge\tChild\t2\t0\t0\t0\tNS\t\n\tAdult†\t599\t198\t320\t33.1\t\n\tElderly‡\t23\t4\t5\t17.4\t\nEthinic groups\tJapanese\t589\t191\t304\t32.4\tNS\t\n\tOthers\t35\t11\t21\t31.4\t\nHistory of treatment with antiretrovirals\tAbsent\t213\t83\t132\t39.0\tp = 0.015*\t\n\tPresent\t411\t119\t193\t29.0\t\nHistory of allergy\tAbsent\t322\t80\t129\t24.8\tp <0.0001**\t\n\tPresent\t210\t92\t148\t43.8\t\n\tUnknown\t92\t30\t48\t32.6\t\t\nComplications\tAbsent\t158\t39\t53\t24.7\tp = 0.018*\t\n\tPresent\t466\t163\t272\t35.0\t\nRenal impairment\tAbsent\t586\t186\t299\t31.7\tNS\t\n\tPresent\t38\t16\t26\t42.1\t\nHepatic disorder\tAbsent\t461\t142\t213\t30.8\tNS\t\n\tPresent\t163\t60\t112\t36.8\t\nHaemophilia\tAbsent\t584\t189\t300\t32.4\tNS\t\n\tPresent\t40\t13\t25\t32.5\t\nNumber of concomitant anti-HIV drugs§\t1 drug\t284\t78\t126\t27.5\tp = 0.019*\t\n\t2 drugs\t263\t89\t131\t33.8\t\n\t3 drugs\t62\t27\t46\t43.6\t\n\t4 drugs ≤\t15\t8\t22\t53.3\t\nCDC classification\tA\t240\t84\t141\t35.0\tNS\t\n\tB\t34\t11\t17\t32.4\t\n\tC\t121\t47\t73\t38.8\t\n\tUnknown\t228\t60\t94\t26.3\t\t\nNS, no statistical significance.\n\n† ≥15 to ≤64 years.\n\n‡ Elderly patients.\n\n§ Total numbers throughout the observed periods.\n\n* p < 0.05.\n\n** p < 0.01.\n\nTable 5 The background characteristics that are associated with the frequency of ADR†\n\nFactors\tOdds ratio\t95% confidence interval\t\nHistory of treatment with antiretrovirals\t0.52\t0.36–0.76\t\nHistory of allergy\t2.01\t1.40–2.88\t\nComplications\t1.80\t1.15–2.81\t\nNumber of concomitant anti-HIV drugs\t1.36\t1.10–1.69\t\nFor history of allergy, ‘unknown’ was regarded as ‘absent’; for CDC classification, ‘unknown’ was regarded as ‘category A’\n\nThe incidence of ADR in the group without history of anti-HIV drug therapy (treatment naïve [TN]) was 39.0% (83/213), which was significantly higher than those having history of anti-HIV drug therapy (treatment experienced [TE]) (29.0%, 119/411) (p < 0.05). When analysed by system organ class, the incidence of ‘skin and subcutaneous tissue disorders’ was significantly higher in TN (9.39%, 20/213) than in TE (1.22%, 5/411) (p < 0.0001), which was mainly driven by the larger number of cases developing rash in TN (13 cases) than in TE (one case). A possible explanation for these differences is that many of the TE patients had received component of Epzicom, namely Ziagen (abacavir) and/or Epivir (lamivudine) prior to Epzicom. The incidence of ‘metabolism and nutrition disorders’ such as hyperglycaemia, hypertriglycaeridaemia was higher among TN patients (data not shown), suggesting the possibility that in TE patients, these disorders had already been induced by anti-HIV drugs and were counted as complications at the start of Epzicom. The incidence of ADR was 43.8% (92/210) in the group having history of allergy, which was significantly higher than in those without history of allergy (24.8%, 80/322) (p < 0.01), which seemed to have been mainly driven by ‘rash’ (13/210 vs 4/322, p = 0.004). The incidence of ADRs became higher as the number of anti-HIV drugs concomitantly used increased recording 27.5% (78/284), 33.8% (89/263), 43.5% (27/62) and 53.3% (8/15) when the number of concomitant anti-HIV drugs was one, two, three and four, respectively (p < 0.05), suggesting the influence from multiple-drug-combined therapy.\n\nHypersensitivity\nOnset of hypersensitivity reaction was investigated on the basis of the survey forms filled by the physicians, using the criteria in Table 1. Four cases of survey-defined hypersensitivity were reported (Table 6), with the incidence of 0.64% (4/624), all of whom were abacavir naïve patients. Therefore, when calculating the incidence limiting to the abacavir naïve patients, the incidence was 0.9% (4/445). Close association of HLA-B*5701 with abacavir-induced hypersensitivity reaction has been described,12–20 which rarely expressed in Japanese people.21 Nevertheless, in the present survey, all of the patients who developed hypersensitivity were Japanese. The symptoms of hypersensitivity were ‘rash’, ‘malaise + vomiting’, ‘fever + rash’ and ‘drug eruption’ (one case each). All of these symptoms were non-serious and disappeared or improved.\n\nTable 6 Patients presented hypersensitivity\n\n\tAdverse reaction\tAssociation\tSeverity\tOutcome\tTime to onset (days)\tSex\tAge\tComplications\tConcomitant suspected products\tComment from physicians\t\n1\tRash\tAssociated\tNot serious\tAmeliorated\t61\tMale\t28\tFactor IX deficiency, Hepatitis C, Atrial septal defect, Pulmonary hypertension\t–\t\t\n2\tVomiting, Malaise\tNot ruled out\tNot serious\tRecovered\t152\tFemale\t32\tOesophageal candidiasis, Acute lymphocytic leukaemia\t–\t\t\n3\tRash, Pyrexia\tNot ruled out\tNot serious\tRecovered\t9\tMale\t46\tHepatitis B\tLPV/rtv\tAssociation with HIV infection, LPV/rtv and Epzicom cannot be ruled out.\t\n4\tDrug eruption\tNot ruled out\tNot serious\tAmeliorated\t13\tMale\t38\t–\tLPV/rtv\tAssociation with HIV infection, LPV/rtv and Epzicom cannot be ruled out.\t\nddI, didanosine; d4T, stavudine; AZT, zidovudine; NVP, nevirapine; 3TC, lamivudine; LPV/rtv, lopinavir/ritonavir; TDF, tenofovir disoproxil fumarate; EFV, efavirenz.\n\nDuration of Epzicom treatment prior to onset of adverse drug reactions\nAmong the 202 patients having developed ADR (323 reactions in total), the duration of Epzicom treatment before onset of ADR was known in 187 patients. After the start of Epzicom, ADR developed within 180 days in 63.9% (129/202), between 181 and 365 days (1 year) in 78.2% (158/202), and on Day 366 and later in 14.4% (29/202). The frequent ADRs occurred within 180 days were hyperlipidaemia (25 cases), rash (14 cases), blood bilirubin increased (14 cases), hypertriglyceridaemia (13 cases) and so on. The most frequent ADRs developed on Day 366 and later was hyperlipidaemia (15 cases).\n\nPregnant cases\nInformation on pregnant women was collected on one case during the survey period (with one newborn collected as well). In this case, non-serious ‘aggravation of anaemia’ (56 days after the start of Epzicom) and ‘aggravation of nausea’ (28 days after the start of Epzicom) developed during the course of pregnancy (Epzicom had been started 142 days before the delivery). The causal relationship to the product was not ‘ruled out’. A normal baby was delivered at gestational age of 36 weeks by a caesarean section. Mild anaemia and transient tachypnea were reported in the neonate on the date of birth.\n\nEffectiveness analysis\nEffectiveness analysis was performed on only TN patients whose HIV surrogate markers (plasma viral load and CD4 + T-cell count) at baseline and after the start of Epzicom were available. Among the TN patients who received therapy including Epzicom for 12 consecutive months, the percentages of patients with plasma HIV-RNA <400 copies/mL and <50 RNA copies/mL were 97.5% (130/134) and 74.6% (101/134), respectively. In addition, among the TN patients treated for 24 consecutive months, the percentages were 97.5% (74/76) and 73.7% (56/76), respectively (Figure 1a). When the patients were stratified according the baseline HIV-RNA level (cutoff level: 100 000 copies/mL), plasma viral load at 12 and 24 months was <400 copies/mL in the majority cases, whereas the percentage of cases <50 RNA copies/mL was lower regardless of the baseline viral load (<100 000 RNA copies/mL, 77.8% [12 months], 80.0% [24 months]; >100 000 RNA copies/mL, 70.5% [12 months], 61.5% [24 months]) (Figure 1b and 1c). The mean CD4 + T lymphocyte count increased from 180/μL (baseline) to 444/μL after 24 months of the Epzicom treatment (Figure 2).\n\nFigure 1 Proportion of treatment-naïve subjects who achieved <50 or <400 HIV-RNA copies/mL after 12 and 24 months of treatment with ABC/3TC containing regimen. (a) All treatment-naïve HIV + subjects, (b) treatment-naïve subjects with baseline pVL <100 000 RNA copies/mL, and (c) treatment-naïve subjects with baseline pVL >100 000 RNA copies/mL. Note that the denominators are those who were on Epzicom treatment for the given duration, therefore not including those who stopped Epzicom earlier\n\nFigure 2 Change in mean CD4 + T-cell count after initiation of ABC/3TC in treatment-naïve HIV + subjects. Mean absolute CD4 + T-cell count is shown in the solid line, and the vertical bars indicate standard deviation. Note that the number of subjects shown is those whose CD4+ T-cell count was available at each time point\n\nDISCUSSION\nOn the basis of the 10-year post-marketing survey on Ziagen Tablet (abacavir sulfate 300 mg), we recently reported that the incidence of serious ADR associated with abacavir was 1.9% (12/643) and that no death occurred from the use of this drug, indicating abacavir can be used relatively safely for Japanese HIV-positive patients22. Lamivudine has been marketed for over 10 years in Japan and used not only for HIV infection but also for Hepatitis B virus infection,23–25 showing superior tolerability. The present post-marketing surveillance on Epzicom Tablet (a combination of abacavir and lamivudine) in Japanese patients was expected to yield more useful information, particularly for abacavir.\n\nThe incidence of ADR reported in this survey was clearly lower than those in the post-marketing survey on Ziagen tablet. The most feasible explanation for this was because substantial part of the patients had received Ziagen (abacavir) or Epivir (lamivudine) before starting Epzicom, few of them presented new ADRs upon switching to Epzicom. A couple of other factors might have contributed to this finding, including ‘trend toward early diagnosis and initiation of cART’ before patients becoming sick. Likewise, improved safety profile of other anti-HIV drugs concomitantly used might have affected the findings.\n\nA recent meta-analysis by the US FDA denied the possibility that abacavir is associated with MI.26 However, this possibility is one of the major reasons why the combination abacavir/lamivudine has not been listed as a preferred NRTI backbone for TN patients in the DHHS Guidelines.1 The incidence of IHD is known to be lower in Japanese people than in Western people,27–29 yet the possibility of IHD is sometimes taken into account when physicians prescribe abacavir to Japanese patients. In the present survey, analysis of the data combined from post-marketing surveys on Ziagen Tablet22 and Epzicom Tablet revealed no case developing IHD among 1087 patients treated with abacavir (2452.99 person-years). This result seems to serve as information useful in prescription of this product in Japanese population. However, regular pharmacovigilance activity is of paramount importance to monitor any signal for the risk of MI by this drug for patient safety.\n\nIn the post-marketing survey on Ziagen, 15 cases of hypersensitivity (2.3%) were reported, whereas the incidence of hypersensitivity was only 0.9% (4/445) in this Epzicom survey, which reassures that the risk of hypersensitivity to abacavir in Japanese population is substantially low; nevertheless, in view of the report on cases of suspected hypersensitivity among patients not expressing HLA-B*5701,13 it is necessary to monitor patients carefully when Epzicom is used.\n\nRegarding effectiveness, because ACTG5202 Study demonstrated that abacavir/lamivudine (ABC/3TC) is inferior to tenofovir/emtricitabine (TDF/FTC) in patients with baseline virus load over 100 000 RNA copies/mL,6 it has been one of the reason why the DHHS guideline does not list ABC/3TC as preferred NRTI backbone.1 However, other studies reported no difference in effectiveness between the two arms.5,30,31 In the present survey, TN patients with baseline plasma virus load over 100 000 copies/mL showed relatively good virological responses; however, we could not make any definite conclusion because it was non-controlled observational study designed for safety surveillance. Although data generation on effectiveness of ABC/3TC when used with modern powerful key drugs such as boosted darunavir or raltegravir has been evolving,32,33 evidence from controlled clinical trials should be generated for the fair evaluation for the effectiveness of Epzicom.\n\nIn conclusion, the present survey convinced abacavir and lamivudine can be used relatively safely in Japanese HIV-positive population. However, regular pharmacovigilance should be continued for patient safety.\n\nCONFLICT OF INTEREST\nTomoko Kurita, Tomomi Kitaichi, Takako Nagao, Toshiyuki Miura and Yoshifumi Kitazono are employees of ViiV Healthcare K. K.\n\nKEY POINTS\nAbacavir/lamivudine fixed-dose combination tablet can be well tolerated by Japanese HIV + people.\n\nHypersensitivity reaction to abacavir was observed in 0.9% of treatment-naive HIV + patients.\n\nNo case of myocardial infarction associated with abacavir administration was observed among 624 cases (1107.3 person-years).\n\nETHICS STATEMENT\nThis was a surveillance mandated by the Japanese regulatory authority to collect information from all of the patients receiving the drug. IRB approval were obtained where appropriate according to institutional rule.\n\nWe would like to express our gratitude to the physicians who cooperated in the present survey and provided valuable data.\n==== Refs\nREFERENCES\n1 DHHS 2012 Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services [cited 2012 Dec 15th]; Available from: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf \n2 MHLW 2012 Anti HIV Therapy Guideline in Japan [cited 2012 Dec 15th]; Available from: http://www.haart-support.jp/guideline.htm \n3 EACS 2011 EACS Guidelines [cited 2012 Dec 15th]; Version 6.1; Available from: http://www.europeanaidsclinicalsociety.org/index.php?option=com_content&view=article&id=59&Itemid=41 \n4 Thompson MA Aberg JA Hoy JF Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel JAMA 2012 308 387 402 22820792 \n5 Smith KY Patel P Fine D Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment AIDS 2009 23 1547 1556 19542866 \n6 Sax PE Tierney C Collier AC Abacavir–lamivudine versus tenofovir–emtricitabine for initial HIV-1 therapy N Engl J Med 2009 361 2230 2240 19952143 \n7 Lamarca A Clumeck N Plettenberg A Efficacy and safety of a once-daily fixed-dose combination of abacavir/lamivudine compared with abacavir twice daily and lamivudine once daily as separate entities in antiretroviral-experienced HIV-1-infected patients (CAL30001 Study) J Acquir Immune Defic Syndr 2006 41 598 606 16652033 \n8 Sosa N Hill-Zabala C Dejesus E Abacavir and lamivudine fixed-dose combination tablet once daily compared with abacavir and lamivudine twice daily in HIV-infected patients over 48 weeks (ESS30008, SEAL) J Acquir Immune Defic Syndr 2005 40 422 427 16280696 \n9 Moyle GJ DeJesus E Cahn P Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the Ziagen Once Daily in Antiretroviral Combination Study J Acquir Immune Defic Syndr 2005 38 417 425 15764958 \n10 DeJesus E Herrera G Teofilo E Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults Clin Infect Dis 2004 39 1038 1046 15472858 \n11 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults MMWR Recomm Rep 1992 41 1 19 \n12 Sabin CA Worm SW Weber R Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration Lancet 2008 371 1417 1426 18387667 \n13 Mallal S Phillips E Carosi G HLA-B*5701 screening for hypersensitivity to abacavir N Engl J Med 2008 358 568 579 18256392 \n14 Zucman D Truchis P Majerholc C Prospective screening for human leukocyte antigen-B*5701 avoids abacavir hypersensitivity reaction in the ethnically mixed French HIV population J Acquir Immune Defic Syndr 2007 45 1 3 17356469 \n15 Waters LJ Mandalia S Gazzard B Prospective HLA-B*5701 screening and abacavir hypersensitivity: a single centre experience AIDS 2007 21 2533 2534 18025891 \n16 Rodriguez-Novoa S Garcia-Gasco P Blanco F Value of the HLA-B*5701 allele to predict abacavir hypersensitivity in Spaniards AIDS Res Hum Retroviruses 2007 23 1374 1376 18184080 \n17 Lucas A Nolan D Mallal S HLA-B*5701 screening for susceptibility to abacavir hypersensitivity J Antimicrob Chemother 2007 59 591 593 17317695 \n18 Gervasoni C Vigano O Grinelli E Abacavir hypersensitivity reaction after switching from the twice-daily to the once-daily formulation AIDS Patient Care STDS 2007 21 1 3 17263652 \n19 Watson ME Pimenta JM Spreen WR HLA-B*5701 and abacavir hypersensitivity Pharmacogenetics 2004 14 783 4 author reply 784 15564887 \n20 Martin AM Nolan D Gaudieri S Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant Proc Natl Acad Sci U S A 2004 101 4180 4185 15024131 \n21 Tanaka H Akaza T Juji T Report of the Japanese Central Bone Marrow Data Center Clin Transpl 1996 139 144 9286563 \n22 Kurita T Kitaichi T Nagao T Miura T Kitazono Y Safety analysis of Ziagen® (abacavir sulfate) in postmarketing surveillance in Japan Pharmacoepidemiol Drug Saf DOI: 10.1002/pds.3589 \n23 Pramoolsinsup C Management of viral hepatitis B J Gastroenterol Hepatol 2002 17 Suppl S125 145 12000599 \n24 Schiff ER Lamivudine for hepatitis B in clinical practice J Med Virol 2000 61 386 391 10861651 \n25 Canadian consensus conference on the management of viral hepatitis. Canadian Association for the Study of the Liver Can J Gastroenterol 2000 14 Suppl B 5B 20B \n26 Ding X Andraca-Carrera E Cooper C No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis J Acquir Immune Defic Syndr 2012 61 4 441 447 22932321 \n27 Ishikawa S Kayaba K Gotoh T Incidence of total stroke, stroke subtypes, and myocardial infarction in the Japanese population: the JMS Cohort Study J Epidemiol 2008 18 144 150 18603825 \n28 Menotti A Keys A Kromhout D Inter-cohort differences in coronary heart disease mortality in the 25-year follow-up of the seven countries study Eur J Epidemiol 1993 9 527 536 8307138 \n29 Robertson TL Kato H Rhoads GG Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California. Incidence of myocardial infarction and death from coronary heart disease Am J Cardiol 1977 39 239 243 835482 \n30 Ha B Liao QM Dix LP Virologic response and safety of the abacavir/lamivudine fixed-dose formulation as part of highly active antiretroviral therapy: analyses of six clinical studies HIV Clin Trials 2009 10 65 75 19487176 \n31 Tan DH Chan K Raboud J Comparison of abacavir/lamivudine and tenofovir/emtricitabine among treatment-naive HIV-infected patients initiating therapy J Acquir Immune Defic Syndr 2011 58 38 46 21709570 \n32 Nishijima T Tsukada K Teruya K Efficacy and safety of once-daily ritonavir-boosted darunavir and abacavir/lamivudine for treatment-naive patients: a pilot study AIDS 2012 26 649 651 22233654 \n33 Young B Vanig T DeJesus E 96-week results of a pilot study of abacavir/lamivudine and raltegravir in antiretroviral-naive HIV-1-infected patients: the SHIELD trial HIV Clin Trials 2011 12 228 233 22044859\n\n",
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"keywords": "Japan; abacavir; human immunodeficiency virus; hypersensitivity; lamivudine; myocardial infarction; pharmacoepidemiology",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D004338:Drug Combinations; D004342:Drug Hypersensitivity; D015658:HIV Infections; D006801:Humans; D015994:Incidence; D007564:Japan; D019259:Lamivudine; D017202:Myocardial Ischemia; D011358:Product Surveillance, Postmarketing",
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"title": "Safety analysis of Epzicom® (lamivudine/abacavir sulfate) in post-marketing surveillance in Japan.",
"title_normalized": "safety analysis of epzicom lamivudine abacavir sulfate in post marketing surveillance in japan"
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"abstract": "Patients with a known genetic cause of aortic root dilation usually have a single underlying aetiology, either a single gene defect as in Marfan syndrome or chromosomal anomaly as in Turner syndrome. However, it is possible, although unlikely, for a patient to inherit multiple independent risk factors for aortic root dilation. We describe such a patient, who inherited Marfan syndrome and a very unusual form of mosaic Turner syndrome. Long-term follow-up of this patient may provide insight into the natural history of this unique genetic combination.",
"affiliations": "Division of Biological Sciences, Section of Pediatric Cardiology, University of Chicago, Chicago, IL, USA.;Division of Biological Sciences, Section of Pediatric Cardiology, University of Chicago, Chicago, IL, USA.",
"authors": "Groner|Abraham|A|https://orcid.org/0000-0002-3284-3163;Qadir|Asad|A|",
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"country": "England",
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"issue": "30(12)",
"journal": "Cardiology in the young",
"keywords": "Marfan syndrome; Mosaic Turner syndrome; aortic root dilation",
"medline_ta": "Cardiol Young",
"mesh_terms": "D002648:Child; D004106:Dilatation; D004108:Dilatation, Pathologic; D006801:Humans; D008382:Marfan Syndrome; D012307:Risk Factors; D014424:Turner Syndrome",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "1976-1977",
"pmc": null,
"pmid": "33023689",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Aortic root dilation in a child with Marfan syndrome and mosaic Turner syndrome.",
"title_normalized": "aortic root dilation in a child with marfan syndrome and mosaic turner syndrome"
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"abstract": "Intravenous injection of buprenorphine as a cause of livedoid dermatitis is a recently described phenomenon. This report reviews the brief literature of this finding, and presents a case of livedoid dermatitis of both heels following injection more than one day prior, and thesuccessful treatment with nifedipine monotherapy.",
"affiliations": "Vanderbilt University, Nashville, TN, USA.;Vanderbilt University, Nashville, TN, USA.;Vanderbilt University, Nashville, TN, USA.;Vanderbilt University, Nashville, TN, USA.",
"authors": "Wheless|Lee|L|;Zhu|Lilly|L|;Mashayekhi|Mona|M|;Fissell|Rachel B|RB|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961662978610.1177_2324709616629786ArticleLivedoid Dermatitis Treated With Nifedipine Wheless Lee MD, PhD1Zhu Lilly MD1Mashayekhi Mona MD, PhD1Fissell Rachel B. MD, MS11 Vanderbilt University, Nashville, TN, USARachel B. Fissell, MD, MS, Department of Medicine, Vanderbilt University, 1161 21st Ave S, Nashville, TN 37232, USA. Email: Rachel.Fissell@vanderbilt.edu2 2 2016 Jan-Mar 2016 4 1 23247096166297863 7 2015 29 12 2015 © 2016 American Federation for Medical Research2016American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).Intravenous injection of buprenorphine as a cause of livedoid dermatitis is a recently described phenomenon. This report reviews the brief literature of this finding, and presents a case of livedoid dermatitis of both heels following injection more than one day prior, and thesuccessful treatment with nifedipine monotherapy.\n\nlivedoid dermatitissubstance-related disorderscover-dateJanuary-March 2016\n==== Body\nIntroduction\nIntravenous injection of buprenorphine as a cause of livedoid dermatitis is a recently described phenomenon.1,2 This report presents a successful treatment of a case of buprenorphine-induced livedoid dermatitis with nifedipine monotherapy.\n\nCase Presentation\nA 34-year-old Caucasian male with past medical history notable for intravenous drug abuse was admitted to the general medicine service with chief complaint of rash, pain, and edema in his heels for the past 1 to 2 days concerning for cellulitis. The patient reported he had been unable to find veins in his upper extremities, and so had been injecting buprenorphine into his posterior tibial veins. The rash had started on his left heel and shortly thereafter appeared on his right heel in a symmetric distribution. The exam on admission was notable for a slightly purpuric mottled erythema that blanched with residual petechiae on his heels and plantar arches. The patient had a history 1 month prior of gangrenous infection of the penis that grew methicillin-resistant Staphylococcus aureus following similar injection into the dorsal vein of his penis. He was therefore started on empiric clindamycin. The rash continued to evolve with increased pain and swelling, with the development of a reticular, nonblanching border (Figure 1). The patient had remained afebrile, with no leukocytosis, no increased warmth of the eruption, and negative blood cultures. At this time, it was felt this was not a cellulitis, but rather livedoid dermatitis secondary to injection of buprenorphine due to the clinical appearance and history.1,2 Labs drawn during the patient’s previous admission 1 month prior were negative for coagulopathy or vasculitis, including HIV, hepatitis B and C serologies, as were repeat viral serologies. A full vasculitis workup was not repeated during this admission. On hospital day 3 there was further increased erythema, edema, and pain with concern for impending ulceration.3 One hypothesis for the underlying mechanism of livedoid dermatitis is local vasospasm.4,5 Because of its utility in treating Raynaud’s phenomenon, which is also thought to be caused by local vasospasm, a trial of nifedipine was started. The patient’s clinical presentation slowly improved over the following 2 days and was discharged home with follow-up appointments made with psychiatry and his primary care physician. Despite these efforts, he has been lost to follow-up.\n\nFigure 1. Hospital day 2 with development of classic livedoid appearance, increased edema.\n\nDiscussion\nLivedoid dermatitis is an uncommon and preventable complication resulting from inadvertent intra- or peri-arterial injections leading to inflammation, vasospasm, or embolism of insoluble particulates from injections.4,5 Recently, this has been recognized among intravenous drug abusers, with case series published in France showing that livedoid dermatitis occurs more often in individuals with prior complications from intravenous drug use.6,7 Biopsies of the skin have suggested that, in some cases, emboli of the starch from the crushed buprenorphine tablets occludes the microvasculature in the affected area, leading to local inflammation and necrosis.6 As such, treatment modalities have tended to focus on reperfusion and vasodilatation, usually requiring intravenous medications, and often surgical intervention.\n\nMultiple case reports have described treatment with a combination of vasodilatory drugs such as pentoxiphylline or alprostadil, heparin, or systemic steroids.4,8 If the disease progresses to necrosis with ulceration, early debridement has been recommended to prevent secondary infection, a complication already seen in this patient on a prior admission.\n\nSkin changes typically present within hours to days, with a mean time to skin necrosis of 12 days.7 Our patient’s story fits well within the expected timeframe, with likely necrosis of skin. Given the concern for impending ulceration, a confirmatory biopsy was not obtained. Roughly one third of the patients in a small case series had ulceration requiring surgical repair, while others resolved with scarring, and still others with no lasting effects. While the natural course of the lesion is unknown, the patient’s lesions did show clinical improvement coinciding with treatment with nifedipine, and a clinical effect cannot be excluded.\n\nSeveral aspects of this case warrant further consideration. First, this form of livedoid dermatitis presents in a subacute timeframe, as opposed to the near-immediate pain and necrosis seen in classic Nicolau syndrome. The classical presentation also occurs more often following intramuscular injections, with several medications implicated, including nonsteroidal anti-inflammatory drugs, certain antibiotics, and notably a case was reported following a patient’s self-injection of the tumor necrosis factor-α inhibitor etanercept.9,10 The delayed onset thus can present as a diagnostic dilemma, often being mistaken for a cellulitis in its initial stages, as it was in this case. Second, the later presentation also makes the question of vasodilation and reperfusion less straightforward. In instances where hyperacute presentation occurs, the immediate obstruction and ischemia necessitate an immediate response to restore perfusion to the affected area. However, in patients who present days after the inciting injection, irreversible damage should have already occurred if a similar occlusive event had happened. Skin biopsies in other cases have shown microemboli of the starch particles, indicating that vascular obstruction plays a role; however, to what degree is still unknown. Finally, the bilateral presentation in this case is uncommon. However, with the known history of injection into both posterior tibial veins within a 12- to 24-hour period, it seems likely that the same preparation of drug was injected at both sites with the same result.\n\nConclusions\nLivedoid dermatitis following buprenorphine injection is a recently described phenomenon with a delayed presentation compared to other causes of this disease. While the exact mechanism is not known, evidence suggests (a) emboli of particulate matter from the crushed pills, (b) local vasospasm, and (c) local inflammation. Treatment of cases usually involves reperfusion with anticoagulation and vasodilators. Lesions that ulcerate often require surgical repair. Herein we describe a case of buprenorphine-induced livedoid dermatitis that was treated with nifedipine monotherapy whose clinical course showed improvement coinciding with nifedipine imitation.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1 \nPierre-Alexandre J François le P Abdellah S Karim T Christian de G Frédérique C. \nAn unusual case of livedoid and necrotic lesions in a drug addict . Am J Dermatopathol . 2007 ;29 :72 -74 .17284966 \n2 \nSchneider P Duong TA Ortonne N Bagot M Bouaziz JD. \nLivedoid and necrotic skin lesions due to intra-arterial buprenorphine injections evidenced by Maltese cross-shaped histologic bodies . Arch Dermatol . 2010 ;146 :208 -209 .20157043 \n3 \nPotier A Leclech C Croue A Chappard D Verret JL. \nNecrotic livedo after injection of buprenorphine (Subutex) [in French] . Ann Dermatol Venereol . 2007 ;134 :148 -150 .17375011 \n4 \nLuton K Garcia C Poletti E Koester G. \nNicolau syndrome: three cases and review . Int J Dermatol . 2006 ;45 :1326 -1328 .17076716 \n5 \nCorazza M Capozzi O Virgilit A. \nFive cases of livedo-like dermatitis (Nicolau’s syndrome) due to bismuth salts and various other non-steroidal anti-inflammatory drugs . J Eur Acad Dermatol Venereol . 2001 ;15 :585 -588 .11843224 \n6 \nBouquié R Wainstein L Pilet P \nCrushed and injected buprenorphine tablets: characteristics of princeps and generic solutions . PLoS One . 9 (12 ):e113991 .25474108 \n7 \nWainstein L Bernier C Gérardin M \nLivedo-like dermatitis and necrotic lesions after high-dose buprenorphine injections: a national French survey . Br J Dermatol . 2015 ;172 :1412 -1414 .25353069 \n8 \nRuffieux P Salomon D Saurat JH. \nLivedo-like dermatitis (Nicolau’s syndrome): a review of three cases . Dermatology . 1996 ;193 :368 -371 .8993974 \n9 \nGuarneri C Bevelacqua V Polimeni G. \nEmbolia cutis medicamentosa (Nicolau syndrome) . QJM . 2012 ;105 :1127 -1128 .21990368 \n10 \nGuarneri C Polimeni G. \nNicolau syndrome following etanercept administration . Am J Clin Dermatol . 2010 ;11 (suppl 1 ):51 -52 .20586511\n\n",
"fulltext_license": "CC BY",
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"journal": "Journal of investigative medicine high impact case reports",
"keywords": "livedoid dermatitis; substance-related disorders",
"medline_ta": "J Investig Med High Impact Case Rep",
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"title": "Livedoid Dermatitis Treated With Nifedipine.",
"title_normalized": "livedoid dermatitis treated with nifedipine"
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"abstract": "After orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC), recurrent HCC mostly develops within 2 years. All cases of de novo HCC described so far occurred later than 2 years after OLT. Prevention of post-transplantation HCC has usually been tried to achieve by curing or controlling recurrent liver disease. This has been rationale for treatment with interferon (IFN)/ribavirin of HCV-recurrence in patients after OLT, transplanted for advanced HCV-induced liver disease and/or HCC. The availability of new and more efficient drugs has improved chances also for previously difficult-to-treat HCV-positive patients.\n\n\n\nA 75 year-old male patient who had undergone OLT for decompensated HCV-cirrhosis in 2009, and bilio-digestive surgery in 2011 under tracrolimus (0.5 mg/day) and prednisone (5 mg/day) immunosuppressive therapy, started to receive antiviral treatment for recurrent HCV-infection of graft with 200 mg/day ribavirin in combination with ledipasvir and sofosbuvir by the end of October 2015. Because of multiple side effects (anemia, asthenia, infections, and reduction of kidney functions - palliated by treatment with erythropoietin), treatment was stopped after 16 weeks. At the third control, a minimal increase in alpha-fetoprotein (AFP) serum level to 10 μg/L was measured 8 months after therapy, whereas both liver sonography and serum transaminases were normal. The patient's general condition; however, remained poor, and a magnetic resonance imaging (MRI) of abdomen was performed 2 months later. A nodule of 3 cm in diameter with a pseudocapsule was found centrally in the liver. The patient had to be hospitalized for recurrent infections of the lung, overt ascites and peritonitis. Rapid tumor growth (10 cm) was detected during last stay in hospital (April 2017), concomitant with a rise of AFP-serum levels to 91 μg/L. The family decided to take the patient home, and best supportive care was provided by a general practitioner, local nurses and the patient's dedicated wife until his death.\n\n\n\nBefore treating OLT patients with HCV graft reinfection one should not only consider possible advantages of newly effective antiviral-therapies, but also life expectancy and possible side effects (difficult to manage at an outpatient service basis), including severe disadvantages such as the development of HCC.",
"affiliations": "Department of Gastroenterology and Endocrinology, University Medical Center Goettingen, Robert-Koch-Street 40, D-37075, Goettingen, Germany. gramado@med.uni-goettingen.de.;General Practitioner, National health care system, Palazzago, BG, Italy.;Gastro-Centro, Via Trevano 38, 6900, Lugano, Switzerland.;Institute of Anatomy and Cell Biology, University Medical Center, Kreuzbering 36, 37075, Goettingen, Germany.",
"authors": "Ramadori|Giuliano|G|;Bosio|Patrizia|P|;Moriconi|Federico|F|;Malik|Ihtzaz A|IA|",
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"doi": "10.1186/s12885-018-4175-2",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 417510.1186/s12885-018-4175-2Case ReportCase report: 8 years after liver transplantation: de novo hepatocellular carcinoma 8 months after HCV clearance through IFN-free antiviral therapy Ramadori Giuliano +49(0) 15142461999gramado@med.uni-goettingen.de 1Bosio Patrizia pbosio8@gmail.com 2Moriconi Federico federicomoriconi@bluewin.ch 3Malik Ihtzaz A. i.malik@med.uni-goettingen.de 41 0000 0001 0482 5331grid.411984.1Department of Gastroenterology and Endocrinology, University Medical Center Goettingen, Robert-Koch-Street 40, D-37075 Goettingen, Germany 2 General Practitioner, National health care system, Palazzago, BG Italy 3 Gastro-Centro, Via Trevano 38, 6900 Lugano, Switzerland 4 0000 0001 0482 5331grid.411984.1Institute of Anatomy and Cell Biology, University Medical Center, Kreuzbering 36, 37075 Goettingen, Germany 6 3 2018 6 3 2018 2018 18 2574 9 2017 1 3 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\nAfter orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC), recurrent HCC mostly develops within 2 years. All cases of de novo HCC described so far occurred later than 2 years after OLT. Prevention of post-transplantation HCC has usually been tried to achieve by curing or controlling recurrent liver disease. This has been rationale for treatment with interferon (IFN)/ribavirin of HCV-recurrence in patients after OLT, transplanted for advanced HCV-induced liver disease and/or HCC. The availability of new and more efficient drugs has improved chances also for previously difficult-to-treat HCV-positive patients.\n\nCase presentation\nA 75 year-old male patient who had undergone OLT for decompensated HCV-cirrhosis in 2009, and bilio-digestive surgery in 2011 under tracrolimus (0.5 mg/day) and prednisone (5 mg/day) immunosuppressive therapy, started to receive antiviral treatment for recurrent HCV-infection of graft with 200 mg/day ribavirin in combination with ledipasvir and sofosbuvir by the end of October 2015. Because of multiple side effects (anemia, asthenia, infections, and reduction of kidney functions - palliated by treatment with erythropoietin), treatment was stopped after 16 weeks. At the third control, a minimal increase in alpha-fetoprotein (AFP) serum level to 10 μg/L was measured 8 months after therapy, whereas both liver sonography and serum transaminases were normal. The patient’s general condition; however, remained poor, and a magnetic resonance imaging (MRI) of abdomen was performed 2 months later. A nodule of 3 cm in diameter with a pseudocapsule was found centrally in the liver. The patient had to be hospitalized for recurrent infections of the lung, overt ascites and peritonitis. Rapid tumor growth (10 cm) was detected during last stay in hospital (April 2017), concomitant with a rise of AFP-serum levels to 91 μg/L. The family decided to take the patient home, and best supportive care was provided by a general practitioner, local nurses and the patient’s dedicated wife until his death.\n\nConclusion\nBefore treating OLT patients with HCV graft reinfection one should not only consider possible advantages of newly effective antiviral-therapies, but also life expectancy and possible side effects (difficult to manage at an outpatient service basis), including severe disadvantages such as the development of HCC.\n\nKeywords\nHepatocellular carcinomaLiver transplantationHepatitis C virusInterferonRibavirinissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nWorldwide, approximately 180 million people are infected with the hepatitis C virus (HCV) [1]. Twenty to 30% of the infected people will develop liver cirrhosis, and among these, appr. 5% are in danger to develop liver cancer [2]. In the IFN era, about 50% of the patients infected with HCV genotype 1 (G1) achieved sustained virological response (SVR) [3]. HCV-infection is considered to be a major cause of liver cancer development [4], and infections may still develop in cirrhotic patients even after HCV-eradication [5]. Recently, an interesting French nationwide report pointed out that only 8% of the reported liver tumor cases were specifically due to HCV-infection [6]. This could be an explanation for the fact that, statistically, HCV-eradication may not guarantee longer life expectancy compared to persons not having received HCV-eradication [7]. HCV-induced liver cirrhosis and liver cancer are the key indicators for liver transplantation [8]. Chronic hepatitis and cirrhosis may quickly develop after reinfection of the graft in HCV-patients receiving orthotopic liver transplantation (OLT) for HCV-positive advanced liver cirrhosis or hepatocellular carcinoma (HCC) [9, 10]. In transplant centers, HCV-eradication therapy has been performed before and/or after transplantation, and successful viral elimination has been reported under combination of Peg-IFN and ribavirin, administered for different periods [11, 12]. Sustained virological response after both OLT and kidney transplantation has been shown to improve the overall survival in patients with HCV-infection [13–18].\n\nNowadays, anti HCV-therapies have been successively replaced by IFN-free direct-acting-antiviral (DAA) agents with or without ribavirin, leading to a reduction of therapy duration (12–24 weeks), and to an improvement of viral elimination rates to almost 100% for all difficulty grades and viral genotypes [19, 20]. In 2015, the combination of ladispovir / sofusbovir and ribavirin for 24 weeks in patients with HCV-reinfection after OLT was considered gold-standard, with therapy beginning at any time after transplantation [20].\n\nRecurrence of HCC has been observed in a number of cases, even after successful elimination of HCV before or after OLT [21–24]. De novo HCC-development after OLT, however, is a very rare event, and only a few cases have been described so far [25]. A few reports demonstrated an increase of HCC development or recurrence in patients with liver cirrhosis due to HCV-infection and SVR after IFN-free treatment [26, 27] outside the transplantation setting. In contrast, de novo HCC development after having achieved SVR in patients transplanted for HCV-cirrhosis has not yet been described [25].\n\nCase presentation\nIn July 2009, a 69-year-old male patient with decompensated HCV-cirrhosis underwent OLT. Postoperative time was complicated by bile duct anastomosis leakage, which was then treated with surgical bilio-digestive anastomosis in 2011. In 2012, liver histology showed bridging fibrosis, but no clear signs of cirrhosis. During the following years, a mild subclinical cholestasis was treated with oral deoxycholic acid. Immunosuppression was performed with tacrolimus (0.5 mg/day) and prednisone (5 mg/day). Despite viral reinfection and repeated episodes of cholangitis with pruritus, successfully treated with antibiotics, graft function was preserved with acceptable quality of life. As electrography on the graft reached 25 kPa, therapy with ledipasvir (90 mg) / sofusbovir (400 mg) combined with a reduced dosage of ribavirin (200 mg) was started by the end of October 2015. While HCV-negativity was found after 4 weeks of therapy, severe asthenia, loss of appetite and repeated infections developed together with progressive anemia. The latter persisted in spite of weekly subcutaneous administration of erythropoietin. Subsequently, reduction of kidney glomerular filtration rate developed. For this reason, therapy was stopped after 16 weeks while the patient developed ascites and edema of the legs in spite of improvement of liver stiffness down to 15 kPa. After two episodes of pneumonia and repeated laboratory and sonography surveillance (performed by experienced radiologists), 8 months after the end of treatment a first mild increase of serum AFP was detected, while ultrasonography (Fig. 1) did not detect any nodules in the liver. Two months later, a nodule of 3 cm size was detected by multiphasic-MRI (performed with administration of Gd-BOPTA) in the center of the left hepatic lobe (segment 2 (S2)), and a second smaller (1.5 cm) nodule in S4. The hyperintensity of the main lesion on T1-weighted images with enhancement in the arterial phase and with delayed portal venous wash-out [28] was judged to be suspicious for HCC according to the guidelines of the European Society for Medical Oncology (ESMO) (Figs. 2, 3 and 4). The multitude of the lesions led to the decision of therapeutic non-intervention, and best supportive care was offered to the patient in a tertiary care hospital.Fig. 1 Liver ultrasound examination performed 10 months after the end of treatment when AFP was 10 ng/ml. No signs of liver cirrhosis and no signs of tumor were detectable\n\nFig. 2 MRI-investigation of the liver 12 months after end of treatment with SVR; a nodule (3 cm diameter) with the characteristic of a HCC was detected in the left liver lobe (arrow), while a further small nodule was suspected (smaller arrow). No signs of cirrhosis were detectable\n\nFig. 3 Additional slice of the MRI showing the nodule in S2 (arrow) 12 months after the end of treatment and SVR\n\nFig. 4 MRI investigation of the liver as described in Fig. 2. A third nodule (1.2 cm diameter) was described in the right liver lobe (arrow)\n\n\n\nGeneral physical conditions continuously worsened. An MRI of the liver performed by the end of April 2017 (Figs. 5 and 6) showed a massive increase in size of the former central nodule to 10 cm, completely occupying the left liver lobe, accompanied by an increase of serum AFP levels to 91 ng/ ml (Table 1). The family decided to take the patient home where he was having palliative care from his dedicated wife, from his home doctor and nurse.Fig. 5 MRI-investigation 16 months after end of treatment. A rapid growth of the nodule in the left liver lobe was appreciable\n\nFig. 6 MRI of the liver as described in Fig. 2; the size of the subcapsular nodule (smaller arrow) has not increased compared to that of Fig. 1. The supposed third nodule (Fig. 4) was not confirmed\n\nTable 1 Characteristics of the patient with de novo tumor in the liver graft\n\n\t05/15\t01/16\t06/16\t10/16\t01/17\t04/17\t\nBW\t63\t63\t65\t\t\t68\t\nALT\t55\t25\t15\t12\t17\t11\t\nAST\t75\t36\t24\t24\t40\t64\t\nAP\t295\t304\t269\t326\t285\t320\t\nYGT\t291\t295\t210\t287\t267\t315\t\nBILI\t1.01\t1.28\t1.03\t0.92\t0.86\t1.35\t\nTP\t6.1\t6.2\t5.6\t6.1\t5.8\t5.1\t\nAlba\t3.8\t3.8\t3.6\t3.7\t2.9\t2.8\t\nCrea\t1.1\t1.08\t1.36\t1.7\t1.26\t1.86\t\nPLT\t138\t137\t129\t203\t140\t182\t\nINR\t1.17\t1.15\t\t\t1.43\t1.28\t\nAFP\t\t6.1\t6.3\t10.2\t\t91\t\nFibro/Scan (kPa)\t25\t25\t16\t15.3\t\t\t\naAlbumin (20%) infusions were given depending on availability\n\n\n\nDiscussion\nHCV-infection alone or in combination with other damaging noxae such as alcoholic beverages or xenobiotics can lead to chronic hepatitis, cirrhosis and liver cancer (HCC). Risk of tumor development has been shown to be significantly reduced in patients who achieved sustained virological response (SVR) after antiviral therapy consisting of IFN-alpha and ribavirin. Long-term follow-up studies will reveal whether this is the case also for the highly effective new IFN-free therapies with directly-acting-antiviral (DAA) drugs with or without ribavirin [5, 29–32].\n\nDecompensated liver cirrhosis and liver cancer still remain the principal indications for liver transplantation. Recurrence of HCV-infection in the graft, however, is a common adverse event immediately after liver transplantation. Reinfection and the concomitant administration of various drugs leads to the development of liver cirrhosis in about 20 to 30% of the transplanted patients within 5 years after transplantation, with reduction of overall survival compared to alcoholic liver disease [10]. The introduction of new drugs has ignited the discussion about the timing when therapy should be administered, namely before or after transplantation, and, if after transplantation, at which time point exactly?\n\nSome reports have initiated a debate about the possibility of an increased frequency of liver cancer, which may be seen within months after the end of treatment in patients with SVR, who were previously operated for HCC-resection [26]. An increased incidence of HCC has also been reported in patients with liver cirrhosis after SVR achieved with IFN-free therapy [27]. This danger seems to be higher in older patients with more advanced cirrhosis [33–42]. Recurrence of liver tumor after OLT for HCC (mostly outside the liver) is a well-known complication, and the advantages of antiviral therapy during the patient’s stay on the waiting list [26, 43] or after OLT has not yet been proven.\n\nAlthough we cannot exclude the possibility of the presence of tumor cells in liver at the beginning of DAA-therapy, this is the first case report on de novo liver cancer shortly after DAA-induced HCV-elimination in a patient who received long-term treatment after OLT. It is not yet clear how anti-viral treatment could be responsible for tumor development and/or acceleration of tumor growth. One possibility is that prolonged immunosuppression may be aggravated by antiviral agents (including ribavirin), thereby supporting the growth of scattered tumor cells, which have escaped immunosurveillance and were already present at the start of antiviral therapy.\n\nDevelopment of de novo HCC in patients transplanted for advanced liver cirrhosis without clinical signs of cancer is a very rare event. In fact, it has been thought that successful antiviral therapy and alcohol abstinence should prevent cirrhosis and carcinogenesis in the graft, and patients may rather die for other medical complications before the occurrence of cirrhosis and cancer.\n\nIndeed, the early appearance of HCC in the graft after transplantation may represent the recurrence of a pre-existing tumor in the explanted liver, which was not detectable at the time of transplantation. This can only be proven through molecular analyses of the tumor material, which would allow the identification of donor or recipient origin. De novo HCC has also been reported in patients with HCV-reinfection, who achieved SVR after antiviral therapy with IFN and ribavirin [44]. Recurrence of cirrhosis has been confirmed to be a risk factor for de novo HCC-development in the re-infected graft, as is true for patients with HCV-positive liver diseases before transplantation. In one reported case, a tumor developed in a 59-year-old female patient transplanted for HCV-positive HCC, 6 years after living-donor liver transplantation and 2 years after signs of decompensated liver cirrhosis. She was successfully treated with antiviral therapy (Peg-IFN and ribavirin) for 48 weeks [44]. A CT-scan of the liver detected a hepatic nodule of 1 cm size, which was radiologically diagnosed as a classical HCC. The patient had higher AFP-serum levels during 6 months after CT-scan. Liver function tests were, however, within the normal range. Tumor resection was performed, and a tumor of 0.9 cm in size with trabecular growth and desmoplastic changes was diagnosed histologically. The non-tumorous liver tissue was cirrhotic with inflammatory infiltrates of the fibrotic septa. Genotyping of DNA samples extracted from the tumorous and non-tumorous tissue from the graft and the donor indicated that it was a de novo HCC, diagnosed 2 years after end of treatment, and about 2.5 years after confirmation of negative serum HCV-RNA level under antiviral treatment. Our patient developed detectable tumors and a minor increase in serum-AFP level 12 months after start of DAA-therapy and 8 months after the end of therapy. HCC was diagnosed based on the MRI-finding of liver tumor(s), and elevated AFP-serum level. However, in consideration of the reduced physical conditions and of the rather decreasing liver function parameters, in spite of normal transaminase serum levels, no further local or systemic anti-tumoral therapeutic measures were taken into consideration while a rapid and massive growth of the main tumor was detectable 4 months later.\n\nAt this time, patient had to be hospitalized for ascites edema of the legs, attacks of abdominal pain and fever. Recurrent bacterial peritonitis was treated with antibiotics. When diagnosis of a growing tumor was confirmed by MRI, he was sent home for best supportive care by his dedicated wife, home doctor and nurse until his death (June 12th, 2017).\n\nConclusions\nDecision of treating patients suffering of HCV-infection after liver transplantation with DAA-drugs should take in consideration possible side effects including cancer development and life expectancy.\n\nAbbreviations\nAFPAlpha-fetoprotein\n\nDAADirect-acting antiviral\n\nEPOErythropoetin\n\nG1Genotype 1\n\nHCCHepatocellular carcinoma\n\nHCVHepatitis C virus\n\nIFNInterferon\n\nMRIMagnetic resonance imaging\n\nOLTOrthotopic liver transplantation\n\nSVRSustained virological response\n\nAcknowledgements\nWe thank the patient and his family for consent and participation.\n\nFunding\nNot applicable\n\nAvailability of data and materials\nAll data, which is generated and analyzed is included in this report.\n\nAuthors’ contributions\nGR, PB and FM collected and analyzed the data: GR and IAM interpreted the data. All authors were involved in writing manuscript, and final version of the manuscript is read and approved by all authors.\n\nEthics approval and consent to participate\nNot applicable\n\nConsent for publication\nWritten informed consent was obtained from the patient and his guardians for participation in the study design, data collection and treatment as well as publication. The case report was prepared according to CARE guidelines.\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. Mohd Hanafiah K Groeger J Flaxman AD Wiersma ST Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence Hepatology 2013 57 1333 1342 10.1002/hep.26141 23172780 \n2. Westbrook RH Dusheiko G Natural history of hepatitis C J Hepatol 2014 61 S58 S68 10.1016/j.jhep.2014.07.012 25443346 \n3. Amanzada A Schneider S Moriconi F Lindhorst A Suermann T van Thiel DH Early anemia and rapid virological response improve the predictive efficiency of IL28B-genotype for treatment outcome to antiviral combination therapy in patients infected with chronic HCV genotype 1 J Med Virol 2012 84 1208 1216 10.1002/jmv.23323 22711348 \n4. Morgan RL Baack B Smith BD Yartel A Pitasi M Falck-Ytter Y Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies Ann Intern Med 2013 158 329 337 10.7326/0003-4819-158-5-201303050-00005 23460056 \n5. Li DK Chung RT Impact of hepatitis C virus eradication on hepatocellular carcinogenesis Cancer 2015 121 2874 2882 10.1002/cncr.29528 26079399 \n6. Goutté N Sogni P Bendersky N Barbare JC Falissard B Farges O Geographical variations in incidence, management and survival of hepatocellular carcinoma in a western country J Hepatol 2017 66 537 544 10.1016/j.jhep.2016.10.015 27773614 \n7. Innes H McDonald S Hayes P Dillon JF Allen S Goldberg D Mortality in hepatitis C patients who achieve a sustained viral response compared to the general population J Hepatol 2017 66 19 27 10.1016/j.jhep.2016.08.004 27545496 \n8. Roche B Samuel D Antiviral therapy in HCV-infected cirrhotics awaiting liver transplantation: a costly strategy for mixed virological results J Hepatol 2009 50 652 654 10.1016/j.jhep.2009.01.008 19231019 \n9. Féray C Caccamo L Alexander GJ Ducot B Gugenheim J Casanovas T European collaborative study on factors influencing outcome after liver transplantation for hepatitis C. European concerted action on viral hepatitis (EUROHEP) group Gastroenterology 1999 117 619 625 10.1016/S0016-5085(99)70454-3 10464137 \n10. Forns X García-Retortillo M Serrano T Feliu A Suarez F de la Mata M Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation J Hepatol 2003 39 389 396 10.1016/S0168-8278(03)00310-6 12927925 \n11. Everson GT Trotter J Forman L Kugelmas M Halprin A Fey B Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy Hepatology 2005 42 255 262 10.1002/hep.20793 16025497 \n12. Crespo G Mariño Z Navasa M Forns X Viral hepatitis in liver transplantation Gastroenterology 2012 142 1373 1383.e1 10.1053/j.gastro.2012.02.011 22537446 \n13. Everson GT Terrault NA Lok AS Rodrigo DR Brown RS Saab S A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis C after liver transplantation Hepatology 2013 57 1752 1762 10.1002/hep.25976 22821361 \n14. Aleman S Rahbin N Weiland O Davidsdottir L Hedenstierna M Rose N A risk for hepatocellular carcinoma persists long-term after sustained virologic response in patients with hepatitis C-associated liver cirrhosis Clin Infect Dis 2013 57 230 236 10.1093/cid/cit234 23616492 \n15. Jiménez-Pérez M González-Grande R Rando-Muñoz FJ Management of recurrent hepatitis C virus after liver transplantation World J Gastroenterol 2014 20 16409 16417 10.3748/wjg.v20.i44.16409 25469009 \n16. Berenguer M Schuppan D Progression of liver fibrosis in post-transplant hepatitis C: mechanisms, assessment and treatment J Hepatol 2013 58 1028 1041 10.1016/j.jhep.2012.12.014 23262248 \n17. Dumitra S Alabbad SI Barkun JS Dumitra TC Coutsinos D Metrakos PP Hepatitis C infection and hepatocellular carcinoma in liver transplantation: a 20-year experience HPB 2013 15 724 731 10.1111/hpb.12041 23490176 \n18. Sanai FM Mousa D Al-Mdani A Al-Shoail G Al-Ashgar H Al Meshari K Safety and efficacy of peginterferon-α2a plus ribavirin treatment in renal transplant recipients with chronic hepatitis C J Hepatol 2013 58 1096 1103 10.1016/j.jhep.2013.02.004 23428875 \n19. Fagiuoli S Ravasio R Lucà MG Baldan A Pecere S Vitale A Management of hepatitis C infection before and after liver transplantation World J Gastroenterol 2015 21 4447 4456 10.3748/wjg.v21.i15.4447 25914454 \n20. Coilly A Roche B Duclos-Vallée J-C Samuel D Optimum timing of treatment for hepatitis C infection relative to liver transplantation Lancet Gastroenterol Hepatol 2016 1 165 172 10.1016/S2468-1253(16)30008-5 28404073 \n21. Singal AK Freeman DH Anand BS Meta-analysis: interferon improves outcomes following ablation or resection of hepatocellular carcinoma Aliment Pharmacol Ther 2010 32 851 858 10.1111/j.1365-2036.2010.04414.x 20659285 \n22. Xu J Li J Chen J Liu Z-J Effect of adjuvant interferon therapy on hepatitis b/c virus-related hepatocellular carcinoma after curative therapy - meta-analysis Adv Clin Exp Med Off Organ Wroclaw Med Univ 2015 24 331 340 10.17219/acem/29760 \n23. Hsu Y-C Ho HJ Wu M-S Lin J-T Wu C-Y Postoperative peg-interferon plus ribavirin is associated with reduced recurrence of hepatitis C virus-related hepatocellular carcinoma Hepatology 2013 58 150 157 10.1002/hep.26300 23389758 \n24. Zhang D-W Song T-Q Zhang T Wu Q Kong D-L Li Q Adjuvant interferon for early or late recurrence of hepatocellular carcinoma and mortality from hepatocellular carcinoma following curative treatment: a meta-analysis with comparison of different types of hepatitis Mol Clin Oncol 2014 2 1125 1134 10.3892/mco.2014.386 25279210 \n25. Trevisani F Garuti F Cucchetti A Lenzi B Bernardi M De novo hepatocellular carcinoma of liver allograft: a neglected issue Cancer Lett 2015 357 47 54 10.1016/j.canlet.2014.11.032 25444925 \n26. Reig M Mariño Z Perelló C Iñarrairaegui M Ribeiro A Lens S Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy J Hepatol 2016 65 719 726 10.1016/j.jhep.2016.04.008 27084592 \n27. Conti F Buonfiglioli F Scuteri A Crespi C Bolondi L Caraceni P Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals J Hepatol 2016 65 727 733 10.1016/j.jhep.2016.06.015 27349488 \n28. Lencioni R Cioni D Crocetti L Della Pina C Bartolozzi C Magnetic resonance imaging of liver tumors J Hepatol 2004 40 162 171 10.1016/S0168-8278(03)00455-0 14672629 \n29. Hézode C Bronowicki J-P Ideal oral combinations to eradicate HCV: the role of ribavirin J Hepatol 2016 64 215 225 10.1016/j.jhep.2015.09.009 26409316 \n30. Wirth TC Manns MP The impact of the revolution in hepatitis C treatment on hepatocellular carcinoma Ann Oncol 2016 27 1467 1474 10.1093/annonc/mdw219 27226385 \n31. Poordad F Schiff ER Vierling JM Landis C Fontana RJ Yang R Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence Hepatology 2016 63 1493 1505 10.1002/hep.28446 26754432 \n32. Nahon P Bourcier V Layese R Audureau E Cagnot C Marcellin P Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications Gastroenterology 2017 152 142 156.e2 10.1053/j.gastro.2016.09.009 27641509 \n33. Nault J-C Colombo M Hepatocellular carcinoma and direct acting antiviral treatments: controversy after the revolution J Hepatol 2016 65 663 665 10.1016/j.jhep.2016.07.004 27417216 \n34. Toyoda H Kumada T Tada T Changes in patient backgrounds may increase the incidence of HCC after SVR in the era of IFN-free therapy for HCV Hepatology 2016 64 1818 1819 10.1002/hep.28632 27136189 \n35. Ravi S Axley P Jones D Kodali S Simpson H McGuire BM Unusually high rates of hepatocellular carcinoma after treatment with direct-acting antiviral therapy for hepatitis C related cirrhosis Gastroenterology 2017 152 911 912 10.1053/j.gastro.2016.12.021 28161225 \n36. Tsai P-C Huang C-F Yu M-L Unexpected early tumor recurrence in patients with hepatitis C virus-related hepatocellular carcinoma undergoing interferon-free therapy: issue of the interval between HCC treatment and antiviral therapy J Hepatol 2017 66 464 10.1016/j.jhep.2016.10.035 27840227 \n37. Kolly P Dufour J-F A strong message is needed to address the issue of HCC recurrence after DAA therapy J Hepatol 2016 65 1268 1269 10.1016/j.jhep.2016.07.032 27480589 \n38. Carrat F Nahon P Duclos-Vallée JC Pageaux GP Fontaine H Pol S Reply to “a strong message is needed to address the issue of HCC recurrence after DAA therapy” J Hepatol 2016 65 1269 1270 10.1016/j.jhep.2016.07.030 27480588 \n39. Zavaglia C Okolicsanyi S Cesarini L Mazzarelli C Pontecorvi V Ciaccio A Is the risk of neoplastic recurrence increased after prescribing direct-acting antivirals for HCV patients whose HCC was previously cured? J Hepatol 2017 66 236 237 10.1016/j.jhep.2016.08.016 27592303 \n40. Zeng Q-L Li Z-Q Liang H-X Xu G-H Li C-X Zhang D-W Unexpected high incidence of hepatocellular carcinoma in patients with hepatitis C in the era of DAAs: too alarming? J Hepatol 2016 65 1068 1069 10.1016/j.jhep.2016.07.029 27476763 \n41. Torres HA Vauthey J-N Economides MP Mahale P Kaseb A Hepatocellular carcinoma recurrence after treatment with direct-acting antivirals: first, do no harm by withdrawing treatment J Hepatol 2016 65 862 864 10.1016/j.jhep.2016.05.034 27255582 \n42. Reig M Torres F Mariño Z Forns X Bruix J Reply to “direct antiviral agents and risk for hepatocellular carcinoma (HCC) early recurrence: much ado about nothing” J Hepatol 2016 65 864 865 10.1016/j.jhep.2016.05.036 27255581 \n43. Yang JD Aqel BA Pungpapong S Gores GJ Roberts LR Leise MD Direct acting antiviral therapy and tumor recurrence after liver transplantation for hepatitis C-associated hepatocellular carcinoma J Hepatol 2016 65 859 860 10.1016/j.jhep.2016.06.023 27392425 \n44. Morita K Taketomi A Soejima Y Ikegami T Fukuhara T Iguchi T De novo hepatocellular carcinoma in a liver graft with sustained hepatitis C virus clearance after living donor liver transplantation Liver Transpl 2009 15 1412 1416 10.1002/lt.21894 19877253\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "18(1)",
"journal": "BMC cancer",
"keywords": "Hepatitis C virus; Hepatocellular carcinoma; Interferon; Liver transplantation; Ribavirin",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D006528:Carcinoma, Hepatocellular; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D008111:Liver Function Tests; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D013997:Time Factors",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "257",
"pmc": null,
"pmid": "29510685",
"pubdate": "2018-03-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22821361;23490176;27255582;19877253;26079399;27480588;27476763;27840227;25469009;27255581;27480589;27545496;27392425;28161225;25914454;26409316;28404073;27226385;19231019;25279210;27417216;27084592;12927925;25443346;23389758;22537446;23616492;14672629;27641509;26754432;23460056;25444925;27773614;23262248;27136189;20659285;25931368;10464137;22711348;23428875;27592303;27349488;23172780;16025497",
"title": "Case report: 8 years after liver transplantation: de novo hepatocellular carcinoma 8 months after HCV clearance through IFN-free antiviral therapy.",
"title_normalized": "case report 8 years after liver transplantation de novo hepatocellular carcinoma 8 months after hcv clearance through ifn free antiviral therapy"
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"abstract": "Zidovudine (AZT) treatment during pregnancy, delivery, and the postnatal period is associated with adverse effects in the neonate such as bone marrow suppression, elevation in aspartate aminotransferase activity, and lactic acidosis. With antiretroviral therapy (ART) now being recommended for life in HIV-infected pregnant women, infants born to these mothers and on breastfeeds are going to be exposed to antiretrovirals for a longer duration. We report a rare case of an HIV-exposed infant who received AZT prophylaxis for 6 weeks after birth and was on exclusive breastfeed while the mother was on ART and presented with unexplained severe metabolic acidosis and encephalopathy.",
"affiliations": "Pediatric HIV Clinic, Department of Pediatrics, B. J. Wadia Hospital for Children, Mumbai, Maharashtra, India.;Pediatric HIV Clinic, Department of Pediatrics, B. J. Wadia Hospital for Children, Mumbai, Maharashtra, India.",
"authors": "Shah|Ira|I|;Kathwate|Jagdish|J|",
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"fulltext": "\n==== Front\nIndian J Sex Transm Dis AIDS\nIJSTD\nIndian Journal of Sexually Transmitted Diseases and AIDS\n2589-0557 2589-0565 Wolters Kluwer - Medknow India \n\nIJSTD-41-122\n10.4103/ijstd.IJSTD_83_16\nCase Reports\nMetabolic acidosis and encephalopathy in an HIV-exposed infant on breastfeeding and maternal antiretroviral therapy\nShah Ira Kathwate Jagdish Pediatric HIV Clinic, Department of Pediatrics, B. J. Wadia Hospital for Children, Mumbai, Maharashtra, India\nAddress for correspondence: Dr. Ira Shah, 1/B Saguna, 271/B Street Francis Road, Vile Parle (W), Mumbai - 400 056, Maharashtra, India. E-mail: irashah@pediatriconcall.com\nJan-Jun 2020 \n18 6 2020 \n41 1 122 124\n01 9 2016 05 12 2019 30 12 2019 Copyright: © 2020 Indian Journal of Sexually Transmitted Diseases and AIDS2020This 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.Zidovudine (AZT) treatment during pregnancy, delivery, and the postnatal period is associated with adverse effects in the neonate such as bone marrow suppression, elevation in aspartate aminotransferase activity, and lactic acidosis. With antiretroviral therapy (ART) now being recommended for life in HIV-infected pregnant women, infants born to these mothers and on breastfeeds are going to be exposed to antiretrovirals for a longer duration. We report a rare case of an HIV-exposed infant who received AZT prophylaxis for 6 weeks after birth and was on exclusive breastfeed while the mother was on ART and presented with unexplained severe metabolic acidosis and encephalopathy.\n\nAntiretroviralbreastfeedingmetabolic acidosis\n==== Body\nINTRODUCTION\nThe introduction of antiretrovirals (ARVs) in HIV-infected pregnant women has drastically decreased vertical transmission of HIV. However, changes in both immunological response and hematological parameters have been detected in HIV-exposed uninfected newborns and attributed to both HIV protein exposure in utero and due to exposure to ARVs for a prolonged time.[1] Further, mitochondrial dysfunction in infants exposed to nucleoside reverse transcriptase inhibitors in utero has been reported, which could lead to lactic acidosis (LA).[23] With ARV therapy (ART) now recommended in pregnant women for life for the prevention of vertical transmission of HIV and who still continue breastfeeding,[4] infants born to HIV-infected mothers will now be exposed to longer duration of ARV through breastfeeds. We report a rare case of an HIV-exposed infant who received zidovudine (AZT) prophylaxis for 6 weeks after birth and was on exclusive breastfeed while the mother was on ART and presented with unexplained severe metabolic acidosis and encephalopathy.\n\nCASE REPORT\nA 4-month-old HIV-exposed female infant presented to the emergency department with multifocal convulsion, dystonic posturing, and altered sensorium. She was born at 35–36 weeks of gestation by emergency cesarean section due to cord prolapse. The mother was diagnosed to be HIV infected before pregnancy and was on ART consisting of AZT, lamivudine (3TC), and nevirapine (NVP), which she continued till date. Her CD4 count was 560 cells/mm3 at the time of delivery. The baby also received single-dose NPV after birth and then AZT prophylaxis for 6 weeks. The child was exclusively breastfed. At presentation, the child had pallor, altered sensorium, and dystonic posturing. Anterior fontanel was at level and reflexes were brisk though tone was normal, and there was no focal neurological deficit. She had acidotic breathing with hepatomegaly. Other systemic examination was normal. Complete blood count was normal except hypochromic, microcytic anemia (hemoglobin was 9 g/dl). Liver and renal functions were normal, but arterial blood gas analysis showed severe metabolic acidosis (pH: 7.14, bicarbonate: 4.2 mEq/L) with a high anion gap of 30. Serum electrolytes were as follows: sodium: 138 mEq/L and potassium: 4.3 mEq/L. Septic screen in the form of C-reactive protein and blood culture was negative. Plasma sugar was 256 mg/dl, and urine was negative for ketones. The child was treated with intravenous fluids and anticonvulsants. Her sensorium gradually improved. Computed tomography brain revealed bilateral basal ganglia hypodensities suggestive of metabolic encephalopathy [Figure 1]. Serum lactate levels were sent after 24 h of hospitalization and after correction of acidosis which was normal (14 mEq/L [normal: 12–22]). Subsequent blood sugars were normal. Serum ammonia was 70 mmol/L (normal: 30–90 mmol/L), and urinary organic acids screen was normal. Electroencephalogram revealed generalized slowing. Mother was advised to stop breastfeeds and start replacement feeds. Child's HIV polymerase chain reaction was negative. The patient was put on thiamine, biotin, carnitine, and coenzyme Q supplements and regular physiotherapy. She is on regular follow-up.\n\nFigure 1 Computed tomography brain showing bilateral basal ganglia hypodensities\n\nDISCUSSION\nA mitochondrial toxicity (LA) in infants exposed to long-term regimens of ARV therapy (ART) used for the prevention of mother-to-child transmission of HIV is a known but rare entity.[5] The proposed mechanism for LA is inhibition of mitochondrial DNA (mtDNA) polymerase γ leading to mtDNA depletion. Walker et al. showed that AZT and the combination AZT/3TC can produce raised lactate levels and cell death without a reduction in or deletions of mtDNA in an in vitro study.[6] In large study in France, with 3779 HIV-exposed child, Blanche et al. have found that eight children had mitochondrial dysfunction of which two died, three presented with delayed neurological symptoms, and three were symptom free but had severe biological or neurological abnormalities. Four of these children had been exposed to combined AZT and 3TC, and four to AZT alone.[3] Noguera et al. confirmed the hypothesis that zidovudine-exposed children had a significant risk of transient asymptomatic hyperlactatemia.[7] Several cohorts reported that a significant number of exposed but asymptomatic children had increased lactate levels within the 6-week postnatal phase of the ARV prophylaxis exposure. The serum lactate measurement was considered as a surrogate marker of mitochondrial dysfunction and can be used to investigate mitochondrial toxicity.[8] Similarly, in our patient, there was prolonged exposure to ARVs through breastfeeds which could have led to severe metabolic acidosis, leading to encephalopathy. Although serum lactate was normal, it was most probably due to sending the sample late for testing. Human studies have shown that ARVs administered to nursing mothers are present in their breast milk, but the extent of ARV transfer from mother to infant via breast milk is variable with lamivudine, and NVP is transferred to infants via breast milk in biologically significant concentrations.[9] Administration of essential cofactors such as thiamine, riboflavin, L-carnitine, Vitamin C, and antioxidants have been used as therapy for congenital mitochondrial diseases.[10] Similarly, in our patient, we have started coenzyme Q, carnitine, biotin, and riboflavin.\n\nWith ART now being recommended for life in HIV-infected pregnant women and continuation of breastfeeding, infants born to these mothers are going to be exposed to ARVs for a longer duration. These children should be monitored very closely to prevent the adverse effect of mitochondrial toxicity of these drugs.\n\nDeclaration of patient consent\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\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Shah I Immunological and hematological effects of perinatal exposure to antiretroviral drugs in HIV exposed but uninfected children Indian Pediatr 2013 50 565 6 23942399 \n2 Shah I Lactic acidosis in HIV-exposed infants with perinatal exposure to antiretroviral therapy Ann Trop Paediatr 2009 29 257 61 19941748 \n3 Blanche S Tardieu M Rustin P Slama A Barret B Firtion G Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues Lancet 1999 354 1084 9 10509500 \n4 Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection; 2013 Last accessed on 2013 Nov 15 Available from: http://wwwwhoint/hiv/top ics/strategic_use \n5 Scalfaro P Chesaux JJ Buchwalder PA Biollaz J Micheli JL Severe transient neonatal lactic acidosis during prophylactic zidovudine treatment Intensive Care Med 1998 24 247 50 9565807 \n6 Walker UA Stezer B Venhoff N Increased long-term mitochondrial toxicity in pyrimidine nucleoside combinations 3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV Athens 2001 Abstract no 18 \n7 Noguera A Fortuny C Muñoz-Almagro C Sanchez E Vilaseca MA Artuch R Hyperlactatemia in human immunodeficiency virus-uninfected infants who are exposed to antiretrovirals Pediatrics 2004 114 e598 603 15492359 \n8 Alimenti A Burdge DR Ogilvie GS Money DM Forbes JC Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to perinatal antiretroviral therapy Pediatr Infect Dis J 2003 22 782 9 14506368 \n9 Mirochnick M Thomas T Capparelli E Zeh C Holland D Masaba R Antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy Antimicrob Agents Chemother 2009 53 1170 6 19114673 \n10 ter Hofstede HJ de Marie S Foudraine NA Danner SA Brinkman K Clinical features and risk factors of lactic acidosis following long-term antiretroviral therapy: 4 fatal cases Int J STD AIDS 2000 11 611 6 10997508\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2589-0557",
"issue": "41(1)",
"journal": "Indian journal of sexually transmitted diseases and AIDS",
"keywords": "Antiretroviral; breastfeeding; metabolic acidosis",
"medline_ta": "Indian J Sex Transm Dis AIDS",
"mesh_terms": null,
"nlm_unique_id": "101730896",
"other_id": null,
"pages": "122-124",
"pmc": null,
"pmid": "33063000",
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"title": "Metabolic acidosis and encephalopathy in an HIV-exposed infant on breastfeeding and maternal antiretroviral therapy.",
"title_normalized": "metabolic acidosis and encephalopathy in an hiv exposed infant on breastfeeding and maternal antiretroviral therapy"
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"abstract": "A 23-year-old woman developed ischemic stroke (IS) 8 to 12 hours after ingestion of sumatriptan (ST) and then developed mucosal bleeding secondary to acute thrombocytopenia likely due to dipyridamole (DP) on the 10th day poststroke. Sumatriptan-associated IS and DP-induced thrombocytopenia are rare events in themselves and their sequential occurrence in the same patient is quite exceptional. We compare our case to other similar cases in the literature.",
"affiliations": "Care of the Elderly, Royal Preston Hospital, Preston, United Kingdom.",
"authors": "Adams|Carolyn|C|;Dhirendra|Allen|A|;Ames|Paul R J|PR|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D058825:Serotonin 5-HT1 Receptor Agonists; D004176:Dipyridamole; D018170:Sumatriptan",
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"journal": "Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis",
"keywords": null,
"medline_ta": "Clin Appl Thromb Hemost",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D002545:Brain Ischemia; D004176:Dipyridamole; D005260:Female; D006470:Hemorrhage; D006801:Humans; D007049:Iatrogenic Disease; D010975:Platelet Aggregation Inhibitors; D058825:Serotonin 5-HT1 Receptor Agonists; D020521:Stroke; D018170:Sumatriptan; D013921:Thrombocytopenia",
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"references": null,
"title": "Ischemic stroke followed by acute thrombocytopenia: a double iatrogenic whammy.",
"title_normalized": "ischemic stroke followed by acute thrombocytopenia a double iatrogenic whammy"
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"abstract": "BACKGROUND\nVaginal laceration during coitus is not a rare occurrence; however, vaginal perforation from coitus is uncommon and occurs in less than 1% of nonobstetric genital tract injuries. Limited case reports exist discussing the recognition and management of vaginal perforation. Previously described management is commonly performed with laparotomy.\n\n\nMETHODS\nWe report a case of postcoital vaginal laceration and posterior fornix perforation in an adolescent with hemoperitoneum, pneumoperitoneum, and subsequent hypovolemic shock, and describe a laparoscopic approach for repair.\n\n\nCONCLUSIONS\nVaginal perforation with subsequent peritonitis and hemodynamic instability is a rare outcome in an adolescent who presents to the emergency department with pain or bleeding in the setting of recent penile intercourse. Delays in recognition can lead to further patient compromise, with potential morbidity or mortality. In this patient cohort, we suggest maintaining a high clinical suspicion for this sequela, and a low threshold for surgery with perforations greater than 1 cm. In the event that surgical management is warranted, we recommend a laparoscopic approach to increase visibility and to improve postoperative outcomes.",
"affiliations": "Department of Obstetrics, Gynecology and Women's Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York. Electronic address: alcohen212@gmail.com.;Department of Obstetrics, Gynecology and Women's Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.;Department of Obstetrics, Gynecology and Women's Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.",
"authors": "Cohen|Alexa|A|;Ulrich|Amanda|A|;Semenyuk|Natalie|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpag.2020.05.001",
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"issue": "33(5)",
"journal": "Journal of pediatric and adolescent gynecology",
"keywords": "Adolescent; Intercourse; Laparoscopy; Vaginal perforation",
"medline_ta": "J Pediatr Adolesc Gynecol",
"mesh_terms": "D000293:Adolescent; D003075:Coitus; D005260:Female; D006470:Hemorrhage; D006801:Humans; D022125:Lacerations; D010535:Laparoscopy; D008297:Male; D010538:Peritonitis; D011027:Pneumoperitoneum; D012769:Shock; D014621:Vagina",
"nlm_unique_id": "9610774",
"other_id": null,
"pages": "594-598",
"pmc": null,
"pmid": "32416268",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A Laparoscopic Approach to Postcoital Vaginal Perforation in an Adolescent with Peritonitis and Hypovolemic Shock.",
"title_normalized": "a laparoscopic approach to postcoital vaginal perforation in an adolescent with peritonitis and hypovolemic shock"
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"abstract": "BACKGROUND\nCarotid angioplasty and stenting (CAS) of the cervical segment is a safe and effective procedure for the treatment of carotid artery disease. In rare cases, this procedure causes intracranial hemorrhage (ICH), which is described most often as an ipsilateral intra-parenchymal hematoma. This ICH is the result of a cerebral hyperperfusion syndrome (CHS). Isolated subarachnoid hemorrhage may occur exceptionally, with only 9 cases that have been reported in the literature.\n\n\nMETHODS\nWe reported a case of a 71-year-old man who presented a massive non-aneurysmal subarachnoid hemorrhage one hour after angioplasty and stenting of the cervical segment of the left internal carotid artery. Medical and surgical management included external ventricular drain placement. Rebleeding occurred two days later, worsening the patient's clinical condition. Finally, the patient died 2 weeks later.\n\n\nCONCLUSIONS\nThis rare presentation of ICH following CAS allows us to discuss the risk factors, complications and management of CHS.",
"affiliations": "CHU de Caen, Department of Neurosurgery, Avenue de la Côte de Nacre, 14000 Caen, France; Université Caen Normandie, Medical School, 14000 Caen, France. Electronic address: arthur.leclerc@neurochirurgie.fr.;CHU de Rouen, Department of Neurosurgery, 76000 Rouen, France; Université Rouen Normandie, Medical School, 76000 Rouen, France.;CHU de Rouen, Department of Neurosurgery, 76000 Rouen, France; Université Rouen Normandie, Medical School, 76000 Rouen, France.;CHU de Rouen, Department of Neurosurgery, 76000 Rouen, France; Université Rouen Normandie, Medical School, 76000 Rouen, France.;CHU de Rouen, Department of Neurosurgery, 76000 Rouen, France.",
"authors": "Leclerc|A|A|;Goia|A|A|;Gilard|V|V|;Derrey|S|S|;Curey|S|S|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.neuchi.2021.04.003",
"fulltext": null,
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"issn_linking": "0028-3770",
"issue": null,
"journal": "Neuro-Chirurgie",
"keywords": "Carotid stenting; Cerebral hyperperfusion syndrome; Intracranial hemorrhage; Subarachnoid hemorrhage",
"medline_ta": "Neurochirurgie",
"mesh_terms": null,
"nlm_unique_id": "0401057",
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"pmc": null,
"pmid": "33895172",
"pubdate": "2021-04-22",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Massive non-aneurysmal subarachnoid hemorrhage after cervical carotid angioplasty and stenting: A case report and review of the literature.",
"title_normalized": "massive non aneurysmal subarachnoid hemorrhage after cervical carotid angioplasty and stenting a case report and review of the literature"
} | [
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"abstract": "This observational safety study used national registers to compare the real world cardiovascular and skeletal safety of zoledronic acid (ZA) against oral bisphosphonates (oBP) and untreated population controls.\n\n\n\nPropensity score matched cohort study in Sweden and Denmark.\n\n\n\nMatched cohort 1 included 8739 ZA users and 25,577 oBP users while matched cohort 2 included 8731 ZA users and 25,924 untreated subjects. In comparison to oBP users, heart failure risk was higher in ZA users, with an adjusted HR (adj) (95%CI) of 1.17 (1.04;1.32) and a higher all-cause mortality (adj HR 1.24 (1.15; 1.34)), however, there was no increased risk of cardiovascular mortality. In the comparison to untreated subjects, ZA users showed a higher risk of atrial fibrillation, adj HR 1.18 (1.05;1.32), arrhythmias adj HR 1.18 (1.06;1.31), and heart failure, adj HR 1.38 (1.24;1.54). Cardiovascular mortality was lower in ZA users (adj HR 0.87 (0.77; 0.98)) and risk of adverse skeletal outcomes was significantly higher, reflecting more severe osteoporosis in these patients. There was no association of cardiovascular risk with increasing exposure time. Sensitivity analyses produced similar findings with no substantial changes in event rates.\n\n\n\nWe noted an increased risk of heart failure, fractures and death among ZA users compared with oral BP. The risk of cardiovascular and skeletal outcomes was higher in ZA users than in matched population controls, but there was no increase in cardiovascular mortality in ZA users compared to oral BP or untreated controls. Despite propensity score matching, it is not possible to determine with certainty whether the increased risk of cardiovascular outcomes is consistent with a true drug effect or higher baseline risk in patients who begin ZA treatment.",
"affiliations": "OPEN, Department of Clinical Research, University of Southern Denmark and Odense University Hospital, Odense, Denmark.;OPEN, Department of Clinical Research, University of Southern Denmark and Odense University Hospital, Odense, Denmark.;Novartis Healthcare Pvt. Ltd., Hyderabad, India.;Novartis Pharma AG, Basel, Switzerland.;Novartis Healthcare Pvt. Ltd., Hyderabad, India.;Department of Endocrinology, Rikshospitalet and University of Oslo, Oslo, Norway.;Centre for Pharmacoepidemiology, Clinical Epidemiology Unit, Karolinska Institutet Stockholm, Sweden; Department of Drug Design and Pharmacology, University of Copenhagen, Denmark.;OPEN, Department of Clinical Research, University of Southern Denmark and Odense University Hospital, Odense, Denmark; Department of Medicine, Holbæk, Hospital, Denmark. Electronic address: b.abrahamsen@physician.dk.",
"authors": "Rubin|Katrine Hass|KH|;Möller|Sören|S|;Choudhury|Anup|A|;Zorina|Olesya|O|;Kalsekar|Sameer|S|;Eriksen|Erik F|EF|;Andersen|Morten|M|;Abrahamsen|Bo|B|",
"chemical_list": "D050071:Bone Density Conservation Agents; D000077211:Zoledronic Acid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bone.2020.115296",
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"issue": "134()",
"journal": "Bone",
"keywords": "Cardiovascular risk; Matched cohorts; Observational cohort study; Propensity score; Skeletal risk; Zoledronic acid",
"medline_ta": "Bone",
"mesh_terms": "D050071:Bone Density Conservation Agents; D015331:Cohort Studies; D003718:Denmark; D006801:Humans; D010024:Osteoporosis; D012042:Registries; D012307:Risk Factors; D013548:Sweden; D000077211:Zoledronic Acid",
"nlm_unique_id": "8504048",
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"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cardiovascular and skeletal safety of zoledronic acid in osteoporosis observational, matched cohort study using Danish and Swedish health registries.",
"title_normalized": "cardiovascular and skeletal safety of zoledronic acid in osteoporosis observational matched cohort study using danish and swedish health registries"
} | [
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"activesubstancename": "ZOLEDRONIC ACID"
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"abstract": "Nitrofurantoin-induced diffuse lung toxicity is well documented in the literature but is often misdiagnosed. We describe an 82-year-old female medicated with nitrofurantoin for the previous 2 years who was admitted for dyspnoea, dry cough and fatigue for 4 months. She was febrile and tachypnoeic and she presented with bilateral basal crackles, hypoxaemic respiratory failure and slightly elevated C-reactive protein levels. A chest radiograph showed bilateral air-space consolidation and interstitial infiltrates and the high-resolution computed tomography scan was evocative of a perilobular pattern of organising pneumonia (OP). Due to the clinical-radiological context, she was diagnosed with a presumable nitrofurantoin-induced OP. She was started on prednisolone 60 mg daily with a progressive improvement. It is important that clinicians are aware of the spectrum of side effects associated with nitrofurantoin so as to monitor patients.\nIt is crucial to ensure that a thorough medical history with a systems review and a complete drug history are carried out.Chronic pulmonary toxicity due to nitrofurantoin is rare and it occurs primarily in older women who have been prescribed relatively small doses of nitrofurantoin for UTI prevention.The cessation of nitrofurantoin is the basis of the treatment and may be sufficient for clinical and radiological improvement.",
"affiliations": "Department of Internal Medicine Centro Hospitalar Baixo Vouga, Aveiro, Portugal.;Department of Pneumology, Centro Hospitalar Baixo Vouga, Aveiro, Portugal.;Department of Internal Medicine Centro Hospitalar Baixo Vouga, Aveiro, Portugal.;Department of Pneumology, Centro Hospitalar Baixo Vouga, Aveiro, Portugal.;Department of Internal Medicine Centro Hospitalar Baixo Vouga, Aveiro, Portugal.",
"authors": "Almeida|Paulo|P|;Seixas|Eduarda|E|;Pinheiro|Beatriz|B|;Ferreira|Pedro|P|;Araújo|Ana|A|",
"chemical_list": null,
"country": "Italy",
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"doi": "10.12890/2019_001295",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2019_0012951295-1-9741-1-10-20191028ArticlesConsider Nitrofurantoin as a Cause of Lung Injury Almeida Paulo 1Seixas Eduarda 2Pinheiro Beatriz 1Ferreira Pedro 2Araújo Ana 1\n1 Department of Internal Medicine Centro Hospitalar Baixo Vouga, Aveiro, Portugal\n2 Department of Pneumology, Centro Hospitalar Baixo Vouga, Aveiro, Portugal2019 30 10 2019 6 11 00129524 9 2019 15 10 2019 © EFIM 20192019This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseNitrofurantoin-induced diffuse lung toxicity is well documented in the literature but is often misdiagnosed. We describe an 82-year-old female medicated with nitrofurantoin for the previous 2 years who was admitted for dyspnoea, dry cough and fatigue for 4 months. She was febrile and tachypnoeic and she presented with bilateral basal crackles, hypoxaemic respiratory failure and slightly elevated C-reactive protein levels. A chest radiograph showed bilateral air-space consolidation and interstitial infiltrates and the high-resolution computed tomography scan was evocative of a perilobular pattern of organising pneumonia (OP). Due to the clinical–radiological context, she was diagnosed with a presumable nitrofurantoin-induced OP. She was started on prednisolone 60 mg daily with a progressive improvement. It is important that clinicians are aware of the spectrum of side effects associated with nitrofurantoin so as to monitor patients.\n\nLEARNING POINTS\nIt is crucial to ensure that a thorough medical history with a systems review and a complete drug history are carried out.\n\nChronic pulmonary toxicity due to nitrofurantoin is rare and it occurs primarily in older women who have been prescribed relatively small doses of nitrofurantoin for UTI prevention.\n\nThe cessation of nitrofurantoin is the basis of the treatment and may be sufficient for clinical and radiological improvement.\n\nNitrofurantoinpulmonary toxicitydrug-induced lung toxicityorganising pneumonia\n==== Body\nCASE DESCRIPTION\nAn 82-year-old Caucasian female was admitted to the medical ward with worsening dyspnoea, shortness of breath, longstanding dry cough, intermittent fever and intense fatigue for approximately 4 months. She was hospitalised approximately 3 months previously due to a community-acquired pneumonia and treated with empiric antibiotherapy with a temporary improvement. She had hypertension controlled with losartan and urinary incontinence medicated with trospium chloride. No other medication was initially reported. She was a non-smoker with no occupational exposure or allergies. Upon examination, she was febrile (38.0ºC), tachypnoeic and hypoxaemic with an SpO2 of 87% on room air. Chest auscultation revealed bilateral basal inspiratory crackles. Laboratory workup showed elevated C-reactive protein (3.0 mg/dl [<0.50]) and lactate dehydrogenase (1498 U/l [120–246]) levels and hypoxaemic respiratory failure (PaO2/FiO2 ratio=235). A chest radiograph (CXR) exposed bilateral air-space consolidation and interstitial infiltrates (Fig. 1A).\n\nDuring the hospital stay, a slight hypertransaminasaemia (AST 147 U/l [<40] and ALT 142 U/l [<49]) was noted with a positive anti-mitochondrial M2 antibody. Blood cultures and viral serologies were negative. Thyroid function, brain natriuretic peptide, abdominal ultrasonography and echocardiogram assessments were normal. A high-resolution computed tomography scan (HRCT) revealed large, bilateral and basal areas of patchy alveolar infiltration, bilateral ground-glass opacification and some thick-walled bronchi with distortion (Fig. 2). The pattern was highly suggestive of a “perilobular variant” of organising pneumonia (OP). Flexible bronchoscopy was unremarkable and the bronchoalveolar lavage (BAL) presented a cellular profile compatible with OP (63% lymphocytes [CD4/CD8 ratio 0.7], 8% neutrophils and 26% macrophages). Cytological, bacteriological and mycobacteriological examinations of BAL were negative. Lung function testing revealed a restrictive pattern [Tiffeneau index 0.76, FVC 62.4% predicted] with a diffusing capacity of the lungs for carbon monoxide (DLCO) of 29.7% predicted. A thorough medical history with a systems review was conducted and the patient reported recurrent urinary tract infections (UTI) that resolved after taking a “vitamin” advised by a family member. Upon accessing the computer drug-dispensing software, it was discovered that the patient was taking nitrofurantoin 100 mg every day for the past 2 years that had been prescribed by the family doctor at her request.\n\nWithin the described context, a diagnosis of nitrofurantoin-induced OP was assumed. Due to old age and the presence of an elusive perilobular pattern for OP, a decision was made not to pursue biopsy. The patient was started on prednisolone 0.75 mg/kg/day with a rapid and sustained improvement making her discharge possible. The drug was obviously discontinued. After 12 weeks the patient was asymptomatic with a normal laboratory workup, a 20% improvement in FVC (82% predicted), a 16% improvement in DLCO (45.6% predicted) and radiographic normalisation (Fig. 1B). She completed the planned tapering of prednisolone with clinical stability.\n\nDISCUSSION\nNitrofurantoin is an antibacterial agent commonly used for treatment and prevention of UTI. The incidence of pulmonary toxicity due to nitrofurantoin is estimated to lie between 0.0001% and 0.001%[1]. Although rare, nitrofurantoin-induced diffuse lung toxicity is one of the most commonly reported pulmonary drug toxicities, reflecting the increased popularity of the drug[2]. Female sex, accountable for 85–95% of cases, renal impairment and older age are associated with higher risk of this toxicity[3,4]. This phenomenon is not dose-related and can have an acute onset (approximately 90% of cases) or a chronic presentation[1,3]. Chronic pulmonary toxicity is seen primarily in older women who have been prescribed relatively small doses of nitrofurantoin for UTI prevention[3,4]. Clinical presentation is nonspecific and less intense than in acute reactions, making diagnosis more challenging. There is a delay between the time of initial exposure to nitrofurantoin and the insidious onset of symptoms. The initial complementary examinations are focused on excluding other diagnoses, notably other interstitial lung diseases. Laboratory abnormalities may include positive anti-nuclear, anti-smooth muscle and anti-neutrophil cytoplasmic antibody results[3,4], as in our patient, and may not indicate a rheumatic disease. Bilateral and basal lung infiltrates are seen on CXR in 94% of patients[1]. The HRCT shows frequently bilateral ground-glass attenuation, irregular linear opacities, bibasal air-space consolidation and fibrosis[1,2,5]. Lung function assessment generally reveals restrictive physiology and the BAL cellular profile can reveal lymphocytosis, neutrophilia or eosinophilia[3]. Lung biopsy is not always necessary in a highly suspicious context[3].\n\nThe cessation of nitrofurantoin is the basis of the treatment and may be sufficient for clinical and radiological improvement[2,3]. Re-exposure to nitrofurantoin is not advised due to the high likelihood of recurrence[3,5]. For patients with severe respiratory compromise, as for our patient, glucocorticoids can be necessary and a prednisolone-equivalent dose of 0.75 mg/kg per day is initially given for the first 1 to 3 months, with a tapering regimen as tolerated for a total duration of 6–12 months[3,5]. Most patients will improve after 2 to 12 weeks, although mild fibrotic changes persisted long-term in two-thirds of patients[3].\n\nThis reaction is well documented in the literature, but is often misdiagnosed, resulting in unnecessary treatment, longer hospital stay and increased morbi-mortality[2]. Similar to other cases, our patient was initially admitted for presumed pneumonia. The score of 6 on the Naranjo Adverse Drug Reaction Probability Scale indicated that the patient’s OP was probably related to nitrofurantoin. Thus, a definitive diagnosis of a secondary OP pattern of lung injury related to nitrofurantoin was made in light of: a compatible history of exposure to nitrofurantoin; restrictive lung physiology; a HRCT pattern of OP; a supporting BAL profile; exclusion of other diagnoses; a clear clinical and radiological improvement after cessation of the drug and corticosteroid therapy.\n\nIn the case described, the patient did not recognise nitrofurantoin as a drug with toxic potential and therefore did not report taking it. On the other hand, the medical team tends to communicate poorly with patients, relying too much on computer records to make the medical history. Thorough medical history and therapeutic reconciliation must be part of every physician’s routine. In addition, to avoid similar cases, communication between physicians, carers and pharmacists should be improved and the population should be educated regarding the iatrogenic potential of any drug. When clinicians cannot avoid the use of nitrofurantoin, they should be aware of the potential lung injury and carefully monitor patients.\n\nConflicts of Interests: The Authors declare that there are no competing interest\n\nFigure 1 1A: Chest radiograph (CXR) at patient’s admission with bilateral air-space consolidation and interstitial infiltrates.\n\n1B: Follow-up CXR at 12 weeks showing resolution of the previous parenchymal abnormalities\n\nFigure 2 The high-resolution computed tomography scan (HRCT) revealed large and bilateral areas of patchy alveolar infiltration and linear opacities, the largest with evident are as of an air bronchogram, mainly at the bases; bilateral ground-glass opacification, involving the most organised densification areas; some thick-walled bronchi with distortion and appereance suggestive of small traction bronchiectactis\n==== Refs\nREFERENCES\n1 Browning ET Huckleberry JM Barrow WB Restauri NL Kemme DJ Cool CD Downstaging of non-small-cell lung cancer through identification of reversible drug toxicity J Clin Oncol 2016 34 e6 8 24799494 \n2 Kabbara WK Kordahi MC Nitrofurantoin-induced pulmonary toxicity: a case report and review of the literature J Infect Public Health 2015 8 309 313 25747822 \n3 de Zeeuw J Gillissen AG Nitrofurantoin-induced pulmonary injury UpToDate 2018 http://www.uptodate.com accessed September 1, 2019 \n4 Roden AC Camus P Iatrogenic pulmonary lesions Semin Diagn Pathol 2018 35 260 271 29631763 \n5 Kanji Z Su VC Mainra R Nitrofurantoin-induced pulmonary reaction involving respiratory symptoms: case report Can J Hosp Pharm 2011 64 362 365 22479089\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2284-2594",
"issue": "6(11)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Nitrofurantoin; drug-induced lung toxicity; organising pneumonia; pulmonary toxicity",
"medline_ta": "Eur J Case Rep Intern Med",
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"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001295",
"pmc": null,
"pmid": "31890712",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "22479089;24799494;25747822;29631763",
"title": "Consider Nitrofurantoin as a Cause of Lung Injury.",
"title_normalized": "consider nitrofurantoin as a cause of lung injury"
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"companynumb": "PT-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-231644",
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"activesubstancename": "NITROFURANTOIN"
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{
"abstract": "Vancomycin induced thrombocytopenia (VIT) is an uncommon side effect of vancomycin which can manifest from mild petechiae to life-threatening bleed. Decreased renal clearance of vancomycin results in prolonged thrombocytopenia by antibody-mediated platelet destruction in the presence of vancomycin. Improvement in thrombocytopenia is achieved with the elimination of vancomycin. We describe a patient with end stage renal disease who experienced a protracted course of thrombocytopenia from vancomycin. We illustrate the mechanism of thrombocytopenia and the treatment modalities used by us and those described in literature. VIT is an important differential in patients with thrombocytopenia admitted to the hospital.",
"affiliations": "Hematology/Oncology Department, Ochsner Louisiana State University of Health Sciences, Shreveport, Louisiana, USA.;Department of Internal Medicine, Ochsner Louisiana State University of Health Sciences, Shreveport, Louisiana, USA.;Hematology/Oncology Department, Ochsner Louisiana State University of Health Sciences, Shreveport, Louisiana, USA.",
"authors": "Ajit|Nisha Elizabeth|NE|;Devarashetty|Sindhu Priya|SP|;Master|Samip|S|",
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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.com 10.1159/000503418cro-0012-0749Case ReportVancomycin Induced Thrombocytopenia – Protracted Course in a Hemodialysis Patient Ajit Nisha Elizabeth a*Devarashetty Sindhu Priya bMaster Samip caHematology/Oncology Department, Ochsner Louisiana State University of Health Sciences, Shreveport, Louisiana, USAbDepartment of Internal Medicine, Ochsner Louisiana State University of Health Sciences, Shreveport, Louisiana, USAcHematology/Oncology Department, Ochsner Louisiana State University of Health Sciences, Shreveport, Louisiana, USA*Nisha Elizabeth Ajit, Hematology/Oncology Department. Feist-Weiller Cancer Center, Ochsner Louisiana State University of Health Sciences, 1501 Kings Highway, Shreveport, LA 71103 (USA), E-Mail nisha.ajit06@gmail.comSep-Dec 2019 2 10 2019 2 10 2019 12 3 749 754 13 9 2019 17 9 2019 2019 Copyright © 2019 by S. Karger AG, Basel2019This 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.Vancomycin induced thrombocytopenia (VIT) is an uncommon side effect of vancomycin which can manifest from mild petechiae to life-threatening bleed. Decreased renal clearance of vancomycin results in prolonged thrombocytopenia by antibody-mediated platelet destruction in the presence of vancomycin. Improvement in thrombocytopenia is achieved with the elimination of vancomycin. We describe a patient with end stage renal disease who experienced a protracted course of thrombocytopenia from vancomycin. We illustrate the mechanism of thrombocytopenia and the treatment modalities used by us and those described in literature. VIT is an important differential in patients with thrombocytopenia admitted to the hospital.\n\nKeywords\nVancomycinDrug induced thrombocytopeniaEnd stage renal disease\n==== Body\nIntroduction\nDrug-induced thrombocytopenia is a well-recognized entity and a common hematology consult.\n\nWe present a case of protracted thrombocytopenia from vancomycin in a patient with end-stage renal disease. We also attempt to illustrate the relationship between serum vancomycin levels and platelet count, and thereby depict that immune mediated platelet destruction occurs in the presence of vancomycin. The use and utility of rituximab in persistent thrombocytopenia is also discussed.\n\nCase Report\n61-year-old male with a history of polycystic kidney disease, end stage renal disease and hepatitis C was admitted with a bleed in a right renal cyst which was treated with embolization. On admission the hemogram was normal other than hemoglobin of 11.6. He was started on antibiotics with vancomycin and Zosyn on Day 4 of hospitalization for fever. On Day 9 patient had drop in platelets to 15 (Fig. 1). As all infectious work up was negative antibiotics were stopped. Heparin induced thrombocytopenia panel was sent and was negative. Patient also had epistaxis from the nose, florid ecchymosis on the abdomen, thighs, chest wall, and upper extremities requiring platelets transfusions and nasal packing for the epistaxis. DIC panel was normal and peripheral smear showed decreased platelets with no schistocytes and normal WBC's. He was given Intravenous immunoglobulins on Day 11–13 at a dose of 1 g/kg/day. Patient was started on prednisone at 1 mg/kg/daily on Day 14. On Day 16, patient became severely hypotensive with BP 80/50 mm Hg and short of breath. CT abdomen and pelvis showed a new hemorrhage around the left kidney. Urology and IR deferred invasive procedures due to platelet count being <10 K/μL. A direct Coombs test done was positive, whereas on admission it had been negative, demonstrating hemolysis in addition to bleeding in the form of recurrent epistaxis, ecchymosis and melena causing severe anemia. Daily platelets and packed red blood cells were administered. Eltrombopag was started on Day 17 at a dose of 50 mg daily. He received hemodialysis every 48 h and darbepoetin weekly. Platelet count 1 h after transfusion showed no increase indicating platelet antibody-mediated destruction. Platelet drug dependent antibody panel was sent on Day 18 and flow cytometry demonstrated that IgG antibodies were positive in the patient sera without vancomycin; with introduction of vancomycin, both IgG and IgM antibodies to vancomycin became positive. On Day 24, 25 and 26, patient received plasma exchange in an effort to remove drug-induced antibodies. Patient also concurrently received CRRT for effecting greater vancomycin clearance. Vancomycin random levels drawn during the hospital course are depicted in Figure 1. On Day 31, patient was given Rituximab 375 mg/m2 as platelets continued to be less than 10 K/μL. On Day 35, the platelet count doubled to 39 K/μL. On Day 37, patient became severely hypotensive with complaints of black stools and pain in the left flank. CT angiography found a recurrent bleed in the left kidney and he underwent IR guided embolization of the one of the segmental branches of the left renal artery. Platelet continued to improve and by Day 44 were within the normal range (245 u/L). On Day 47, patient was discharged with platelets of 322 K/μL and prednisone at tapering doses over 4 weeks.\n\nDiscussion\nVancomycin is bactericidal macrolide antibiotic used for suspected or confirmed gram-positive infections including methicillin resistant staph aureus [1]. Vancomycin-induced thrombocytopenia (VIT) while reported as early as 1985, is still a lesser known complication of the drug [2]. Patients had a wide spectrum of presentation, ranging from asymptomatic to florid petechial hemorrhages, ecchymoses, and oozing from the buccal mucosa, venipuncture sites to hematuria, lower gastrointestinal bleeding, and intrapulmonary hemorrhages [3, 4, 5]. In contrast to other drug-induced thrombocytopenia, bleeding is more severe and wet purpura have been commonly reported in the literature [6]. The mechanism of thrombocytopenia which has been largely proposed is a quinine type of antibody mediated destruction [7]. Vancomycin's interaction with platelet glycoprotein IIb/IIIa results in an antibody which weakly targets GP IIb/IIIa on the membrane; however, the presence of vancomycin provides the complementary electrostatic charges required to increase the binding affinity between the glycoprotein on the platelets and binding region of the antibody causing cell lysis [6, 7, 8]. Platelet destruction occurs only in the presence of vancomycin; hence, discontinuation of the drug followed by its renal clearance caused resolution of thrombocytopenia in most reports [3]. Testing for drug-dependent platelet antibody is recommended and is done in a reference lab (Blood Center of Wisconsin). The test uses O group platelets and incubates it with the patient's sera; after an hour of incubation, the platelets are washed with or without the implicated drug solution. Human IgG bound to the platelets is detected using anti Fc Ig derived from goats. These tests, though widely done are neither validated or standardized [9]. Poor responsiveness to platelet transfusions is a feature of this disease due to rapid destruction of platelets [4]. The median time for resolution of thrombocytopenia (platelet count of at least 150,000 per cubic millimeter) after vancomycin was stopped was 7.5 days [6]. In our patient, the duration of thrombocytopenia was 32 days from discontinuation of vancomycin. The prolonged duration was likely from decreased serum clearance of vancomycin due to end-stage renal disease and poor clearance of vancomycin with low flux hemodialysis [6]. Vancomycin is significantly dialyzable using high flux membranes for hemodialysis such as polysulfone, polyacrylonitrile, etc. and with continuous renal replacement therapy: hence, the rationale behind CRRT use in our patient. We used prednisone, IVIG, thrombo-mimetic agent eltrombopag and plasma exchange to treat the thrombocytopenia. The above modalities have all been used in published studies and did not show improvement in thrombocytopenia which was similar to our experience [3]. Our patient also had IVIG-mediated hemolysis in addition to bleeding, which complicated the clinical picture this was evidenced by a direct Coombs test done on admission which was negative, but which became positive after IVIG was given.\n\nIn patients with thrombocytopenia, the etiology is often unclear and the differential is broad, being comprised of sepsis, disseminated intravascular coagulation, TTP, atypical HUS, heparin- induced thrombocytopenia, other drug-induced thrombocytopenia, and post-transfusion purpura. In vancomycin induced thrombocytopenia, median time to development on thrombocytopenia varied ranging from 2–21 days after initiation of vancomycin [10, 11, 12]. In many reports, the thrombocytopenia developed with the first exposure to vancomycin, whereas in other occurrences it required two exposures. The time to nadir platelet count was on an average 8 days and the nadir varied from 100,000 to 2,000 K/mL [3, 6] In heparin-induced thrombocytopenia, the median time for development of thrombocytopenia is 7–10 days after exposure to heparin, a high 4T score and then later positive antibodies to heparin on the ELISA testing point to the diagnosis [13]. Post transfusion purpura is severe thrombocytopenia by antibodies to platelet HPA-1a antigen. These antibodies are generated by alloimmunization from blood transfusions, multiparity, etc. These factors should be considered, in addition to testing for HPA genotyping and HPA-1a antibody in the patient's sera. Unlike VIT, PTP responds to intravenous immunoglobulin and plasma exchange [14]. Leukocytosis in sepsis, anemia from hemolysis and renal dysfunction seen in TTP and atypical HUS, schistocytes on peripheral smear, and coagulation derangements are other clues to delineate other possibilities. A careful history of both home and hospital-administered drugs is imperative.\n\nRituximab (375 mg/m2, single dose), an anti-CD-20 monoclonal antibody was given to our patient, after which his platelet count doubled within 96 h and improved to normal thereafter. However, he had received 3 cycles of CRRT and his vancomycin serum levels were less than 0.8 mcg/mL, prior to the initiation of rituximab. As this is a single patient report, it is uncertain if the resolution of thrombocytopenia was directly a result of rituximab versus a gradual improvement secondary to elimination of serum vancomycin and thereby, decreased platelet destruction. We found only one reported case in which rituximab was used specifically for refractory VIT [15]. This case was an ESRD patient with VIT persisting for greater than 30 days; however, in contrast to our patient he was given weekly rituximab (375 mg/m2) for a total for 4 doses before platelet count returned to normal. Rituximab, an anti-CD 20 monoclonal antibody, is hypothesized to bind to CD 20 on the memory B cells and block the synthesis of drug-induced antibodies to Gp IIb/IIIa [15]. In patients with persistent severe thrombocytopenia (platelet count <10,000 K/μL) and or major bleeding, the use of rituximab earlier, rather than later, in the hospital course is perhaps a more astute decision.\n\nDrug sensitivity persists indefinitely once the patient develops DITP. In several reported cases on repeat exposure to vancomycin, the platelet count has plunged to critical levels [10, 16]. Patients should be educated and their chart labeled as having an allergy to the drug causing DITP, which should never be used. Drug-dependent antibodies typically do not cross-react with different drugs that have a similar molecular structure and so different drugs from the same class can be used [7].\n\nIn some reported cases, the thrombocytopenia developed only on the second exposure to vancomycin and it has been postulated that prior sensitization to vancomycin was present [6, 17]. In this case, the serum of the patient prior to vancomycin showed IgG antibodies to vancomycin and the post-exposure serum showed both IgG and IgM antibodies to the drug [17]. The thrombocytopenia in these reported cases developed within hours to a day of reintroduction to vancomycin; thus, it is an anamnestic antibody response. However, in the majority of cases, there is no history of prior vancomycin use reported. We hypothesize that the sensitization and the anamnestic response happens during the same single exposure such as occurred in our patient, when thrombocytopenia developed after a few days of treatment with vancomycin. Whereas if the development of thrombocytopenia is rapid, it might be worthwhile to explore if there was a history of vancomycin use. As per existing reports, there have been no risk factors identified that can predict which patients will develop severe thrombocytopenia in exposure to vancomycin. Thus, it is crucial to consider this etiology among our differentials of thrombocytopenia.\n\nConclusion\nVancomycin-induced thrombocytopenia, though well reported, is a less clinically recognized entity. It is important to be aware of this adverse effect as the thrombocytopenia is often severe, with significant bleeding. In an era where broad spectrum antibiotic coverage is becoming the norm, it is important to consider if gram positive, specifically MRSA coverage, is required before starting vancomycin. It is equally critical never to administer vancomycin in patients who experienced thrombocytopenia from it.\n\nStatement of Ethics\nPatient is deceased. Patient's son has given verbal consent to publish the case report.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nThere was no funding provided for the writing of this manuscript.\n\nAuthor Contributions\nNisha Ajit did the literature review, wrote and edited the manuscript. She was also involved in the patient management. Sindhu Priya Devarashetty reviewed the literature and wrote the manuscript. Samip Master supervised the patient management and reviewed the manuscript.\n\nFig. 1 Graph depicting the platelet counts and vancomycin random levels during hospitalization in reference to timing of treatment modalities.\n==== Refs\nReferences\n1 Ruggero MA Abdelghany O Topal JE Vancomycin-induced thrombocytopenia without isolation of a drug-dependent antibody Pharmacotherapy 2012 11 32 (11) e321 5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23065779 23065779 \n2 Walker RW Heaton A Thrombocytopenia due to vancomycin Lancet 1985 4 1 (8434) 932 Available from: https://linkinghub.elsevier.com/retrieve/pii/S0140673685917106 \n3 Mohammadi M Jahangard-Rafsanjani Z Sarayani A Hadjibabaei M Taghizadeh-Ghehi M Vancomycin-Induced Thrombocytopenia: A Narrative Review Drug Saf 2017 1 40 (1) 49 59 27848200 \n4 Lobo N Ejiofor K Thurairaja R Khan MS Life-threatening haematuria caused by vancomycin-induced thrombocytopenia. Case Reports [Internet] 2015 Feb 25 2015 (feb25 1):bcr2014208192–bcr2014208192. Available from: http://casereports.bmj.com/cgi/doi/10.1136/bcr-2014-208192 \n5 Holden VK Varonin DR Severe, Refractory Thrombocytopenia in a Critically Ill Patient Caused by Vancomycin Induced Antibodies J Clin Med Ther [Internet] 2017 2 (1) Available from: http://www.imedpub.com/articles/severe-refractory-thrombocytopenia-in-a-critically-ill-patient-caused-byvancomycin-induced-antibodies.php?aid=18147 \n6 Von Drygalski A Curtis BR Bougie DW McFarland JG Ahl S Limbu I Vancomycin-induced immune thrombocytopenia N Engl J Med 2007 3 356 (9) 904 10 Available from: http://www.nejm.org/doi/abs/10.1056/NEJMoa065066 17329697 \n7 Aster RH Bougie DW Drug-induced immune thrombocytopenia N Engl J Med 2007 8 357 (6) 580 7 Available from: http://www.nejm.org/doi/abs/10.1056/NEJMra066469 17687133 \n8 Aster RH Curtis BR McFarland JG Bougie DW Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management J Thromb Haemost 2009 6 7 (6) 911 8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19344362 19344362 \n9 Arnold DM Kukaswadia S Nazi I Esmail A Dewar L Smith JW A systematic evaluation of laboratory testing for drug-induced immune thrombocytopenia J Thromb Haemost 2013 1 11 (1) 169 76 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23121994 23121994 \n10 Marraffa J Guharoy R Duggan D Rose F Nazeer S Vancomycin-induced thrombocytopenia: a case proven with rechallenge Pharmacotherapy 2003 9 23 (9) 1195 8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/14524652 14524652 \n11 Shah RA Musthaq A Khardori N Vancomycin-induced thrombocytopenia in a 60-year-old man: a case report J Med Case Reports 2009 6 3 (1) 7290 \n12 Swanenberg I Bhalla S Altshuler D Adelman M Colon L Sloane M Severe Thrombocytopenia Induced by Vancomycin-Dependent Anti-Platelet Antibodies Chest 2017 10 152 (4) A299 Available from: https://linkinghub.elsevier.com/retrieve/pii/S0012369217318433 \n13 Arepally GM Heparin-induced thrombocytopenia. Blood [Internet] 2017 May 25 129 (21) 2864 2872 Available from: http://www.bloodjournal.org/content/129/21/2864.abstract \n14 Hitomi Yokoyama AP Dezan MR Costa TH Aravechia MG Mota MA Kutner JM Diagnosis and Management Of POST-Transfusion Purpura - Case Report. Conti FM, editor Blood [Internet] 2013 Nov 15 122 (21) 4834 4834 Available from: http://www.bloodjournal.org/content/122/21/4834.abstract \n15 Pascual BO Solis MA Ramos VB Juan IG Torregrosa IM García RR [Thrombocytopenia in a patient on peritoneal dialysis] Nefrologia 2008 28 (4) 453 5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18662155 18662155 \n16 Howard CE Adams LA Admire JL Chu MA Alred GL Vancomycin-induced thrombocytopenia: a challenge and rechallenge Ann Pharmacother 1997 3 31 (3) 315 8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9066938 9066938 \n17 Kenney B Tormey CA Acute vancomycin-dependent immune thrombocytopenia as an anamnestic response Platelets 2008 8 19 (5) 379 83 Available from: http://www.tandfonline.com/doi/full/10.1080/09537100802082280 18791945\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "12(3)",
"journal": "Case reports in oncology",
"keywords": "Drug induced thrombocytopenia; End stage renal disease; Vancomycin",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "749-754",
"pmc": null,
"pmid": "31762746",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "2858779;18662155;17687133;23065779;17329697;23121994;19344362;19830166;25716041;18791945;9066938;14524652;27848200;28416511",
"title": "Vancomycin Induced Thrombocytopenia - Protracted Course in a Hemodialysis Patient.",
"title_normalized": "vancomycin induced thrombocytopenia protracted course in a hemodialysis patient"
} | [
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"activesubstancename": "PREDNISONE"
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{
"abstract": "Cocaine adulterated levamisole is an increasingly reported cause of skin necrosis, arthralgia and systemic vasculitis, but renal involvement is uncommon. We present a case of a 40-year-old Hispanic man with a history of cocaine abuse who presented with acute kidney injury to the rheumatology clinic where he was being treated for chronic inflammatory arthritis. He was found to have a serum creatinine of 2.5 mg/dL, microscopic haematuria and subnephrotic proteinuria, along with positive proteinase 3, myeloperoxidase, anticardiolipin antibodies and an elevated antinuclear antibody titre. The renal pathology revealed focal necrotising glomerulonephritis with crescentic features and mild immune type deposition. The patient was treated with cocaine abstinence, pulse dose steroids followed by maintenance prednisone, rituximab and cyclophosphamide. His renal function subsequently improved but did not normalise. We believe that his incomplete improvement was due to the degree of kidney injury on presentation as well as recidivism with cocaine use.",
"affiliations": "Department of Medicine, Jacobi Medical Center, Bronx, New York, USA.;Department of Pathology, NewYork-Presbyterian Hospital, New York, New York, USA.;Department of Medicine, Jacobi Medical Center, Bronx, New York, USA.;Department of Medicine, Jacobi Medical Center, Bronx, New York, USA.;Department of Medicine, Jacobi Medical Center, Bronx, New York, USA.",
"authors": "Kumar|Dileep|D|;Batal|Ibrahim|I|;Jim|Belinda|B|;Mendez|Barbara|B|;Anis|Kisra|K|",
"chemical_list": "D000969:Antinematodal Agents; D007166:Immunosuppressive Agents; D013256:Steroids; D007978:Levamisole; D003404:Creatinine; D003042:Cocaine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225913",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "acute renal failure; chronic renal failure; drug misuse (including addiction); hematuria; vasculitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D000969:Antinematodal Agents; D003042:Cocaine; D003404:Creatinine; D005921:Glomerulonephritis; D005923:Glomerulosclerosis, Focal Segmental; D006417:Hematuria; D006801:Humans; D007166:Immunosuppressive Agents; D007978:Levamisole; D008297:Male; D011507:Proteinuria; D013256:Steroids; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30232205",
"pubdate": "2018-09-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28194438;26290761;26092827;28842398;26855022;21980179;28132051;27247374;27446086;3754161;20668440;22677078;29937233;24296074;80661;25398064;26985374",
"title": "Unusual case of levamisole-induced dual-positive ANCA vasculitis and crescentic glomerulonephritis.",
"title_normalized": "unusual case of levamisole induced dual positive anca vasculitis and crescentic glomerulonephritis"
} | [
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"activesubstancename": "HYDROCHLOROTHIAZIDE"
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{
"abstract": "Since the introduction of tyrosine kinase inhibitors in gastrointestinal stromal tumor patients, the median survival of patients has increased from less than 1 to more than 5 years. The chronic use of a tyrosine kinase inhibitor has an impact on quality of life because of its toxicity. Adequate supportive therapy is therefore important. We describe a female patient with a metastatic gastrointestinal stromal tumor. During treatment with the c-KIT inhibitor imatinib, she developed severe therapy-limiting skin toxicity. After several different supportive attempts, the combination of doxycycline and clemastine proved to be the solution, enabling successful chronic treatment with imatinib. Chronic use of doxycycline and clemastine is useful in the management of skin toxicity caused by c-KIT inhibitors, enabling the needed long-term use of these kind of anticancer drugs without hampering the quality of life.",
"affiliations": "Departments of aMedical Oncology bPharmacy cDermatology, Radboud University Medical Centre, Nijmegen, The Netherlands.",
"authors": "Desar|Ingrid M E|IM|;van Herpen|Carla M L|CM|;van Erp|Nielka P|NP|;Kaal|Suzanne E J|SE|;van de Kerkhof|Peter C M|PC|;van der Graaf|Winette T A|WT|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D002974:Clemastine; D004318:Doxycycline",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000359",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "27(6)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D002974:Clemastine; D004318:Doxycycline; D005260:Female; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D000068877:Imatinib Mesylate; D047428:Protein Kinase Inhibitors; D012871:Skin Diseases",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "576-9",
"pmc": null,
"pmid": "26982239",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A successful approach to overcome imatinib-induced skin toxicity in a GIST patient.",
"title_normalized": "a successful approach to overcome imatinib induced skin toxicity in a gist patient"
} | [
{
"companynumb": "NL-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-118857",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMATINIB"
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"abstract": "We report a case of allergic acute tubulointerstitial nephritis (TIN) induced by acetaminophen in a 48-year-old Japanese man with no past medical history. Two days after receiving the non-steroidal anti-inflammatory drug (NSAID) loxoprofen for left shoulder pain, he developed cold symptoms such as fever and sore throat. He then took a 300 mg dose of acetaminophen three times a day and a 100 mg dose of minocycline hydrochloride twice a day for 7 days. Because there was no improvement in his symptoms, he consulted a local clinic again, where blood tests revealed renal insufficiency, and he was, then, referred to our hospital for evaluation of kidney function. Renal biopsy revealed acute TIN, and Ga-67 scintigraphy showed diffuse uptake in bilateral kidneys. A drug-induced lymphocyte stimulation test (DLST) was positive for acetaminophen and negative for loxoprofen and minocycline. Based on these findings, we made a diagnosis of acetaminophen-induced TIN. We treated the patient with three courses of semi-pulse steroid therapy, after which his fever went down, and his serum creatinine level recovered from 2.09 to 1.43 mg/dL. Although we medical doctors think that therapeutic dose of acetaminophen retains high safety, it is important to keep in mind that acetaminophen can cause allergic acute TIN.",
"affiliations": "Division of Nephrology, Department of Medicine, Yachiyo Medical Center, Tokyo Women's Medical University, Chiba, Japan.;Division of Nephrology, Department of Medicine, Yachiyo Medical Center, Tokyo Women's Medical University, Chiba, Japan. fzk11643@nifty.com.;Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan.;Division of Nephrology, Department of Medicine, Yachiyo Medical Center, Tokyo Women's Medical University, Chiba, Japan.",
"authors": "Inoue|Dan|D|;Usui|Ryosuke|R|;Nitta|Kosaku|K|;Koike|Minako|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-017-0272-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "6(2)",
"journal": "CEN case reports",
"keywords": "Acetaminophen; Acute tubulointerstitial nephritis; Steroid therapy",
"medline_ta": "CEN Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "185-188",
"pmc": null,
"pmid": "28801780",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article",
"references": "2031841;7579069;20863222;17624227;21496243;18185501;707534;25030567;26200186;2113219;6343056;9459649;6604293;12825841;14671029;5109868",
"title": "A case of acetaminophen-induced acute tubulointerstitial nephritis in adult.",
"title_normalized": "a case of acetaminophen induced acute tubulointerstitial nephritis in adult"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK201711182",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE"
},
... |
{
"abstract": "Bortezomib is a proteasome inhibitor that has been widely adopted for the treatment of hematological malignancies, including multiple myeloma and lymphoma, and has been considered significantly more tolerable compared with traditional chemotherapeutic drugs. Bortezomib has some potential side effects that involve a number of systems, including the gastrointestinal, hematological, nervous and musculoskeletal systems; however, involvement of the endocrine system is rare. We herein report the case of a patient treated for multiple myeloma who developed the syndrome of inappropriate antidiuretic hormone secretion after bortezomib was added to his chemotherapy regimen. Following treatment with an infusion of hypertonic saline and fluid restriction for >2 months, the serum sodium level gradually recovered.",
"affiliations": "Department of Hematology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China.;Department of Hematology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China.",
"authors": "Lv|Cheng-Lan|CL|;Li|Juan|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2017.1366",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "7(4)",
"journal": "Molecular and clinical oncology",
"keywords": "bortezomib; multiple myeloma; syndrome of inappropriate antidiuretic hormone secretion",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "667-672",
"pmc": null,
"pmid": "28856001",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": "18166843;14657528;20056759;16005577;20164215;17507705;16178003;12431963;12566898;19786667;19699382;16971665;15461622;18063878;15613699;16181228;13469824;12714279;19751154;15958804;10505693;20142578",
"title": "Bortezomib as a probable cause of the syndrome of inappropriate antidiuretic hormone secretion: A case report and review of the literature.",
"title_normalized": "bortezomib as a probable cause of the syndrome of inappropriate antidiuretic hormone secretion a case report and review of the literature"
} | [
{
"companynumb": "CN-TAKEDA-2017MPI007714",
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"occurcountry": "CN",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
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"drugadditional": null,
... |
{
"abstract": "Richter transformation (RT) is defined as the transformation of chronic lymphocytic leukemia (CLL) to a high-grade B cell lymphoma. It usually carries a dismal prognosis and represents an unmet need for novel therapeutic interventions. We report a case of an 80-year-old male who developed double-hit (DH) RT with translocations of MYC and BCL6 after 5 years of watchful waiting for standard-risk CLL. He was treated with induction therapy consisting of 4 cycles of anthracycline-based chemoimmunotherapy (CIT) and 2 cycles of platinum-based CIT with intrathecal methotrexate for CNS prophylaxis followed by continuous maintenance therapy with ibrutinib. He achieved complete remission after the induction therapy. At the time of writing, four and a half years after the diagnosis with DH-RT, he remains in complete remission without evidence of RT or CLL. The novel therapeutic approach used in successful treatment of this patient should be further explored.",
"affiliations": "Department of Hematology and Medical Oncology, Mayo Clinic Hospital, Jacksonville City, FL, 32224, USA.;Department of Hematology and Medical Oncology, Mayo Clinic Hospital, Jacksonville City, FL, 32224, USA.;Department of Pathology, Mayo Clinic Hospital, Jacksonville City, FL, 32224, USA.;Department of Hematology and Medical Oncology, Mayo Clinic Hospital, Jacksonville City, FL, 32224, USA.",
"authors": "Seegobin|Karan|K|0000-0002-2739-7357;Alhaj Moustafa|Muhamad|M|0000-0001-8582-1219;Jiang|Liuyan|L|0000-0002-9851-985X;Tun|Han W|HW|0000-0002-9184-094X",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/BLCTT.S330008",
"fulltext": "\n==== Front\nBlood Lymphat Cancer\nBlood Lymphat Cancer\nblctt\nBlood and Lymphatic Cancer: Targets and Therapy\n1179-9889\nDove\n\n330008\n10.2147/BLCTT.S330008\nCase Report\nSuccessful Non-Transplant Treatment of Double Hit Richter Transformation with Long-Term Remission\nSeegobin et al\nSeegobin et al\nhttp://orcid.org/0000-0002-2739-7357\nSeegobin Karan 1\nhttp://orcid.org/0000-0001-8582-1219\nAlhaj Moustafa Muhamad 1\nhttp://orcid.org/0000-0002-9851-985X\nJiang Liuyan 2\nhttp://orcid.org/0000-0002-9184-094X\nTun Han W 1\n1 Department of Hematology and Medical Oncology, Mayo Clinic Hospital, Jacksonville City, FL, 32224, USA\n2 Department of Pathology, Mayo Clinic Hospital, Jacksonville City, FL, 32224, USA\nCorrespondence: Karan Seegobin Department of Hematology and Medical Oncology, Mayo Clinic Hospital, Jacksonville City, FL, 32224, USA Email seegobin.karan@mayo.edu\n22 9 2021\n2021\n11 6772\n11 8 2021\n15 9 2021\n© 2021 Seegobin et al.\n2021\nSeegobin et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ 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).\nAbstract\n\nRichter transformation (RT) is defined as the transformation of chronic lymphocytic leukemia (CLL) to a high-grade B cell lymphoma. It usually carries a dismal prognosis and represents an unmet need for novel therapeutic interventions. We report a case of an 80-year-old male who developed double-hit (DH) RT with translocations of MYC and BCL6 after 5 years of watchful waiting for standard-risk CLL. He was treated with induction therapy consisting of 4 cycles of anthracycline-based chemoimmunotherapy (CIT) and 2 cycles of platinum-based CIT with intrathecal methotrexate for CNS prophylaxis followed by continuous maintenance therapy with ibrutinib. He achieved complete remission after the induction therapy. At the time of writing, four and a half years after the diagnosis with DH-RT, he remains in complete remission without evidence of RT or CLL. The novel therapeutic approach used in successful treatment of this patient should be further explored.\n\nKeywords\n\nRichter transformation\nRT\nchronic lymphocytic leukemia\nCLL\ndouble hit lymphoma\nibrutinib maintenance\nno funding There is no funding to report.\n==== Body\npmcPlain Language Summary\n\nChronic lymphocytic leukemia and a high-grade B cell lymphoma are both different types of blood cancers. In some patients, chronic lymphocytic leukemia can transform into a high-grade B cell lymphoma in some patients, which behaves more aggressively, and this is known as Richter transformation. If the transformed lymphoma express MYC and BCL6/BCL2, it is termed double hit, and this implies a more aggressive lymphoma. The standard treatment for high-grade B cell lymphoma involves the use of chemotherapy and immunotherapy. After completing treatment with chemotherapy and immunotherapy, this transformed lymphoma is at high risk for returning. Bone marrow transplant is a potential option to reduce the risk of the lymphoma returning; however, not everyone is eligible for this. There is a lack of information and guidance on how to effectively prevent this transformed lymphoma from returning, especially in persons who are not eligible for bone marrow transplant. If the lymphoma does return, there are several treatment options available. This list continues to expand as the field moves forward. One of which is a new drug called Ibrutinib, which inhibits an enzyme in the cancer and prevents its growth. Incorporating these new agents in the upfront treatment setting has not been studied in clinical trials. We describe a case of continuous ibrutinib maintenance after response to initial chemoimmunotherapy that resulted in long-term remission in a patient with Richter transformation.\n\nIntroduction\n\nRichter transformation (RT) is defined as the transformation of chronic lymphocytic leukemia (CLL) to a high-grade B cell lymphoma and is seen in approximately 2–8% of CLL patients.1,2 Double-hit/Triple-hit (DH/TH) RT has been sparsely reported in the literature. A lot more needs to be elucidated on this subset of RT, especially with regard to effective therapeutic approach. We report a case of a 76-year-old male who developed DH-RT after 5 years of watchful waiting for standard-risk CLL. He was successfully treated with induction CIT followed by continuous maintenance therapy with ibrutinib, achieving long-term continuous complete remission.\n\nCase\n\nThe patient is an 80-year-old male with a past medical history of Rai stage I standard-risk CLL characterized by 13q deletion by Fluorescent in-situ hybridization analysis (FISH), mutated status of immunoglobulin heavy chain variable region (IGHV), and negative expression of CD38 and ZAP-70 on peripheral blood flow cytometry. TP53 was negative. He initially presented with atypical lymphocytosis, and bilateral axillary lymphadenopathy, retroperitoneal lymphadenopathy, and pelvic lymphadenopathy. Bone marrow biopsy (Figure 1A) showed nodular proliferation of neoplastic lymphocytes, immunohistochemistry (Figure 1B) revealed the lymphocytes positive for CD23, flow cytometry analysis (Figure 1C) confirmed lymphocytes positive for CD20 and predominantly negative for CD38, FISH study (Figure 1D) revealed loss of D13S319 signal, which indicated the deletion of 13q. He was asymptomatic from CLL and was put under watchful waiting. After about 5 years of watchful waiting, he presented with progressive worsening of pelvic pain over a period of 3 weeks. Laboratory workup showed white cell count 10.8 [3.4–9.6x10ʌ9/L], Absolute lymphocyte count 1.28 [0.95–3.07 x10ʌ9/L], Hb 13.2 [13.2–16.6g/dL], platelet 153 [135–317x10ʌ9/L], lactate dehydrogenase 256 [122–222U/L]. Renal function and liver function were within normal limits. CT imaging showed a new left pelvic sidewall mass 7.6 cm in maximum transverse dimension (Figure 2A), hypermetabolic on PET however it was unable to accurately measure SUVs in this mass due to concentrated radiotracer within the involved left ureter (Figure 2B), there was also associated left hydronephrosis (Figure 2C), and increased pelvic mesenteric lymphadenopathy and external iliac lymphadenopathy. Other areas of lymphadenopathy were unchanged compared to previous scans. CT-guided core biopsy of the pelvic mass showed a diffusely infiltrating large atypical cells (yellow arrow) with intermixed clusters of small lymphocytes (black arrow) (Figure 3A). Immunohistochemical studies showed both small and large lymphocytes were strongly positive for CD20 (Figure 3B). While the small lymphocytes showed aberrant expression of CD5 (Figure 3C) and CD23 (Figure 3D), the large lymphocytes were negative for CD5 and CD23 but positive for BCL6 (Figure 3E) with a high proliferative rate by ki-67 (Figure 3F). FISH analysis with break-apart probes demonstrated MYC gene rearrangement (Figure 3G), arrows indicate separation of 5ʹMYC and 3ʹMYC) and BCL6 gene rearrangement (Figure 3H), arrows indicate separation of 3ʹBCL6 and 5ʹBCL6), which confirmed the diagnosis of “double-hit” large cell lymphoma. Pathologic findings are consistent with high grade B cell lymphoma coexisting with CLL in the same tumour. FISH for CLL showed persistence of 13q deletion and no new additional cytogenetic abnormality. These features supported a diagnosis of DH-RT with MYC and BCL6 rearrangements. CSF analysis (cytology and flow cytometry) was negative. Left ureteric stent was placed to relieve hydronephrosis. He was initially treated with one cycle RCHOP (Rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, hydroxydoxorubicin 50 mg/m2, vincristine 1.4 mg/m2, and prednisone 100 mg/m2) without dose adjustment or GCSF support; and then switched to dose adjusted REPOCH (Rituximab 375 mg/m2, etoposide 50 mg/m2/day, prednisone 60 mg/m2/day, vincristine 0.4 mg/m2/day, cyclophosphamide 750 mg/m2, and hydroxydoxorubicin 10 mg/m2/day), intrathecal methotrexate 15mg for CNS prophylaxis (with each cycle) and GCSF support with Neulasta 6mg subcutaneous. Restaging following 3 cycles of REPOCH showed marked partial response. He tolerated the first two cycles well without any hematologic toxicity, however after the third cycle of REPOCH, ECHO performed for shortness of breath showed EF of 52% compared to 62% pre-treatment. He also had grade 2 anemia (hemoglobin of 9.6 g/dL) and grade 1 thrombocytopenia with platelet of (97 x10 ʌ9/L). He did not have any neutropenia. He was switched to treatment with two cycles of RICE chemoimmunotherapy (Rituximab 375 mg/m2, ifosfamide 5000 mg/m2/day (with 20% dose reduction), carboplatin AUC = 5 (with 20% dose reduction), and etoposide 100 mg/m2/day (with 20% dose reduction)), with Neulasta support 6mg subcutaneous. Dose reduction was done in light of the prior reduction in ejection fraction and cytopenias. PET scan after completing cycle 6 showed complete remission with no evidence of disease activity (Figure 2D). Three months after completion of induction chemoimmunotherapy, he was started on maintenance therapy with ibrutinib 420 mg daily. About a month before the writing of this report, he was diagnosed with COVID-19 pneumonia requiring hospitalization for one month. He was recently discharged from the hospital and has been recovering well. Ibrutinib has been on hold with the plan to resume soon. The last imaging scans (CT chest, abdomen, and pelvis) performed during recent hospitalization did not show any lymphadenopathy or splenomegaly. Peripheral blood tests have not shown any evidence of CLL. At the time of writing of this manuscript, he remains in complete remission at four and a half years after the diagnosis of DH-RT.Figure 1 The bone marrow biopsy showed nodular proliferation of neoplastic lymphocytes (A, H&E x 20). Immunohistochemistry revealed the lymphocytes positive for CD23 (B, x 20). Flow cytometry analysis confirmed lymphocytes positive for CD20 and predominantly negative for CD38 (C). FISH study revealed loss ofD13S319 signal, which indicated the deletion of 13q (D).\n\nFigure 2 (A) Pretreatment CT imaging showed a left pelvic sidewall mass, pelvic mesenteric lymphadenopathy, and external iliac lymphadenopathy. (B). Pretreatment PET shows hypermetabolic pelvic lesion however unable to accurately measure SUVs in this mass due to concentrated radiotracer within the involved left ureter. (C). Pretreatment CT imaging showed associated left hydronephrosis. (D) Post treatment PET scan after 6 cycles of induction therapy showed low level metabolic activity within the left pelvic sidewall mass, SUV max 2.1, no evidence for recurrence.\n\nFigure 3 The core needle biopsy of the pelvic mass showed a diffusely infiltrating large atypical cells (yellow arrow) with intermixed clusters of small lymphocytes (black arrow) (A, H&E x 20). Immunohistochemical studies showed both small and large lymphocytes were strongly positive for CD20 (B, x 20). While the small lymphocytes showed aberrant expression of CD5 (C, x 20) and CD23 (D, x 20), the large lymphocytes were negative for CD5 and CD23 but positive for BCL6 (E, x 20) with a high proliferative rate by ki-67 (F x 20). FISH analysis with break-apart probes demonstrated MYC gene rearrangement (G, arrows indicate separation of 5ʹMYC and 3ʹMYC) and BCL6 gene rearrangement (H, arrows indicate separation of 3ʹBCL6 and 5ʹBCL6), which confirmed the diagnosis of “double-hit” large cell lymphoma.\n\nDiscussion\n\nWe report a case of DH-RT with MYC and BCL6 translocations successfully treated with induction CIT followed by continuous maintenance therapy with ibrutinib resulting in continuous complete remission at four and a half years so far after the diagnosis of DH-RT. DH/TH RT is rather uncommon and has not been well characterized. In the largest series on RT with a total of 204 patients, it represents 12.1% of RT cases (8/66) in which gene rearrangement data on MYC, BCL2, and BCL6 are available.3 In this series, median overall survival for DH/TH RT is about 14 months with no survivor at 24-month follow-up. In one case report, a patient with DH-RT with MYC and BCL6 translocation survived for 9 months following the diagnosis of DH-RT.2 Our patient has done quite well compared to those survival outcomes.\n\nThe median time to transformation from CLL to RT is 4 years, with a rate of 0.5%/year.1 Our patient developed DH-RT five years after the initial diagnosis of CLL. RT is characterized by rapid disease kinetics,1 and clinically presents with rapidly enlarging lymphadenopathy, constitutional symptoms, elevated LDH, and frequent extra nodal tissue involvement.3 The clinical presentation of DH-RT in our case is classic with sudden onset of severe and progressive pelvic pain related to rapid enlargement of pelvic lymph nodes. The gold standard for diagnosis is tissue biopsy and should be performed in those with suspected RT and an SUV max of 5 or greater on PET, with excisional biopsy being preferred.4,5 The median survival after transformation is about 12 months; patients who had no prior CLL treatment have better overall survival (OS), with a median OS of approximately four years.6 Untreated status in our case before the onset of DH-RT may have contributed to excellent treatment outcome.\n\nWe were not able to perform molecular studies to establish a clonal relationship between CLL and DH-RT. However, the biopsy showed coexistence of DH-RT and CLL in the same pelvic tumor. As such, it is quite likely that CLL and DH-RT are clonally related in our case.\n\nR-CHOP-like therapy is most frequently used in the management of RT.2 However, it has limited efficacy, and higher intensity chemotherapy has not been shown to improve outcomes.6,7 In select cases, autologous stem cell transplant is associated with relative long-term survival, where the median post-transplant survival is 55.4 months.6 Novel therapeutic agents such as Bruton’s tyrosine kinase (BTK) inhibitors, B-cell lymphoma 2 (BCL-2) inhibitor, and checkpoint inhibitors have shown activity against RT, but the survival benefit is limited.8\n\nThe best therapeutic approach for DH/TH RT is not known. Our patient was induced with anthracycline-based CIT (one cycle of RCHOP and three cycles of dose-escalated REPOCH) followed by platinum-based CIT (two cycles of RICE). REPOCH has been used as the standard CIT for DH/TH lymphomas.9 He responded well-achieving complete remission following anthracycline-based CIT.\n\nIbrutinib has been shown to be effective in both CLL and RS.10 There have been reports of ibrutinib being used upfront in patients with RS with good response.5 In one study of ibrutinib in 85 pretreated CLL patients, the overall response rate (ORR) was 71%.10 In another study of 3 patients with RS who did not respond well to initial rituximab-based chemoimmunotherapy regimens and subsequently treated with ibrutinib due to lack of response; the median duration of ibrutinib therapy was 6.1 months, all patients experienced an improvement in constitutional symptoms, 1 patient had a complete response and 2 patients had a partial response.10 Ibrutinib was well tolerated, and no patient required discontinuation because of adverse events.\n\nDespite these data, the role of ibrutinib maintenance after induction CIT in the management of RT has not been tested in clinical trials. It is quite likely that ibrutinib maintenance plays an important role in achieving an excellent survival outcome in our case.\n\nIn conclusion, we report a case of DH-RT successfully treated with induction CIT followed by ibrutinib maintenance achieving an excellent survival outcome. This novel non-transplant therapeutic approach should be further explored for management of RT.\n\nEthics Approvall\n\nInstitutional approval was not required to publish the case details.\n\nConsent\n\nWritten and informed consent was obtained from the patient for publication of this case report.\n\nAuthorship Contributions\n\nAll authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.\n\nDisclosure\n\nAll authors have no conflicts of interest to declare.\n==== Refs\nReferences\n\n1. ParikhSA, RabeKG, CallTG, et al. Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. Br J Haematol. 2013;162 (6 ):774–782. doi:10.1111/bjh.12458 23841899\n2. RogersTS, GardnerJA, DevittKA. High-grade B-cell lymphoma with MYC and BCL6 rearrangements associated with Richter transformation of chronic lymphocytic leukemia. Autops Case Rep. 2019;9 (3 ):e2019090. doi:10.4322/acr.2019.090 31440479\n3. RossiD, SpinaV, GaidanoG. Biology and treatment of Richter syndrome. Blood. 2018;131 (25 ):2761–2772. doi:10.1182/blood-2018-01-791376 29692342\n4. WangYC, RabeKG, BoldMS, et al. The role of F-18-FDG-PET in detecting Richter transformation of chronic lymphocytic leukemia in patients receiving therapy with a B-cell receptor inhibitor. Haematologica. 2020;105 (11 ):2675–2678. doi:10.3324/haematol.2019.240564 33131260\n5. WangYC, DingW. Richter transformation of chronic lymphocytic leukemia in the era of novel agents. Clin Adv Hematol Onc. 2020;18 (6 ):348–357.\n6. WangYC, TschautscherMA, RabeKG, et al. Clinical characteristics and outcomes of Richter transformation: experience of 204 patients from a single center. Haematologica. 2020;105 (3 ):765–773. doi:10.3324/haematol.2019.224121 31197071\n7. RogersKA, HuangY, RuppertAS, et al. A single-institution retrospective cohort study of first-line R-EPOCH chemoimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukaemia karyotype as an adverse prognostic factor. Br J Haematol. 2018;180 (2 ):259–266. doi:10.1111/bjh.15035 29193006\n8. DingW. Richter transformation in the era of novel agents. Hematology Am Soc Hematol Educ Program. 2018;2018 (1 ):256–263. doi:10.1182/asheducation-2018.1.256 30504319\n9. PhuocV, Sandoval-SusJ, ChavezJC. Drug therapy for double-hit lymphoma. Drugs Context. 2019;8 :1–13. doi:10.7573/dic.2019-8-1\n10. TsangM, ShanafeltTD, CallTG, et al. The efficacy of ibrutinib in the treatment of Richter syndrome. Blood. 2015;125 (10 ):1676–1678. doi:10.1182/blood-2014-12-610782 25745187\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-9889",
"issue": "11()",
"journal": "Blood and lymphatic cancer : targets and therapy",
"keywords": "CLL; RT; Richter transformation; chronic lymphocytic leukemia; double hit lymphoma; ibrutinib maintenance",
"medline_ta": "Blood Lymphat Cancer",
"mesh_terms": null,
"nlm_unique_id": "101596730",
"other_id": null,
"pages": "67-72",
"pmc": null,
"pmid": "34588837",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32649656;33131260;29692342;30504319;31440479;31844420;29193006;25745187;23841899;31197071",
"title": "Successful Non-Transplant Treatment of Double Hit Richter Transformation with Long-Term Remission.",
"title_normalized": "successful non transplant treatment of double hit richter transformation with long term remission"
} | [
{
"companynumb": "US-MLMSERVICE-20211125-3236753-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
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... |
{
"abstract": "Dear Editor, Nicolau's syndrome, also called embolia cutis medicamentosa or livedoid dermatitis, is a rare injection site reaction characterized by immediate intense pain at the injection site followed by erythema and a hemorrhagic patch with a livedoid reticular pattern after injections of non-steroidal anti-inflammatory drugs (NSAIDS), antiepileptics, antibiotics, antihistaminics, corticosteroids, etc. (1). To the best of our knowledge, only one case of Nicolau's syndrome has been reported after the use of triamcinolone acetonide. Herein we report two cases of Nicolau's syndrome caused by intramuscular injections of triamcinolone acetonide and diclofenac sodium, respectively. CASE 1 A 24-year-old male patient presented with severe pain and bluish discoloration of the right arm for 2 days, which he had noticed shortly after receiving an intramuscular injection of triamcinolone for recurrent episodes of urticaria by a local practitioner in the right deltoid region. On examination, there was a livedoid pattern of non-blanchable, violaceous discoloration extending from the deltoid area to the distal third of the forearm with associated induration (Figure 1, a, b). The local area was warm and tender to the touch. There was no regional lymphadenopathy, and the rest of the examination was normal. The patient's platelet count, bleeding and clotting times, prothrombin time, and international normalized ratio (INR) were unremarkable. There was no previous history of any bleeding disorder. The patient denied any intake of drugs like aspirin, warfarin, etc. Subsequently, the patient developed an ulcer on the forearm, which was managed by topical and systemic antibiotics to prevent any secondary infection of the wound. CASE 2 A 40-year-old female patient presented with complaints of pain and discoloration of the left gluteal region after receiving an intramuscular injection of diclofenac sodium for her arthralgia. A large ecchymotic patch with reticular borders was found on the gluteal region, extending to the lateral aspect of thigh (Figure 2). It was tender to the touch, non-indurated, and the local temperature was raised. There was no regional lymphadenopathy. No other abnormality was detected on examination. All routine investigations were within normal limits. Platelet count, bleeding, clotting and prothrombin times, and international normalized ratio (INR) were within normal limits. The lesions resolved within few weeks without any complications. Nicolau syndrome was first described in the early 1920s by Freudenthal and Nicolau as an adverse effect of using intramuscular injections of bismuth salts in the treatment of syphilis. Since then, several case reports of this disease occurring after intramuscular, intra-articular, intravenous, and subcutaneous injections have appeared in the literature associated with a variety of drugs like NSAIDs, vitamin K, penicillin, antihistamines, corticosteroids, local anesthetics, vaccines, polidocanol, and pegylated interferon alpha (1). The pathogenesis of Nicolau syndrome is unknown, though intra and periarterial injection of the drug is a possible cause. Stimulation of the sympathetic nerve due to periarterial injection causes spasms and consequent ischemia. Inadvertent intra-arterial injections may cause emboli and occlusion. A lipophilic drug may penetrate the vessel and produce physical occlusion like fat embolism. Cytotoxic drugs may produce perivascular inflammation and ischemic necrosis. NSAIDs are believed to additionally induce ischemic necrosis due to their inhibition of cyclooxygenase and, consequently, prostaglandins (2). The clinical features of the disease have been divided into three phases in a review by Kim et al. (3). The authors describe an initial phase characterized by intense pain with subsequent erythema. This is followed 1-3 days later by an acute phase, when an indurated, tender plaque with livedoid pattern develops. The final phase occurs between 5 days and 2 weeks later. Necrosis ensues in this stage, with possible ulceration. Diagnosis is chiefly clinical, and histopathology shows necrotic changes and vascular thrombosis. However, a biopsy was not performed in our cases because both lesions were painful. Management strategies are variable and range from conservative management with analgesics and antibiotics to active surgical debridement (4). Complications include deformities, contractures or even death. The patient in our first case developed ulceration which healed normally, while the second case resolved without any complications. Nicolau syndrome can be avoided by precautions such as aspirating the needle before injecting to check for blood, use of Z-track injection technique, proper site of injection, avoiding large doses at a single site, and regular change of sites if multiple injections are to be given (5). Nicolau syndrome is a rare disease. There are a few case reports of it occurring after diclofenac injection (1-5). We could only find one case report of this syndrome after intramuscular injection (IM) of triamcinolone in a patient with lichen planus (3), and our case is the second reported case of this syndrome as a result of triamcinolone acetonide injection, which adds to the significance to the present article.",
"affiliations": "Assist. Prof. Tasleem Arif, MD, Postgraduate Department of Dermatology, STDs and Leprosy, Jawaharlal Nehru Medical College (JNMC), Aligarh Muslim University, Aligarh, India; dr_tasleem_arif@yahoo.com.",
"authors": "Adil|Mohammad|M|;Amin|Syed Suhail|SS|;Arif|Tasleem|T|",
"chemical_list": "D007166:Immunosuppressive Agents; D014222:Triamcinolone Acetonide",
"country": "Croatia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1330-027X",
"issue": "25(3)",
"journal": "Acta dermatovenerologica Croatica : ADC",
"keywords": null,
"medline_ta": "Acta Dermatovenerol Croat",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D065148:Nicolau Syndrome; D014222:Triamcinolone Acetonide; D055815:Young Adult",
"nlm_unique_id": "9433781",
"other_id": null,
"pages": "251-253",
"pmc": null,
"pmid": "29252181",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nicolau's syndrome: A rare but preventable iatrogenic disease.",
"title_normalized": "nicolau s syndrome a rare but preventable iatrogenic disease"
} | [
{
"companynumb": "IN-MACLEODS PHARMACEUTICALS US LTD-MAC2021032846",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
... |
{
"abstract": "Venous thromboembolism (VTE) can be a life-threatening medical condition that may lead to leg swelling, respiratory distress and death.\n\n\n\nThe AMSP (Arzneimittelsicherheit in der Psychiatrie) is a continuous multicentre drug surveillance programme that assesses severe adverse drug reactions during treatment of psychiatric inpatients. We report on a total of 264,422 inpatients who were treated with antipsychotics (APs) and monitored from 1993 to 2011 in 99 psychiatric hospitals.\n\n\n\nDuring this period VTE events were reported for 89 inpatients, corresponding to an occurrence rate of 34 cases per 100,000 inpatient admissions treated with APs or 43 cases per 10,000 person-years. The occurrence of VTE was greatest in patients over the age of 65 years of age with mood disorders. The chemical class of butyrophenones (48/100,000) followed by atypical APs (36/100,000) showed the highest occurrence rate for VTE compared to thioxanthenes (23/100,000), which were less associated with VTE. If imputed alone, pipamperone (61/100,000) and risperidone (55/100,000) were most frequently associated with VTE. In general, there was no difference in occurrence rate of VTE between high- and low-potency APs.\n\n\n\nThese results suggest that clinicians should consider AP drug exposure as a potential risk factor for VTE for patients older than 65 years. Additionally, the diagnosis of an affective disorder seems to increase the risk for VTE.",
"affiliations": "a Department of Psychiatry , Medical University of Graz , Graz , Austria.;b Department of Psychiatry , Ludwig-Maximilians-University , Munich , Germany.;c Sigmund Freud Hospital Graz , Graz , Austria.;d Department of Psychiatry, Social Psychiatry and Psychotherapy , Hannover Medical School , Hannover , Germany.;d Department of Psychiatry, Social Psychiatry and Psychotherapy , Hannover Medical School , Hannover , Germany.;b Department of Psychiatry , Ludwig-Maximilians-University , Munich , Germany.;e Department of Angiology , Medical University of Graz , Graz , Austria.;f Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry , Medical University of Vienna , Vienna , Austria.;f Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry , Medical University of Vienna , Vienna , Austria.;a Department of Psychiatry , Medical University of Graz , Graz , Austria.;a Department of Psychiatry , Medical University of Graz , Graz , Austria.;f Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry , Medical University of Vienna , Vienna , Austria.",
"authors": "Letmaier|Martin|M|;Grohmann|Renate|R|;Kren|Christiana|C|;Toto|Sermin|S|;Bleich|Stefan|S|;Engel|Rolf|R|;Gary|Thomas|T|;Papageorgiou|Konstantinos|K|;Konstantinidis|Anastasios|A|;Holl|Anna Katharina|AK|;Painold|Annamaria|A|;Kasper|Siegfried|S|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1080/15622975.2017.1285048",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1562-2975",
"issue": "19(3)",
"journal": "The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry",
"keywords": "Venous thromboembolism; adverse drug reactions; antipsychotics; deep vein thrombosis; drug surveillance; pulmonary embolism",
"medline_ta": "World J Biol Psychiatry",
"mesh_terms": "D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents; D016903:Drug Monitoring; D005260:Female; D005858:Germany; D006778:Hospitals, Psychiatric; D006801:Humans; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D019964:Mood Disorders; D060735:Pharmacovigilance; D016730:Program Development; D054556:Venous Thromboembolism",
"nlm_unique_id": "101120023",
"other_id": null,
"pages": "175-186",
"pmc": null,
"pmid": "28112047",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Venous thromboembolism during treatment with antipsychotics: Results of a drug surveillance programme.",
"title_normalized": "venous thromboembolism during treatment with antipsychotics results of a drug surveillance programme"
} | [
{
"companynumb": "AT-ALKEM LABORATORIES LIMITED-AT-ALKEM-2018-02581",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"druga... |
{
"abstract": "Infectious endocarditis (IE) typically occurs in the setting of intravenous drug use, prosthetic heart valves, or rheumatic heart disease. However, there are a few reports of IE occurring in the setting of immunosuppression secondary to cancer and/or chemotherapy. Here, we present a case of a cancer patient who developed anterior spinal artery (ASA) syndrome secondary to a septic embolus from IE.\nA 78-year-old male with a history of gastroesophageal cancer treated with chemotherapy and radiation presented to the hospital after a fall at home. He reported experiencing dyspnea and orthopnea for two weeks prior to presentation. In the ED, his vital signs were stable, and his examination was significant for a flaccid paralysis of the right lower extremity. Diagnosis of septic emboli secondary to IE was made after the echocardiogram showed the presence of vegetations on the aortic valve, blood cultures were positive for Streptococcus mitis, and thoracic spine MRI was indicative of an infarction at T10.\nThis case highlights the presence of IE in the setting of cancer and chemotherapy. Although cancer is a rare cause of IE, clinicians must maintain a high index of suspicion in order to minimize the sequelae of IE.",
"affiliations": "Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.;Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.;Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.;Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA.;Department of Infectious Disease, Jersey Shore University Medical Center, Neptune, NJ, USA.",
"authors": "Mahtabfar|Aria|A|0000-0002-4026-7821;Eshraghi|Hamoon|H|0000-0002-5103-1435;D'Souza|Melroy|M|;Berrigan|William|W|;Casey|Kathleen|K|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1155/2018/9658120",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2018/9658120Case ReportA Case of Anterior Spinal Artery Syndrome Caused by Streptococcus mitis Endocarditis http://orcid.org/0000-0002-4026-7821Mahtabfar Aria am1823@rwjms.rutgers.edu\n1\nhttp://orcid.org/0000-0002-5103-1435Eshraghi Hamoon \n1\nD'Souza Melroy \n1\nBerrigan William \n2\nCasey Kathleen \n3\n\n1Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA\n2Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA\n3Department of Infectious Disease, Jersey Shore University Medical Center, Neptune, NJ, USAAcademic Editor: Thomas R. Chauncey\n\n2018 29 1 2018 2018 96581202 10 2017 26 12 2017 Copyright © 2018 Aria Mahtabfar et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\n Infectious endocarditis (IE) typically occurs in the setting of intravenous drug use, prosthetic heart valves, or rheumatic heart disease. However, there are a few reports of IE occurring in the setting of immunosuppression secondary to cancer and/or chemotherapy. Here, we present a case of a cancer patient who developed anterior spinal artery (ASA) syndrome secondary to a septic embolus from IE. \n\nCase Presentation\n A 78-year-old male with a history of gastroesophageal cancer treated with chemotherapy and radiation presented to the hospital after a fall at home. He reported experiencing dyspnea and orthopnea for two weeks prior to presentation. In the ED, his vital signs were stable, and his examination was significant for a flaccid paralysis of the right lower extremity. Diagnosis of septic emboli secondary to IE was made after the echocardiogram showed the presence of vegetations on the aortic valve, blood cultures were positive for Streptococcus mitis, and thoracic spine MRI was indicative of an infarction at T10. \n\nDiscussion\n This case highlights the presence of IE in the setting of cancer and chemotherapy. Although cancer is a rare cause of IE, clinicians must maintain a high index of suspicion in order to minimize the sequelae of IE.\n==== Body\n1. Introduction\nInfectious endocarditis (IE) characteristically occurs after endothelial damage to native heart valves and fibrin deposition, which is followed by thrombus formation that serves as a nidus for bacterial invasion [1]. In developing nations, IE is usually caused from rheumatic heart disease, while in developed nations IE is secondary to congenital heart malformations, degenerative valvular disease, intravenous drug use (IVDU), and cancer [1]. The organisms that cause IE are typically (80–90%) gram-positive bacteria, including Staphylococcus, Streptococcus, and Enterococcus species [1].\n\n\nStreptococcus mitis (S. mitis), along with other viridans group streptococci (VGS), is a commensal bacterium in the oropharynx. It typically causes an asymptomatic and transient bacteremia in the immunocompetent host but can lead to IE in the setting of valvular disease [1]. In an immunocompromised host, S. mitis can lead to a clinically significant bacteremia and IE [2]. For instance, patients with malignancy and neutropenia are susceptible to severe bacteremia and VGS shock syndrome secondary to S. mitis infection [3, 4]. Interestingly, amongst over 600 neutropenic patients across both studies, there were no patients that developed clinically significant IE from S. mitis infection, indicating that IE may not occur in the setting of neutropenia.\n\nHere, we present the case of a patient with a history of cancer and a normal neutrophil count who developed IE secondary to S. mitis infection leading to anterior spinal artery (ASA) syndrome.\n\n2. Case Presentation\nA 78-year-old male with a history of gastroesophageal (G-E) junction carcinoma, treated at the time with chemotherapy (capecitabine) and radiation, arrived in the emergency room after a fall at home. He got out of bed and began walking, and his right leg “gave out.” The patient denied any recent trauma, pain, or loss of consciousness. He reported having paroxysmal nocturnal dyspnea and orthopnea for the past few weeks and he also reported no history of valvular disease and intravenous drug use.\n\nOn presentation, his temperature was 98F, blood pressure was 118/53 mmHg, heart rate was 86 beats per minute, respiratory rate was 12 breaths per minute, and oxygen saturation was 94%. There were no murmurs, lungs were clear to auscultation, and he had a flaccid paralysis of the right lower extremity at and below the level of the hip. Sensation to pinprick, light touch, vibration, and proprioception were intact bilaterally. Patellar reflexes were 2+ and symmetric. Plantar reflex was upgoing on the right lower extremity.\n\nNotable lab values were a brain natriuretic peptide > 5000 pg/mL (<100) and a white blood count of 13.8 × 103/uL. A transthoracic echocardiogram revealed a mobile mass on the aortic valve, which was suspicious for vegetation (Figure 1). Blood cultures revealed the presence of gram-positive cocci in pairs and chains and were later shown to be S. mitis. Organism was identified via MALDI in addition to examining colony morphology and optochin sensitivity to help differentiate from other bacterial species. Brain magnetic resonance imaging (MRI) showed old ischemic changes. A thoracic spine MRI subsequently showed abnormal signaling at the level of T10 consistent with cord infarction (Figure 2).\n\nThe clinical picture was indicative of infective endocarditis, given that both the major criteria of the modified Duke criteria were met. Furthermore, the acute onset of focal neurological deficits was secondary to a septic embolus causing a spinal artery infarction. Vancomycin was initiated empirically and was changed to ceftriaxone based on the organism's antimicrobial sensitivities. After eight days of antibiotic therapy, blood cultures showed no growth of the organism. However, the patient's neurological condition worsened to a bilateral lower extremity paralysis and decreased sensation to touch, pain, and temperature bilaterally; vibration and proprioception sensation remained intact. He was discharged to a rehabilitation facility after two weeks and treated for an additional two weeks. Upon discharge, there was no improvement of his motor and sensory symptoms.\n\n3. Discussion\nWe present a case of IE of a native aortic valve that subsequently dislodged a septic embolus and caused an occlusion of the artery of Adamkiewicz, leading to ASA syndrome. Given that this patient reported no history of valvular disease, rheumatic fever, or intravenous drug use, the emergence of IE was likely secondary to the immunosuppression caused by the G-E junction carcinoma and the subsequent chemotherapy. Although not a common cause of IE, cancer is a risk factor for IE in developed nations [1]. The association between S. bovis endocarditis and the development of colorectal cancer has been established for over 50 years; however, there remains a dearth of literature regarding the onset of endocarditis after the diagnosis and treatment of cancer [5]. The increased incidence of IE in cancer patients is in large part due to invasive techniques and indwelling devices, which was illustrated in one study which discovered that central venous catheters were responsible for almost a quarter of IE in cancer patients [6].\n\n\nS. mitis is most commonly implicated in subacute endocarditis but can cause fulminant IE in the setting of immunosuppression as this patient likely had an attenuated immune response after receiving chemotherapy [7, 8]. As mentioned above, IE in cancer patients is commonly due to the use of catheters; however, the most common site of VGS in all patients is the gastrointestinal tract [9]. Therefore, it is also possible that the bacteria entered the patient's bloodstream after routine oral care or secondary to the G-E junction carcinoma and subsequent radiation therapy. Cancer and radiation cause a disruption in the integrity of the gastrointestinal tract's normal mucosal barrier, thereby allowing for the invasion of bacteria that would not normally penetrate into the blood. Once in the bloodstream, S. mitis can become clinically aggressive, lead to IE, and cause the release of several septic emboli in the immunocompromised patient [8].\n\nIn this patient, septic emboli from the aortic valve caused an infarction of the artery of Adamkiewicz, which is the largest spinal radicular artery and the only radicular artery to the ASA between T9 and T12 in most patients. While other regions of the spinal cord contain many collateral circulations with the ASA, this unique vascular supply makes the low thoracic region especially vulnerable to ASA syndrome [10]. The ASA supplies the anterior two-thirds of the spinal cord. Symptoms of ASA syndrome include complete motor loss below the level of the lesion as well as loss of pain and temperature sensation due to loss of the corticospinal and spinothalamic tracts, respectively; this patient exhibited findings consistent with ASA syndrome. Proprioception and vibratory sensation remained intact due to preservation of the dorsal columns, which are supplied by a pair of posterior spinal arteries. Septic emboli do not typically cause ASA syndrome, and the only documented case has been in an IVDU [11].\n\nThis case is the first presentation of ASA syndrome emerging secondary to S. mitis IE in a patient with malignancy [7]. Patients undergoing chemotherapy should be thoroughly assessed when there is any clinical suspicion for bacteremia or endocarditis given the likelihood of S. mitis infection, which may be resistant to penicillins and fluoroquinolones [7]. A recent study of pathogens in human breast milk showed that 83.3% of S. mitis isolates were resistant to at least one antibiotic, and of those, half were resistant to three or more antibiotics [12]. Furthermore, S. mitis can cause severe bacteremia in cancer patients with neutropenia. However, this case highlights that patients who have a normal neutrophil count should be monitored for IE as well. Therefore, we advise clinicians to maintain a high index of suspicion of S. mitis infective endocarditis given the high morbidity and mortality associated with the infection.\n\nWe look forward to future clinical vignettes regarding the development of IE in patients who are immunosuppressed from cancer and/or chemotherapy.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Transthoracic echocardiogram showing vegetation at the valley of the aortic valve cusp.\n\nFigure 2 Focal area of abnormal signaling with nonenhancement at the level of T10.\n==== Refs\n1 Cahill T. J. Prendergast B. D. Infective endocarditis The Lancet 2016 387 10021 882 893 10.1016/s0140-6736(15)00067-7 2-s2.0-84959487788 \n2 Mitchell J. \nStreptococcus mitis : walking the line between commensalism and pathogenesis Molecular Oral Microbiology 2011 26 2 89 98 10.1111/j.2041-1014.2010.00601.x 2-s2.0-79952353786 21375700 \n3 Shelburne S. A. Sahasrabhojane P. Saldana M. \nStreptococcus mitis strains causing severe clinical disease in cancer patients Emerging Infectious Diseases 2014 20 5 762 771 10.3201/eid2005.130953 2-s2.0-84898846252 24750901 \n4 Shelburne S. A. Lasky R. E. Sahasrabhojane P. Tarrand J. T. Rolston K. V. I. Development and validation of a clinical model to predict the presence of β-lactam resistance in viridans group streptococci causing bacteremia in neutropenic cancer patients Clinical Infectious Diseases 2014 59 2 223 230 10.1093/cid/ciu260 2-s2.0-84904023132 24755857 \n5 Galdy S. Nastasi G. Streptococcus bovis endocarditis and colon cancer: myth or reality? A case report and literature review BMJ Case Reports 2012 2012 10.1136/bcr-2012-006961 2-s2.0-84872178656 \n6 Fernández-Cruz A. Muñoz P. Sandoval C. Infective endocarditis in patients with cancer: a consequence of invasive procedures or a harbinger of neoplasm? Medicine (Baltimore) 2017 96 38 p. e7913 10.1097/MD.0000000000007913 28930826 \n7 Matsui N. Ito M. Kuramae H. Inukai T. Sakai A. Okugawa M. Infective endocarditis caused by multidrug-resistant Streptococcus mitis in a combined immunocompromised patient: an autopsy case report Journal of Infection and Chemotherapy 2013 19 2 321 325 10.1007/s10156-012-0465-9 2-s2.0-84880699877 22965841 \n8 Deo S. V. Park S. J. Infective endocarditis with multiple septic emboli due to Streptococcus mitis : a wolf in sheep’s clothing Heart, Lung and Circulation 2014 23 4 e124 e126 10.1016/j.hlc.2013.10.099 2-s2.0-84897039712 \n9 Shelburne S. A. Chaftari A.-M. Jamal M. Identification and characterization of catheter-related bloodstream infections due to viridans group streptococci in patients with cancer American Journal of Infection Control 2014 42 10 1127 1129 10.1016/j.ajic.2014.06.012 2-s2.0-84908216757 25278410 \n10 Hurst R. W. Spinal Vascular Disorders: Magnetic Resonance Imaging of the Brain and Spine 1996 2nd Philadelphia, PA, USA Lippincott-Raven \n11 Jong G. M. Chung Y. C. Young C. Tsai L. M. Polymicrobial infective endocarditis with anterior spinal artery syndrome in a drug addict Southeast Asian Journal of Tropical Medicine and Public Health 1993 24 202 205 8362298 \n12 Marín M. Arroyo R. Espinosa-Martos I. Fernández L. Rodríguez J. M. Identification of emerging human mastitis pathogens by MALDI-TOF and assessment of their antibiotic resistance patterns Frontiers in Microbiology 2017 8 p. 1258\n\n",
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"abstract": "Hepatitis E is an acute self-limiting disease caused by hepatitis E virus (HEV). Recent reports show that HEV can induce chronic hepatitis or be reactivated in immunocompromised hosts. We report a 63-year-old woman with rheumatoid arthritis (RA) who developed hepatitis E during treatment with tocilizumab. Analysis of serially stocked serum samples confirmed that hepatitis was caused by primary infection with HEV and not by viral reactivation. Her liver function improved after discontinuing tocilizumab and remained within the normal range without reactivation of HEV for >5 years after restarting tocilizumab. We also reviewed the published cases of hepatitis E that developed during RA treatment.",
"affiliations": "Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Japan.;Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Japan.;Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Japan.;Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Japan.;Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Japan.;Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Japan.;Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan.;Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Japan.;Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan.;Division of Gastroenterology and Hepatology Internal Medicine, Saitama Medical University, Saitama, Japan.;Department of Rheumatology and Nephrology, Japan Red Cross Maebashi Hospital, Maebashi, Japan.;Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Japan.",
"authors": "Ikeuchi|Hidekazu|H|0000-0002-0768-7090;Koinuma|Kana|K|;Nakasatomi|Masao|M|0000-0002-8612-8915;Sakairi|Toru|T|;Kaneko|Yoriaki|Y|;Maeshima|Akito|A|;Yamazaki|Yuichi|Y|;Okamoto|Hiroaki|H|;Mimura|Toshihide|T|0000-0002-9050-0855;Mochida|Satoshi|S|;Nojima|Yoshihisa|Y|;Hiromura|Keiju|K|0000-0002-9490-8364",
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"fulltext": "\n==== Front\nCase Rep RheumatolCase Rep RheumatolCRIRHCase Reports in Rheumatology2090-68892090-6897Hindawi 10.1155/2018/6873276Case ReportHepatitis E during Tocilizumab Therapy in a Patient with Rheumatoid Arthritis: Case Report and Literature Review http://orcid.org/0000-0002-0768-7090Ikeuchi Hidekazu hikeuchi@gunma-u.ac.jp\n1\nKoinuma Kana \n1\nhttp://orcid.org/0000-0002-8612-8915Nakasatomi Masao \n1\nSakairi Toru \n1\nKaneko Yoriaki \n1\nMaeshima Akito \n1\nYamazaki Yuichi \n2\nOkamoto Hiroaki \n3\nhttp://orcid.org/0000-0002-9050-0855Mimura Toshihide \n4\nMochida Satoshi \n5\nNojima Yoshihisa \n6\nhttp://orcid.org/0000-0002-9490-8364Hiromura Keiju \n1\n\n1Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Japan\n2Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan\n3Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Japan\n4Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan\n5Division of Gastroenterology and Hepatology Internal Medicine, Saitama Medical University, Saitama, Japan\n6Department of Rheumatology and Nephrology, Japan Red Cross Maebashi Hospital, Maebashi, JapanAcademic Editor: Shigeko Inokuma\n\n2018 26 7 2018 2018 68732769 2 2018 27 6 2018 Copyright © 2018 Hidekazu Ikeuchi et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Hepatitis E is an acute self-limiting disease caused by hepatitis E virus (HEV). Recent reports show that HEV can induce chronic hepatitis or be reactivated in immunocompromised hosts. We report a 63-year-old woman with rheumatoid arthritis (RA) who developed hepatitis E during treatment with tocilizumab. Analysis of serially stocked serum samples confirmed that hepatitis was caused by primary infection with HEV and not by viral reactivation. Her liver function improved after discontinuing tocilizumab and remained within the normal range without reactivation of HEV for >5 years after restarting tocilizumab. We also reviewed the published cases of hepatitis E that developed during RA treatment.\n==== Body\n1. Introduction\nHepatic disorders are some of the most common complications that arise during rheumatoid arthritis (RA) treatment. Routine liver enzyme testing is recommended to detect the side effects of disease-modifying antirheumatic drugs (DMARDs) as well as the reactivation of viruses such as hepatitis type B (HBV), hepatitis type C (HCV), and cytomegalovirus [1, 2].\n\nHepatitis E is a disease of the liver that is caused by hepatitis type E virus (HEV) infection. HEV usually induces acute self-limiting hepatitis in healthy individuals. However, HEV is known to induce chronic hepatitis in immunocompromised hosts, including patients with HIV infection, chemotherapy recipients, and organ transplant recipients [3, 4]. In addition, HEV deterioration has been reported in patients after allogenic stem cell transplantation [5, 6], despite low risk of deterioration [7].\n\nHere, we report a case of hepatitis E that developed during tocilizumab therapy for RA. In this case, we sequentially determined the serum titers of HEV antibodies and RNA before and after the onset of hepatitis using stocked serum samples. In addition, we reviewed the published cases of hepatitis E that occurred during RA treatment with DMARDs.\n\n2. Case Presentation\nA 63-year-old woman visited our outpatient clinic because of general malaise that lasted 6 days. She developed RA at the age of 60 years and had been treated with 400 mg monthly intravenous tocilizumab for the past 10 months and 3 mg/day prednisolone. She had no history of blood transfusion, alcohol use, travel abroad, or raw meat intake, and her joints were not tender or swollen. Disease Activity Score 28-joint count C reactive protein was 1.13. Laboratory data revealed elevated liver enzyme levels: AST, 338 IU/L; ALT, 523 IU/L; ALP, 377 IU/L; and γ-GTP, 68 IU/L. Blood counts, total protein, albumin, total bilirubin, electrolytes, renal tests, C reactive protein, and coagulation test results were almost within normal ranges. Her serum HBV nucleic acid levels were monitored regularly to detect HBV reactivation because she tested positive for antibodies to HBV surface and core antigens without HBs antigen before the initiation of tocilizumab. At admission, HBV DNA levels were within normal range. Tests to detect antibodies to hepatitis A and C were negative. Tests to detect antibodies to Epstein–Barr virus and cytomegalovirus were both negative for immunoglobulin M (IgM) but positive for immunoglobulin G (IgG). Abdominal ultrasound revealed normal liver morphology.\n\nThe patient was diagnosed with HEV infection (genotype 3) because tests to detect anti-HEV immunoglobulin A (IgA) antibody and HEV RNA in her sera were both positive. Tocilizumab, pregabalin, eldecalcitol, and teriparatide were discontinued, and stronger neo-minophagen C and ursodeoxycholic acid were administered. Liver enzyme levels decreased and returned to normal 3 weeks after admission, and she was discharged from our hospital. Results of HEV RNA tests were negative 6 weeks after admission. Tocilizumab and eldecalcitol were reinitiated 4 weeks after liver enzyme normalization. RA remained in remission, and liver enzymes remained stable for the subsequent 5 years under tocilizumab therapy.\n\nBecause she had been a participant in a prospective clinical study to investigate the incidence of HBV reactivation in patients receiving immunosuppressive and/or anticancer therapies [8], her sera that was collected prior to hepatitis E onset had been stored. The use of serially stocked sera for HEV detection was approved by the Ethics Committee of Gunma University Hospital (#15-61). We examined her serum for anti-HEV antibodies and HEV RNA before and after admission (Table 1). Neither anti-HEV antibodies nor HEV RNA was detected in the preadmission samples. In contrast, all of them were positive at admission. Anti-HEV IgM and IgA antibody levels peaked 1 week after admission and declined thereafter. Anti-HEV IgG antibody levels remained elevated until the final observation at 57 months. HEV RNA was detected at 0, 2, and 3 weeks after admission and was undetectable thereafter.\n\n3. Discussion\nHEV was previously believed to cause acute hepatitis but not chronic hepatitis. However, Kamar et al. first reported that chronic HEV infection was observed in patients after organ transplantation [3]. They further reported that HEV infection caused chronic hepatitis in >60% of solid-organ transplant recipients [9]. Chronic HEV infection was also reported in patients with HIV infection and in a patient with malignant lymphoma treated with rituximab [4, 10]. In addition, HEV persistent infection has been reported in recipients of bone marrow transplant under severe immunosuppression [5–7]. Recently, biological DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) are frequently used in RA treatment. Treatment with bDMARDs is reported to increase the risk of hepatitis B virus reactivation in patients with RA [11]. Therefore, chronic transformation of hepatitis E may occur in patients with RA who are treated with bDMARDs or tsDMARDs. In our case, sequential analysis of anti-HEV antibodies and HEV RNA using stocked serum samples clearly confirmed that our patient developed hepatitis as a result of primary acute HEV infection, but not recurrence or chronic infection of HEV. The clinical course of our patient was self-limiting, and the virus was eradicated from the serum without chronic transformation. In addition, there was neither recurrence of hepatitis nor persistent infection of HEV infection during the following 5 years, even after the reintroduction of tocilizumab.\n\nThe case reports of hepatitis E infection in patients with RA are accumulating [12–21]. Table 2 summarizes published cases of hepatitis E developed during the treatment of RA with DMARDs. Of 26 cases including ours, 20 were treated with bDMARDs or tsDMARDs with or without conventional synthetic DMARDs (csDMARDs) and 6 cases were treated with csDMARDs alone. Low-dose steroids were used in 16 cases. In most cases, DMARDs were discontinued for a certain period after the diagnosis of hepatitis. Temporal withdrawal of DMARDs may help the immune system to recover and eliminate HEV. In most patients, liver function was normalized without antiviral therapy. However, 1 patient (case 1) died of fulminant hepatitis, despite treatment with plasma exchange and continuous hemofiltration [12]. The HEV genotype detected in this patient was genotype 4, which is known to be more virulent than genotype 3. In addition, a male patient (case 25) who was administered adalimumab and methotrexate developed chronic hepatitis E [21]. The routine testing revealed elevated liver enzyme levels, and methotrexate, but not adalimumab, was discontinued. Eight months later, he was diagnosed with HEV infection, and adalimumab was discontinued. However, serum HEV RNA remained positive for more than 5 months; therefore, he was treated with ribavirin for 42 days until the test results for serum HEV RNA were negative [21].\n\nIn transplant recipients with chronic HEV infection, antiviral therapy with interferon-α and ribavirin as monotherapy or in combination is recommended if immunosuppressive therapy has to be continued or viral clearance is difficult to achieve even after weakening immunosuppression [22, 23]. In patients with RA who are treated with DMARDs as listed above, only 4 cases were treated with ribavirin and 3 of them had been treated with rituximab. Another patient had been treated with adalimumab before and after notification of elevated liver enzymes for several months and ultimately developed chronic hepatitis E, as described above [14, 15, 19, 21]. Based on these results, antiviral therapy may be considered only in high-risk patients: patients with HEV (genotype 4), those who had been treated with long-lasting and immunosuppressive DMARDs such as rituximab, and those with severe or chronic hepatitis. Further investigation is to clarify the adequate use of ribavirin in acute hepatitis E patients taking DMARDs.\n\nIn summary, we presented a case of RA with hepatitis E that developed during tocilizumab therapy, and we reviewed published cases of hepatitis E among patients with RA on DMARDs treatment. In RA patients whose liver dysfunction was detected at routine examination, the possibility of HEV infection should be considered. In a case of hepatitis E, discontinuation of bDMARDs or tsDMARDs is recommended, and administration of ribavirin may be necessary in high-risk patients. In addition, in our case, tocilizumab was safely used after normalization of liver function for a long term without persistent infection of HEV.\n\nConsent\nThe patient's written informed consent for publication of information about her was obtained.\n\nDisclosure\nParts of this manuscript were reported in Kanto Riumachi (2016; 1: 96–102) in Japanese, from the proceedings of the 47th Kanto Riumachi Conference (Tokyo, Japan).\n\nConflicts of Interest\nKeiju Hiromura has received an honoraria for lectures from Chugai Pharmaceutical, Co., Ltd. Satoshi Mochida has received an honoraria for lectures from Bristol-Myers Squibb, consigned/joint research expenses from Bristol-Myers Squibb and Tanabe Mitsubishi Pharma Co., and scholarship donations from Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., and Takeda Pharmaceutical Co. Ltd. The authors declare that they have no conflicts of interest.\n\nTable 1 Sequential changes of liver enzymes and laboratory tests for hepatitis E.\n\nTime after admission\tAST\tALT\tAnti-HEV IgG\tAnti-HEV IgM\tAnti-HEV IgA\tHEV RNA\t\n(13–33 IU/L∗)\t(6–27 IU/L∗)\t(OD450 < 0.175∗)\t(OD450 < 0.440∗)\t(OD450 < 0.642∗)\t(−)\t\n−30 months\t17\t9\t0.046\t0.043\t0.042\t−\t\n−20 months\t16\t14\t0.047\t0.05\t0.035\t−\t\n−10 months\t19\t14\t0.035\t0.088\t0.04\t−\t\n0\t338\t523\t2.563\t2.845\t2.93\t+\t\n1 week\t44\t137\t2.822\t>3.000\t>3.000\t+\t\n2 weeks\t32\t37\t>3.000\t2.894\t2.296\t+\t\n3 weeks\t22\t18\t2.748\t2.771\t1.499\t+\t\n6 weeks\t27\t25\t2.956\t2.661\t1.113\t−\t\n10 weeks\t22\t15\t>3.000\t2.303\t1.019\t−\t\n14 weeks\t27\t19\t>3.000\t1.863\t0.799\t−\t\n22 weeks\t43\t28\t>3.000\t1.022\t0.536\t−\t\n26 weeks\t31\t26\tNA\tNA\tNA\tNA\t\n57 months\t24\t17\t1.659\t0.176\t0.115\t−\t\n\n∗Normal range. HEV, hepatitis E virus; IgG, immunoglobulin G; IgM, immunoglobulin M; IgA, immunoglobulin A; NA, not available.\n\nTable 2 Summary of cases of hepatitis E during treatment of rheumatoid arthritis.\n\nNumber\tFirst author\tYear\tReference\tSex\tAge\tbDMARDs/tsDMARDs\tStopping bDMARDs/tsDMARDs\tcsDMARDs\tStopping csDMARDs\tPSL (mg/day)\tHEV genotype\tRibavirin\tPeriods for disappearance of HEV RNA\tPrognosis\t\n1\tSugawara\t2009\t[12]\tM\t60\tIFX\tNA\tMTX, BUC\t \t(+)∗\t4\t(−)\tNA\tDied due to fulminant hepatitis\t\n2\tBauer\t2013\t[13]\tF\t68\tABA\tYes\tLEF\tYes\t5\t3\t(−)\tNA\tImproved\t\n3\tRoux\t2013\t[14]\tM\t55\tRTX\tYes\tMTX\tYes\t(+)∗\t3\t(+)\t3 months\tImproved\t\n4\tBauer\t2015\t[15]\tF\t62\tIFX\tYes\tMTX\tYes\t(−)\tNA\t(−)\t4 weeks\tImproved\t\n5\tBauer\t2015\t[15]\tM\t72\tRTX\tNo\tMTX, LEF\tYes\t(−)\tNA\t(−)\tNA\tImproved\t\n6\tBauer\t2015\t[15]\tF\t49\tTCZ\tYes\t(−)\tYes\t3\t3f\t(−)\t6 weeks\tImproved\t\n7\tBauer\t2015\t[15]\tF\t69\tABA\tYes\tLEF\tYes\t5\t3f\t(−)\t6 weeks\tImproved\t\n8\tBauer\t2015\t[15]\tM\t69\tRTX\tNo\tMTX\tNo\t(−)\tNA\t(+)\t10.5 weeks\tImproved\t\n9\tBauer\t2015\t[15]\tM\t61\tRTX\tNo\tLEF\tYes\t3\tNA\t(−)\t8 weeks\tImproved\t\n10\tBauer\t2015\t[15]\tF\t53\tABA\tYes\tMTX\tYes\t(−)\tNA\t(−)\t9 weeks\tImproved\t\n11\tBauer\t2015\t[15]\tF\t44\tRTX\tYes\tMTX\tYes\t(−)\t3c\t(−)\t9.5 weeks\tImproved\t\n12\tBauer\t2015\t[15]\tF\t55\tETN\tYes\tMTX\tYes\t(−)\tNA\t(−)\t4 weeks\tImproved\t\n13\tBauer\t2015\t[15]\tF\t60\tADA\tYes\tMTX\tYes\t4\t3f\t(−)\t8 weeks\tImproved\t\n14\tBauer\t2015\t[15]\tM\t59\tTCZ\tYes\tMTX\tYes\t7\tNA\t(−)\t4 weeks\tImproved\t\n15\tSchultze\t2015\t[16]\tF\t68\t(−)\t \tMTX\tYes\t5∗∗\tNA\t(−)\t40 days\tImproved\t\n16\tLeloy\t2015\t[17]\tF\t33\tTCZ\tYes\t(−)\t \t(−)\tNA\t(−)\tNA\tImproved\t\n17\tKanda\t2015\t[18]\tF\t64\t(−)\t \tMTX, BUC\tNA\t(−)\t3\t(−)\tNA\tImproved\t\n18\tKanda\t2015\t[18]\tF\t74\tTOF\tYes\t(−)\t \t(+)∗\t3\t(−)\tNA\tImproved\t\n19\tKanda\t2015\t[18]\tF\t52\t(−)\t \tMTX\tNA\t(−)\t3\t(−)\tNA\tImproved\t\n20\tVerhoeven\t2016\t[19]\tF\t51\tRTX\tYes\t(−)\t \t(−)\tNA\t(+)\t2 months\tImproved\t\n21\tKobayashi\t2017\t[20]\tF\t58\t(−)\t \tBUC, MIZ, ACT\tNo\t5\tNA\t(−)\tNA\tImproved\t\n22\tKobayashi\t2017\t[20]\tM\t61\tETN\tYes\tMTX\tYes\t3\tNA\t(−)\tNA\tImproved\t\n23\tKobayashi\t2017\t[20]\tM\t67\t(−)\t \tMTX, TAC\tYes\t5\tNA\t(−)\tNA\tImproved\t\n24\tKobayashi\t2017\t[20]\tF\t52\t(−)\t \tMTX, MIZ, TAC\tYes\t4\tNA\t(−)\tNA\tImproved\t\n25\tvan Bijnen\t2017\t[21]\tM\t63\tADA\tYes\tMTX\tYes\t3\t3\t(+)\t42 days after ribavirin\tChronic infection˗improved\t\n26\tOur case\t \t \tF\t63\tTCZ\tYes\t(−)\t \t3\t3e\t(−)\t6 weeks\tImproved\t\nDMARDs, disease-modifying antirheumatic drugs; bDMARDs, biologic DMARDs; csDMARDs, conventional synthetic DMARDs; PSL, prednisolone/prednisone; HEV, hepatitis E virus; IFX, infliximab; RTX, rituximab; TCZ, tocilizumab; ABA, abatacept; ETN, etanercept; TOF, tofacitinib; MTX, methotrexate; BUC, bucillamine; LEF, leflunomide; MIZ, mizoribine; ACT, actarit; TAC, tacrolimus; NA, not available. ∗Dose is not available; ∗∗weekly dosage.\n==== Refs\n1 Saag K. G. Teng G. G. Patkar N. M. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis Arthritis and Rheumatism 2008 59 6 762 784 10.1002/art.23721 2-s2.0-45349090538 18512708 \n2 Singh J. A. Saag K. G. Bridges S. L. Jr. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis Arthritis and Rheumatology 2016 68 1 1 26 10.1002/art.39480 2-s2.0-84952639950 \n3 Kamar N. Selves J. Mansuy J. M. Hepatitis E virus and chronic hepatitis in organ-transplant recipients New England Journal of Medicine 2008 358 8 811 817 10.1056/nejmoa0706992 2-s2.0-39549089297 18287603 \n4 Dalton H. R. Bendall R. P. Keane F. E. Tedder R. S. Ijaz S. Persistent carriage of hepatitis E virus in patients with HIV infection The New England Journal of Medicine 2009 361 10 1025 1027 10.1056/nejmc0903778 2-s2.0-69949124139 19726781 \n5 le Coutre P. Meisel H. Hofmann J. Reactivation of hepatitis E infection in a patient with acute lymphoblastic leukaemia after allogeneic stem cell transplantation Gut 2009 58 5 699 702 10.1136/gut.2008.165571 2-s2.0-66349093169 19359434 \n6 Versluis J. Pas S. D. Agteresch H. J. Hepatitis E virus: an underestimated opportunistic pathogen in recipients of allogeneic hematopoietic stem cell transplantation Blood 2013 122 6 1079 1086 10.1182/blood-2013-03-492363 2-s2.0-84886914384 23794068 \n7 Abravanel F. Mansuy J. M. Huynh A. Low risk of hepatitis E virus reactivation after haematopoietic stem cell transplantation Journal of Clinical Virology 2012 54 2 152 155 10.1016/j.jcv.2012.02.015 2-s2.0-84860322521 22425538 \n8 Mochida S. Nakao M. Nakayama N. Nationwide prospective and retrospective surveys for hepatitis B virus reactivation during immunosuppressive therapies Journal of Gastroenterology 2016 51 10 999 1010 10.1007/s00535-016-1168-2 2-s2.0-84988864309 26831356 \n9 Kamar N. Garrouste C. Haagsma E. B. Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants Gastroenterology 2011 140 5 1481 1489 10.1053/j.gastro.2011.02.050 2-s2.0-79955424791 21354150 \n10 Ollier L. Tieulie N. Sanderson F. Chronic hepatitis after hepatitis E virus infection in a patient with non-Hodgkin lymphoma taking rituximab Annals of Internal Medicine 2009 150 6 430 431 10.7326/0003-4819-150-6-200903170-00026 \n11 Urata Y. Uesato R. Tanaka D. Prevalence of reactivation of hepatitis B virus replication in rheumatoid arthritis patients Modern Rheumatology 2011 21 1 16 23 10.3109/s10165-010-0337-z 20668905 \n12 Sugawara N. Yawata A. Takahashi K. Abe N. Arai M. The third case of fulminant hepatitis associated with “Kitami/Abashiri strain” of hepatitis E virus genotype 4 Kanzo 2009 50 8 473 374 10.2957/kanzo.50.473 2-s2.0-70349325782 \n13 Bauer H. Sibilia J. Moreau P. Messer L. Acute hepatitis E during biotherapy Joint Bone Spine 2013 80 1 91 92 10.1016/j.jbspin.2012.08.001 2-s2.0-84872862902 22999908 \n14 Roux C.H. Anty R. Patouraux S. Euller-Ziegler L. Hepatitis E: are rheumatic patients at risk? Journal of Rheumatology 2013 40 1 p. 99 10.3899/jrheum.120599 2-s2.0-84871867553 \n15 Bauer H. Luxembourger C. Gottenberg J. E. Outcome of hepatitis E virus infection in patients with inflammatory arthritides treated with immunosuppressants: a French retrospective multicenter study Medicine 2015 94 14 p. e675 10.1097/md.0000000000000675 2-s2.0-84929484875 25860212 \n16 Schultze D. Mani B. Dollenmaier G. Sahli R. Zbinden A. Krayenbuhl P. A. Acute Hepatitis E Virus infection with coincident reactivation of Epstein-Barr virus infection in an immunosuppressed patient with rheumatoid arthritis: a case report BMC Infectious Diseases 2015 15 1 p. 474 10.1186/s12879-015-1146-y 2-s2.0-84945920005 \n17 Leroy M. Coiffier G. Pronier C. Triquet L. Perdriger A. Guggenbuhl P. Macrophage activation syndrome with acute hepatitis E during tocilizumab treatment for rheumatoid arthritis Joint Bone Spine 2015 82 4 278 279 10.1016/j.jbspin.2015.01.018 2-s2.0-84937522295 25791259 \n18 Kanda T. Yasui S. Nakamura M. Recent trend of hepatitis E virus infection in Chiba area, Japan: 3 of 5 cases with rheumatoid arthritis Case Reports in Gastroenterology 2015 9 3 317 326 10.1159/000441387 2-s2.0-84993999006 26600768 \n19 Verhoeven F. Weil-Verhoeven D. Di Martino V. Prati C. Thevenot T. Wendling D. Management of acute HVE infection in a patient treated with rituximab for rheumatoid arthritis Joint Bone Spine 2016 83 5 577 578 10.1016/j.jbspin.2015.11.010 2-s2.0-84961990456 27055728 \n20 Kobayashi D. Ito S. Takai C. Type-E hepatitis in rheumatoid arthritis patients Modern Rheumatology Case Reports 2017 1 2 30 34 10.1080/24725625.2017.1288344 \n21 van Bijnen S. T. Ledeboer M. Martens H. A. Chronic hepatitis E in a patient with rheumatoid arthritis treated with adalimumab and methotrexate Rheumatology 2017 56 3 497 498 10.1093/rheumatology/kew388 2-s2.0-85028538708 27940593 \n22 Kamar N. Bendall R. Legrand-Abravanel F. Hepatitis E The Lancet 2012 379 9835 2477 2488 10.1016/s0140-6736(11)61849-7 2-s2.0-84862896570 \n23 Kamar N. Izopet J. Tripon S. Ribavirin for chronic hepatitis E virus infection in transplant recipients New England Journal of Medicine 2014 370 12 1111 1120 10.1056/nejmoa1215246 2-s2.0-84896480771 24645943\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6897",
"issue": "2018()",
"journal": "Case reports in rheumatology",
"keywords": null,
"medline_ta": "Case Rep Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "101585353",
"other_id": null,
"pages": "6873276",
"pmc": null,
"pmid": "30147981",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "19293084;19359434;20668905;23280171;27055728;26831356;22549046;26545940;23794068;18512708;26511098;19726781;26600768;25791259;24645943;27940593;22425538;18287603;21354150;25860212;22999908",
"title": "Hepatitis E during Tocilizumab Therapy in a Patient with Rheumatoid Arthritis: Case Report and Literature Review.",
"title_normalized": "hepatitis e during tocilizumab therapy in a patient with rheumatoid arthritis case report and literature review"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1030461",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Melanoma differentiation-associated gene 5 (MDA5) antibody, also known as anti-CADM140 antibody is recognised to be associated with rapidly progressive interstitial lung disease, which can be fatal within 3 months. It is also known to be associated with amyopathic dermatomyositis. We report a case of MDA5 antibody-associated interstitial pneumonia with autoimmune features, without cutaneous features of dermatomyositis, in a Sudanese patient with dual positive antibodies to Ro52. The patient notably had several features associated with poor prognosis, including age, high serum ferritin level, anti-Ro52 antibodies and progressive lung infiltrates during treatment.",
"affiliations": "Rheumatology Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia lihen.hong@sa.gov.au.;Rheumatology Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.;Rheumatology Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.",
"authors": "Hong|Lih En|LE|http://orcid.org/0000-0003-1964-4087;Proudman|Susanna|S|;Limaye|Vidya|V|",
"chemical_list": "D001323:Autoantibodies; D000072640:Interferon-Induced Helicase, IFIH1",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-234946",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(11)",
"journal": "BMJ case reports",
"keywords": "connective tissue disease; immunology; interstitial lung disease; lung function; radiology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001323:Autoantibodies; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D008168:Lung; D017563:Lung Diseases, Interstitial; D008875:Middle Aged; D011379:Prognosis; D012131:Respiratory Insufficiency; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33257351",
"pubdate": "2020-11-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Interstitial pneumonia with autoimmune features in a patient with melanoma differentiation-associated gene 5 (MDA5) antibody.",
"title_normalized": "interstitial pneumonia with autoimmune features in a patient with melanoma differentiation associated gene 5 mda5 antibody"
} | [
{
"companynumb": "AU-PFIZER INC-2021331360",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
{
"abstract": "The basic surgical treatment for avascular necrosis of the femur head is core decompression. In this report we discuss a case where the patient developed compartment syndrome after core decompression surgery with history of anticoagulant use. A 49-year-old man, who was using Coumadin 5 mg once daily due to aortic valve replacement and atrial fibrillation, had undergone core decompression surgery done due to stage 2 femur head avascular necrosis (AVN). He later developed isolated anterior thigh compartment syndrome for which fasciotomy was performed. Every surgical intervention to the extremities of patients with anticoagulant treatment should be considered high risk for compartment syndrome, even if appropriate precautions are taken. It is necessary to clinically observe for a sufficient duration to be able to identify symptoms.",
"affiliations": "Department of Orthopaedics, Selçuk Un?vercity, Konya, Turkey.;Orthopedics and Traumatology Department, Selcuk University Medicine Faculty.;Department of Orthopaedics, Selçuk Un?vercity, Konya, Turkey.;Department of Orthopaedics, Selçuk Un?vercity, Konya, Turkey.",
"authors": "Ciftci|Sadettin|S|;Gulec|Ali|A|;Mercan|Numan|N|;Yildrim|Ahmet|A|",
"chemical_list": null,
"country": "Pakistan",
"delete": false,
"doi": "10.5455/JPMA.36021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-9982",
"issue": "70(9)",
"journal": "JPMA. The Journal of the Pakistan Medical Association",
"keywords": "compartment syndrome, core de-compression, avascular necrosis.\n ",
"medline_ta": "J Pak Med Assoc",
"mesh_terms": "D003161:Compartment Syndromes; D019299:Decompression, Surgical; D005270:Femur Head; D005271:Femur Head Necrosis; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "7501162",
"other_id": null,
"pages": "1642-1644",
"pmc": null,
"pmid": "33040128",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A new complication of femur head core decompression surgery: compartment syndrome.",
"title_normalized": "a new complication of femur head core decompression surgery compartment syndrome"
} | [
{
"companynumb": "TR-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-091352",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"dr... |
{
"abstract": "DRESS syndrome (Drug rash with Eosinophilia and Systemic Symptoms) is an idiosyncratic reaction (type B), characterized by peripheral eosinophilia and systemic symptoms, such as fever, rash, lymphadenopathy, hepatitis, atypical lymphocytes and elevation of liver enzymes at least twice its normal level or increase of alanine amino transferase (ALT) >100 U/L. Its incidence is of 1/1,000 to 10,000 exposures and its mortality is of 10%-20%. Treatment is based on steroids and on the suspension of the suspect drug. This paper reports the cases of six patients with DRESS syndrome attended at Centro Medico Nacional Siglo XXI, Mexico City, from September 2012 to September 2013, which accounted for 12.5% of patients attended with adverse reactions to drugs.",
"affiliations": "Hospital de Especialidades, Centro Médico Nacional Siglo XXI. Avenida Cuauhtémoc 330, 06720 México, DF. aeri_05@hotmail.com.",
"authors": "López-Rocha|Eunice|E|;Blancas|Lizbeth|L|;Rodríguez-Mireles|Karen|K|;Gaspar-López|Arturo|A|;O'Farrill-Romanillos|Patricia|P|;Amaya-Mejía|Adela|A|;Galindo-Pacheco|Lucy|L|;Campos-Romero|Freya|F|;Aguilar-Hinojosa|Nadia|N|;Suárez|Guadalupe|G|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000927:Anticonvulsants; D002220:Carbamazepine; D010672:Phenytoin",
"country": "Mexico",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-5151",
"issue": "61(1)",
"journal": "Revista alergia Mexico (Tecamachalco, Puebla, Mexico : 1993)",
"keywords": "DRESS syndrome; Drug-reactions; Eosinophilia; Exantema; Systemic symptoms",
"medline_ta": "Rev Alerg Mex",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000927:Anticonvulsants; D002220:Carbamazepine; D003937:Diagnosis, Differential; D004198:Disease Susceptibility; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D006801:Humans; D008297:Male; D008800:Mexico; D008875:Middle Aged; D008954:Models, Biological; D010672:Phenytoin; D015995:Prevalence; D014505:Urban Population; D055815:Young Adult",
"nlm_unique_id": "9438824",
"other_id": null,
"pages": "14-23",
"pmc": null,
"pmid": "24912998",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Prevalence of DRESS syndrome.",
"title_normalized": "prevalence of dress syndrome"
} | [
{
"companynumb": "MX-ACTAVIS-2014-17818",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": null,
"... |
{
"abstract": "The prevalence of secondary cancers associated with the breast cancer treatment has increased, which is due to the administration of cytotoxic/hormonal drugs as well as radiotherapy. A 54-year-old female patient with a history of breast cancer for 4 years and receiving tamoxifen the hematology clinic with fatigue and nosebleed. Laboratory parameters were revealed pancytopenia. The bone marrow biopsy finding was compatible with CD20 positive high-grade B cell lymphoma resembling diffuse large B cell lymphoma. The patient started to receive a chemotherapy. Her hemogram values displayed an improvement after the second cycle. However, interim PET-BT, performed after the fourth cycle, showed an incomplete response in cervical lymphatic nodes. Then, a tru-cut biopsy was performed resulting in breast cancer metastasis. This is an unusual case of secondary-DLBCL presenting with pancytopenia and occuring 4 years after the diagnosis of breast cancer. In conclusion, clinicians should carefully set the dosage of chemotherapy drugs to avoid the long-term side effects associated with such drugs.",
"affiliations": "University of Health Sciences, Istanbul Training and Research Hospital, Department of Hematology, Istanbul, Turkey.;University of Health Sciences, Istanbul Training and Research Hospital, Department of Hematology, Istanbul, Turkey.;University of Health Sciences, Istanbul Training and Research Hospital, Department of Pathology, Istanbul, Turkey.;University of Health Sciences, Istanbul Training and Research Hospital, Department of Hematology, Istanbul, Turkey.;University of Health Sciences, Istanbul Training and Research Hospital, Department of Hematology, Istanbul, Turkey.;University of Health Sciences, Istanbul Training and Research Hospital, Department of Hematology, Istanbul, Turkey.",
"authors": "Karismaz|Abdulkadir|A|;Dogu|Mehmet Hilmi|MH|;Huq|Gülben|G|;Altindal|Sermin|S|;Yokus|Osman|O|;Suyani|Elif|E|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen",
"country": "Uganda",
"delete": false,
"doi": "10.11604/pamj.2018.31.125.15057",
"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-31-12510.11604/pamj.2018.31.125.15057Case ReportA diffuse large B cell lymphoma emerging with breast cancer relapse Karismaz Abdulkadir 1Dogu Mehmet Hilmi 1Huq Gülben 2Altindal Sermin 1Yokus Osman 1Suyani Elif 1&1 University of Health Sciences, Istanbul Training and Research Hospital, Department of Hematology, Istanbul, Turkey2 University of Health Sciences, Istanbul Training and Research Hospital, Department of Pathology, Istanbul, Turkey& Corresponding author: Elif Suyani, University of Health Sciences, Istanbul Training and Research Hospital, Department of Hematology, Istanbul, Turkey19 10 2018 2018 31 12502 2 2018 25 5 2018 © Abdulkadir Karismaz et al.2018The Pan African Medical Journal - ISSN 1937-8688. This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The prevalence of secondary cancers associated with the breast cancer treatment has increased, which is due to the administration of cytotoxic/hormonal drugs as well as radiotherapy. A 54-year-old female patient with a history of breast cancer for 4 years and receiving tamoxifen the hematology clinic with fatigue and nosebleed. Laboratory parameters were revealed pancytopenia. The bone marrow biopsy finding was compatible with CD20 positive high-grade B cell lymphoma resembling diffuse large B cell lymphoma. The patient started to receive a chemotherapy. Her hemogram values displayed an improvement after the second cycle. However, interim PET-BT, performed after the fourth cycle, showed an incomplete response in cervical lymphatic nodes. Then, a tru-cut biopsy was performed resulting in breast cancer metastasis. This is an unusual case of secondary-DLBCL presenting with pancytopenia and occuring 4 years after the diagnosis of breast cancer. In conclusion, clinicians should carefully set the dosage of chemotherapy drugs to avoid the long-term side effects associated with such drugs.\n\nBreast cancerlymphomatherapy-related hematological malignancies\n==== Body\nIntroduction\nBreast cancer is among the most common tumors occurring in women, and recently, survival rates of the patients have progressively improved owing to neoadjuvant, adjuvant, endocrine and targeted therapies. However, chemotherapy-associated long-term side effects have gradually been on the rise in these patients. Adjuvant chemotherapies comprising particularly alkylating agents and topoisomerase inhibitors may increase the risk of leukemia especially in patients with early-stage breast cancer [1-3]. Prophylactic or adjuvant chemotherapy administered due to early-stage breast cancer is demonstrated to increase 10-year hematological cancer risk by 0.5%, which is twice higher than those reported in previous studies [4]. While the most prevalent hematological cancers associated with the treatment are acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) [2, 3], treatment-associated lymphomas constitute quite a rare clinical picture [5, 6]. This report presents a secondary diffuse large B-cell lymphoma emerging with breast cancer relapse.\n\nPatient and observation\nA 54-year-old female patient referred to the hematology clinic with fatigue and nosebleed. She had a history of type-2 diabetes mellitus and breast cancer. The patient was diagnosed with breast cancer four years ago and underwent a mastectomy followed by radiotherapy and chemotherapy, and she has been receiving tamoxifen since that time. The chemotherapy protocol was inaccessible because the chemotherapy was administered in Syria. The physical examination revealed a swollen right arm, ecchymoses in arms, and fixed, firm, painless cervical lymphadenopathies, the largest of which was 2x2cm in size and located on the right. Laboratory parameters were as follows: white blood cell count: 3.62 x 109/L with 0.84x109/L neutrophils, hemoglobin: 11 g/dL, platelet count: 10x109/L. Biochemical, liver and renal function test results were normal. HBsAg, Anti-HBS, Anti-HCV and Anti-HIV test results were negative. Platelet count by peripheral smear was compatible with the hemogram count without any atypical cells. The lymph node biopsy could not be performed since the platelet count did not rise despite transfusion. Instead, bone marrow aspiration and biopsy were performed for diagnostic purposes. The biopsy finding was compatible with CD20 positive high-grade B cell lymphoma resembling diffuse large B cell lymphoma (Figure 1 (A, B)). Body 18Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) performed for staging revealed following lymphadenopathies: 1.3x0.8cm-sized at the right parotid gland inferior (SUVmax: 11.8), right inferior jugular area (SUVmax: 13.1), and 2x1.5 cm-sized (largest) (SUVmax: 6.8) in the right deep cervical location. The patient started to receive a chemotherapy protocol combining rituximab-cyclophosphamide-doxorubicin-vincristine-prednisolone (R-CHOP). Her hemogram values displayed an improvement after the second cycle. However, interim PET-BT, performed after the fourth cycle, showed an incomplete response in cervical lymphatic nodes. Then, a tru-cut biopsy was performed from the lymph node in the neck as blood values were better. The patient continued to receive R-CHOP until the biopsy result was obtained. R-CHOP was stopped at the sixth cycle. The lymph node biopsy result showed breast cancer metastasis (Figure 1 (C, D)). She underwent a bone marrow biopsy after six cycles of R-CHOP, which revealed that the lymphoma infiltration disappeared. The patient's breast cancer treatment continues.\n\nFigure 1 A) carcinoma infiltration in solid islands wiping the lymph node structure; B) diffuse and strong pankeratin positivity in carcinoma cells; C) extensive infiltration in the bone marrow, presenting a diffuse pattern, consisting of cells in large centroblastic morphology; D) extensive and strong CD20 expression in the bone marrow infiltration\n\nDiscussion\nBreast cancer is one of the most common causes of cancer-related deaths in women. Although the mortality rate related to breast cancer has decreased lately with the development of early diagnosis and treatment techniques, the prevalence of secondary cancers associated with the treatment has increased due to the administration of cytotoxic/hormonal drugs as well as radiotherapy [2, 3]. Regarding the hematological malignancies, lymphomas are encountered rarely compared to AML and MDS in those patients [2, 3]. Given the high prevalence of breast cancer, these findings indicate that the number of patients under the risk of secondary cancer triggered by treatment might be actually higher than expected. The secondary cancers associated with breast cancer chemotherapy are largely associated with alkylating agents and topoisomerase II inhibitors [7]. Alkylating agents cause gene mutations and deletions in the long arms of chromosomes 5 and 7 by cross linking with DNA. Those gene mutations affect IL-3, IL-4 and other genes which are active in cell proliferation. Deletions, in turn, may activate RAS and trigger tumor suppressing gene mutations, which cause excessive cell proliferation, differentiation, and eventually leukemia [8]. Topoisomerase II inhibitors create a complex with DNA and topoisomerase II enzyme, block the enzyme activity and result in broken DNA fibers. Those broken fibers cause a rearrangement mostly in the acute lymphoblastic leukemia (ALL)-1 gene site and DNA damage, which may thus end in leukemia [9]. Similar events constitute the underlying mechanism of secondary lymphomas in patients who are applied breast cancer chemotherapy. And secondary lymphomas are usually expected to occur 5 years after the initial therapy [10]. This is an unusual case of secondary-DLBCL presenting with pancytopenia and occurring 4 years after the diagnosis of breast cancer. Since presence of pancytopenia in a breast cancer patient usually suggests the development of either leukemia or bone marrow metastases, a bone marrow biopsy showing lymphoma infiltration was astonishing. Also, the lymph nodes were involved with breast cancer unexpectedly. It was critically important to perform the sampling to distinguish it from lymphoma and make the treatment decision on this difference. And other important issue is the timing of the lymphoma diagnosis that is 4 years after the breast cancer diagnosis and probably less than 4 years after the treatment, leading to raise the doubt whether the patient's lymphoma was secondary or already existed at the time of diagnosis of the breast cancer.\n\nConclusion\nClinicians should carefully set the dosage of chemotherapy drugs, especially topoisomerase II inhibitors and alkylating agents, to avoid the long-term side effects associated with such drugs.\n\nCompeting interests\nThe authors declare no competing interests.\n\nAuthors’ contributions\nAll the authors have read and agreed to the final manuscript.\n==== Refs\nReferences\n1 Wolff AC Blackford AL Visvanathan K Risk of marrow neoplasms after adjuvant breast cancer therapy: the national comprehensive cancer network experience J Clin Oncol 2015 33 4 340 8 25534386 \n2 Bernard-Marty C Mano M Paesmans M Second malignancies following adjuvant chemotherapy: 6-year results from a Belgian randomized study comparing cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with an anthracycline-based regimen in adjuvant treatment of node-positive breast cancer patients Ann Oncol 2003 5 14 5 693 8 12702521 \n3 Praga C Bergh J Bliss J Bonneterre J Cesana B Coombes RC Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide J Clin Oncol 2005 6 20 23 18 4179 91 15961765 \n4 Fisher B Rockette H Fisher ER Leukemia in breast cancer patients following adjuvant chemotherapy or postoperative radiation: the NSABP experience J Clin Oncol 1985 3 12 1640 1658 3906049 \n5 Rossi D Sarti D Malerba L Secondary bone marrow malignancies after adjuvant chemotherapy for breast cancer: a report of 2 cases and a review of the literature Tumori 2016 11 11 102 Suppl 2 \n6 Zhang B Zhang X Li M Kong L Deng X Yu J How breast cancer chemotherapy increases the risk of leukemia: thoughts about a case of diffuse large B-cell lymphoma and leukemia after breast cancer chemotherapy Cancer Biol Ther 2016 2 17 2 125 8 26861804 \n7 Yagita M Ieki Y Onishi R Therapy-related leukemia and myelodysplasia following oral administration of etoposide for recurrent breast cancer Int J Oncol 1998 13 1 91 6 9625808 \n8 Takemoto Y Hata T Kamino K Leukemia developing after 131I treatment for thyroid cancer in a patient with Werner's syndrome: molecular and cytogenetic studies: molecular and cytogenetic studies Intern Med 1995 34 9 863 7 8580557 \n9 Felix CA Hosler MR Winick NJ Masterson M Wilson AE Lange BJ ALL-1 gene rearrangements in DNA topoisomerase II inhibitor-related leukemia in children Blood 1995 85 11 3250 6 7756657 \n10 Krishnan B Morgan GJ Non-Hodgkin lymphoma secondary to cancer chemotherapy Cancer Epidemiol Biomarkers Prev 2007 3 16 3 377 80 17372233\n\n",
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"issue": "31()",
"journal": "The Pan African medical journal",
"keywords": "Breast cancer; lymphoma; therapy-related hematological malignancies",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000328:Adult; D018931:Antineoplastic Agents, Hormonal; D001706:Biopsy; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D009364:Neoplasm Recurrence, Local; D010198:Pancytopenia; D013629:Tamoxifen",
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"title": "A diffuse large B cell lymphoma emerging with breast cancer relapse.",
"title_normalized": "a diffuse large b cell lymphoma emerging with breast cancer relapse"
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"abstract": "The ovarian Growing Teratoma Syndrome (GTS) is a rare condition among patients with primary Non-Seminomatous Germ Cell Tumours (NSGCT) presenting with enlarging masses during or after appropriate chemotherapy in the context of normalized serum markers. Several modes of dissemination are suggested, with the most frequent site of metastasis being the peritoneum. We report a case of a young patient with primary ovarian mixed NSGCT, who presented with Growing Teratoma Syndrome not only in the peritoneum but also within a trocar site after an initial surgery consisting in the laparoscopic morcellation and extraction of the ovarian neoplasm. Beside the rarity of this clinical entity, it also demonstrates the utmost importance of the safe laparoscopic management of all complex ovarian masses.",
"affiliations": "CHU of Liège, Department of Obstetrics and Gynaecology, 4000 Liège, Belgium. ; Institut Claudius Regaud, Comprehensive Cancer Center, Department of Surgical Oncology, 31000 Toulouse, France.;Institut Claudius Regaud, Comprehensive Cancer Center, Department of Surgical Oncology, 31000 Toulouse, France.;CHU of Liège, Department of Obstetrics and Gynaecology, 4000 Liège, Belgium.;Institut Claudius Regaud, Comprehensive Cancer Center, Department of Radiology, 31000 Toulouse, France.;Institut Claudius Regaud, Comprehensive Cancer Center, Department of Pathology, 31000 Toulouse, France.;Institut Claudius Regaud, Comprehensive Cancer Center, Department of Surgical Oncology, 31000 Toulouse, France.",
"authors": "De Cuypere|M|M|;Martinez|A|A|;Kridelka|F|F|;Balague|G|G|;Maisongrosse|V|V|;Ferron|G|G|",
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"fulltext": "\n==== Front\nFacts Views Vis ObgynFacts Views Vis ObgynFacts, Views & Vision in ObGyn2032-0418Universa Press 25593702Case ReportDisseminated ovarian Growing Teratoma Syndrome: a case report highlighting surgical safety issues De Cuypere M. 12Martinez A. 2Kridelka F. 1Balague G. 3Maisongrosse V. 4Ferron G. 21 CHU of Liège, Department of Obstetrics and Gynaecology, 4000 Liège, Belgium.\n2 Institut Claudius Regaud, Comprehensive Cancer Center, Department of Surgical Oncology, 31000 Toulouse, France.\n3 Institut Claudius Regaud, Comprehensive Cancer Center, Department of Radiology, 31000 Toulouse, France.\n4 Institut Claudius Regaud, Comprehensive Cancer Center, Department of Pathology, 31000 Toulouse, France.\n\nCorrespondence at: mdecuypere@chu.ulg.ac.be2014 6 4 250 253 Copyright: © 2014 Facts, Views & Vision2014This 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.The ovarian Growing Teratoma Syndrome (GTS) is a rare condition among patients with primary Non-Seminomatous Germ Cell Tumours (NSGCT) presenting with enlarging masses during or after appropriate chemotherapy in the context of normalized serum markers. Several modes of dissemination are suggested, with the most frequent site of metastasis being the peritoneum.\n\nWe report a case of a young patient with primary ovarian mixed NSGCT, who presented with Growing Teratoma Syndrome not only in the peritoneum but also within a trocar site after an initial surgery consisting in the laparoscopic morcellation and extraction of the ovarian neoplasm.\n\nBeside the rarity of this clinical entity, it also demonstrates the utmost importance of the safe laparoscopic management of all complex ovarian masses.\n\nGrowing Teratoma Syndromeovarian germ cell tumourport site metastasisiatrogenic peritoneal dissemination\n==== Body\nIntroduction\nThe Growing Teratoma Syndrome (GTS) is defined as the occurrence of a tumour mass consisting exclusively of mature teratoma, combined with normal tumour marker levels, during or after chemotherapy in patients with Non Seminomatous Germ Cell Tumours (Logothetis et al., 1982).\n\nIn 1969, Smithers (1969) published the first report of benign maturation among five patients whose primary neoplasm was of testicular origin. In this context, GTS is diagnosed in the retroperitoneum (80%) or at the thoracic level (André et al., 2000). When GTS occurs after an ovarian germ cell tumour, the peritoneal surface is the most frequent location (Djordjevic et al., 2007).\n\nThe incidence of the Growing Teratoma Syndrome is estimated to be 1,9 to 7,6% in testicular Non Seminomatous Germ Cell Tumours (Logothetis et al., 1982) and is even rarer in women.\n\nWe report the case of a Growing Teratoma Syndrome with a specific profile of concomitant peritoneal and abdominal wall distribution in a young woman with a primary ovarian mixed germ cell tumour. Initial surgery consisted in the laparoscopic morcellation and extraction of the ovarian neoplasm followed by chemotherapy.\n\nCase report\nIn 2009, a 19-year-old woman undergoes investigations for abdominal and pelvic discomfort. A 20 cm large complex pelvic mass is diagnosed. Serum tumour marker study shows elevated LDH (473 IU/l range 190-390 IU/l) and a-foetoprotein (9710 ng/ml normal < 8.5 ng/ml). Human Chorionic Gonadotropin (HCG) dosage is negative. Laparoscopic evaluation confirms a tumour in the left ovary. Despite the tumour size and its heterogeneous appearance, the laparoscopic approach is continued and necessitates the mass to be morcellated before removal. Surgical records mention a difficult extraction by increasing the left iliac port incision with ‘a priori’ no peritoneal contamination. The pathology report confirms a mixed ovarian yolk sac and immature teratoma tumour. Postoperative Positron Emission Tomography reveals an abnormal uptake at the level of the right ovary. Pelvic and para-aortic enlarged lymph nodes are noted. Four cycles of adjuvant chemotherapy with a triple association of bleomycin, etoposide and cisplatin (BEP) are prescribed and a complete biological and radiological response is obtained. Subsequently, the patient benefits from a 3 monthly follow-up based on clinical examination, repeated PET CT and a-foetoprotein dosage.\n\nIn April 2011, the PET demonstrates a large hypermetabolic lesion in the right iliac region associated with a left fixation above the bladder. The patient remains however asymptomatic and the tumour markers are negative.\n\nOne year later (May 2011) the patient is referred for complementary investigations and treatment. The MRI confirms a pelvic relapse with vesicular like lesions, englobing the uterus, the right ovary and the left iliac vessels region (Fig. 1). Additionally metastatic lesions are described in the posterior aspect of the left rectus abdominis muscle below the left iliac fossa incision performed at the time of surgery for the tumour extraction.\n\nJune 2011, a laparotomy is performed with extended peritonectomy, omentectomy, appendicectomy, splenectomy and right salpingo-oophorectomy (after cryopreservation). Wide excision of the transfixated abdominal wall lesions predominantly in the left iliac region necessitates an abdominal repair. Tumour burden was resected to no macroscopic residual disease. The histology report reveals multiple localizations of pluritissular mature teratoma without immature nor yolk sac elements (Fig. 2). No adjuvant treatment is recommended. The patient, followed up on a 3 monthly basis with clinical examination, radiological and biological evaluation, remains in complete remission up to July 2014.\n\nFig. 1 MRI abdomen pelvis, T2 axial image, important pelvic cavity invasion with vesicular like lesions, englobing the uterus, the left iliac region with involvement of the posterior fascia of the left rectus abdominis muscle..\nFig. 2 Pathologic findings of growing teratoma (right bottom) in contact with the striated muscle of the rectus abdominis muscle (HES ×50).\nDiscussion\nThe observation of a growing tumour mass after/or during treatment of a malignancy is, by default, considered as a treatment failure. However in the context of regressing tumour markers after chemotherapy for Non Seminomatous Germ Cell Tumours, the clinician should also consider the likelihood of a Growing Teratoma Syndrome.\n\nLogothetis et al. (1982) reported 6 cases of male patients with mixed testicular NSGCT with growing isolated metastasis during chemotherapy. Complete secondary cytoreduction was achieved in all six patients. Surprisingly, the final pathology report mentioned only mature teratoma in the presumed relapse. All patients remained in long-term complete remission and it was considered that benign teratomatous tissue could mimic recurrent disease by increasing in size or persisting during chemotherapy.\n\nDiSaia et al. (1977) characterized this event as “Chemotherapeutic Retroconversion” (CR). Others, as Djordevic B et al. (2007) stated that CR could not be considered as synonymous for GTS, because CR only refers to immature teratomas (and not to mixed Non Seminomatous Germ Cell tumours of the ovary) and to non-expanding metastatic masses.\n\nThree criteria are mandatory to define GTS: (1) an evolving tumour mass or finding a new tumour mass during or after chemotherapy for NSGCT, (2) the regression of previously increased tumour markers (aFP, HCG or both) and (3) the presence of only mature teratoma on the final histology (Zagamé et al., 2006; Spiess et al., 2007). GTS is usually diagnosed in the twenties (Djordjevic et al., 2007) and may occur after a primary pure immature teratoma or a mixed NSGCT. There is no consensus regarding the necessary conditions underlying the development of GTS. André et al. (2000) consider that (1) the existence of mature teratoma in the first tumour, (2) insufficient dissection of the latter and (3) the absence of response of the metastasis after chemotherapy are predictors of the development of GTS. Zagamé et al. (2006) stressed the necessity of primary peritoneal involvement as well as the existence of mainly immature neuroectodermal elements in the primary neoplasm. Djordjevic et al. (2007) also mention that GTS would be unlikely to occur if the first recurrences were not within 24 months of the original presentation of an ovarian Non Seminomatous Germ cell tumour.\n\nThe aetiology of GTS remains unclear. Main hypotheses are that chemotherapy may selectively inactivate the immature elements with subsequent growth of the remaining mature tumour cells or may change the cells behaviour with immature germ cells transforming into benign teratomatous elements (André et al., 2000).\n\nFor patients with primary ovarian NSGCT and initial peritoneal extension, GTS occurs in the majority of cases in the peritoneal cavity (Tangjitgamol et al., 2006; Zagamé et al., 2006). However, in a recent single case report of GTS after FIGO stage 1C mixed ovarian germ cell tumour, three simultaneous ways of dissemination are suggested: peritoneal, lymphatic and hematogenous (Shibata et al., 2013). Distant relapses (liver, chest, mediastinum) or retroperitoneal GTS (para-aortic lymph nodes) are more common after testicular germ cell tumours (Logothetis et al., 1982; André et al., 2000). Distant GTS suggests the existence of metastatic malignant cells in these regions at the time of the initial diagnosis.\n\nThe impact of the surgical management (laparotomy versus endoscopy) and its associated risk of peroperative tumour dissemination has been questioned by Sengar and Kulkarni (2010) who report a case of GTS in the subcutaneous tissue of a patient with immature ovarian teratoma at an early FIGO stage taken in charge by laparoscopy. The present case report with laparoscopic morcellation of a 20 cm suspicious pelvic mass and subsequent abdominal port-site GTS, further supports the potential iatrogenic role of unsafe and inadequate surgery in terms of increased risk of GTS secondary to abdominal wall implants.\n\nSurgery is the cornerstone of the management of GTS. Early diagnosis is, in this respect, crucial as late diagnosis could result in complex surgery and significant symptoms due to mechanical pressure with subsequent important morbidity and mortality (André et al., 2000; Spiess et al., 2007). Another indication for surgical excision is the known potential malignant transformation in all 3 embryologic lineages of a mature teratoma (André et al., 2000). The complete resection of GTS is mandatory, as ovarian GTS recurrence is reported with rates of 50 to 83% when incompletely resected versus 0 to 4% when complete resection is obtained (Tangjitgamol et al., 2006; Spiess et al., 2007).\n\nNon-resectable masses of GTS may be managed with a-2 interferon but the regression is usually slow, generally partial and regrowth of the lesion is often observed after treatment discontinuation (André et al., 2000). Other medical therapies such as all-trans retinoic acid, bevacizumab and the selective cyclin-independent kinase 4/6 inhibitor PD-0,332,991 resulted in disease stabilization and clinical improvement in some case reports (Veenstra and Vaughn, 2011).\n\nFollow-up with serum tumour markers (aFP, hCG, LDH) alone is sub-optimal accuracy and should be combined with regular morphologic imaging (MRI / CT Scan) (Hain and Maisey, 2003; Nimkin et al., 2004). While the FDG-PET can accurately identify germ cell residual masses, its utility in assessing residual mature teratoma is unclear due to the inability in distinguishing necrosis from mature teratoma (Hain and Maisey, 2003; Aide et al., 2007). As reported by Hariprasad et al. (2008) we also experienced positive FDG-PET uptake in the pelvis which eventually could be explained by a high glucose metabolism from brain tissue in mature teratoma.\n\nConclusion\nThe ovarian Growing Teratoma Syndrome is a rare entity but should be suspected when tumour masses persist or develop with normal tumour markers, during or after adjuvant chemotherapy for non-seminomatous germ cell ovarian neoplasia. The diagnosis requires histologic confirmation with presence of mature teratomatous elements exclusively. Optimal cytoreduction with no macroscopic residual disease is essential and reported as the management of choice for GTS with subsequent favourable prognosis. Regular follow-up is recommended.\n\nThe present case report highlights the utmost importance of an optimal surgical approach for all suspicious complex adnexal masses presenting in young patients. Mass rupture, incomplete resection and tumour cells spillage must be avoided as much as possible because it worsens the patient prognosis and may result in iatrogenic GTS requiring aggressive surgical management to obtain complete cytoreduction.\n==== Refs\nAide N Comoz F Savin E Enlarging residual mass after treatment of a NSGCT: Growing Teratoma Syndrome or recurrence J Clin Oncol 2007 25 4494 4496 17906212 \nAndré F Fizazi K Culine S The Growing Teratoma Syndrome: results of therapy and long- term follow-up of 33 patients Eur J Cancer 2000 36 1389 1394 10899652 \nDiSaia PJ Saltz A Kagan AR Chemotherapeutic retroconversion of immature teratoma of the ovary Obstet Gynecol 1977 49 346 350 65751 \nDjordjevic B Euscher E Malpica A Growing Teratoma Syndrome of the ovary: Review of literature and first report of a carcinoid tumor arising in a growing teratoma of the ovary Am J Surg Pathol 2007 31 1913 1918 18043048 \nHain SF Maisey MN Positron emission tomography for urological tumours BJU Int 2003 92 159 164 12823366 \nHariprasad R Kumar L Janga D Growing Teratoma Syndrome of the ovary Int J Clin Oncol 2008 13 83 87 18307026 \nLogothetis CJ Samuels ML Trindade A The Growing Teratoma Syndrome Cancer 1982 50 1629 1635 6288220 \nNimkin K Gupta P McCauley R The Growing Teratoma Syndrome Pediatr Radiol 2004 34 259 262 14551755 \nSengar AR Kulkarni JN Growing Teratoma Syndrome in a post laparoscopic excision of ovarian immature teratoma J Gynecol Oncol 2010 21 129 131 20613905 \nShibata K Kajiyama H Kikkawa F Growing Teratoma Syndrome of the ovary showing three patterns of metastasis Case Rep Oncol 2013 6 544 549 24348391 \nSmithers DW Maturation in human tumours Lancet 1969 2 949 952 4186609 \nSpiess PE Kassouf W Brown GA Surgical management of Growing Teratoma Syndrome. The M.D. Anderson Cancer Center Experience J Urol 2007 177 1330 1334 17382725 \nTangjitgamol S Manusirivithaya S Leelahakorn S The Growing Teratoma Syndrome: a case report and review of the literature Int J Gynecol Cancer Suppl.1 2006 16 384 390 16515629 \nVeenstra CM Vaughn DJ Third-line chemotherapy and novel agents for metastatic germ cell tumors Hematol Oncol Clin N Am 2011 25 577 591 \nZagamé L Pautier P Duvillard P Growing Teratoma Syndrome after ovarian germ cell tumors Obstet Gynecol 2006 108 509 514 16946208\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2032-0418",
"issue": "6(4)",
"journal": "Facts, views & vision in ObGyn",
"keywords": "Growing Teratoma Syndrome; iatrogenic peritoneal dissemination; ovarian germ cell tumour; port site metastasis",
"medline_ta": "Facts Views Vis Obgyn",
"mesh_terms": null,
"nlm_unique_id": "101578773",
"other_id": null,
"pages": "250-3",
"pmc": null,
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"title": "Disseminated ovarian Growing Teratoma Syndrome: a case -report highlighting surgical safety issues.",
"title_normalized": "disseminated ovarian growing teratoma syndrome a case report highlighting surgical safety issues"
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"abstract": "BACKGROUND\nEverolimus, a potent mammalian target of rapamycin (mTOR) inhibitor, has shown anticancer activity against various types of cancer, including renal cell carcinoma (RCC); however, little information is available on the efficacy and safety of the combination of everolimus and radiotherapy. We report a case of radiation-induced esophagitis that might have been exacerbated by the sequential administration of everolimus.\n\n\nMETHODS\nA 63-year-old Japanese man with RCC complained of back pain, and magnetic resonance imaging revealed vertebral metastases. He received radiotherapy (30 Gy/10 fractions) to the T6-10 vertebrae. Everolimus was administered immediately after the completion of radiotherapy. One week later, he complained of dysphagia, nausea and vomiting. An endoscopic examination of the esophagus showed erosive esophagitis in the middle to lower portions of his thoracic esophagus, corresponding to the irradiation field.\n\n\nCONCLUSIONS\nClinicians should be aware that everolimus might lead to the unexpected exacerbation of radiation toxicities.",
"affiliations": "Departments of Medical Oncology, Toranomon Hospital, Tokyo, Japan.",
"authors": "Miura|Yuji|Y|;Suyama|Koichi|K|;Shimomura|Akihiko|A|;Miyakawa|Jimpei|J|;Kobayashi|Hiroki|H|;Uki|Akiyoshi|A|;Okaneya|Toshikazu|T|;Takano|Toshimi|T|",
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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 10.1159/000353309cro-0006-0320Published online: June, 2013Radiation-Induced Esophagitis Exacerbated by Everolimus Miura Yuji a*Suyama Koichi aShimomura Akihiko aMiyakawa Jimpei bKobayashi Hiroki cUki Akiyoshi cOkaneya Toshikazu bTakano Toshimi aaDepartments of Medical Oncology, Toranomon Hospital, Tokyo, JapanbDepartments of Radiology, Toranomon Hospital, Tokyo, JapancDepartments of Urology, Toranomon Hospital, Tokyo, Japan*Yuji Miura, MD, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470 (Japan), E-Mail yujmiura@mac.comMay-Aug 2013 15 6 2013 15 6 2013 6 2 320 324 Copyright © 2013 by S. Karger AG, Basel2013This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Background\nEverolimus, a potent mammalian target of rapamycin (mTOR) inhibitor, has shown anticancer activity against various types of cancer, including renal cell carcinoma (RCC); however, little information is available on the efficacy and safety of the combination of everolimus and radiotherapy. We report a case of radiation-induced esophagitis that might have been exacerbated by the sequential administration of everolimus.\n\nCase Presentation\nA 63-year-old Japanese man with RCC complained of back pain, and magnetic resonance imaging revealed vertebral metastases. He received radiotherapy (30 Gy/10 fractions) to the T6–10 vertebrae. Everolimus was administered immediately after the completion of radiotherapy. One week later, he complained of dysphagia, nausea and vomiting. An endoscopic examination of the esophagus showed erosive esophagitis in the middle to lower portions of his thoracic esophagus, corresponding to the irradiation field.\n\nConclusion\nClinicians should be aware that everolimus might lead to the unexpected exacerbation of radiation toxicities.\n\nKey words\nMammalian target of rapamycinRenal cell carcinomaRadiation recall syndrome\n==== Body\nBackground\nRenal cell carcinoma (RCC) accounts for 80–85% of all primary kidney neoplasms [1]. There are approximately 65,000 new cases of RCC and 14,000 deaths from RCC each year in the USA [2]. Twenty-five to 30% of patients newly diagnosed with RCC have metastases at initial presentation, and 20–30% of patients with localized RCC experience relapse after radical nephrectomy over the course of several years of follow-up [1]. Frequent sites of metastasis include the lung, bone and liver.\n\nRecently, advances in the understanding of the biology of RCC have led to the development of targeted agents such as vascular endothelial growth factor receptor inhibitors and mammalian target of rapamycin (mTOR) inhibitors. Patients with metastatic RCC or those who develop recurrent metastases following prior treatment generally receive systemic chemotherapy using these molecular targeted agents. Meanwhile, treatment of symptomatic metastases includes radiotherapy or surgical procedures. External beam radiotherapy is one of the standard palliative treatments for painful bone metastasis, which is the second most common site of metastasis in RCC. However, it is unknown whether the continual administration of molecular targeted agents during palliative radiotherapy is safe or not. Everolimus, a potent mTOR inhibitor, has shown anticancer activity against various types of cancer, including RCC. Some preclinical studies have shown that mTOR inhibitors are potential radiosensitizers [3]. However, little information is available on the clinical efficacy or safety of the combination of mTOR inhibitors and radiotherapy.\n\nWe report a case of radiation-induced esophagitis that might have been exacerbated by the sequential administration of everolimus.\n\nCase Presentation\nA 63-year-old man was diagnosed with RCC (papillary cell carcinoma) and underwent a nephrectomy in December 2006. Four years later, lung metastases were found and a lung metastasectomy was performed. However, the lung metastases recurred in June 2011, and sunitinib therapy was initiated. The lung metastases improved, and the sunitinib treatment was continued for 12 months. In July 2012, the patient complained of back pain, and magnetic resonance imaging and a technetium bone scintigraphy examination revealed multiple vertebral metastases. Treatment with everolimus (10 mg daily) was initiated as second-line systemic therapy, and nonsteroidal anti-inflammatory drugs as well as oxycodone analgesics were also administered. One week later, the patient's back pain persisted, and we temporarily discontinued the everolimus treatment and initiated irradiation to the T6–10 vertebrae at 30 Gy in 10 fractions over a 2-week period. Everolimus (10 mg daily) was reinitiated immediately after the completion of the radiotherapy. One week after receiving the everolimus, the patient complained of dysphagia, nausea and vomiting. An endoscopic examination of the esophagus showed erosive esophagitis in the middle to lower portions of his thoracic esophagus (fig. 1), corresponding to the irradiation field (fig. 2a, b). Everolimus was discontinued, and his symptoms gradually resolved. One month later, a repeat endoscopy showed a remarkable improvement in the esophageal erosions (fig. 3).\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the editor of this journal.\n\nDiscussion\nThis case suggests that everolimus administration might exacerbate or augment radiation toxicity. Generally, a radiation dose of 30 Gy delivered in 10 fractions would rarely cause radiation-induced esophagitis. Several hypotheses can be proposed concerning the pathogenesis of severe esophagitis associated with everolimus and radiotherapy.\n\nFirst, the administration of everolimus immediately after radiation might contribute to the development of radiation recall syndrome. Radiation recall syndrome is an inflammatory reaction that occurs when certain promoting agents are administered during or soon after radiotherapy [4]. The biologic basis of this syndrome is unknown. Although it most commonly develops in the skin, other sites such as the gastrointestinal tract (esophagus, small intestine, etc.) and lung have also been reported [5]. Radiation recall syndrome has been associated with various drugs, including everolimus [5, 6]. A previous study reported that 3 patients who received an mTOR inhibitor (everolimus or temsirolimus) developed gastritis, bladder stenosis and colitis related to radiation recall syndrome [6]. In that study, the time interval between the completion of radiotherapy and the recall reaction ranged from 2 months to 4 years [6]. However, the 1-week interval in the present case differs from that described in previous reports.\n\nSecond, everolimus might contribute to enhanced radiation toxicity. Preclinical data have suggested the synergic effects of mTOR inhibitors when combined with radiation [7, 8]. One mechanism for enhancing the antitumor effect is thought to be an increase in antiangio-genesis efficacy when mTOR inhibitors are combined with radiotherapy. Shinohara et al. [8] reported that everolimus combined with radiation significantly reduced the tumor vasculature in a glioma xenograft. Another mechanism of radiosensitization is the inhibition of DNA double-strand break repair by mTOR inhibitors. Chen et al. [9] have demonstrated that rapamycin combined with ionizing radiation inhibited homologous recombination and nonhomologous end joining, two major pathways for the repair of radiation-induced DNA double-strand breaks. These mechanisms are consistent with the exacerbation of radiation toxicity induced by mTOR inhibitors. The two major mechanisms of radiation-induced mucositis are the impairment of vascular endothelial cells and DNA strand breaks, leading to cell death in the basal layer of the epithelium.\n\nSome clinical data have shown the efficacy of concurrent mTOR inhibitors and radiotherapy; however, little information is available on the toxicity of concurrent radiation and mTOR inhibitors [10, 11].\n\nConclusion\nLittle clinical evidence regarding the safety of mTOR inhibitors when used in combination with radiation has been reported. Clinicians should be aware that such combinations might lead to the unexpected exacerbation of radiation toxicities. Further clinical studies on the safety and efficacy of radiotherapy combined with mTOR inhibitors are warranted.\n\nDisclosure Statement\nThe authors declare that they have no competing interests.\n\nAcknowledgement\nThe authors thank Dr. Richard L. Theriault (Department of Breast Medical Oncology, University of Texas, MD Anderson Cancer Center) and the Japan TeamOncology Program for their educational programs.\n\nFig. 1 Radiation-induced esophagitis. Endoscopy examination reveals erosion and erythema in the middle to lower portions of the thoracic esophagus.\n\nFig. 2 Irradiation field for vertebral metastases (T6–10). The irradiated region for vertebral metastases (T6–10) is shown in the horizontal (a) and coronal (b) sections. Blue areas show the esophagus and upper stomach.\n\nFig. 3 Repeat endoscopy 1 month after discontinuation of everolimus shows a remarkable improvement in the esophageal erosions.\n==== Refs\nReferences\n1 Motzer RJ Bander NH Nanus DM Renal-cell carcinoma N Engl J Med 1996 335 865 875 8778606 \n2 Siegel R Naishadham D Jemal A Cancer statistics, 2013 CA Cancer J Clin 2013 63 11 30 23335087 \n3 Murphy JD Spalding AC Somnay YR Markwart S Ray ME Hamstra DA Inhibition of mTOR radiosensitizes soft tissue sarcoma and tumor vasculature Clin Cancer Res 2009 15 589 596 19147764 \n4 Caloglu M Yurut-Caloglu V Cosar-Alas R Saynak M Karagol H Uzal C An ambiguous phenomenon of radiation and drugs: recall reactions Onkologie 2007 30 209 214 17396045 \n5 Azria D Magne N Zouhair A Castadot P Culine S Ychou M Stupp R Van Houtte P Dubois JB Ozsahin M Radiation recall: a well recognized but neglected phenomenon Cancer Treat Rev 2005 31 555 570 16168567 \n6 Bourgier C Massard C Moldovan C Soria JC Deutsch E Total recall of radiotherapy with mTOR inhibitors: a novel and potentially frequent side-effect? Ann Oncol 2011 22 485 486 21278224 \n7 Eshleman JS Carlson BL Mladek AC Kastner BD Shide KL Sarkaria JN Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy Cancer Res 2002 62 7291 7297 12499272 \n8 Shinohara ET Cao C Niermann K Mu Y Zeng F Hallahan DE Lu B Enhanced radiation damage of tumor vasculature by mTOR inhibitors Oncogene 2005 24 5414 5422 15940265 \n9 Chen H Ma Z Vanderwaal RP Feng Z Gonzalez-Suarez I Wang S Zhang J Roti Roti JL Gonzalo S Zhang J The mTOR inhibitor rapamycin suppresses DNA double-strand break repair Radiat Res 2011 175 214 224 21268715 \n10 Sarkaria JN Galanis E Wu W Dietz AB Kaufmann TJ Gustafson MP Brown PD Uhm JH Rao RD Doyle L Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks Clin Cancer Res 2010 16 5573 5580 20921209 \n11 Sarkaria JN Galanis E Wu W Peller PJ Giannini C Brown PD Uhm JH McGraw S Jaeckle KA Buckner JC North Central Cancer Treatment Group Phase I trial N057K of everolimus (RAD001) and temozolomide in combination with radiation therapy in patients with newly diagnosed glioblastoma multiforme Int J Radiat Oncol Biol Phys 2011 81 468 475 20864273\n\n",
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"keywords": "Mammalian target of rapamycin; Radiation recall syndrome; Renal cell carcinoma",
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"title": "Radiation-induced esophagitis exacerbated by everolimus.",
"title_normalized": "radiation induced esophagitis exacerbated by everolimus"
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"abstract": "OBJECTIVE\nPatients with HER2-positive metastatic breast cancer (MBC) usually receive many years of trastuzumab treatment. It is unknown whether these patients require continuous left ventricular ejection fraction (LVEF) monitoring. We studied a real-world cohort to identify risk factors for cardiotoxicity to select patients in whom LVEF monitoring could be omitted.\n\n\nMETHODS\nWe included patients with HER2-positive MBC who received > 1 cycle of trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Cardiotoxicity was defined as LVEF < 50% that declined > 10%-points and was categorized into non-severe cardiotoxicity (LVEF 40-50%) and severe cardiotoxicity (LVEF < 40%). Multivariable Cox and mixed model analyses were performed to identify risk factors associated with cardiotoxicity. Additionally, we explored the reversibility of cardiotoxicity in patients who continued trastuzumab.\n\n\nRESULTS\nIn total, 429 patients were included. Median follow-up for cardiotoxicity was 15 months (interquartile range 8-31 months). The yearly incidence of non-severe + severe cardiotoxicity in the first and second year was 11.7% and 9.1%, respectively, which decreased thereafter. The yearly incidence of severe cardiotoxicity was low (2.8%) and stable over time. In non-smoking patients with baseline LVEF > 60% and no cardiotoxicity during prior neoadjuvant/adjuvant treatment, the cumulative incidence of severe cardiotoxicity was 3.1% after 4 years of trastuzumab. Despite continuing trastuzumab, LVEF decline was reversible in 56% of patients with non-severe cardiotoxicity and in 33% with severe cardiotoxicity.\n\n\nCONCLUSIONS\nSerial cardiac monitoring can be safely omitted in non-smoking patients with baseline LVEF > 60% and without cardiotoxicity during prior neoadjuvant/adjuvant treatment.",
"affiliations": "Department of Internal Medicine, Albert Schweitzer Hospital, 3300 AK, Dordrecht, South-Holland, The Netherlands. n.i.bouwer@asz.nl.;Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Biostatistics, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.;Department of Medical Oncology, Erasmus MC, Cancer Institute, Rotterdam, The Netherlands.;Department of Internal Medicine, Albert Schweitzer Hospital, 3300 AK, Dordrecht, South-Holland, The Netherlands.;Department of Medical Oncology, Reinier de Graaf Hospital, Delft, The Netherlands.;Department of Medical Oncology, Amphia Hospital, Breda, The Netherlands.;Department of Medical Oncology, Sint Antonius Hospital, Utrecht, The Netherlands.;Department of Medical Oncology, Ikazia Hospital, Rotterdam, The Netherlands.;Department of Medical Oncology, Haga Hospital, The Hague, The Netherlands.;Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Cardiology, Albert Schweitzer Hospital, Dordrecht, The Netherlands.;Department of Cardiology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.;Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Internal Medicine, Albert Schweitzer Hospital, 3300 AK, Dordrecht, South-Holland, The Netherlands.;Department of Medical Oncology, Erasmus MC, Cancer Institute, Rotterdam, The Netherlands.",
"authors": "Bouwer|N I|NI|http://orcid.org/0000-0002-2048-2233;Steenbruggen|T G|TG|;van Rosmalen|J|J|;Rier|H N|HN|;Kitzen|J J E M|JJEM|;van Bekkum|M L|ML|;Tije|A J Ten|AJT|;de Jong|P C|PC|;Drooger|J C|JC|;Holterhues|C|C|;Smorenburg|C H|CH|;Kofflard|M J M|MJM|;Boersma|E|E|;Sonke|G S|GS|;Levin|M-D|MD|;Jager|A|A|",
"chemical_list": "D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "Netherlands",
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"doi": "10.1007/s10549-020-06039-w",
"fulltext": "\n==== Front\nBreast Cancer Res Treat\nBreast Cancer Res Treat\nBreast Cancer Research and Treatment\n0167-6806\n1573-7217\nSpringer US New York\n\n33394273\n6039\n10.1007/s10549-020-06039-w\nEpidemiology\nCardiotoxicity during long-term trastuzumab use in patients with HER2-positive metastatic breast cancer: who needs cardiac monitoring?\nhttp://orcid.org/0000-0002-2048-2233\nBouwer N. I. n.i.bouwer@asz.nl\n\n12\nSteenbruggen T. G. 3\nvan Rosmalen J. 4\nRier H. N. 5\nKitzen J. J. E. M. 1\nvan Bekkum M. L. 6\nTije A. J. Ten 7\nde Jong P. C. 8\nDrooger J. C. 9\nHolterhues C. 10\nSmorenburg C. H. 3\nKofflard M. J. M. 2\nBoersma E. 11\nSonke G. S. 3\nLevin M.-D. 1\nJager A. 5\n1 grid.413972.a 0000 0004 0396 792X Department of Internal Medicine, Albert Schweitzer Hospital, 3300 AK Dordrecht, South-Holland The Netherlands\n2 grid.413972.a 0000 0004 0396 792X Department of Cardiology, Albert Schweitzer Hospital, Dordrecht, The Netherlands\n3 grid.430814.a Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands\n4 grid.5645.2 000000040459992X Department of Biostatistics, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands\n5 grid.508717.c 0000 0004 0637 3764 Department of Medical Oncology, Erasmus MC, Cancer Institute, Rotterdam, The Netherlands\n6 grid.415868.6 0000 0004 0624 5690 Department of Medical Oncology, Reinier de Graaf Hospital, Delft, The Netherlands\n7 grid.413711.1 Department of Medical Oncology, Amphia Hospital, Breda, The Netherlands\n8 grid.415960.f 0000 0004 0622 1269 Department of Medical Oncology, Sint Antonius Hospital, Utrecht, The Netherlands\n9 grid.414565.7 0000 0004 0568 7120 Department of Medical Oncology, Ikazia Hospital, Rotterdam, The Netherlands\n10 grid.413591.b 0000 0004 0568 6689 Department of Medical Oncology, Haga Hospital, The Hague, The Netherlands\n11 grid.5645.2 000000040459992X Department of Cardiology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands\n4 1 2021\n4 1 2021\n2021\n186 3 851862\n14 9 2020\n25 11 2020\n© The Author(s) 2021\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nPurpose\n\nPatients with HER2-positive metastatic breast cancer (MBC) usually receive many years of trastuzumab treatment. It is unknown whether these patients require continuous left ventricular ejection fraction (LVEF) monitoring. We studied a real-world cohort to identify risk factors for cardiotoxicity to select patients in whom LVEF monitoring could be omitted.\n\nMethods\n\nWe included patients with HER2-positive MBC who received > 1 cycle of trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Cardiotoxicity was defined as LVEF < 50% that declined > 10%-points and was categorized into non-severe cardiotoxicity (LVEF 40–50%) and severe cardiotoxicity (LVEF < 40%). Multivariable Cox and mixed model analyses were performed to identify risk factors associated with cardiotoxicity. Additionally, we explored the reversibility of cardiotoxicity in patients who continued trastuzumab.\n\nResults\n\nIn total, 429 patients were included. Median follow-up for cardiotoxicity was 15 months (interquartile range 8–31 months). The yearly incidence of non-severe + severe cardiotoxicity in the first and second year was 11.7% and 9.1%, respectively, which decreased thereafter. The yearly incidence of severe cardiotoxicity was low (2.8%) and stable over time. In non-smoking patients with baseline LVEF > 60% and no cardiotoxicity during prior neoadjuvant/adjuvant treatment, the cumulative incidence of severe cardiotoxicity was 3.1% after 4 years of trastuzumab. Despite continuing trastuzumab, LVEF decline was reversible in 56% of patients with non-severe cardiotoxicity and in 33% with severe cardiotoxicity.\n\nConclusions\n\nSerial cardiac monitoring can be safely omitted in non-smoking patients with baseline LVEF > 60% and without cardiotoxicity during prior neoadjuvant/adjuvant treatment.\n\nSupplementary Information\n\nThe online version of this article (10.1007/s10549-020-06039-w) contains supplementary material, which is available to authorized users.\n\nKeywords\n\nHER2-positive metastatic breast cancer\nTrastuzumab treatment\nCardiotoxicity\nLVEF monitoring\nScreening for cardiotoxicity\nPromotiefonds Albert Schweitzer HospitalStichting A Sister's Hope (NL)Stichting [Z]aan de Wandelissue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2021\n==== Body\nIntroduction\n\nTrastuzumab is a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER2) that has greatly improved the outcome of patients with HER2-positive breast cancer in both the primary and metastatic setting [1–3]. Trastuzumab toxicity is generally mild, although left ventricle ejection fraction (LVEF) decline (cardiotoxicity) is a well-known side effect that is mostly seen in combination with concurrent or sequential anthracycline treatment [3]. Regular LVEF monitoring at a 3-monthly interval is therefore recommended during 1 year of neoadjuvant and/or adjuvant trastuzumab treatment; however, during metastatic treatment no specific time interval of LVEF monitoring is recommended [4]. Since the median overall survival of patients with HER2-positive metastatic breast cancer (MBC) is well over 4 years with continuous use of trastuzumab, the cumulative burden of LVEF monitoring can be high [5, 6]. The incidence of cardiotoxicity during long-term treatment for HER2-positive MBC, however, is not well-known and neither are risk factors for trastuzumab-associated cardiotoxicity in this setting.\n\nTwo studies investigated cardiotoxicity over time during trastuzumab treatment in patients with MBC [7, 8]. The first study found a cumulative incidence of cardiotoxicity of 12.7% and 28.5% after 1 and 3 years of trastuzumab use, respectively [7]. They defined cardiotoxicity as LVEF decline > 20%-points from baseline or LVEF < 50% or symptoms of congestive heart failure. The LVEF recovered in a vast majority of the patients (84%) after discontinuation of trastuzumab with or without cardio-protective treatment. However, reversibility of cardiotoxicity after continuation of trastuzumab has not been described yet. A second study observed a cumulative incidence of cardiotoxicity of 5.3% after 3 years of trastuzumab use. However, they used a composite endpoint that included myocardial ischaemia, heart failure, rhythm disorder, and other cardiac diseases [8]. Data on long-term sequelae were not available. Lastly, risk factors for developing cardiotoxicity during long-term trastuzumab treatment could be similar to those causing cardiotoxicity during 1 year of trastuzumab treatment [9–11]; however, this has not been investigated yet.\n\nTherefore, we studied cardiotoxicity during long-term trastuzumab treatment in patients with HER2-positive MBC in an observational historic multicentre cohort study and risk factors associated with cardiotoxicity in this setting to select patients in whom LVEF monitoring could be omitted. Additionally, we evaluated the reversibility of cardiotoxicity in patients who continued trastuzumab.\n\nMethods\n\nPatients and data collection\n\nWe included patients with HER2-positive MBC who received > 1 cycle of trastuzumab-based treatment in one of eight participating Dutch hospitals between January 2000 and December 2014, as described before [12]. Patients were identified using the Netherlands Cancer Registry. Patients were excluded in case no baseline LVEF measurement was available within 30 days before the first trastuzumab administration for MBC, baseline LVEF < 50%, no follow-up LVEF measurements were available during trastuzumab use, and in case of incomplete clinical data in the medical records.\n\nTrained investigators systematically retrieved data on patient and tumour characteristics, treatment, and LVEF measurements from medical records. Medical Ethics Commission of all participating hospitals approved this comprehensive data collection.\n\nEndpoints\n\nWe defined non-severe + severe cardiotoxicity and severe cardiotoxicity based on guidelines of the European Society of Cardiology (ESC) [13] and the European Society of Medical Oncology (ESMO) [4], respectively. First, non-severe + severe cardiotoxicity is defined as (1) LVEF decline > 10%-points from baseline and LVEF < 50% measured with multigated acquisition (MUGA) scan or (2) decline from good/normal cardiac function to at least mild cardiac dysfunction and at least mild cardiac dysfunction measured with echocardiography if MUGA was not available. After a decline in LVEF found with MUGA scan, in some cases this was followed by an echocardiography to exclude false negative low LVEF measurements. In case both investigations were performed, echocardiography was used to define cardiotoxicity. Second, severe cardiotoxicity is defined as (1) LVEF < 40% measured with MUGA scan or (2) moderate or severe cardiac dysfunction measured with echocardiography if MUGA was not available [13]. Since patients with LVEF < 50% at baseline were excluded, patients with LVEF < 40% had by definition a LVEF decline of > 10%-points compared to baseline. Lastly, non-severe cardiotoxicity was defined as (1) LVEF < 50% but > 40% or mild cardiac dysfunction measured with echocardiography. The time to non-severe + severe cardiotoxicity, non-severe cardiotoxicity or severe cardiotoxicity was calculated from start of trastuzumab treatment for MBC to the first occurrence of non-severe + severe cardiotoxicity.\n\nFor the analyses of reversibility, non-severe + severe cardiotoxicity was categorized into non-severe cardiotoxicity and severe cardiotoxicity. Reversibility of cardiotoxicity was defined as any LVEF increase to a value < 5% below baseline, partially reversibility as any absolute LVEF increase ≥ 10% from nadir and to a value > 5% below baseline, and irreversibility as any absolute LVEF increase < 10% from nadir and to a value > 5% below baseline [14]. The frequency of LVEF measurements was determined by the treating physician.\n\nStatistical analyses\n\nContinuous variables are presented as medians with interquartile range (IQR) for non-normal distribution, and as means with standard deviations for normal distribution. Categorical variables are presented as percentages.\n\nMedian follow-up for cardiotoxicity was calculated from start of trastuzumab for MBC until 6 months after last trastuzumab dose or until last LVEF measurement, whichever came first. Discontinuation of trastuzumab treatment was defined as any stop or interruption of trastuzumab treatment. The yearly incidence of cardiotoxicity was investigated. Patients were at risk for cardiotoxicity when receiving LVEF measurements during trastuzumab treatment. After the first development of non-severe cardiotoxicity, patients were no longer at risk for non-severe cardiotoxicity. However, these patients were still at risk for severe cardiotoxicity. After developing severe cardiotoxicity, patients were no longer at risk for any type of cardiotoxicity.\n\nWe used univariable and multivariable Cox proportional hazards (PH) analyses to determine which baseline variables were associated with non-severe + severe cardiotoxicity and severe cardiotoxicity, and to find a group of patients at low risk of cardiotoxicity. All variables were determined at start of trastuzumab treatment for MBC. Independent variables statistically significant at 0.10 level in univariable analysis or known risk factors for cardiotoxicity from literature were included in the multivariable analysis. The Cox PH assumption was verified using the Schoenfeld residuals test and was not violated. Multivariable cause-specific Cox PH models were built with similar variables to investigate potential competing risk from death with non-severe + severe cardiotoxicity or severe cardiotoxicity. In this analysis, patients are censored in case of death due to any cause.\n\nThe following variables were included in the analyses: age, BMI, hypertension, diabetes mellitus, smoking, history of cardiac disease, baseline LVEF < 60%, cardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracycline, prior cumulative anthracycline exposure, radiation exposure to the breast. BMI was categorized in BMI < 25 kg/m2, 25–30 kg/m2, and > 30 kg/m2. Hypertension was defined as a history of systolic blood pressure > 130 mmHg or diastolic blood pressure > 80 mmHg or the use of antihypertensive medication [15]. History of cardiac disease was defined as the history of either arrhythmia, cardiac valve deficiency, cardiomyopathy or coronary artery disease. Cardiotoxicity during prior treatment was defined LVEF decline > 10%-points to a LVEF < 50% during neoadjuvant/adjuvant treatment with trastuzumab and/or anthracycline. Prior cumulative anthracycline exposure was defined as the number of courses anthracycline before trastuzumab in palliative setting. Radiation exposure was categorized in left-sided, right-sided or unknown side. Last, de novo metastatic breast cancer was defined as metastatic disease at time of diagnosis or development of metastases within 3 months of diagnosis.\n\nFor the multivariable Cox PH analyses, missing information on diabetes mellitus, hypertension, smoking, history of cardiac disease, radiotherapy side and cardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracycline was imputed using fully conditional specification with 100 imputations. Estimates were pooled over imputed data sets using Rubin’s rules. A sensitivity analysis with a complete case analysis was conducted to investigate robustness of the imputation procedure. In the cause-specific Cox PH analyses, missing values were imputed using substantive model compatible fully conditional specification with 100 imputations. Additionally, sensitivity analyses were performed by investigating the number of LVEF measurements as a risk factor for cardiotoxicity in a Cox PH analysis to investigate detection bias. LVEF measurements up until the development of cardiotoxicity were taken into account in these analyses.\n\nTo study the relation between the independent variables and continuous LVEF measurements during total follow-up, linear mixed effects model (LMM) analysis was conducted. Risk factors that are related to a LVEF decline, but not with the definition of cardiotoxicity, were investigated in this analysis. In addition to the variables used in the Cox PH analysis, this model allows to investigate time varying variables, namely the cumulative trastuzumab exposure at each LVEF measurement calculated from start trastuzumab to each LVEF measurement (in months). The fit of the LMM was adjusted by the non-linear curve observed from the predicted values plot (data not shown) [16]. The effect of time since start trastuzumab was modelled using restricted cubic splines, with the number of knots (4) chosen using information criteria. Random intercept and random slope of time since start of trastuzumab were included to account for within-patient correlations between repeated measurements.\n\nInverse Kaplan–Meier curves stratified for significant risk factors were used to investigate the cumulative incidence of non-severe + severe cardiotoxicity and severe cardiotoxicity for the number of significant risk factors from the Cox PH analysis.\n\nData analyses were performed using SPSS (version 24.0) and R (version 3.4.3), in particular the packages “lme”, “splines”, “JointAI”, “smcfcs” and “mice”.\n\nResults\n\nPatient characteristics\n\nBetween January 2000 and December 2014, 745 patients with HER2-positive MBC were identified in the eight participating Dutch hospitals. After excluding patients who had no baseline LVEF measurement (n = 193), a baseline LVEF measurement < 50% (n = 41), no LVEF measurement during trastuzumab treatment (n = 55), or in whom no additional data collection was possible (n = 18), 429 patients were eligible for current analyses (Supplementary Figure S1). In general, no difference was observed between included and excluded patients, except for a lower percentage of patients receiving prior neoadjuvant/adjuvant trastuzumab in the latter (Supplementary Table S1). Patient and treatment characteristics are shown in Table 1. Of all patients, 311 (72%) had metachronous distant metastases and 118 (28%) had synchronous distant metastases at disease presentation.Table 1 Baseline characteristics of all included patients (n = 429)\n\nClinical and treatment characteristics\tNo. (%), median [IQR]\t\nAge (years)a\t54 [46–61]\t\nHormonal receptor statusb\t\t\n Positive\t235 (55)\t\n Negative\t172 (40)\t\n Unknown\t22 (5)\t\nNeoadjuvant/adjuvant chemotherapy\t\t\n No\t213 (50)\t\n Anthracyclines + trastuzumab\t65 (15)\t\n Anthracyclines without trastuzumab\t120 (28)\t\n Trastuzumab without anthracyclines\t19 (4)\t\n Other\t12 (3)\t\nDuration of neoadjuvant/adjuvant trastuzumab (months)\t12 [12–12]\t\nPrior cumulative anthracycline exposure (courses)a,c,d\t0 [0–4]\t\nAdjuvant radiotherapy\t\t\n No\t171 (40)\t\n Left side\t126 (29)\t\n Right side\t100 (23)\t\n Side unknown\t32 (8)\t\nCardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracyclines\t\t\n No\t329 (77)\t\n Yes\t15 (4)\t\n Unknown\t85 (20)\t\nBaseline LVEF (%)a\t\t\n ≥ 60\t198 (46)\t\n < 60\t231 (54)\t\nBMI (kg/m2)a\t\t\n < 25\t164 (49)\t\n 25–30\t130 (30)\t\n > 30\t44 (10)\t\n Unknown\t91 (21)\t\nHistory of cardiac disease\t\t\n No\t379 (88)\t\n Yes\t35 (8)\t\n Unknown\t15 (4)\t\nDiabetes mellitusa\t\t\n No\t387 (90)\t\n Yes\t28 (7)\t\n Unknown\t14 (3)\t\nHypertensiona\t\t\n No\t314 (73)\t\n Yes\t98 (23)\t\n Unknown\t17% (4)\t\nHypercholesterolemiaa\t\t\n No\t210 (49)\t\n Yes\t37 (9)\t\n Unknown\t182 (42)\t\nSmokinga\t\t\n No\t203 (47)\t\n Yes\t90 (21)\t\n Unknown\t136 (32)\t\nIQR interquartile range, LVEF left ventricle ejection fraction, BMI body mass index, MUGA scan, multigated acquisition scan, MRI magnetic resonance imaging, MBC metastatic breast cancer\n\naAt start of palliative trastuzumab treatment; for definition see Methods section\n\nbEstrogen and progesterone receptor positivity was defined as ≥ 10% positive nuclear staining [17]\n\ncNumber of courses before palliative trastuzumab treatment\n\ndCould consist of doxorubicin or epirubicin courses\n\nPatients were followed for cardiotoxicity with a median of 15 months (IQR 8–31). The median overall survival for all patients was 42 months (IQR 25–71). Median frequency of LVEF monitoring was 4 times annually (IQR 3–5) with a median total number of LVEF measurements of 4 during follow-up (IQR 2–7). Most commonly used cardiac imaging modality for LVEF assessment was the MUGA scan in 358 patients (83%). Echocardiography (4%) or CMR (0.2%) or a combination of both (13%) was performed less often.\n\nIncidence of non-severe + severe and severe cardiotoxicity over time\n\nDuring total follow-up, 94 patients (22%) developed non-severe + severe cardiotoxicity. In the first year of trastuzumab treatment, the incidence of non-severe + severe cardiotoxicity was 11.7% (Fig. 1). The yearly incidence gradually decreased over the following years (i.e. 9.1% in year 2 to 3.6% in year 6). The median time to develop non-severe + severe cardiotoxicity from start of trastuzumab for MBC was 11 months (IQR 5–23).Fig. 1 Yearly incidence of non-severe + severe cardiotoxicity and severe cardiotoxicity during long-term trastuzumab treatment\n\nIn total, 25 patients (6%) developed severe cardiotoxicity. In the first year of trastuzumab treatment, the incidence of severe cardiotoxicity was 2.8% (Fig. 1). The yearly incidence of severe cardiotoxicity the next years remained stable (i.e. 1.9% in year 2 to 2.4% in year 6). The median time to severe cardiotoxicity was 10 months (IQR 6–25).\n\nRisk factors associated with non-severe + severe cardiotoxicity and severe cardiotoxicity\n\nRisk factors independently associated with non-severe + severe cardiotoxicity were BMI > 30 kg/m2 (adjusted [a]HR 2.16, 95% CI 1.15–4.06), smoking (aHR 1.73, 95% CI 1.05–2.85), cardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracyclines (aHR 4.48, 95% CI 1.56–12.87). Prior neoadjuvant/adjuvant trastuzumab (aHR 0.38, 95% CI 0.18–0.82) was associated with less non-severe + severe cardiotoxicity (Table 2).Table 2 Risk factors present at start of trastuzumab treatment for MBC associated with developing non-severe + severe cardiotoxicity\n\n\tUnivariable Cox PHa\tMultivariable Cox PHa\t\n\tHR\t95% CI\tp-value\tAdjusted HR\t95% CI\tp-value\t\nAge (years)\t1.01\t0.99–1.02\t0.574\t1.01\t0.99–1.03\t0.254\t\nBMI (kg/m2)\t\t\t\t\t\t\t\n < 25\tRef\t\t\t\t\t\t\n 25–30\t1.29\t0.76–2.17\t0.340\t1.24\t0.73–2.12\t0.423\t\n > 30\t2.05\t1.13–3.73\t0.018\t2.16\t1.15–4.06\t0.017\t\nHypertension\t1.23\t0.77–1.95\t0.386\t\t\t\t\nDiabetes mellitus\t1.20\t0.55–2.64\t0.651\t\t\t\t\nSmoking\t1.89\t1.13–3.16\t0.016\t1.73\t1.05–2.85\t0.031\t\nHistory of cardiac disease\t1.36\t0.71–2.60\t0.352\t\t\t\t\nBaseline LVEF (%)\t\t\t\t\t\t\t\n ≥ 60\tRef\t\t\t\t\t\t\n < 60\t1.60\t1.05–2.44\t0.030\t1.52\t0.97–2.40\t0.071\t\nPrior neoadjuvant/adjuvant trastuzumab\t0.60\t0.33–1.10\t0.097\t0.38\t0.18–0.82\t0.014\t\nCardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracyclines\t2.36\t1.05–5.30\t0.037\t4.48\t1.56–12.87\t0.005\t\nCumulative anthracycline exposure (total number of courses)b\t1.05\t0.98–1.14\t0.155\t1.05\t0.97–1.15\t0.247\t\nAdjuvant radiotherapy\t\t\t\t\t\t\t\n No\tRef\t\t\t\t\t\t\n Left side\t1.01\t0.62–1.65\t0.977\t\t\t\t\n Right side\t1.00\t0.57–1.73\t0.987\t\t\t\t\n Side unknown\t1.22\t0.57–2.62\t0.615\t\t\t\t\nDe novo metastatic breast cancer\t0.78\t0.48–1.26\t0.313\t0.81\t0.47–1.40\t0.451\t\nPH proportional hazards, HR hazard ratio, CI confidence interval, BMI body mass index, LVEF left ventricle ejection fraction, MBC metastatic breast cancer, REF reference category\n\naBased on multiple imputations with MICE of diabetes mellitus, hypertension, smoking, history of cardiac disease, local radiotherapy of the breast and prior cardiotoxicity during treatment with trastuzumab or anthracyclines, where death is a censoring event\n\nbA course consist of doxorubicin 60 mg/m2 or epirubicin 100 mg/m2\n\nRisk factors independently associated with severe cardiotoxicity were smoking (aHR 6.15, 95% CI 2.12–17.82), baseline LVEF < 60% (aHR 7.64, 95% CI 1.70–34.43) and cardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracycline (aHR 5.60, 95% CI 1.03–30.42, Table 3).Table 3 Risk factors present at start of trastuzumab treatment for MBC associated with developing severe cardiotoxicity\n\n\tUnivariable Cox PHa\tMultivariable Cox PHa\t\n\tHR\t95% CI\tp-value\tAdjusted HR\t95% CI\tp-value\t\nAge (years)\t1.00\t0.97–1.04\t0.926\t\t\t\t\nBMI (kg/m2)\t\t\t\t\t\t\t\n < 25\tRef\t\t\t\t\t\n 25–30\t1.02\t0.76–2.17\t0.975\t\t\t\t\n > 30\t1.99\t1.13–3.73\t0.188\t\t\t\t\nHypertension\t1.39\t0.57–3.35\t0.468\t\t\t\t\nDiabetes mellitus\t0.65\t0.09–4.82\t0.673\t\t\t\t\nSmoking\t6.61\t2.23–19.60\t < 0.001\t6.15\t2.12–17.82\t < 0.001\t\nHistory of cardiac disease\t2.61\t0.98–6.96\t0.056\t\t\t\t\nBaseline LVEF(%)\t\t\t\t\t\t\t\n ≥ 60\tRef\t\t\t\t\t\t\n < 60\t9.91\t2.34–42.05\t0.002\t7.64\t1.70–34.43\t0.008\t\nPrior neoadjuvant/adjuvant trastuzumab\t1.07\t0.40–2.87\t0.891\t\t\t\t\nCardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracycline\t3.30\t0.87–12.56\t0.079\t5.60\t1.03–30.42\t0.045\t\nCumulative anthracycline exposure (total number of courses)b\t1.21\t1.07–1.37\t0.003\t1.15\t1.00–1.33\t0.051\t\nAdjuvant radiotherapy\t\t\t\t\t\t\t\n No\tRef\t\t\t\t\t\t\n Left side\t1.01\t0.41–2.53\t0.975\t\t\t\t\n Right side\t0.73\t0.23–2.31\t0.597\t\t\t\t\n Unknown side\t0.56\t0.07–4.34\t0.577\t\t\t\t\nDe novo metastatic breast cancer\t0.46\t0.16–1.34\t0.153\t\t\t\t\nPH proportional hazards, HR hazard ratio, CI confidence interval, BMI body mass index, LVEF left ventricle ejection fraction, MBC metastatic breast cancer, REF reference category\n\naBased on multiple imputations with MICE diabetes mellitus, hypertension, smoking, history of cardiac disease, local radiotherapy of the breast and prior cardiotoxicity during treatment with trastuzumab or anthracyclines, where death is a censoring event\n\nbA course consist of doxorubicin 60 mg/m2 or epirubicin 100 mg/m2\n\nCause-specific Cox PH analyses, taking competing risk between cardiotoxicity and death into account, showed similar risk factors associated with non-severe + severe cardiotoxicity and severe cardiotoxicity (Supplementary Table S2).\n\nLMM analysis (Table 4) also showed similar risk factors that were associated with LVEF differences over time as the Cox PH analyses (Tables 2 and 3). This means that patients who smoked on average had 2.77%-points lower LVEFs at the same time point compared to patients who did not smoke (Table 4; p < 0.001).Table 4 Risk factors present at start of trastuzumab for MBC associated with continuous LVEF differences at each time point during total follow-up\n\n\tEstimated absolute LVEF difference at each time point (%)a\t95% CI\tTail-probability\t\nCumulative trastuzumab exposure (months)b\t0.27\t− 0.06 to 0.51\t0.163\t\nAge (years)\t0.02\t− 0.05 to 0.09\t0.642\t\nBMI (kg/m2)\t\t\t\t\n < 25\tRef\t\t\t\n 25–30\t− 1.04\t− 2.90 to 0.73\t0.237\t\n > 30\t− 1.09\t− 3.44 to 1.30\t0.389\t\nHypertension\t0.67\t− 1.13 to 2.47\t0.461\t\nDiabetes mellitus\t− 0.71\t− 3.62 to 2.14\t0.624\t\nSmoking\t− 2.77\t− 5.26 to − 0.66\t0.013\t\nHistory of cardiac disease\t0.40\t− 2.21 to 3.04\t0.766\t\nBaseline LVEF (%)\t\t\t\t\n ≥ 60\tRef\t\t\t\n < 60\t− 6.72\t− 8.17 to − 5.28\t < 0.001\t\nPrior neoadjuvant/adjuvant trastuzumab\t2.11\t− 0.09 to 4.31\t0.060\t\nCardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracyclines\t− 13.70\t− 22.64 to − 5.45\t < 0.001\t\nCumulative anthracycline exposure (total number of courses)c\t− 0.38\t− 0.69 to 0.08\t0.012\t\nAdjuvant radiotherapy\t\t\t\t\n No\tRef\t\t\t\n Left side\t0.20\t− 1.61 to 2.02\t0.827\t\n Right side\t0.44\t− 1.54 to 2.43\t0.662\t\n Side unknown\t1.46\t− 1.38 to 4.26\t0.307\t\nDe novo metastatic breast cancer\t1.39\t− 0.45 to 3.24\t0.144\t\nLVEF left ventricle ejection fraction, CI credible interval, BMI body mass index, MBC metastatic breast cancer, REF reference category\n\naBased on multiple imputations with MICE of diabetes mellitus, hypertension, smoking, history of cardiac disease, local radiotherapy of the breast and prior cardiotoxicity during treatment with trastuzumab or anthracyclines\n\nbFrom start of palliative trastuzumab treatment to each LVEF measurement\n\ncA course consist of doxorubicin 60 mg/m2 or epirubicin 100 mg/m2\n\nCumulative incidence of cardiotoxicity per relevant risk factors\n\nThe identified significant risk factors from the Cox PH analyses (Tables 2 and 3) were used to identify a patient group at low risk for cardiotoxicity, regardless of their effect size. In total, 241 patients had no relevant risk factors, 152 patients 1 risk factor and 36 patients 2 or 3 risk factors. Regarding relevant risk factors for severe cardiotoxicity, 242 had no risk factors, 158 patients 1 risk factors and 29 patients 2 or 3 risk factors. Patients without relevant risk factors for severe cardiotoxicity had a low cumulative incidence of 3.1% after a total follow-up of 4 years (Fig. 2). The cumulative incidence for both non-severe + severe cardiotoxicity and severe cardiotoxicity increases in case of more relevant risk factors.Fig. 2 Cumulative incidence of non-severe + severe and severe cardiotoxicity with respect to the number of relevant risk factors.\n\nNote Solid lines indicate cumulative incidence; dashed lines indicate corresponding 95% CI of the cumulative incidence. For non-severe + severe cardiotoxicity, the following risk factors were included: BMI > 30 kg/m2, smoking and cardiotoxicity during prior neoadjuvant/ adjuvant treatment with trastuzumab and/or anthracyclines (Table 2). For severe cardiotoxicity, the following risk factors were included: smoking, cardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracyclines and baseline LVEF < 60% (Table 3)\n\nSensitivity analyses evaluating detection bias of cardiotoxicity\n\nPatients who received 0–2 LVEF measurements annually had lower risk of non-severe + severe cardiotoxicity and severe cardiotoxicity compared to patients who received 3–4 LVEF measurements annually (HR 0.43, 95% CI 0.24–0.78), however not of severe cardiotoxicity (HR 0.66, 95% CI 0.22–1.97). Additionally, patients who received > 4 LVEF measurements annually had higher risk of non-severe + severe cardiotoxicity (HR 6.39, 95% CI 3.57–11.41) and severe cardiotoxicity (HR 3.65, 95% CI 1.38–9.62).\n\nReversibility of non-severe + severe cardiotoxicity and severe cardiotoxicity\n\nTo explore the reversibility of cardiotoxicity, we categorized the patients who developed non-severe + severe cardiotoxicity into non-severe cardiotoxicity (n = 69) and severe cardiotoxicity (n = 25), of whom reversibility could be analysed in 58 patients with non-severe cardiotoxicity and 16 patients with severe cardiotoxicity (Fig. 3).Fig. 3 Swimmers plot of all patients who developed cardiotoxicity and received LVEF measurements thereafter (n = 74).\n\nIn total, the LVEF decline was reversible in 34 out of 58 patients (59%) who developed non-severe cardiotoxicity (Fig. 3 and Supplementary Figure S2). Among the 15 patients who discontinued trastuzumab for at least one cycle after non-severe cardiotoxicity, 7 patients received LVEF measurements. Of those patients, the LVEF was reversible in 4 patients (57%), partially reversible in 1 patient (14%) and irreversible in 2 patients (29%). Of the 43 patients who continued trastuzumab, 23 (56%) had normalization of LVEF, in 6 (15%) the LVEF decline was partially reversible and in 12 (29%) irreversible. Of all patients developing non-severe cardiotoxicity, 23% had cardiac symptoms including shortness of breath or angina pectoris. The reversibility was independent of the presence of cardiac symptoms.\n\nThe LVEF decline was reversible in 6 out of the 16 patients (35%) who developed severe cardiotoxicity and received LVEF measurements (Fig. 3 and Supplementary Figure S2). Among the 19 patients who discontinued trastuzumab after severe cardiotoxicity, the LVEF decline was reversible in 4 patients (40%), partially reversible in 3 patients (30%) and irreversible in 3 patients (30%). Among the 6 patients who continued trastuzumab after severe cardiotoxicity, the LVEF decline was reversible in 2 patients (33%), partially reversible in 3 patients (50%) and irreversible in 1 patient (17%). In the five patients with reversible severe cardiotoxicity, trastuzumab could be continued safely without recurring cardiotoxicity for a mean duration of 17 months (range 3–35). Of all patients who developed severe cardiotoxicity, 72% had cardiac symptoms. The reversibility was independent of the presence of cardiac symptoms.\n\nDiscussion\n\nIn this study, we showed that among patients with HER2-positive MBC the yearly incidence of non-severe + severe cardiotoxicity was highest in the first 2 years of trastuzumab (11.7% and 9.1%, respectively) and gradually decreased over time. The median time to develop non-severe + severe cardiotoxicity was 11 months. The yearly incidence of severe cardiotoxicity was low over time (range 1.2–2.8%) with a median time to develop severe cardiotoxicity of 10 months. In non-smoking patients with baseline LVEF > 60% and no cardiotoxicity during prior neoadjuvant/adjuvant treatment (i.e. no relevant risk factors), the cumulative incidence of severe cardiotoxicity was limited to 3.1% after 4 years. Physicians often continued trastuzumab treatment despite cardiotoxicity, i.e. 62% in case of non-severe cardiotoxicity and 24% in case of severe cardiotoxicity. Interestingly, reversibility was relatively high among those who continued trastuzumab (71% after non-severe cardiotoxicity and 83% after severe cardiotoxicity of whom 56% and 33% fully recovered, respectively). Taken together, our data show the limited clinical relevance of regular cardiac monitoring by LVEF measurements in patients without relevant risk factors, stressing the need for an alternative monitor schedule.\n\nThe incidence of cardiotoxicity observed in this study was lower than reported in some other studies investigating cardiotoxicity of trastuzumab in the advanced setting [3, 7, 18]. This might be explained by the fact that these studies included patients treated with concomitant and higher doses of anthracyclines than our study [3, 18]. In addition, some studies used other imaging modalities besides MUGA scan and had a less strict criteria to define cardiotoxicity [7, 18].\n\nWe aimed to identify subgroups with particular low risk of developing cardiotoxicity in order to tailor cardiac monitoring. In our study, high BMI, smoking, cardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracyclines and baseline LVEF < 60% were found to be statistically significant independent risk factors for cardiotoxicity, whereas other cardiovascular risk factors were not. This might be due to the fact that our study population consisted of relatively young patients (median age was 54 years) with a good LVEF (> 50%) before starting trastuzumab. In the study of Rossi et al., age was an important risk factor for cardiotoxicity among patients receiving trastuzumab for HER2-positive MBC [8]. In the study of Guarneri et al., baseline LVEF and time from last anthracycline administration were important risk factors [7]. In addition, a recent study indicated that polymorphism HER2-Ile655 A > G is a risk factor for developing cardiotoxicity during trastuzumab [19]. Whether this risk factor will help personalizing cardiac monitoring in patients with HER2-positive MBC remains to be investigated.\n\nBy combining the incidence of cardiotoxicity over time with an individual cardiovascular risk profile, a tailored cardiac monitoring recommendation could be given, in case a yearly incidence of severe cardiotoxicity of less than 1%, while on average in women aged ≥ 50 in Europe the yearly incidence of heart failure ranges between 0.2 and 2.2% [20], is considered acceptable. This would result in the following recommendations. First, for patients with a baseline LVEF above 60%, without cardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracycline and who do not smoke, further serial cardiac monitoring during trastuzumab treatment could be omitted, since the cumulative incidence of severe cardiotoxicity in these patients after 4 years of trastuzumab treatment is low (3.1%). Second, for patients with ≥ 1 risk factor, cardiac monitoring during the first 3 years would be recommended as the yearly increase and absolute numbers of non-severe + severe cardiotoxicity were low after 3 years. Thereafter, cardiac monitoring could be performed in case of cardiac symptoms. The high reversibility rates of cardiotoxicity in a substantial number of patients with MBC, even after continuing trastuzumab, support our proposed individualized LVEF monitoring scheme during (long-term) trastuzumab treatment.\n\nWe did not have sufficient data on the use or start of cardio-protective medication which could be of value in determining trastuzumab continuation after cardiotoxicity and in evaluating the reversibility of cardiotoxicity. Furthermore, we could not assess whether the use or start of cardio-protective medication could be helpful for the proposed individualized LVEF monitoring schemes. Medication, including ACE inhibitors (perindopril, lisinopril), beta-blockers (carvedilol, bisoprolol) or angiotensin receptor blocker (candesartan), has shown to attenuate LVEF declines and thereby potentially increase the reversibility of LVEF declines [21–25].\n\nTo the best of our knowledge, this study is the largest in number with the longest follow-up duration investigating the reversibility of cardiotoxicity during trastuzumab in patients with HER2-positive MBC. Although the historical observational design of this cohort study provided a valuable opportunity to investigate clinical practice, some limitations inherent to historic cohorts should be mentioned. First, not all variables could retrospectively be collected and therefore not all variables, for example medication use and total dose of anthracycline treatment (mg/m2) and radiation treatment (Gy), could be investigated. Although some missing data were observed for other variables as well, these variables could be used after multiple imputation as sensitivity analysis with complete case analysis showed similar risk factors associated with non-severe + severe cardiotoxicity as after multiple imputations (Supplementary Table S3). Second, due to the lack of clear cardiac monitoring guidelines, the timing of the LVEF measurements was not standardized but chosen by the treating physician. Therefore, ascertainment of cardiotoxicity could be delayed and detection bias cannot be excluded. However, information bias cannot have influenced the incidence of cardiotoxicity as LVEF measurements after cardiotoxicity were not taken into account. Third, most LVEFs (83%) were measured by MUGA scanning with a known high inter-observer and intra-observer variability in measuring the LVEF [26, 27]. However, by using a LMM analysis that takes into account all available LVEF measurements, the effect of this variability is minimized. Fourth, in estimating the cumulative incidence of cardiotoxicity per number of relevant risk factors, the effect size of the individual risk factors was not taken into account. Fifth, as the primary endpoint of the study was the development of cardiotoxicity, we did not investigate other cardiac co-morbidities that could develop over time. In addition, due to the median follow-up of the study of 15 months, we were unable to assess this. Last, only 26 patients (6%) in our cohort received dual HER2-targeted therapy, which is the current standard of first-line treatment for patients with HER2-positive MBC. However, as pertuzumab does not increases the risk of cardiotoxicity [28], the results of this study are likely to be applicable to daily clinical practice.\n\nConclusion\n\nThe cumulative incidence of severe cardiotoxicity in non-smoking patients with a baseline LVEF above 60% who had no cardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracycline after 4 years of trastuzumab treatment is low (3.1%). Therefore, serial cardiac monitoring can be omitted in these patients during long-term trastuzumab use.\n\nSupplementary Information\n\nBelow is the link to the electronic supplementary material.Electronic supplementary material 1 (DOCX 199 kb)\n\nAcknowledgements\n\nWe thank Caroline Pauwels-Heemskerk for her assistance with identifying patients in the Netherlands Cancer Institute’s tumor registry and Jorine Rigterink for her assistance with collecting data in the Netherlands Cancer Institute.\n\nAuthor contributions\n\nJJEMK, MLB, AJT, PCJ, JCD, CH, CHS, GSS and AJ were involved in patient inclusion and data acquisition. NIB, TGS and HNR extracted the data from the electronic patient files. NIB, TGS, JR, MJMK, EB, GSS, MDL and AJ advised and performed the data analysis. NIB wrote the manuscript. All authors critically reviewed and approved the final manuscript.\n\nFunding\n\nThis study was funded by the Promotiefonds of the Albert Schweitzer Hospital, Dordrecht, The Netherlands and by Stichting A Sister’s Hope, and Stichting [Z]aan de Wandel. These foundations had no involvement in the conduct of the study.\n\nCompliance with ethical standards\n\nConflict of interest\n\nTGS received funding from Memidis Pharma outside the current project. GSS has received institutional research funding from AstraZeneca, Merck, Novartis and Roche. The other authors have no relevant financial or non-financial interests to disclose.\n\nEthical approval\n\nAll procedures performed in this study involving human participants were in accordance with the ethical standard of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.\n\nInformed consent\n\nInformed consent was waived by institutional review boards for this retrospective study.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Piccart-Gebhart MJ Procter M Leyland-Jones B Goldhirsch A Untch M Smith I Gianni L Baselga J Bell R Jackisch C Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer N Engl J Med 2005 353 16 1659 1672 10.1056/NEJMoa052306 16236737\n2. Romond EH Perez EA Bryant J Suman VJ Geyer CE Jr Davidson NE Tan-Chiu E Martino S Paik S Kaufman PA Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer N Engl J Med 2005 353 16 1673 1684 10.1056/NEJMoa052122 16236738\n3. Slamon DJ Leyland-Jones B Shak S Fuchs H Paton V Bajamonde A Fleming T Eiermann W Wolter J Pegram M Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 N Engl J Med 2001 344 11 783 792 10.1056/NEJM200103153441101 11248153\n4. Curigliano G Lenihan D Fradley M Ganatra S Barac A Blaes A Herrmann J Porter C Lyon AR Lancellotti P Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations Ann Oncol 2020 31 2 171 190 10.1016/j.annonc.2019.10.023 31959335\n5. Petrelli F Barni S A pooled analysis of 2618 patients treated with trastuzumab beyond progression for advanced breast cancer Clin Breast Cancer 2013 13 2 81 87 10.1016/j.clbc.2012.11.008 23276465\n6. Swain SM Baselga J Kim SB Ro J Semiglazov V Campone M Ciruelos E Ferrero JM Schneeweiss A Heeson S Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer N Engl J Med 2015 372 8 724 734 10.1056/NEJMoa1413513 25693012\n7. Guarneri V Lenihan DJ Valero V Durand JB Broglio K Hess KR Michaud LB Gonzalez-Angulo AM Hortobagyi GN Esteva FJ Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience J Clin Oncol 2006 24 25 4107 4115 10.1200/JCO.2005.04.9551 16908934\n8. Rossi M Carioli G Bonifazi M Zambelli A Franchi M Moja L Zambon A Corrao G La Vecchia C Zocchetti C Trastuzumab for HER2+ metastatic breast cancer in clinical practice: cardiotoxicity and overall survival Eur J Cancer 2016 52 41 49 10.1016/j.ejca.2015.09.012 26630533\n9. Armenian SH Lacchetti C Barac A Carver J Constine LS Denduluri N Dent S Douglas PS Durand JB Ewer M Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline J Clin Oncol 2017 35 8 893 911 10.1200/JCO.2016.70.5400 27918725\n10. Onitilo AA Engel JM Stankowski RV Cardiovascular toxicity associated with adjuvant trastuzumab therapy: prevalence, patient characteristics, and risk factors Ther Adv Drug Saf 2014 5 4 154 166 10.1177/2042098614529603 25083270\n11. Jawa Z Perez RM Garlie L Singh M Qamar R Khandheria BK Jahangir A Shi Y Risk factors of trastuzumab-induced cardiotoxicity in breast cancer: a meta-analysis Medicine (Baltimore) 2016 95 44 e5195 10.1097/MD.0000000000005195 27858859\n12. Steenbruggen TG Bouwer NI Smorenburg CH Rier HN Jager A Beelen K ten Tije AJ de Jong PC Drooger JC Holterhues C Radiological complete remission in HER2-positive metastatic breast cancer patients: what to do with trastuzumab? Breast Cancer Res Treat 2019 178 597 605 10.1007/s10549-019-05427-1 31493033\n13. Zamorano JL Lancellotti P Rodriguez Munoz D Aboyans V Asteggiano R Galderisi M Habib G Lenihan DJ Lip GYH Lyon AR 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for practice guidelines: the task force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC) Eur Heart J 2016 37 36 2768 2801 10.1093/eurheartj/ehw211 27567406\n14. Plana JC Galderisi M Barac A Ewer MS Ky B Scherrer-Crosbie M Ganame J Sebag IA Agler DA Badano LP Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging Eur Heart J Cardiovasc Imaging 2014 15 10 1063 1093 10.1093/ehjci/jeu192 25239940\n15. Whelton PK Carey RM Aronow WS Casey DE Jr Collins KJ Dennison Himmelfarb C DePalma SM Gidding S Jamerson KA Jones DW 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the american college of cardiology/American Heart Association task force on clinical practice guidelines J Am Coll Cardiol 2018 71 19 e127 e248 10.1016/j.jacc.2017.11.006 29146535\n16. Durrleman S Simon R Flexible regression models with cubic splines Stat Med 1989 8 5 551 561 10.1002/sim.4780080504 2657958\n17. Senkus E Kyriakides S Ohno S Penault-Llorca F Poortmans P Rutgers E Zackrisson S Cardoso F Committee EG Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Ann Oncol 2015 26 Suppl 5 v8 30 10.1093/annonc/mdv298 26314782\n18. Untch M Muscholl M Tjulandin S Jonat W Meerpohl HG Lichinitser M Manikhas AG Coumbos A Kreienberg R du Bois A First-line trastuzumab plus epirubicin and cyclophosphamide therapy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: cardiac safety and efficacy data from the herceptin, cyclophosphamide, and epirubicin (HERCULES) trial J Clin Oncol 2010 28 9 1473 1480 10.1200/JCO.2009.21.9709 20177030\n19. Isabel B Celia G Francisco Javier M-P Jose Manuel G Fernando R-S Predictor of trastuzumab-induced cardiotoxicity in breast cancer (BC) patients: HER2/neu 655 polymorphisms, biochemical and clinical features J Clin Oncol 2020 38 15_suppl 1033 1033 10.1200/JCO.2020.38.15_suppl.1033\n20. Ho KK Pinsky JL Kannel WB Levy D The epidemiology of heart failure: the Framingham Study J Am Coll Cardiol 1993 22 4 Suppl A 6A 13A 10.1016/0735-1097(93)90455-A 8509564\n21. Gulati G Heck SL Ree AH Hoffmann P Schulz-Menger J Fagerland MW Gravdehaug B von Knobelsdorff-Brenkenhoff F Bratland A Storas TH Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol Eur Heart J 2016 37 21 1671 1680 10.1093/eurheartj/ehw022 26903532\n22. Lynce F Barac A Geng X Dang C Yu AF Smith KL Gallagher C Pohlmann PR Nunes R Herbolsheimer P Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEaRt study Breast Cancer Res Treat 2019 175 3 595 603 10.1007/s10549-019-05191-2 30852761\n23. Nowsheen S Aziz K Park JY Lerman A Villarraga HR Ruddy KJ Herrmann J Trastuzumab in female breast cancer patients with reduced left ventricular ejection fraction J Am Heart Assoc 2018 7 15 e008637 10.1161/JAHA.118.008637 30371238\n24. Pituskin E Mackey JR Koshman S Jassal D Pitz M Haykowsky MJ Pagano JJ Chow K Thompson RB Vos LJ Multidisciplinary approach to novel therapies in cardio-oncology research (MANTICORE 101-Breast): a randomized trial for the prevention of trastuzumab-associated cardiotoxicity J Clin Oncol 2017 35 8 870 877 10.1200/JCO.2016.68.7830 27893331\n25. Guglin M Krischer J Tamura R Fink A Bello-Matricaria L McCaskill-Stevens W Munster PN Randomized trial of lisinopril versus carvedilol to prevent trastuzumab cardiotoxicity in patients with breast cancer J Am Coll Cardiol 2019 73 22 2859 2868 10.1016/j.jacc.2019.03.495 31171092\n26. Bailey EA Bailey DL Results from an Australian and New Zealand audit of left ventricular ejection fraction from gated heart pool scan analysis Nucl Med Commun 2012 33 1 102 111 10.1097/MNM.0b013e32834c2f0b 22001719\n27. Huang H Nijjar PS Misialek JR Blaes A Derrico NP Kazmirczak F Klem I Farzaneh-Far A Shenoy C Accuracy of left ventricular ejection fraction by contemporary multiple gated acquisition scanning in patients with cancer: comparison with cardiovascular magnetic resonance J Cardiovasc Magn Reson 2017 19 1 34 10.1186/s12968-017-0348-4 28335788\n28. Baselga J Cortes J Kim SB Im SA Hegg R Im YH Roman L Pedrini JL Pienkowski T Knott A Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer N Engl J Med 2012 366 2 109 119 10.1056/NEJMoa1113216 22149875\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0167-6806",
"issue": "186(3)",
"journal": "Breast cancer research and treatment",
"keywords": "Cardiotoxicity; HER2-positive metastatic breast cancer; LVEF monitoring; Screening for cardiotoxicity; Trastuzumab treatment",
"medline_ta": "Breast Cancer Res Treat",
"mesh_terms": "D001943:Breast Neoplasms; D066126:Cardiotoxicity; D005260:Female; D006801:Humans; D018719:Receptor, ErbB-2; D013318:Stroke Volume; D000068878:Trastuzumab; D016277:Ventricular Function, Left",
"nlm_unique_id": "8111104",
"other_id": null,
"pages": "851-862",
"pmc": null,
"pmid": "33394273",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": "22001719;26314782;23276465;26630533;27893331;20177030;27858859;31959335;27567406;26903532;31493033;28335788;2657958;25693012;25239940;16236738;27918725;25083270;22149875;29146535;31171092;16236737;11248153;16908934;30371238;8376698;30852761",
"title": "Cardiotoxicity during long-term trastuzumab use in patients with HER2-positive metastatic breast cancer: who needs cardiac monitoring?",
"title_normalized": "cardiotoxicity during long term trastuzumab use in patients with her2 positive metastatic breast cancer who needs cardiac monitoring"
} | [
{
"companynumb": "NL-MYLANLABS-2021M1030000",
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"patient": {
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"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
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... |
{
"abstract": "A 42-year-old woman with a history of cholangiocarcinoma on adjuvant chemotherapy with capecitabine presented with painless haematochezia. She was found to have an isolated twenty-five mm ulcer in the ascending colon. Biopsies of the ulceration demonstrated typical cytomegalovirus (CMV) inclusions and her peripheral blood CMV PCR was significantly elevated. This is an unusual case of a solitary proximal colon ulcer. Non-steroidal anti-inflammatory drugs, inflammatory bowel disease and malignancy, are the most frequent causes of isolated ulcers in the proximal colon. Gastrointestinal (GI) CMV disease most commonly causes CMV colitis and is considered rare outside of the transplant population and other severely immunosuppressed patient groups. Patients who have received chemotherapy may also be at risk for GI CMV disease. The diagnosis should be suspected in patients who present with haematochezia or watery diarrhoea within a broad window of time after receiving chemotherapy.",
"affiliations": "Department of Internal Medicine, University of Florida, Gainesville, Florida, USA.;Department of Internal Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.;Florida Cancer Affiliates Ocala, Ocala, Florida, USA.;Gastroenterology, University of Florida College of Medicine, Gainesville, Florida, USA.",
"authors": "Case|Robert|R|;Stoner|Patrick|P|;Myrick|Samuel|S|;Zimmermann|Ellen|E|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000998:Antiviral Agents; D000069287:Capecitabine; D000077483:Valacyclovir",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-226355",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(2)",
"journal": "BMJ case reports",
"keywords": "GI bleeding; Infection (gastroenterology)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000964:Antimetabolites, Antineoplastic; D000998:Antiviral Agents; D001650:Bile Duct Neoplasms; D000069287:Capecitabine; D017024:Chemotherapy, Adjuvant; D018281:Cholangiocarcinoma; D003092:Colitis; D044682:Colon, Ascending; D003586:Cytomegalovirus Infections; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D016867:Immunocompromised Host; D016577:Pancreaticoduodenectomy; D012307:Risk Factors; D014456:Ulcer; D000077483:Valacyclovir",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30739086",
"pubdate": "2019-02-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22588614;15844689;23737154;17026558;24853055;7092539;1546927;15070995;15911429;8215005;24267497;25075497",
"title": "Solitary ascending colon ulcer diagnosed as gastrointestinal CMV disease.",
"title_normalized": "solitary ascending colon ulcer diagnosed as gastrointestinal cmv disease"
} | [
{
"companynumb": "US-TEVA-2019-US-1030000",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nN,N-dimethyltryptamine (DMT) is a 5-hydroxytryptamine 2A and 1A receptor agonist that exhibits potent psychoactive properties in humans. Recreational use of this drug has increased precipitously and is likely to result in an increase in patients presenting with substance-induced psychoses. The present case provides an early example of substance-induced psychosis attributable to repeated use of DMT.\n\n\nMETHODS\nA 42-year-old white man, with no significant past psychiatric history, was brought to the emergency department by the police and was found to exhibit disinhibited behavior, elevated affect, disorganized thought process, and delusions of reference. Laboratory studies revealed elevated creatinine kinase level indicative of rhabdomyolysis. The patient endorsed recent and repeated use of DMT, as well as long-term Cannabis (marijuana) use. Over the course of the next 3 weeks, the patient was successfully treated with quetiapine for psychosis, divalproex sodium (Depakote) for impulsivity, gabapentin for anxiety, and hydroxyzine for sleep, which resulted in the resolution of his symptoms and development of reasonable insight and judgment. Approximately 6 months after discharge, the patient remained treatment compliant, as well as drug and symptom free.\n\n\nCONCLUSIONS\nThis case report illustrates an important example of substance-induced psychosis that resolved with antipsychotic treatment in a 42-year-old white man with no past psychiatric history likely attributable to the use of DMT. Given the increasing use of this substance, the emergency department, primary care, and inpatient services are likely to see a significant increase in similar cases.",
"affiliations": "*Psychiatry Residency Training Program, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles; and †Veterans Affairs West Los Angeles Medical Center, Los Angeles, CA.",
"authors": "Paterson|Neil E|NE|;Darby|W Connor|WC|;Sandhu|Preetpal S|PS|",
"chemical_list": "D014150:Antipsychotic Agents; D006213:Hallucinogens; D000069348:Quetiapine Fumarate; D004130:N,N-Dimethyltryptamine",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000078",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "38(4)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D006213:Hallucinogens; D006801:Humans; D008297:Male; D004130:N,N-Dimethyltryptamine; D011618:Psychotic Disorders; D000069348:Quetiapine Fumarate",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "141-3",
"pmc": null,
"pmid": "26166234",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "N,N-Dimethyltryptamine-Induced Psychosis.",
"title_normalized": "n n dimethyltryptamine induced psychosis"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS INC, USA.-2015GMK019325",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"dru... |
{
"abstract": "Multicentric Castleman's disease (MCD), a polyclonal lymphoproliferative disorder of unknown aetiology, is a well-recognised complication of HIV disease. We present a case of MCD in an HIV-positive patient that is unusual on two counts: our patient's MCD first presented in the context of an immune restoration inflammatory syndrome (IRIS), following the initiation of highly active antiretroviral therapy (HAART). In addition, her MCD was associated with the unusual complication of acquired angioedema (AAE), which resolved following treatment of the MCD. While AAE is frequently found to have an underlying diagnosis of a lymphoproliferative disease, this is the first reported case linking AAE to MCD.",
"affiliations": "Chalmers Sexual Health Centre, NHS Lothian, Edinburgh, UK imali.fernando@live.co.uk.;Chalmers Sexual Health Centre, NHS Lothian, Edinburgh, UK.",
"authors": "Fernando|I|I|;Scott|G|G|",
"chemical_list": "D000970:Antineoplastic Agents; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1177/0956462413516941",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "25(7)",
"journal": "International journal of STD & AIDS",
"keywords": "AIDS; HAART (highly-active anti-retroviral therapy); HHV-8; HIV; Multicentric Castleman’s disease; acquired angioedema; human herpes virus-8; immune restoration inflammatory syndrome",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D000328:Adult; D000799:Angioedema; D000970:Antineoplastic Agents; D023241:Antiretroviral Therapy, Highly Active; D005871:Castleman Disease; D005260:Female; D015658:HIV Infections; D006679:HIV Seropositivity; D015497:HIV-1; D019288:Herpesvirus 8, Human; D006801:Humans; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "523-5",
"pmc": null,
"pmid": "24352125",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of multicentric Castleman's disease in HIV infection with the rare complication of acquired angioedema.",
"title_normalized": "a case of multicentric castleman s disease in hiv infection with the rare complication of acquired angioedema"
} | [
{
"companynumb": "GB-MYLANLABS-2015M1011463",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EFAVIRENZ"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPeriodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome has been considered as a childhood syndrome. The underlying etiology of PFAPA syndrome is unclear however, currently considered as auto-immune inflammatory disease. Recently, a few cases of adult-onset of PFAPA syndrome have been reported. However, there is no report about the successful management of pregnancy complicated with PFAPA syndrome.\n\n\nMETHODS\nThe patient was a 31-year-old woman who developed recurrent episodes of high fever associated with cervical adenitis, pharyngitis and vomiting started 9 months after a delivery. She was diagnosed with PFAPA syndrome and cimetidine 800 mg/day was initiated. Since then, these symptoms got better. Cimetidine treatment was discontinued since she became pregnant (6 weeks of pregnancy). Except one febrile episode at 8 weeks gestation, she did not develop a febrile episode during pregnancy. Peripheral blood Th1/Th2 ratio was decreased from the first trimester to the second trimester of pregnancy. Then again, the ratio was steadily elevated during the third trimester. At 38 weeks, she delivered a live born infant without any complication. Two months after delivery, she developed PFAPA syndrome again and cimetidine treatment was re-initiated. However, febrile episodes were not controlled well, and Th1/Th2 ratio was further elevated compared to pregnancy status. Colchicine 0.5 mg once a day was initiated. Symptoms were diminished and Th1/Th2 ratio was gradually decreased.\n\n\nCONCLUSIONS\nThere was no case report of pregnancy complicated with PFAPA syndrome, though there were several reports of adult-onset PFAPA cases without pregnancy. The current case may be the first case report of a successful pregnancy complicated with PFAPA. In this case, PFAPA symptoms were ameliorated during pregnancy, but reappeared after delivery. We speculate that PFAPA syndrome, a Th1 type immune disorder, might be improved due to the Th1 to Th2 shifting, which was induced by pregnancy. It is necessary to investigate further about PFAPA syndrome with pregnancy and Th1/Th2 immune responses in the future.",
"affiliations": "Department of Obstetrics and Gynecology, School of Medicine, Fukushima Medical University, 1-Hikarigaoka, Fukushima, 960-1247, Japan.;Reproductive Medicine and Immunology, Department of Obstetrics and Gynecology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 830 West End Court, Suite 400, Vernon Hills, IL, 60061, USA. joanne.kwakkim@rosalindfranklin.edu.;Department of Obstetrics and Gynecology, School of Medicine, Fukushima Medical University, 1-Hikarigaoka, Fukushima, 960-1247, Japan.;Fukushima Medical Center for Children and Women, School of Medicine, Fukushima Medical University, 1-Hikarigaoka, Fukushima, 960-1247, Japan.",
"authors": "Ota|Kuniaki|K|;Kwak-Kim|Joanne|J|;Takahashi|Toshifumi|T|;Mizunuma|Hideki|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12884-018-1854-6",
"fulltext": "\n==== Front\nBMC Pregnancy ChildbirthBMC Pregnancy ChildbirthBMC Pregnancy and Childbirth1471-2393BioMed Central London 185410.1186/s12884-018-1854-6Case ReportPregnancy complicated with PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) syndrome: a case report Ota Kuniaki kuniakiota@gmail.com 12Kwak-Kim Joanne +1-847-247-6904joanne.kwakkim@rosalindfranklin.edu 3Takahashi Toshifumi totakaha@fmu.ac.jp 12Mizunuma Hideki mizurin@fmu.ac.jp 21 0000 0001 1017 9540grid.411582.bDepartment of Obstetrics and Gynecology, School of Medicine, Fukushima Medical University, 1-Hikarigaoka, Fukushima, 960-1247 Japan 2 0000 0001 1017 9540grid.411582.bFukushima Medical Center for Children and Women, School of Medicine, Fukushima Medical University, 1-Hikarigaoka, Fukushima, 960-1247 Japan 3 0000 0004 0388 7807grid.262641.5Reproductive Medicine and Immunology, Department of Obstetrics and Gynecology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 830 West End Court, Suite 400, Vernon Hills, IL 60061 USA 4 6 2018 4 6 2018 2018 18 20721 2 2018 25 5 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPeriodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome has been considered as a childhood syndrome. The underlying etiology of PFAPA syndrome is unclear however, currently considered as auto-immune inflammatory disease. Recently, a few cases of adult-onset of PFAPA syndrome have been reported. However, there is no report about the successful management of pregnancy complicated with PFAPA syndrome.\n\nCase presentation\nThe patient was a 31-year-old woman who developed recurrent episodes of high fever associated with cervical adenitis, pharyngitis and vomiting started 9 months after a delivery. She was diagnosed with PFAPA syndrome and cimetidine 800 mg/day was initiated. Since then, these symptoms got better. Cimetidine treatment was discontinued since she became pregnant (6 weeks of pregnancy). Except one febrile episode at 8 weeks gestation, she did not develop a febrile episode during pregnancy.\n\nPeripheral blood Th1/Th2 ratio was decreased from the first trimester to the second trimester of pregnancy. Then again, the ratio was steadily elevated during the third trimester. At 38 weeks, she delivered a live born infant without any complication. Two months after delivery, she developed PFAPA syndrome again and cimetidine treatment was re-initiated. However, febrile episodes were not controlled well, and Th1/Th2 ratio was further elevated compared to pregnancy status. Colchicine 0.5 mg once a day was initiated. Symptoms were diminished and Th1/Th2 ratio was gradually decreased.\n\nConclusion\nThere was no case report of pregnancy complicated with PFAPA syndrome, though there were several reports of adult-onset PFAPA cases without pregnancy. The current case may be the first case report of a successful pregnancy complicated with PFAPA. In this case, PFAPA symptoms were ameliorated during pregnancy, but reappeared after delivery. We speculate that PFAPA syndrome, a Th1 type immune disorder, might be improved due to the Th1 to Th2 shifting, which was induced by pregnancy. It is necessary to investigate further about PFAPA syndrome with pregnancy and Th1/Th2 immune responses in the future.\n\nKeywords\nPFAPAPregnancyTh1/Th2Adult onsetPeriodic feverAphthous stomatitisPharyngitisCervical adenitisissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nPFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) syndrome which was first reported in 1987, is the most common autoimmune inflammatory fever disorder in childhood worldwide [1]. It is characterized by predictably periodic high fever lasting for approximately 4 days (ranges 2 to7 days) and associated with at least one of three clinical symptoms, such as pharyngitis, cervical adenitis and aphthous stomatitis [2]. The underlying etiology of the disease is still unknown, and the diagnosis is made with the clinical criteria proposed by Thomas et al. [2]; 1) Periodic fevers with an early age of onset (< 5 years of age), 2) Symptoms in the absence of upper respiratory tract infection with at least 1 of the following clinical signs: a) aphtous stomatitis, b) cervical lymphadenitis, c) pharyngitis, 3) Exclusive of cyclic neutropenia, 4) Completely asymptomatic interval between episodes, 5) Normal growth and development. Furthermore, PFAPA is required to exclude other diseases of recurrent fevers in childhood, such as malignancies, autoimmune and infectious disease. Genetic variants of the innate immune system, such as familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS) are also included as the differential diagnosis since PFAPA syndrome is currently supposed the pathogenesis of abnormal host immune response [3]. To date, some researchers reported that adult-onset of PFAPA syndrome, though PFAPA syndrome is basically pediatric disease and usually settles in adolescence [4, 5].\n\nWe would like to present a case of successful pregnancy complicated with PFAPA syndrome. We believe this is the first report of pregnancy complicated with PFAPA, since PFAPA primarily affects preschool-age children [6] and is rarely occurred in adults [7].\n\nCase presentation\nThe patient was a healthy 31-year-old woman who had an uneventful delivery of a live born infant at term 4 years ago. Nine months after the delivery, she developed recurrent episodes of high fever (39 °C) followed by cervical adenitis, pharyngitis and vomiting. A disease-free interval, which ranges 4 to 8 weeks, was observed between the periodic fever episodes, and a menstrual cycle was not related to the onset of a febrile episode.\n\nElevated C-reactive protein (peak value of 13.9 mg/dL) was noticed. Other laboratory studies, including immunoglobulin levels, serum complement level, immuno-phenotypic characterization of lymphocytes, HIV, CMV and EBV serology, and antinuclear antibodies, were negative. Genetic tests for genomic DNA from whole blood were conducted to exclude FMF, TRAPS, MKD and CAPS and all were negative. Cyclic neutropenia was excluded by serial neutrophil counts.\n\nHer PFAPA symptoms disappeared spontaneously within 5 days without antibiotic treatment and the elevated CRP level became normal in 10 days from the first day of fever. Finally, PFAPA syndrome was diagnosed according to the Padeh’s criteria, which are not restricted to the age of onset [8]. To prevent future febrile episodes, cimetidine 400 mg twice daily was started, and 60 mg of intravenous prednisolone was given during a febrile attack. During the subsequent febrile episodes, PFAPA symptoms were lessened. After 8 months passed, she became pregnant and quit cimetidine at the 6th week of gestation by herself. She then developed only one febrile episode at 8th week of gestation without any subsequent febrile episode during pregnancy, possibly due to altered maternal immunity with advanced pregnancy.\n\nT helper (Th)1/Th2 cell ratios were analyzed every 2~ 6 weeks during pregnancy (Fig. 1). IFN-gamma/ IL-4 producing CD3+/CD4+ T helper cell ratios were elevated during the first trimester. During the second trimester, Th1/Th2 ratios were decreased. CRP remained in the normal ranges during entire pregnancy. Whereas Th1/Th2 ratios were increased gradually even without a febrile episode during the third trimester. At 38 weeks, she developed a premature rupture of membrane and delivered a normal healthy male infant, weighing 2873 g. The Apgar scores (1 and 5 min) were 9 and 10 respectively. Two months after delivery, she developed an episode of high fever associated with cervical adenitis, pharyngitis and vomiting as she did prior to pregnancy. Cimetidine was re-initiated. Th1/Th2 ratio was 25.5 (Fig. 1). Febrile episodes became worse in severity and frequency and Th1/Th2 ratio was further elevated to 33.4 one month later. Colchicine 0.5 mg once a day was added. Th1/Th2 ratio started to decrease gradually (Fig. 2). Currently, febrile episodes remain shorter and milder.Fig. 1 Th1/Th2 cell ratio (IFN-γ/IL-4 T helper cell ratio) was analyzed by flow cytometric analysis. An acquisition gate was established based on CD4 staining and side scatter (SCC) which included peripheral blood mononuclear cells (left). Dot plot analysis of IFN-γ and IL-4 expressing CD4+ T cells from the patient. Numbers indicate percent gated cells (right)\n\nFig. 2 Time course plot of Th1/Th2 cell ratios (IFN-γ/IL-4 T helper cell ratio) from early pregnancy to postpartum 1 year. The white box indicates the period of cimetidine treatment and the slant bow indicates the period of colchicine treatment\n\n\n\nDiscussion and conclusions\nA case of pregnancy complicated with PFAPA syndrome has not been reported despite some reported adult-onset cases [7]. Although the exact pathogenesis of PFAPA has yet to be elucidated, it is considered as a polygenic autoinflammatory disease in which a microbial trigger might give rise to the activation of innate immune system and recruitment of activated T cells in a susceptible host, leading to Th1 driven immune responses [9]. On the other hand, the predominant Th2-type immunity has been observed during normal pregnancy. Maternal tolerance toward fetal allo-antigens was explained by the predominant Th2-type immunity during pregnancy for protecting the fetus from maternal Th1-immunity [10]. During normal pregnancy, Th1/Th2 ratio increases transiently during implantation period, and then decreases after implantation is over. During the third trimester, Th1/Th2 ratio increases for the preparation of parturition. Persistently increased Th1/Th2 ratios have been associated with multiple implantation failures and repeated pregnancy losses [11, 12]. In this case, Th1/Th2 ratio was elevated during the early first trimester of pregnancy. However, she could succeed in pregnancy and deliver despite the predominant Th1-type immunity which is harmful to pregnancy maintenance. We speculate that PFAPA by Th1 immune disorder might be ameliorated during the second trimester of pregnancy possibly due to the predominant Th2 immunity established during pregnancy. Furthermore, pregnancy complicated with PFAPA can be treated as normal perinatal course since symptoms are relieved by shifted Th2 immunity. It is necessary to pay sufficient attention because febrile episodes are rapidly exacerbated after parturition.\n\nAbbreviations\nCAPSCryopyrin-associated periodic syndromes\n\nCDCluster of differentiation\n\nCMVCytomegalovirus\n\nCRPC-reactive protein\n\nDNADeoxyribonucleic acid\n\nEBVEbstein-Barr virus\n\nFMFFamilial Mediterranean fever\n\nHIVHuman immunodeficiency virus\n\nIFNInterferon\n\nILInterleukin\n\nMKDMevalonate kinase deficiency\n\nPFAPAPeriodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis\n\nTh1/Th2T helper 1/T helper 2\n\nTRAPSTNF receptor-associated periodic syndrome\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\nAuthors’ contributions\nKO designed the study, performed laboratory experiment, analyzed and interpreted the data and prepared the manuscript. JKK contributed the study design and manuscript preparation. TT and HM contributed the data collection and interpretation. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent for publication of the clinical details and/or clinical images was obtained from the patient. 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. Marshall GS Edwards KM Butler J Lawton AR Syndrome of periodic fever, pharyngitis, and aphthous stomatitis J Pediatr 1987 110 1 43 46 10.1016/S0022-3476(87)80285-8 3794885 \n2. Thomas KT Feder HM Jr Lawton AR Edwards KM Periodic fever syndrome in children J Pediatr 1999 135 1 15 21 10.1016/S0022-3476(99)70321-5 10393598 \n3. Stojanov S Hoffmann F Kery A Renner ED Hartl D Lohse P Huss K Fraunberger P Malley JD Zellerer S Cytokine profile in PFAPA syndrome suggests continuous inflammation and reduced anti-inflammatory response Eur Cytokine Netw 2006 17 2 90 97 16840027 \n4. Cavuoto M Bonagura VR Adult-onset periodic fever, aphthous stomatitis, pharyngitis, and adenitis Allergy Asthma Immunol 2008 100 2 170 10.1016/S1081-1206(10)60428-0 \n5. Colotto M Maranghi M Durante C Rossetti M Renzi A Anatra MG PFAPA syndrome in a young adult with a history of tonsillectomy Internal medicine (Tokyo, Japan) 2011 50 3 223 225 10.2169/internalmedicine.50.4421 \n6. Vigo G Zulian F Periodic fevers with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) Autoimmun Rev 2012 12 1 52 55 10.1016/j.autrev.2012.07.021 22878272 \n7. Padeh S Stoffman N Berkun Y Periodic fever accompanied by aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA syndrome) in adults The Israel Medical Association journal : IMAJ 2008 10 5 358 360 18605359 \n8. Padeh S Brezniak N Zemer D Pras E Livneh A Langevitz P Migdal A Pras M Passwell JH Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome J Pediatr 1999 135 1 98 101 10.1016/S0022-3476(99)70335-5 10393612 \n9. Kraszewska-Glomba B Matkowska-Kocjan A Szenborn L The pathogenesis of periodic fever, Aphthous stomatitis, pharyngitis, and cervical adenitis syndrome: a review of current research Mediat Inflamm 2015 2015 563876 10.1155/2015/563876 \n10. Saito S Nakashima A Shima T Ito M Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy Am J Reprod Immunol 2010 63 6 601 610 10.1111/j.1600-0897.2010.00852.x 20455873 \n11. Kwak-Kim J Park JC Ahn HK Kim JW Gilman-Sachs A Immunological modes of pregnancy loss Am J Reprod Immunol 2010 63 6 611 623 10.1111/j.1600-0897.2010.00847.x 20367626 \n12. Kwak-Kim JY Chung-Bang HS Ng SC Ntrivalas EI Mangubat CP Beaman KD Beer AE Gilman-Sachs A Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF Hum Reprod 2003 18 4 767 773 10.1093/humrep/deg156 12660269\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2393",
"issue": "18(1)",
"journal": "BMC pregnancy and childbirth",
"keywords": "Adult onset; Aphthous stomatitis; Cervical adenitis; PFAPA; Periodic fever; Pharyngitis; Pregnancy; Th1/Th2",
"medline_ta": "BMC Pregnancy Childbirth",
"mesh_terms": "D000328:Adult; D005260:Female; D056660:Hereditary Autoinflammatory Diseases; D006801:Humans; D008199:Lymphadenitis; D010612:Pharyngitis; D011247:Pregnancy; D011248:Pregnancy Complications; D013281:Stomatitis, Aphthous; D013577:Syndrome; D002577:Uterine Cervical Diseases",
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"pubdate": "2018-06-04",
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"title": "Pregnancy complicated with PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) syndrome: a case report.",
"title_normalized": "pregnancy complicated with pfapa periodic fever aphthous stomatitis pharyngitis and cervical adenitis syndrome a case report"
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"abstract": "BACKGROUND\nThe traditional Japanese Kampo medicine Yokukansan (TSUMURA Yokukansan extract granules) was originally used to treat neurosis, insomnia, night crying, and irritability and/or agitation in infants and recently it has also been used for neuropsychiatric symptoms in Alzheimer's disease or other dementia in Japan. Furthermore, several recent studies have reported the efficacy of Kampo medicines for various types of headache. Here, we report a case of severe chronic migraine refractory to prophylactic therapy using various western medicines and Japanese Kampo medicines that had resulted in a leave of absence from work, but for which the frequency and severity were markedly decreased by Yokukansan (2.5 g 3 times/d), enabling the patient to return to work fully.\nThe patient was a 39-year-old woman with a diagnosis of migraine without aura, which started around the age of 17 years and had been well managed with oral triptan preparations. However, due to lifestyle changes after childbirth, the frequency and severity of migraine increased at 38 years of age, prompting her to visit our hospital.\nOur initial examination found no neurological abnormality, and our diagnosis was also migraine without aura based on the International Classification of Headache Disorders version 3.\n\n\nMETHODS\nHer migraine had become refractory to several western medicines (lomerizine hydrochloride, propranolol, sodium valproate, amitriptyline, and duloxetine) and 2 Japanese Kampo medicines (Goshuyuto and Chotosan). The migraine episodes worsened, and consequently she took a leave of absence from work.\n\n\nRESULTS\nYokukansan was then tried, and this markedly improved the chronic migraine, enabling her full return to work.\n\n\nCONCLUSIONS\nYokukansan might have exerted a prophylactic effect on chronic migraine via its action on the glutamatergic and serotonergic systems, inhibitory action on orexin A secretion, and anti-inflammatory action. Yokukansan might be useful as a prophylactic for migraine worldwide, and a future large-scale clinical study is warranted.",
"affiliations": "Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.",
"authors": "Akiyama|Hisanao|H|;Hasegawa|Yasuhiro|Y|",
"chemical_list": "D004365:Drugs, Chinese Herbal; C524644:Yi-Gan San",
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"doi": "10.1097/MD.0000000000017000",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31490382MD-D-19-0216510.1097/MD.0000000000017000170005300Research ArticleClinical Case ReportEffectiveness of the traditional Japanese Kampo medicine Yokukansan for chronic migraine A case reportAkiyama Hisanao MD, PhD∗Hasegawa Yasuhiro MD, PhDNA. Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.∗ Correspondence: Hisanao Akiyama, Department of Neurology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan (e-mail: h2akiyama@marianna-u.ac.jp).9 2019 06 9 2019 98 36 e1700020 3 2019 27 6 2019 7 8 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.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. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nThe traditional Japanese Kampo medicine Yokukansan (TSUMURA Yokukansan extract granules) was originally used to treat neurosis, insomnia, night crying, and irritability and/or agitation in infants and recently it has also been used for neuropsychiatric symptoms in Alzheimer's disease or other dementia in Japan. Furthermore, several recent studies have reported the efficacy of Kampo medicines for various types of headache. Here, we report a case of severe chronic migraine refractory to prophylactic therapy using various western medicines and Japanese Kampo medicines that had resulted in a leave of absence from work, but for which the frequency and severity were markedly decreased by Yokukansan (2.5 g 3 times/d), enabling the patient to return to work fully.\n\nPatient concerns:\nThe patient was a 39-year-old woman with a diagnosis of migraine without aura, which started around the age of 17 years and had been well managed with oral triptan preparations. However, due to lifestyle changes after childbirth, the frequency and severity of migraine increased at 38 years of age, prompting her to visit our hospital.\n\nDiagnoses:\nOur initial examination found no neurological abnormality, and our diagnosis was also migraine without aura based on the International Classification of Headache Disorders version 3.\n\nInterventions:\nHer migraine had become refractory to several western medicines (lomerizine hydrochloride, propranolol, sodium valproate, amitriptyline, and duloxetine) and 2 Japanese Kampo medicines (Goshuyuto and Chotosan). The migraine episodes worsened, and consequently she took a leave of absence from work.\n\nOutcomes:\nYokukansan was then tried, and this markedly improved the chronic migraine, enabling her full return to work.\n\nLessons:\nYokukansan might have exerted a prophylactic effect on chronic migraine via its action on the glutamatergic and serotonergic systems, inhibitory action on orexin A secretion, and anti-inflammatory action. Yokukansan might be useful as a prophylactic for migraine worldwide, and a future large-scale clinical study is warranted.\n\nKeywords\nchronic migraineleave of absencetraditional Japanese Kampo medicineYokukansanOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThe efficacy of traditional Japanese Kampo medicines for a number of conditions such as headache has been reported in recent years. The Clinical Practice Guidelines for Chronic Headache published by the Japanese Headache Society recommend (grade B) the use of the following 5 types of traditional Japanese Kampo medicines for migraine: Goshuyuto (evodia decoction), Keishininjinto (cinnamon twig and ginseng decoction), Chotosan (uncaria decoction), Kakkonto (kudzu decoction), and Goreisan (5-ingredient powder with poria).[1] The efficacy of other traditional Japanese Kampo medicines not mentioned in these guidelines has also been shown for various types of headache in several studies.[2–7] Although not commonly used for headache, the traditional Japanese Kampo medicine Yokukansan (TSUMURA Yokukansan extract granules; Tsumura Co Ltd, Tokyo, Japan; Fig. 1) has been reported for various types of headache.[8–14] Derived from the extracts of 7 medicinal herbs, Yokukansan was originally used to treat neurosis, insomnia, night crying, and irritability and/or agitation in infants and is an approved prescription drug in Japan. Recently, there have been several randomized controlled trials and a randomized double-blind placebo-controlled multicenter trial of Yokukansan for neuropsychiatric symptoms in Alzheimer's Disease or other dementia.[15]\n\nFigure 1 TSUMURA Yokukansan extract granules (A: appearance, B: extract granules, C: composition, D: 3D HPLC pattern). Yokukansan in granular form is a galenical preparation containing: Atractylodes lancea rhizome (4.0 g), Poria sclerotium (4.0 g), Cnidium rhizome (3.0 g), Uncaria hook (3.0 g), Japanese Angelica root (3.0 g), Bupleurum root (2.0 g), and Glycyrrhiza (1.5 g). 3D HPLC = 3-dimensional high-performance liquid chromatographic fingerprint.\n\nHere, we report a remarkable case of chronic migraine that had resulted in a leave of absence from work due to refractoriness to prophylactic therapy using various kinds of established western medicines and traditional Japanese Kampo medicines as anti-migraine prophylactic agents. However, the frequency and severity of migraine episodes were markedly decreased by the addition of Yokukansan, enabling the patient to return to work fully.\n\n2 Case presentation\nA female company employee aged 39 years presented to the outpatient clinic in our university hospital in August 2017 with a chief complaint of chronic headache. There was no notable past medical history except for throbbing right frontal headaches without aura that had been occurring 1 or 2 times per month since she was 17 years old, and lasted for half a day for a period of 1 to 3 days once begun. Headaches caused her to avoid routine physical activity and were associated with visual, auditory, and olfactory hypersensitivity, but were relieved approximately 30 minutes after oral administration of 1 tablet (precise dose unknown) of an over-the-counter (OTC) acetylsalicylic acid preparation.\n\nAt age 37 years, 4 months after childbirth, she noticed an increases in the frequency of headaches to 2 or 3 times per month, which coincided with the return of menstruation while reducing the frequency of breastfeeding. The severity of headaches has also increased, with associated nausea but no vomiting. OTC acetylsalicylic acid had become ineffective, and she had to lie down during each episode. She visited a nearby neurosurgery outpatient clinic and was diagnosed as having migraine without aura and tension-type headache based on past medical history. Oral sumatriptan (1 tablet, 50 mg) and self-administered sumatriptan subcutaneous injection (3 mg) were prescribed for pain relief and were effective.\n\nShe returned to work after maternity leave at the age of 38 years and had been busy balancing work and childrearing. However, due to lifestyle changes after childbirth, the frequency and severity of migraine increased at 38 years of age. A tablet or 1 shot of sumatriptan became ineffective. So, she visited the neurosurgery outpatient clinic again, and multi-agent anti-migraine prophylactic therapy was started with sodium valproate (600 mg/d), lomerizine hydrochloride (10 mg/d), and amitriptyline (30 mg/d). However, this therapy caused drowsiness and severely affected her ability to work. Subsequently, she visited our university hospital in July in the same year at the age 39 years.\n\nOur initial examination found no neurological abnormality, and our diagnosis was also migraine without aura based on the International Classification of Headache Disorders version 3 (ICHD-3). We replaced the previously prescribed self-administered sumatriptan with sumatriptan nasal spray (20 mg), because the injection caused discomfort immediately after administration. Two prophylactics (lomerizine hydrochloride, and amitriptyline) were discontinued, and only sodium valproate (600 mg/d) was continued on an outpatient basis (Fig. 2). The effects of both intranasal sumatriptan and newly prescribed oral naratriptan hydrochloride (1 tablet, 2.5 mg) were inadequate. The most effective pain relief was early administration of 2 tablets of sumatriptan (100 mg). However, migraines still occurred 12 to 14 times per month, and the dose of prophylactic sodium valproate was increased to 800 mg/d in November and to 1000 mg/d in December 2017. Migraine frequency remained high in February 2018, and amitriptyline (20 mg/d) was added to replace sodium valproate. However, because of the ensuing drowsiness, she stopped taking the amitriptyline after 3 days and switched it to leftover sodium valproate (1000 mg/d).\n\nFigure 2 Clinical course. Migraine in this patient was refractory to a series of the following western and traditional Japanese Kampo medicines as prophylaxis: lomerizine hydrochloride, propranolol, sodium valproate, amitriptyline, duloxetine, Goshuyuto, and Chotosan. Her condition worsened severely such that she had no option but to take a leave of absence from work. Subsequent Yokukansan therapy markedly reduced the frequency and severity of chronic migraine, enabling a full return to work.\n\nIn April 2018, at age 39 years, management of the recurrent migraine episodes was unsuccessful. One day while at work, she developed a throbbing headache affecting the entire head. Oral sumatriptan (1 tablet) plus loxoprofen (1 tablet, 60 mg) was not effective, and she had to leave work early due to nausea, vomiting, and lightheadedness. She visited a nearby doctor, and returned home after some relief was achieved following drip infusion of an antiemetic and an analgesic. The headaches recurred similarly for 3 days, but were relieved with oral sumatriptan and loxoprofen. In the middle of May 2018, the sodium valproate (1000 mg/d) was deemed ineffective and was terminated. It was replaced by the traditional Japanese Kampo medicine Goshuyuto (7.5 g/d), which was started for prophylaxis. However, this was switched to propranolol (20 mg/d) after repeated episodes of severe headaches that required emergency transfer to the nearby clinic or a general hospital. However, she developed dizziness from the oral propranolol and the headaches still occurred every day for a month, and she could no longer work. Furthermore, oral or self-administered sumatriptan started to cause nausea, and consequently was terminated. The patient subsequently developed depressive symptoms, so duloxetine (20 mg/d) was started as a prophylactic, but she voluntarily stopped this immediately because of palpitations and teeth grinding. Oral Tramcet combined preparation (tramadol hydrochloride 37.5 mg plus acetaminophen 325 mg/tablet, 3 tablets/d) was started in July 2018, with relief of symptoms for 4 to 5 hours; this also was stopped because of drowsiness. The patient then had to take a 1-month leave of absence from work from August 2018. Trial therapy with oral Chotosan (a traditional Japanese Kampo, 7.5 g/d) was started during this period and moderately alleviated the headache, and she managed to make a partial return to work in September. She still needed to take oral sumatriptan every day, even though the pain relief was not adequate; at home, she could do nothing but lie down, and often had to leave work early or be absent from work frequently. Next, tizanidine (3 mg/d) was added as a precaution against tension-type headache. Chotosan was judged ineffective and switched to Yokukansan (7.5 g/d) in November. This switch led to a markedly reduced frequency of needing to leave work early, which decreased to 3 times per month with no full-day absences. There were no episodes of severe headache in December and the frequency also decreased to once per month in late December. As of this writing in June 2019, 6 months have elapsed since we prescribed Yokukansan at 7.5 g/d and the patient even forgets to take sumatriptan tablets to work because her condition is much improved with no signs of aggravation or recrudescence of headache.\n\n3 Discussion\nIn this case, the patient was diagnosed as having migraine without aura based on ICHD-3, and was well managed with triptan preparations until childbirth. However, a hectic lifestyle with stress and fatigue from balancing work and childrearing caused increased frequency and severity of migraine. Several western medicines and traditional Japanese Kampo medicines (Goshuyuto and Chotosan) were administered as prophylaxis, but the chronic migraine was refractory to all such treatments. The patient had chronic migraine (≥15 headache days per month, of which at least 8 were migraine days), and this left her no option but to take a leave of absence from work. Fortunately, she had some relief on taking the traditional Japanese Kampo medicine Yokukansan (TSUMURA Yokukansan extract granules), which markedly reduced the frequency and severity of headaches, enabling her full return to work. We consider this case relevant, even though it is a single case, because Yokukansan appeared to be an effective anti-migraine agent.\n\nAccording to the survey in 1997 by Sakai et al, 8.4% (approximately 8.4 million) of individuals aged 15 years or older have migraines in Japan.[16] Migraines are characterized by severe unilateral throbbing headaches associated with nausea, vomiting, and hypersensitivity to light and sound, and often affect daily life (often patients are confined to bed). Given such severity, the use of prophylaxis is recommended if migraine episodes occur repeatedly or are prolonged (2 times or ≥6 days per month); the dose of nonsteroidal analgesics or triptan preparations is increased; or anxiety about having headaches restricts daily life.[1] In our case, the migraine was refractory to a series of the following agents: antihypertensive agents lomerizine hydrochloride (calcium channel blocker) and propranolol (beta-blocker); the antiepileptic agent sodium valproate; antidepressants amitriptyline and duloxetine, and traditional Japanese Kampo medicines Goshuyuto and Chotosan. When we tried Yokukansan, it markedly reduced the frequency and severity of migraines, enabling the patient's full return to work. Thus, we believe this case is of significance.\n\nYokukansan is a galenical preparation containing Atractylodes lancea rhizome (4.0 g), Poria sclerotium (4.0 g), Cnidium rhizome (3.0 g), Uncaria hook (3.0 g), Japanese Angelica root (3.0 g), Bupleurum root (2.0 g), and Glycyrrhiza (1.5 g) (Fig. 1). Indications include neurosis, insomnia, night crying, and irritability and/or agitation in infants. In adults, its efficacy for behavioral and psychological symptoms of dementia is well known.[15,17] It is not commonly used for treatment of headaches and has not yet been recommended in the Clinical Practice Guideline for Chronic Headache by the Japanese Headache Society 2013.[1] However, the efficacy of Yokukansan, as monotherapy and in combination with other antimigraine agents, was recently reported in the treatment of various types of headache, such as occipital neuralgia, migraine, and headaches caused by medication overuse in the treatment of depression.[8–14] We started Yokukansan based on the assumption that, given her natural drive, the patient did her very best to balance childrearing and work, which made her stressed and consequently worsened her condition resulting in chronic migraine.\n\nThe mechanism of migraine onset has not yet been elucidated, but the trigeminovascular theory is most likely involved.[18] More precisely, upon secretion of vasoactive substances following stimulation of the nerve terminals distributed in intracranial vessels, vasodilatation triggers sterile inflammation and inflammatory response then spreads through the vasculature. This excitation is transmitted to the brain and induces concomitant symptoms (eg, nausea and vomiting) and headache. It is highly likely that the neuropeptide serotonin, its receptors (particularly 5-HT1B/1D receptors widely distributed in cerebral vasculature), and the vasodilator calcitonin gene-related peptide are involved. Nevertheless, the mechanism of action of Yokukansan remains unclear, although the following actions have been reported: (1) suppression of neuronal excitation in the glutamatergic system through suppression of glutamate release action which affects N-methyl-D-aspartic acid receptors, activation of glutamate transporters, adjustment of glutamate uptake, and suppression of increases in the extracellular glutamate level[19–21]; (2) increased extracellular serotonin level in the serotonergic central nervous system through partial agonist effect on 5-HT1A receptors and downregulation of 5-HT1A receptors[22–24]; (3) inhibition of orexin A secretion[25]; and (4) anti-inflammatory effects.[26,27]\n\nThe interplay of these various actions of Yokukansan might have resulted in the marked prophylactic effect against migraine seen in our case.\n\nMany traditional Japanese Kampo medicines, such as Keishininjinto, Kamishoyosan, Saikokeishito, Tokishigyakukagoshuyushokyoto, Goshakusan, Senkyuchachosan, Daisaikoto, Hangebyakujutsutemmato, Tokishakuyakusan, and Keishibukuryogan, have been reported to be effective for headache,[2–7] although they are not yet mentioned in the Clinical Practice Guideline for Chronic Headache.[1] These traditional Japanese Kampo medicines, including Yokukansan, are promising prophylactic agents for migraines that can be used globally. It is therefore desirable to conduct large-scale double-blinded placebo-controlled clinical studies at an early stage to confirm the prophylactic effect of therapy with traditional Japanese Kampo medicines.\n\nAuthor contributions\nConceptualization: Hisanao Akiyama.\n\nInvestigation: Hisanao Akiyama.\n\nSupervision: Yasuhiro Hasegawa.\n\nWriting – original draft: Hisanao Akiyama.\n\nWriting – review and editing: Hisanao Akiyama.\n\nHisanao Akiyama orcid: 0000-0003-4491-6064.\n\nAbbreviations: ICHD-3 = International Classification of Headache Disorders version 3, OTC = over-the-counter.\n\nHow to cite this article: Akiyama H, Hasegawa Y. Effectiveness of the traditional Japanese Kampo medicine Yokukansan for chronic migraine. Medicine 2019;98:36(e17000).\n\nThe Bioethics Committee of St. Marianna University School of Medicine provided a waiver for case presentation.\n\nWritten informed consent for publication was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.\n\nResults of 3-dimensional high-performance liquid chromatographic fingerprint analysis and the pictures of Yokukansan (TSUMURA Yokukansan extract granules) were provided by Tsumura Co. Ltd. Tokyo, Japan.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] The Chronic Headache Clinical Practice Guideline Development Committee. Chapter I Headache: General Considerations. CQ I-15 Are herbal medicines (Kampo) effective? In: Clinical Practice Guideline for Chronic Headache 2013, The Japanese Headache Society (eds), p35-36. Igakusyoin, Tokyo, 2013. Available at: https://www.neurology-jp.org/guidelinem/ch/documents/guideline2013.pdf \nAccessed March 1, 2019.\n[2] Igarashi M Tsutsui S Miura O \nA case of a man suffering from headaches as chief complaints on which kami-shoyo-san was effective . J Japanese Assoc Orient Psychosom Med \n1997 ;12 :72–5 .\n[3] Hasegawa T Nagata K Kiyama K \nA case of chronic headache improved by Kamishoyosan . Pain Kampo Med \n2008 ;18 :62–6 .\n[4] Mizuno S \nKampo therapy for elderly patients with chronic headache, esp., migraine . Pain Kampo Med \n2003 ;13 :108–11 .\n[5] Shigemori Y Inoue T Yakubo S \nEffects of the kampo formula toki-shakuyaku-san on menstrual migraine . Int Med J \n2014 ;21 :401–3 .\n[6] Ozaki S Inoue Y Morita H \nApplication of keishi-bukuryo-gan to muscle-contraction headache – hypothesis of correlation between headache and “Ki”- . Kampo Med \n1991 ;42 :253–8 .\n[7] Imai M Mieda T Iida S \nAnalysis of Japanese herbal medicine (Kampo) used for the treatment of tension type headache in the pain clinic outpatient . Pain Kampo Med \n2017 ;27 :137–41 .\n[8] Mizukami K Asada T Kinoshita T \nA randomized cross-over study of a traditional Japanese medicine (kampo), yokukansan, in the treatment of the behavioural and psychological symptoms of dementia . Int J Neuropsychopharmacol \n2009 ;12 :191–9 .19079814 \n[9] Mitsufuji T Yamamoto T Hayashi Y \nUse of yokukansan foe the treatment of medication overuse headache . J Japanese Assoc Orient Psychosom Med \n2013 ;28 :47–9 .\n[10] Mitsufuji T Yamamoto T Miyake Y \nUse of yokukansan for the treatment of headache caused by medication overuse, second report: effectiveness of administering only yokukansan . J Japanese Assoc Orient Psychosom Med \n2014 ;29 :84–7 .\n[11] Fukaya D Mitsufuji T Soma N \nOne case using Japanese herbal medicine questionnaire for the application of yokukansan and therapeutic effects judgement against medication overuse headache . J Japanese Assoc Orient Psychosom Med \n2015 ;30 :17–21 .\n[12] Kawakami S Uratsuji Y Minowa Y \nEffectiveness of yokukansan for intractable pain in patients with irascible disposition . Pain Kampo Med \n2014 ;24 :65–9 .\n[13] Mitsufuji T Miyake A Ito Y \nSeventy-two-years old male case of hot-bath related headache responded to yokukansan . Pain Kampo Med \n2017 ;27 :119–21 .\n[14] Kimura Y Shimizu S Tanaka A \nEfficacy of yokukansan-based prescriptions for the treatment of patients with headache . Kampo Med \n2008 ;59 :265–71 .\n[15] Furukawa K Tomita N Uematsu D \nRandomized double-blind placebo-controlled multicenter trial of Yokukansan for neuropsychiatric symptoms in Alzheimer's disease . Geriatr Gerontol Int \n2017 ;17 :211–8 .26711658 \n[16] Sakai F Igarashi H \nPrevalence of migraine in Japan: a nationwide survey . Cephalalgia \n1997 ;17 :15–22 .\n[17] Mizoguchi K Ikarashi Y \nMultiple psychopharmacological effects of the traditional Japanese kampo medicine yokukansan, and the brain regions it affects . Front Pharmacol \n2017 ;8 :149.28377723 \n[18] Moskowitz MA Macfarlane R \nNeurovascular and molecular mechanisms in migraine headaches . Cerebrovasc Brain Metab Rev \n1993 ;5 :159–77 .8217498 \n[19] Takeda A Tamano H Itoh H \nAttenuation of abnormal glutamate release in zinc deficiency by zinc and Yokukansan . Neurochem Int \n2008 ;53 :230–5 .18755231 \n[20] Kawakami Z Ikarashi Y Kase Y \nGlycyrrhizin and its metabolite 18 beta-glycyrrhetinic acid in glycyrrhiza, a constituent herb of yokukansan, ameliorate thiamine deficiency-induced dysfunction of glutamate transport in cultured rat cortical astrocytes . Eur J Pharmacol \n2010 ;626 :154–8 .19818347 \n[21] Takeda A Itoh H Tamano H \nSuppressive effect of Yokukansan on excessive release of glutamate and aspartate in the hippocampus of zinc-deficient rats . Nutr Neurosci \n2008 ;11 :41–6 .18510802 \n[22] Terawaki K Ikarashi Y Sekiguchi K \nPartial agonistic effect of yokukansan on human recombinant serotonin 1A receptors expressed in the membranes of Chinese hamster ovary cells . J Ethnopharmacol \n2010 ;127 :306–12 .19913081 \n[23] Nishi A Yamaguchi T Sekiguchi K \nGeissoschizine methyl ether, an alkaloid in Uncaria hook, is a potent serotonin1A receptor agonist and candidate for amelioration of aggressiveness and sociality by yokukansan . Neuroscience \n2012 ;207 :124–36 .22314317 \n[24] Egashira N Iwasaki K Ishibashi A \nRepeated administration of Yokukansan inhibits DOI-induced head-twitch response and decreases expression of 5-hydroxytryptamine (5-HT)2A receptors in the prefrontal cortex . Prog Neuropsychopharmacol Biol Psychiatry \n2008 ;32 :1516–20 .18558456 \n[25] Katayama A Kanda Y Tsukada M \nYokukansan (Kampo medicinal formula) prevents the development of morphine tolerance by inhibiting the secretion of orexin A . Integr Med Res \n2018 ;7 :141–8 .29989049 \n[26] Furuya M Miyako T Tsumori T \nYokukansan promotes hippocampal neurogenesis associated with the suppression of activated microglia in Gunn rat . J Neuroinflammation \n2013 ;10 :145.24305622 \n[27] Honda Y Sunagawa M Yoneyama S \nAnalgesic and anti-stress effects of Yokukansan in rats with adjuvant arthritis . Kampo Med \n2013 ;64 :78–85 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "98(36)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D002908:Chronic Disease; D004365:Drugs, Chinese Herbal; D005260:Female; D006801:Humans; D020835:Medicine, Kampo; D008881:Migraine Disorders",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e17000",
"pmc": null,
"pmid": "31490382",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Effectiveness of the traditional Japanese Kampo medicine Yokukansan for chronic migraine: A case report.",
"title_normalized": "effectiveness of the traditional japanese kampo medicine yokukansan for chronic migraine a case report"
} | [
{
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"patient": {
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{
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"activesubstance": {
"activesubstancename": "SUMATRIPTAN"
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... |
{
"abstract": "OBJECTIVE\nAntiretroviral drugs can cause drug interactions.\n\n\nMETHODS\nThree clinical cases are described regarding HIV-infected patients in which a clinically relevant adverse effect occurred due to a pharmacokinetic interaction.\n\n\nRESULTS\nCase 1: A 43-year old woman being treated with tenofovir DF, emtricitabine and lopinavir/ritonavir who presents ischemia in both upper extremities following an ergotamine syndrome. Case 2: A 54-year old man being treated with zidovudine, lamivudine and lopinavir/ritonavir who presents Cushing syndrome following to use of inhaled fluticasone. Case 3: A 45-year old man being treated with tenofovir DF, emtricitabine and atazanavir/ritonavir who presents a virological failure as consequence of concomitant use of omeprazole.\n\n\nCONCLUSIONS\nPotential drug interactions must be considered when other concomitant drugs are used with antiretroviral therapy especially when one of these is a P 450 cytochrome enzymatic inductor or inhibitor.",
"affiliations": "Servicio de Medicina Interna, Hospital de Móstoles, Madrid, España.",
"authors": "Morales Conejo|M|M|;Moreno Cuerda|V J|VJ|;Abellán Martínez|J|J|;Rubio|R|R|",
"chemical_list": "D044966:Anti-Retroviral Agents; D003577:Cytochrome P-450 Enzyme System",
"country": "Spain",
"delete": false,
"doi": "10.1016/s0014-2565(08)76033-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0014-2565",
"issue": "208(11)",
"journal": "Revista clinica espanola",
"keywords": null,
"medline_ta": "Rev Clin Esp",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D003577:Cytochrome P-450 Enzyme System; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8608576",
"other_id": null,
"pages": "557-60",
"pmc": null,
"pmid": "19121266",
"pubdate": "2008-12",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Serious adverse events derived from the drug interactions of antiretroviral therapy.",
"title_normalized": "serious adverse events derived from the drug interactions of antiretroviral therapy"
} | [
{
"companynumb": "ES-DRREDDYS-GER/SPN/09/0006218",
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"activesubstance": {
"activesubstancename": "ATAZANAVIR SULFATE\\RITONAVIR"
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{
"abstract": "BACKGROUND\nIn the context of coronavirus disease 2019 (COVID-19) pandemic, patients with neuromyelitis optica spectrum disorder (NMOSD) are vulnerable to develop COVID-19 due to the immunosuppressive therapy. The objective of this study is to describe a known case of NMOSD on rituximab who experienced 2 episodes of COVID-19.\n\n\nMETHODS\nA 25-year-old woman, a known case of NMOSD on rituximab was diagnosed with asymptomatic COVID-19. Eight months later, following her last infusion of rituximab, she developed moderate COVID-19. After a partial recovery, she exhibited exacerbation of respiratory symptoms leading to readmission and invasive oxygenation. She was eventually discharged home after 31 days. Her monthly neurological evaluation did not reveal evidence of disease activity. She later received intravenous immunoglobulin and the decision was made to start rituximab again.\n\n\nCONCLUSIONS\nOur case raises the possibility of persistent virus shedding and reactivation of severe acute respiratory syndrome coronavirus-2 in a patient with NMOSD and rituximab therapy. We aimed to emphasize a precise consideration of management of patients with NMOSD during the COVID-19 pandemic.",
"affiliations": "Neuroscience Research Center.;Neurology Department, Beheshti Hospital, Qom University of Medical Sciences, Qom, Iran.;Neuroscience Research Center.",
"authors": "Paybast|Sepideh|S|;Shahrab|Fereshteh|F|;Hejazi|Seyed A|SA|",
"chemical_list": "D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1097/NRL.0000000000000371",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1074-7931",
"issue": "26(6)",
"journal": "The neurologist",
"keywords": null,
"medline_ta": "Neurologist",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D005260:Female; D006801:Humans; D009471:Neuromyelitis Optica; D058873:Pandemics; D000084063:Reinfection; D000069283:Rituximab",
"nlm_unique_id": "9503763",
"other_id": null,
"pages": "281-283",
"pmc": null,
"pmid": "34734909",
"pubdate": "2021-11-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "32241953;33895693;32555424;32242121;32697968;32506726;31162318;32278860;32840608;32619697;32171867;32863782;33303623",
"title": "Recurrence of COVID-19 in a Patient With NMO Spectrum Disorder While Treating With Rituximab: A Case Report and Review of the Literature.",
"title_normalized": "recurrence of covid 19 in a patient with nmo spectrum disorder while treating with rituximab a case report and review of the literature"
} | [
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"activesubstancename": "RITUXIMAB"
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{
"abstract": "Q fever prosthetic valve endocarditis in association with antiphospholipid antibody syndrome (APS) in systemic lupus erythematosus (SLE) has not been previously reported. Here, we report a 22-year-old Saudi female diagnosed with SLE and APS. She had mitral valve replacement with bio-prosthesis five years earlier for Libman-Sack endocarditis. She presented with two months' history of fever, cough, palpitations, and progressive shortness of breath. A transthoracic echocardiogram showed a degenerative mitral valve prosthesis with a large mass causing severe obstruction. Open heart surgery revealed multiple masses on the mitral valve. PCR from the resected tissues was positive for Coxiella burnetii DNA. Q fever serology showed phase two IgG 1:2048, phase one IgG 1:512, and IgM 1:1024. The valve was replaced with a bio-prosthesis. She was well at 12 months of follow-up.",
"affiliations": "Section of Rheumatology, Heart Center, King Faisal Specialist Hospital & Research Center, Saudi Arabia. Electronic address: malabdely@KFSHRC.edu.sa.;Section of Rheumatology, Heart Center, King Faisal Specialist Hospital & Research Center, Saudi Arabia.;Section of Rheumatology, Heart Center, King Faisal Specialist Hospital & Research Center, Saudi Arabia.;Section of Infectious Diseases, Heart Center, King Faisal Specialist Hospital & Research Center, Saudi Arabia.;Department of Medicine, Section of Anatomical Pathology, Heart Center, King Faisal Specialist Hospital & Research Center, Saudi Arabia.;Department of Pathology, of Cardiac Surgery, Heart Center, King Faisal Specialist Hospital & Research Center, Saudi Arabia.;Section of Infectious Diseases, Heart Center, King Faisal Specialist Hospital & Research Center, Saudi Arabia.",
"authors": "Alabdely|Mayyadah H|MH|;Mukhtar|Noha|N|;Alshaikh|Ahmad|A|;Halim|Magid|M|;Mohammed|Shmayel|S|;Pragliola|Claudio|C|;Omrani|Ali S|AS|",
"chemical_list": "D004269:DNA, Bacterial",
"country": "England",
"delete": false,
"doi": "10.1016/j.jiph.2020.02.036",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-0341",
"issue": "13(5)",
"journal": "Journal of infection and public health",
"keywords": "Antiphospholipid; Coxiella burnetii; Endocarditis; Q fever; SLE",
"medline_ta": "J Infect Public Health",
"mesh_terms": "D016736:Antiphospholipid Syndrome; D001705:Bioprosthesis; D006348:Cardiac Surgical Procedures; D016997:Coxiella burnetii; D004269:DNA, Bacterial; D004452:Echocardiography; D004697:Endocarditis, Bacterial; D005260:Female; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008943:Mitral Valve; D008946:Mitral Valve Stenosis; D016133:Polymerase Chain Reaction; D011778:Q Fever; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101487384",
"other_id": null,
"pages": "821-823",
"pmc": null,
"pmid": "32241725",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Q-fever prosthetic valve endocarditis in a patient with SLE and antiphospholipid antibody syndrome.",
"title_normalized": "q fever prosthetic valve endocarditis in a patient with sle and antiphospholipid antibody syndrome"
} | [
{
"companynumb": "NVSC2020SA187810",
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"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Hypertension is the most frequent condition associated with atrial fibrillation (AF) and stroke, the most terrible complication of AF. Achieving blood pressure (BP) goals as well as an adequate antithrombotic treatment are critical to reduce the incidence of stroke. But are interactions between anticoagulants and antihypertensive agents relevant for achieving BP targets? We present the case of a patient with hypertension and AF in which the interaction between losartan and acenocoumarol was associated with an irregular systolic BP control, but after switching to dabigatran, BP control improved. In this report, the possible mechanisms that may explain this change are discussed.",
"affiliations": "Department of Cardiology, Hospital Universitario Ramón y Cajal, Ctra. Colmenar km 9.100, 28034 Madrid, Spain. vbarrios.hrc@salud.madrid.org",
"authors": "Barrios|Vivencio|V|;Escobar|Carlos|C|",
"chemical_list": "D000925:Anticoagulants; D000959:Antihypertensive Agents; D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D000069604:Dabigatran; D000074:Acenocoumarol; D019808:Losartan",
"country": "England",
"delete": false,
"doi": "10.2217/fca.13.18",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1479-6678",
"issue": "9(3)",
"journal": "Future cardiology",
"keywords": null,
"medline_ta": "Future Cardiol",
"mesh_terms": "D000074:Acenocoumarol; D000369:Aged, 80 and over; D000925:Anticoagulants; D000959:Antihypertensive Agents; D000991:Antithrombins; D001281:Atrial Fibrillation; D001562:Benzimidazoles; D000069604:Dabigatran; D004347:Drug Interactions; D006801:Humans; D006973:Hypertension; D019808:Losartan; D008297:Male; D015091:beta-Alanine",
"nlm_unique_id": "101239345",
"other_id": null,
"pages": "321-3",
"pmc": null,
"pmid": "23668738",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Can dabigatran improve blood pressure control?",
"title_normalized": "can dabigatran improve blood pressure control"
} | [
{
"companynumb": "PHHY2013ES058682",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE\\LOSARTAN POTASSIUM"
},
"drugaddit... |
{
"abstract": "Mutlu M, Aslan Y, Kader Ş, Aktürk-Acar F, Dilber E. Clinical signs and symptoms of toxic serum digoxin levels in neonates. Turk J Pediatr 2019; 61: 244-249. Digoxin is widely used in the treatment of congestive heart failure and some arrhythmias. Digoxin toxicity may occur easily because digoxin has a narrow therapeutic index. This retrospective study was conducted to evaluate the clinical signs and symptoms of toxic serum digoxin levels in neonates. Medical reports of the neonates who had serum digoxin concentrations > 2 nanogram/milliliter (ng/ml) were reviewed in terms of patient demographics, serum digoxin concentrations, signs and symptoms of digoxin toxicity, serum digoxin and electrolyte levels, renal function tests, electrocardiograms, echocardiography, and treatments applied. Digoxin toxic levels were identified in the 13 neonates. Of the 13 neonates with digoxin toxic level, 9 (69%) were term and 8 (62%) were female. Twenty-three percent (3/13) of newborn infants were symptomatic. Symptomatic patients had statistically significantly higher serum digoxin levels, at 7.76±2.76 (5.4-10.8) ng/ml, than asymptomatic patients, at 3.31±1.09 (2.02-4.95) (p=0.036). Symptoms related to toxic digoxin levels were observed in the three neonates with plasma digoxin levels > 5 ng/ml. Gastrointestinal and central nervous system symptoms were the major clinic findings. Despite high digoxin levels, no digoxin-related arrhythmia was observed on electrocardiography, other than sinus bradycardia. Two premature neonates were treated with digoxin-specific antibody Fab fragments (DigiFab®) and hypokalemia developed in both of them. Our data suggests that symptoms related with digoxin toxic levels were observed in neonates with plasma digoxin levels > 5 ng/ml. Serum digoxin levels should be measured in case of signs and symptoms of digoxin toxicity or risk factors for such toxicity.",
"affiliations": "Division of Neonatology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey.;Division of Neonatology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey.;Division of Neonatology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey.;Division of Neonatology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey.;Department of Pediatric Cardiology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey.",
"authors": "Mutlu|Mehmet|M|;Aslan|Yakup|Y|;Kader|Şebnem|Ş|;Aktürk-Acar|Filiz|F|;Dilber|Embiya|E|",
"chemical_list": "D002316:Cardiotonic Agents; D004077:Digoxin",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "61(2)",
"journal": "The Turkish journal of pediatrics",
"keywords": "clinical signs and symptoms; digoxin; neonate; toxic level",
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D001145:Arrhythmias, Cardiac; D002316:Cardiotonic Agents; D004077:Digoxin; D018450:Disease Progression; D064420:Drug-Related Side Effects and Adverse Reactions; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D006333:Heart Failure; D006801:Humans; D007118:Immunoassay; D007231:Infant, Newborn; D008297:Male; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "244-249",
"pmc": null,
"pmid": "31951334",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical signs and symptoms of toxic serum digoxin levels in neonates.",
"title_normalized": "clinical signs and symptoms of toxic serum digoxin levels in neonates"
} | [
{
"companynumb": "NVSC2020TR103852",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadditional": "3",
"drugadmi... |
{
"abstract": "We examined the hypothesis that plasma biomarkers and concomitant clinical findings after initial glucocorticoid therapy can accurately predict failure of graft-versus-host-disease (GVHD) treatment and mortality. We analyzed plasma samples and clinical data in 165 patients after 14 days of glucocorticoid therapy and used logistic regression and areas under receiver-operating characteristic curves (AUC) to evaluate associations with treatment failure and nonrelapse mortality (NRM). Initial treatment of GVHD was unsuccessful in 49 patients (30%). For predicting GVHD treatment failure, the best clinical combination (total serum bilirubin and skin GVHD stage: AUC, .70) was competitive with the best biomarker combination (T cell immunoglobulin and mucin domain 3 [TIM3] and [interleukin 1 receptor family encoded by the IL1RL1 gene, ST2]: AUC, .73). The combination of clinical features and biomarker results offered only a slight improvement (AUC, .75). For predicting NRM at 1 year, the best clinical predictor (total serum bilirubin: AUC, .81) was competitive with the best biomarker combination (TIM3 and soluble tumor necrosis factor receptor-1 [sTNFR1]: AUC, .85). The combination offered no improvement (AUC, .85). Infection was the proximate cause of death in virtually all patients. We conclude that after 14 days of glucocorticoid therapy, clinical findings (serum bilirubin, skin GVHD) and plasma biomarkers (TIM3, ST2, sTNFR1) can predict failure of GVHD treatment and NRM. These biomarkers reflect counter-regulatory mechanisms and provide insight into the pathophysiology of GVHD reactions after glucocorticoid treatment. The best predictive models, however, exhibit inadequate positive predictive values for identifying high-risk GVHD cohorts for investigational trials, as only a minority of patients with high-risk GVHD would be identified and most patients would be falsely predicted to have adverse outcomes.",
"affiliations": "Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington School of Medicine, Seattle, Washington.;Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.;Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Biostatistics, University of Washington School of Medicine, Seattle, Washington.;Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington School of Medicine, Seattle, Washington.;Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.;Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington School of Medicine, Seattle, Washington.;Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.;Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington School of Medicine, Seattle, Washington.",
"authors": "McDonald|George B|GB|;Tabellini|Laura|L|;Storer|Barry E|BE|;Martin|Paul J|PJ|;Lawler|Richard L|RL|;Rosinski|Steven L|SL|;Schoch|H Gary|HG|;Hansen|John A|JA|",
"chemical_list": "D015415:Biomarkers; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D047888:Receptors, Tumor Necrosis Factor, Type I; D011239:Prednisolone; D001663:Bilirubin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2017.04.029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "23(8)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Allogeneic; Biomarker; Cause of death; Graft-versus-host disease; Hematopoietic cell transplantation; Marrow transplantation; Mortality; Outcomes; Positive predictive value; Treatment failure",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001663:Bilirubin; D015415:Biomarkers; D002648:Child; D005260:Female; D006086:Graft vs Host Disease; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011239:Prednisolone; D047888:Receptors, Tumor Necrosis Factor, Type I; D013997:Time Factors",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1257-1263",
"pmc": null,
"pmid": "28478120",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": "19660719;15660388;16291587;23791624;27416114;26649819;23165480;25987657;25759146;27856471;24777184;11239407;26446957;26687425;26305035;23041600;19074973;25554746;17244684;23924003;17492053;3131226;2207321;16449522;25814531;26267621;26764356;16537799;26343947;26130705;26551780;26367225;17700598;21105791;26053664;25377785;26729898;27872059;16920559;25682602;27827824",
"title": "Predictive Value of Clinical Findings and Plasma Biomarkers after Fourteen Days of Prednisone Treatment for Acute Graft-versus-host Disease.",
"title_normalized": "predictive value of clinical findings and plasma biomarkers after fourteen days of prednisone treatment for acute graft versus host disease"
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"abstract": "Cutaneous manifestations in hematologic malignancies, especially in leukemia, are not common and may be very variable. Here we report a very unusual case of a patient (female, 70 years old) who was admitted to the hospital in 2016 because of skin lesions on the face, the trunk of the body and the extremities. She had a history of breast cancer in the year 2004 (pT1b, pN0, cM0, L0, V0, R0) which had been resected and treated with adjuvant radiation and chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracile) as well as psoriasis treated with methotrexate and cyclosporine. Because of mild cytopenia a bone marrow aspirate/biopsy was performed showing myelodysplastic syndrome (MDS) with multilineage dysplasia. Cytogenetic review revealed a complex aberrant karyotype denoting adverse outcome. Simultaneously, a skin biopsy could confirm leukemic skin infiltration. Consequently, a therapy with azacitidine was started. After the first cycle the patient developed severe pancytopenia with a percentage of 13% peripheral blasts (previously 0-2%) as well as fever without evidence for infection which was interpreted as progressive disease. Therefore, the therapeutic regimen was changed to a biomodulatory therapy consisting of low-dose azacitidine 75 mg/day (given sc d1-7 of 28), pioglitazone 45 mg/day per os, and all-trans-retinoic acid (ATRA) 45 mg/m2/day per os. After cycle 1 of this combined biomodulatory therapy the patient showed hematologic recovery; besides a mild anemia (hemoglobin 11.1 g/dl) she developed a normal blood count. Moreover, the cutaneous leukemic infiltrates which had been unaffected by the azacitidine ameliorated tremendously after 2 cycles resulting in a complete remission of the skin lesions after cycle 6. In conclusion, we report a very unusual case with cutaneous infiltrates being the first clinical manifestation of hematologic disease, preceding the development of acute myeloid leukemia. While azacitidine alone was ineffective, a combined biomodulatory approach resulted in a complete remission of the cutaneous manifestation.",
"affiliations": "Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.;Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.;Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.;Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.;Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.;Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.",
"authors": "Heudobler|Daniel|D|;Klobuch|Sebastian|S|;Thomas|Simone|S|;Hahn|Joachim|J|;Herr|Wolfgang|W|;Reichle|Albrecht|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fphar.2018.01279",
"fulltext": "\n==== Front\nFront PharmacolFront PharmacolFront. Pharmacol.Frontiers in Pharmacology1663-9812Frontiers Media S.A. 10.3389/fphar.2018.01279PharmacologyOriginal ResearchCutaneous Leukemic Infiltrates Successfully Treated With Biomodulatory Therapy in a Rare Case of Therapy-Related High Risk MDS/AML Heudobler Daniel *Klobuch Sebastian Thomas Simone Hahn Joachim Herr Wolfgang Reichle Albrecht *Department of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyEdited by: Giovanni Li Volti, Università degli Studi di Catania, Italy\n\nReviewed by: Riccardo Masetti, Università degli Studi di Bologna, Italy; Michele Caraglia, Università degli Studi della Campania “Luigi Vanvitelli” Caserta, Italy; Massimo Breccia, Università degli Studi di Roma La Sapienza, Italy\n\n*Correspondence: Daniel Heudobler daniel.heudobler@ukr.deAlbrecht Reichle albrecht.reichle@ukr.deThis article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology\n\n13 11 2018 2018 9 127912 7 2018 18 10 2018 Copyright © 2018 Heudobler, Klobuch, Thomas, Hahn, Herr and Reichle.2018Heudobler, Klobuch, Thomas, Hahn, Herr and ReichleThis 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.Cutaneous manifestations in hematologic malignancies, especially in leukemia, are not common and may be very variable. Here we report a very unusual case of a patient (female, 70 years old) who was admitted to the hospital in 2016 because of skin lesions on the face, the trunk of the body and the extremities. She had a history of breast cancer in the year 2004 (pT1b, pN0, cM0, L0, V0, R0) which had been resected and treated with adjuvant radiation and chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracile) as well as psoriasis treated with methotrexate and cyclosporine. Because of mild cytopenia a bone marrow aspirate/biopsy was performed showing myelodysplastic syndrome (MDS) with multilineage dysplasia. Cytogenetic review revealed a complex aberrant karyotype denoting adverse outcome. Simultaneously, a skin biopsy could confirm leukemic skin infiltration. Consequently, a therapy with azacitidine was started. After the first cycle the patient developed severe pancytopenia with a percentage of 13% peripheral blasts (previously 0–2%) as well as fever without evidence for infection which was interpreted as progressive disease. Therefore, the therapeutic regimen was changed to a biomodulatory therapy consisting of low-dose azacitidine 75 mg/day (given sc d1-7 of 28), pioglitazone 45 mg/day per os, and all-trans-retinoic acid (ATRA) 45 mg/m2/day per os. After cycle 1 of this combined biomodulatory therapy the patient showed hematologic recovery; besides a mild anemia (hemoglobin 11.1 g/dl) she developed a normal blood count. Moreover, the cutaneous leukemic infiltrates which had been unaffected by the azacitidine ameliorated tremendously after 2 cycles resulting in a complete remission of the skin lesions after cycle 6. In conclusion, we report a very unusual case with cutaneous infiltrates being the first clinical manifestation of hematologic disease, preceding the development of acute myeloid leukemia. While azacitidine alone was ineffective, a combined biomodulatory approach resulted in a complete remission of the cutaneous manifestation.\n\nleukemic skin infiltrationmyelodysplastic syndromeacute myeloid leukemiabiomodulatory treatmentanakoinosis\n==== Body\nIntroduction\nClinical presentation\nIn May 2016 a 70-year-old female patient was admitted to the hospital suffering from multiple skin lesions which primarily appeared on the chest, sacrum and the face 3 months ago. Topic as well systemic therapy with (high dose) corticosteroids had been ineffective in the treatment. The patient also complained about pain of the big joints (knees, hips). Fever, night sweats or weight loss were denied. A skin biopsy had already been performed showing no evidence for malignancy or autoimmune disease.\n\nPhysical examination revealed generalized erythematous infiltrated papules on the entire integument, multiple ulcers on both breasts and the back as well as papular erythema on both cheeks (Figures 1A,B). A broad laboratory work-up showed no pathologies besides mild leukopenia (leukocytes 3.8/nl), mild anemia (11 g/dl), and a positive ANA titer (1:160). Re-biopsy of the skin on the right upper arm demonstrated interface dermatitis consistent with the diagnosis of erythema exsudativum, drug rash or dermatomyositis. Chest x-ray and ultrasound of the abdomen showed no pathological findings. A therapy with topic agents as well as systemic corticosteroids (prednisolone 1 mg/kg) was (re-)started leading to minimal improvements.\n\nFigure 1 Cutaneous leukemic skin infiltrates: Skin lesions on the face (A,C,E) and the back of the left upper arm (B,D,F) are shown. Panels (A,B) represent the treatment-naive state. Panels (C,D) show the lesions after one cycle of azacitidine and one cycle of combined biomodulatory therapy. Panels (E,F) demonstrate complete remission of skin lesions after six cycles of biomodulatory treatment.\n\nBackground\nMedical history\nIn 2004, the patient had been diagnosed with papillary breast cancer of the left breast [pT1b, pN0 (0/8), sN0 (0/3), cM0, L0, V0, R0] which had been treated with breast conserving surgery, adjuvant radiation as well as adjuvant chemotherapy (CMF regimen; 6 cycles of cyclophosphamide, methotrexate, 5-fluorouracile). Periodic aftercare examinations showed no evidence for metastatic disease. Due to suspected dermatomyositis a CT-scan of the thorax and abdomen as well as a bone scintigraphy were performed in April 2016 without any pathological finding. Moreover, the patient has a history of psoriasis vulgaris since 1984, which had been treated with methotrexate and cyclosporine. Because of arthrosis, the patient received joint replacement surgery of both knees and the right hip joint.\n\nDiscussion\nDiagnosis\nWithin the next 3 months, the skin lesions showed no improvement upon therapy. Since the laboratory work-up still revealed mild cytopenia (leukocytes 2.8/nl, hemoglobin 10.7 g/dl, MCV 81 fl, thrombocytes 153/nl) a bone marrow biopsy was performed in July 2016 confirming myelodysplastic syndrome with multilineage dysplasia and ringsideroblasts (MDS-RS-MLD): hypercellular marrow with dysplasia in all lineages and 36% ringsideroblasts. Bone marrow blasts (CD34+) were not increased. Because of the preceding chemo-/radiotherapy, the diagnosis therapy-related MDS (t-MDS) was stated. The genetic review revealed a complex aberrant karyotype involving chromosomes 5, 7, 8, 12, 13, 18, 21, and 22 (Karyotype formula: 45,XX,der(5;7)(5pter->5p11::7q22->7q11::5p11->5q11::7q11->7pter)[4]; 45,XX,der(5;7)(5pter->5p11::7q22->7q11::5p11->5q11::7q11->7pter),der(12;18)t(12;18)(p13;q23)del(12)(p12p13)[2]; 45,XX,der(5;7)(5pter->5p11::7q22->7q11::5p11->5q11::7q11->7pter),+8,der(12;18)t(12;18)(p13;q23)del(12)(p12p13),ider(13)(q10)del(13)(q13q22),+21,+22[4]; 46,XX[3]; ISCN: nuc ish 7cen(D7Z1x2),7q31(D7S486x1),8cen(D8Z2x3), 12p13(3′ETV6x1,5′ETV6x2)(3′ETV6 con 5′ETV6x1)[74/100]). Despite positive ringsideroblasts, no mutation in SF3B1 could be found. IPSS-R (Revised International Prognostic Scoring System) (Greenberg et al., 2012) demonstrated high risk disease denoting adverse outcome.\n\nSimultaneously, another skin biopsy was performed. Histological work-up in the reference center revealed mixed perivascular infiltrates consisting of lymphocytes and blasts with a high proliferation rate based on Ki67 staining; immuno-histochemically positivity of the blasts for myeloperoxidase (MPO) and KiM1P could be confirmed while being negative for CD34 (IHC panel: staining for CD3, CD20, CD34, MPO, KiM1P). In conclusion, leukemic skin infiltration could be confirmed.\n\nLeukemic skin infiltrates, also termed leukemic skin (LC), are defined by infiltrates of the epidermis, dermis, or subcutis by neoplastic leukocytes (leukemia cells), resulting in clinically identifiable cutaneous lesions. LCs occur in ~3% of patients with acute myeloid leukemia (AML) (Agis et al., 2002), and less frequently in MDS (Patel et al., 2012); with most frequent association in AML with acute myelomonocytic and monocytic differentiation (involvement in up to 50% of patients) (Kaddu et al., 1999; Pont et al., 2001). Clinical manifestations vary from erythematous papules to plum-colored plaques and nodules that may become purpuric and ulcerate. Skin infiltrates can develop simultaneously, following, or rarely preceding the onset of systemic leukemia (Su, 1994). The latter, termed “aleukemic leukemia cutis,” occurs most often in patients who eventually develop AML. Patients with suspected LC should always undergo biopsy. But like in our case the diagnosis of LC can be challenging: Immuno-histochemistry can be very helpful in the process with MPO resembling a strong marker for myeloid cells while CD34 or CD117 remain very often negative (Traweek et al., 1993; Cronin et al., 2009; Li et al., 2018).\n\nTreatment\nAfter the successful diagnosis of MDS and LC a therapy with azacitidine (given sc 75 mg/m2 d 1–7 of 28) resembling the established first-line therapy in high risk MDS was started in September 2016. At the end of cycle 1 the patient developed severe cytopenia (leukocytes = WBC 0.94/nl, neutrophils 0.27/nl; Figure 2) with a percentage of 13% peripheral blasts (previously 0–2%) as well as fever without evidence for infection. While cytopenia alone could be just a common side effect of azacitidine, the combination of cytopenia, rising peripheral blasts and diminishing clinical condition of the patient (fever without evidence for infection) was interpreted as progressive disease refractory to hypomethylating agents (HMA). Due to rising peripheral blasts transformation to acute myeloid leukemia (AML) was suspected. Unfortunately, this was not confirmed by bone marrow biopsy. With very little therapeutic opportunities outside clinical trials HMA failure is associated with very poor prognosis (Montalban-Bravo et al., 2018). In this situation, the therapeutic regimen was discontinued. After initial cytoreduction with hydroxyurea (500 mg bid for 5 days) the therapeutic regimen was changed to a biomodulatory regimen, consisting of low-dose azacitidine 75 mg/day (given sc d1-7 of 28), pioglitazone 45 mg/day per os, and all-trans-retinoic acid (ATRA) 45 mg/m2/day per os, which already had shown impressive results in chemorefractory AML. Previously five elderly AML patients had been treated with this approach on a compassionate-use basis outside of a clinical trial in the absence of alternative therapeutic options leading to induction of myeloid differentiation in leukemia blasts and resulting in molecular remissions in 3 of 5 patients (Thomas et al., 2015).\n\nFigure 2 Blood counts: Blood counts of leukocytes (WBC), neutrophils and platelets are shown. Left y-axis shows values for WBC und neutrophils, right y-axis for platelets. The shown time period comprises the first cycle azacitidine as well as the first cycle of biomodulatory therapy (day 0 = begin of biomodulatory therapy).\n\nAfter cycle 1 of this combined biomodulatory therapy, the presented patient showed hematologic recovery. Besides a mild anemia (hemoglobin 11.1 g/dl), she developed normal blood counts (Figure 2) with the absence of peripheral blasts. Moreover, the cutaneous leukemic infiltrates which had been unaffected by the azacitidine alone ameliorated tremendously after 2 cycles resulting in a complete remission of the skin lesions after cycle 6 (Figures 1C–F). Unfortunately, on day 1 of the planned 7th cycle of biomodulatory therapy the patient showed diminished peripheral blood counts (leukocytes 0.7/nl, hemoglobin 11.5 g/dl, thrombocytes 67/nl); therapy was stopped and bone marrow biopsy showed progressive AML (40% marrow blasts). Genetic work-up showed clonal evolution with complex aberrant karyotype and two independent mutations in TP53. The treatment was changed to decitabine 20 mg/m2 (given iv d1-5 of 28). After two cycles of decitabine the patient showed rising peripheral blasts up to 60%. Decitabine was discontinued (end of May 2017). A cytoreductive therapy with mitoxantrone iv 10 mg/m2 weekly was started. Despite these changes, the patient died of progressive disease in June 2017.\n\nNevertheless, the response to biomodulatory therapy in this case is very remarkable especially in the context of HMA failure. Concerning LC treatment strategies usually involve systemic as well as local therapy (i.e., radiotherapy, total skin electron beam therapy) (Bakst et al., 2011). Persistent complete remission of LC upon biomodulatory therapy alone is therefore very noteworthy.\n\nCombined transcriptional targeting of peroxisome-proliferator-activated-receptor gamma (PPARγ) and the retinoic acid receptor (RAR) as well as treatment with azacitidine have been previously shown to induce myeloid differentiation and inhibit leukemic cell growth (Curik et al., 2012; Tabe et al., 2012; Faber et al., 2013). The combination of all three drugs probably leads to a synergistic effect. Since such approaches are also widely applicable in heterogenic (chemorefractory) metastatic diseases (Reichle and Vogt, 2008; Hart et al., 2016), the effect can be explained with the new therapeutic concept of “anakoinosis” which means reprogramming of communicative networks (Hart et al., 2015). Anakoinosis means re-establishing of tissue homeostasis by communicatively reprogramming transcriptional networks maintained by tumor and adjacent stroma cells. Therefore, the effects of “anakoinotic” treatments are dependent on the cellular context and the tumor-bearing organ. In the presented case the response to treatment was context-dependent as well (skin vs. bone marrow): it was possible to induce a persistent complete remission of leukemic skin infiltrates, while in the bone marrow (BM) “normal” hematopoiesis was transiently improved resulting in normal blood counts, but eradication of leukemic (stem) cells failed. In AML it is known that direct physical crowding of BM by accumulating leukemic cells does not fully account for hematopoietic failure (Boyd et al., 2017). In this context, the suppression of BM adipocytes plays an important role leading to imbalanced regulation of endogenous hematopoietic stem and progenitor cells, resulting in impaired myelo-erythroid maturation. PPARγ agonists have shown to induce BM adipogenesis, which rescues healthy hematopoietic maturation while repressing leukemic growth (Saiki et al., 2006; Boyd et al., 2017; Ryu et al., 2018). Targeting of the axis between adipogenesis und myelo-erythroid maturation might explain the hematologic improvement in our patient. Although an additional therapeutic agent had been needed to fully eradicate leukemic blasts (progressive disease is most likely due to clonal evolution in the BM), the transient improvement of hematopoiesis shows the effect of biomodulatory treatment on tissue homeostasis.\n\nConcluding remarks\nIn conclusion, we report a very unusual case with cutaneous infiltrates being the first clinical manifestation of hematologic disease, preceding the development of acute myeloid leukemia and therefore resembling a diagnostic challenge. While one cycle of azacitidine showed no effect on the skin lesions, a combined biomodulatory approach resulted in a complete remission of the cutaneous manifestation. Due to its efficacy in the shown cases the biomodulatory therapy is currently investigated within a prospective, randomized, clinical trial (AMLSG26-16/AML-ViVA EudraCT number 2016-000421-39).\n\nMethods\nAll genetics analyses (chromosome banding analysis, FISH und sequencing) have been performed within clinical routine diagnostics at MLL (Munich Leukemia Laboratory, Munich, Germany).\n\nEthics statement\nWritten informed consent of the patient's husband (legal representative) for publication of the case was obtained.\n\nAuthor contributions\nDH, JH, and AR treated the patient. DH and AR wrote the manuscript. All the authors revised the manuscript critically, approved the final manuscript, and agreed to be accountable for all aspects of the manuscript.\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==== Refs\nReferences\nAgis H. Weltermann A. Fonatsch C. Haas O. Mitterbauer G. Müllauer L. . (2002 ). A comparative study on demographic, hematological, and cytogenetic findings and prognosis in acute myeloid leukemia with and without leukemia cutis . Ann. Hematol. \n81 , 90 –95 . 10.1007/s00277-001-0412-9 11907789 \nBakst R. L. Tallman M. S. Douer D. Yahalom J. (2011 ). How I treat extramedullary acute myeloid leukemia . Blood \n118 , 3785 –3793 . 10.1182/blood-2011-04-347229 21795742 \nBoyd A. L. Reid J. C. Salci K. R. Aslostovar L. Benoit Y. D. Shapovalova Z. . (2017 ). 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"journal": "Frontiers in pharmacology",
"keywords": "acute myeloid leukemia; anakoinosis; biomodulatory treatment; leukemic skin infiltration; myelodysplastic syndrome",
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"title": "Cutaneous Leukemic Infiltrates Successfully Treated With Biomodulatory Therapy in a Rare Case of Therapy-Related High Risk MDS/AML.",
"title_normalized": "cutaneous leukemic infiltrates successfully treated with biomodulatory therapy in a rare case of therapy related high risk mds aml"
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"abstract": "Priapism is a urological emergency characterized by abnormally prolonged, painful and irreducible erection. It occurs without a sexual stimulation and habitually exceeds 6 h. About a half of iatrogenic priapisms are believed to be associated with antipsychotics. Until to date, very few cases of aripiprazole-associated priapism were reported.\nIn this case report, we present the clinical findings of a 40-year-old patient that developed priapism after treatment with aripiprazole after his hospitalization for an episode of clinical mania following treatment discontinuation for bipolar I disorder. The management was successful and priapism was resolved spontaneously.\nDespite its low affinity to alpha-1 adrenergic receptors, aripiprazole may be associated with priapism. Several potential factors involved in the pathogenesis of this adverse event have been reported in the literature including history of priapism in a different class of neuroleptics and consumption of psychoactive drugs which are the principal factors found in our case.\nPriapism may occur even during treatment with antipsychotics that have a low affinity to alpha1-adrenergic receptors. All patients on antipsychotics should be informed about the risk of this rare but serious adverse event.",
"affiliations": "Department of Psychiatry, Mohammed VI University Hospital, Faculty of Medicine and Pharmacy, Mohammed I University, Oujda, Morocco.;Department of Psychiatry, Mohammed VI University Hospital, Faculty of Medicine and Pharmacy, Mohammed I University, Oujda, Morocco.;Department of Psychiatry, Mohammed VI University Hospital, Faculty of Medicine and Pharmacy, Mohammed I University, Oujda, Morocco.;Department of Psychiatry, Mohammed VI University Hospital, Faculty of Medicine and Pharmacy, Mohammed I University, Oujda, Morocco.;Department of Psychiatry, Mohammed VI University Hospital, Faculty of Medicine and Pharmacy, Mohammed I University, Oujda, Morocco.",
"authors": "El Jabiry|Salah-Eddine|SE|;Mansour|Atif|A|;Barrimi|Mohammed|M|;Oneib|Bouchra|B|;El Ghazouani|Fatima|F|",
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"fulltext": "\n==== Front\nAnn Med Surg (Lond)\nAnn Med Surg (Lond)\nAnnals of Medicine and Surgery\n2049-0801 Elsevier \n\nS2049-0801(21)00017-0\n10.1016/j.amsu.2021.01.015\nCase Report\nA very rare case of priapism under aripiprazole in a patient followed for bipolar disorder: A CARE-compliant report\nEl Jabiry Salah-Eddine salah-eddine.el-jabiry@ump.ac.ma∗ Mansour Atif Barrimi Mohammed Oneib Bouchra El Ghazouani Fatima Department of Psychiatry, Mohammed VI University Hospital, Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco\n∗ Corresponding author. Lot Najd, Bd Chafaq, No 49 Sidi Yahya, Oujda, Morocco. salah-eddine.el-jabiry@ump.ac.ma\n20 1 2021 \n2 2021 \n20 1 2021 \n62 216 218\n9 12 2020 9 1 2021 9 1 2021 © 2021 The Authors2021This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Introduction and importance\nPriapism is a urological emergency characterized by abnormally prolonged, painful and irreducible erection. It occurs without a sexual stimulation and habitually exceeds 6 h. About a half of iatrogenic priapisms are believed to be associated with antipsychotics. Until to date, very few cases of aripiprazole-associated priapism were reported.\n\nCase presentation\nIn this case report, we present the clinical findings of a 40-year-old patient that developed priapism after treatment with aripiprazole after his hospitalization for an episode of clinical mania following treatment discontinuation for bipolar I disorder. The management was successful and priapism was resolved spontaneously.\n\nClinical discussion\nDespite its low affinity to alpha-1 adrenergic receptors, aripiprazole may be associated with priapism. Several potential factors involved in the pathogenesis of this adverse event have been reported in the literature including history of priapism in a different class of neuroleptics and consumption of psychoactive drugs which are the principal factors found in our case.\n\nConclusion\nPriapism may occur even during treatment with antipsychotics that have a low affinity to alpha1-adrenergic receptors. All patients on antipsychotics should be informed about the risk of this rare but serious adverse event.\n\nHighlights\n• Priapism is a urological emergency characterized by abnormal erection.\n\n• Priapism can be associated with antipsychotics.\n\n• Aripiprazole-associated priapism is very rare.\n\n• Patients treated with aripiprazole should be informed about the risk of priapism.\n\n\n\nKeywords\nPriapismAripiprazoleAntipsychoticsalpha1-adrenergic receptorsCase report\n==== Body\n1 Introduction\nPriapism is a rare condition in which abnormally prolonged (>6 hours), painful, and irreducible erection without any sexual stimulations nor ejaculation can be observed [1]. Despite its rareness, it remains an extremely serious condition that requires appropriate management. Therefore, priapism is a medical and surgical emergency that may lead to severe sequelae, particularly, erectile dysfunction after fibrosis of the cavernous bodies [2]. Iatrogenic origins of priapism, especially associated with pharmacological treatments, are found implicated in 25–40% of the cases in which antipsychotics occupy 50% [3,4]. However, there are few published cases in the literature that reported aripiprazole-induced priapism. In this paper, we report a new case of this association in a patient treated for bipolar I disorder based on CARE-guidelines [5].\n\n1.1 Presentation of case\nOur patient is a 40 year-old male, married, father of a child, and working as a nurse. He has been followed for 18 years for bipolar I disorder diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders V (DSM-V) criteria. He is a chronic user of tobacco at a rate of 30 packets/years and cannabis at a rate of 1 g per day. Cocaine was occasionally used. Moreover, he has a history of priapism induced by chlorpromazine during his hospitalization in 2016 for manic access. In that time, the management of his case required surgical intervention by puncture-washing of the cavernous bodies. After this adverse event, sedative neuroleptics were proscribed for him. Of note, our patient has no other personal or family history including psychiatric disorders. The disease history of our patient dates back to 2005, with the onset of clinical mania that required hospitalization and treatment with escalating doses of sodium valproate to 1500 mg/day. During follow up, the occurrence of several relapses of manic and depressive symptoms were noticed which required his hospitalization with free intervals between episodes. The patient was treated using single agents several including olanzapine (20 mg/day), risperidone (8 mg/day), and sertraline (50 mg/day). The treatments changes were proposed to the patient because of the marked adverse events reported principally sedation and priapism that needed his hospitalization in 2016.\n\nIn 2019, the patient was admitted to our psychiatric hospital for psychomotor excitement, tachypsychia with logorrhea, mood lability, ideas of grandeur and multiple projects, which were associated with insomnia and a tendency to hetero aggressiveness. According to DSM-V criteria, a mania in the context of bipolar I disorder following discontinuation of treatment for negative insight was retained as a diagnosis. Notably, there were no linguistic, cultural or financial issues during the management of our patient. Initially, our patient was treated with aripiprazole at a dose of 15 mg/day in combination with diazepam (30 mg/day). On day 10 of his hospitalization, the patient presented with a persistent and painful erection. He was referred to the urology department for management. A preliminary clinical assessment found no urological abnormalities. The diagnosis of priapism induced by aripiprazole was therefore retained. Fortunately, the erection resolved spontaneously, and the patient started benzodiazepines alone (diazepam 30 mg/day) with surveillance of his clinical and mental status. Subsequently, sodium valproate (1500 mg/day) combined with psychoeducation were proposed to the patient. The choice of this molecule was based on the good improvement and tolerance seen in the previous episodes as reported by the patient. The evolution was marked by the disappearance of manic symptoms, good tolerance, as well as non-recurrence of priapism.\n\n2 Discussion\nDespite the occurrence of aripiprazole-induced priapism is rare, its severity and difficult management should alert the attention of clinicians. Remarkably, a significant strength of our clinical case is the absence of any drug interactions that might justify the association of other molecules with priapism. In fact, our patient was treated with aripiprazole and diazepam only. Importantly, the recognition of this adverse event by the patient allowed us to intervene quickly. This is not always possible especially in patients with non-stabilized mental disorders. The selection of an appropriate treatment for the patient (sodium valproate) was guided by the nature of his psychiatric disorder (bipolar disorder type 1), the previous response to this treatment and the absence of affinity for alpha-1-adrenergic receptors. Therefore, this medication for this indication does not seem to increase the risk for developing priapism.\n\nSeveral lines of evidence on the occurrence of priapism when using antipsychotics have supported the neuromuscular hypothesis that remained the most adopted worldwide. It suggests that antipsychotics-associated priapism depends on the ability of alpha-1-adrenergic receptors blockade of the cavernous bodies [6]. The current published literature reported several clinical cases of priapism associated with the two classes of antipsychotics including classical and atypical molecules [7]. In this perspective, haloperidol, chlorpromazine, levomepromazine and thioridazine are among the classical neuroleptics that have the greatest affinity for alpha-1 adrenergic receptors. Clozapine, quetiapine, risperidone and olanzapine are the atypical antipsychotics with high affinity for these receptors [[8], [9], [10]]. However, aripiprazole has the lowest affinity for this receptor among all atypical antipsychotics [11] (Table 1). Besides, despite this characteristic, cases of priapism induced by aripiprazole have been reported (Table 2). Two previous reports suggested an association between the dose of aripiprazole and priapism [12,13]. In 2006, Mago et al. discussed a case of recurrent priapism that was associated with the administration of aripiprazole [14]. In addition, priapism has been reported when aripiprazole was combined with oxcarbazepine and lithium [15]. Other authors reported a case of priapism with 10 mg of aripiprazole within a few hours of its first administration to patients with schizophrenia [16,17].Table 1 Affinity of antipsychotics to alpha-1 adrenergic receptors.\n\nTable 1Antipsychotics\tAffinity\t\nAmisulpride\t-\t\nAripiprazole\t±\t\nOlanzapine\t++\t\nClozapine\t+++\t\nHaloperidol\t+++\t\nQuetiapine\t+++\t\nRisperidone\t++++\t\nChlorpromazine\t++++\t\nTable 2 Summary of published cases and reports on aripiprazole-associated priapism.\n\nTable 2Author/year\tArticle type\tCountry of origin\tPatient’ gender and age\tPsychiatric disorder\tTreatments and outcomes\t\nNegin et al., 2005 [15]\tLetter to the editor\tUSA\t-Male\n−16\tPervasive developmental disorder and bipolar disorder\t-Oxcarbazepine combined to lithium and aripiprazole\n-After two days of this treatment, two discrete episodes of prolonged penile erection were reported\n-No further prolonged erections were recorded after maintenance treatment with lithium and aripiprazole only\t\nMago et al., 2006 [14]\tLetter to the editor\tUSA\t-Male\n−47\tChronic paranoid schizophrenia\t-Aripiprazole (dose not reported)\n-Recurrent priapism treated by cavernal irrigation and phenylephrine each time combined to pseudoephedrine\n-Lost to follow-up after discharge\t\nAguilar et al., 2009 [13]\tLetter to the editor\tSpain\t-Male\n−23\tSchizophrenic disorder\t-Aripiprazole (20 mg/day) and dipotassium clorazepate.\n-Increase in the dose to 30 mg/day following the activation of the disease\n-Painful erection after two days of treatment for more than 24 hours\n-No similar episodes were noticed after urological intervention and dose reduction of aripiprazole to 20mg/day\t\nHsu et al., 2011 [12]\tLetter to the editor\tTaiwan\t-Male\n−24\tPsychotic disorder (not specified)\t-Initial aripiprazole at a dose of 10mg/day with gradual increase to up to 25mg\n-Priapism was observed following this monotherapy\n-Switching to olanzapine (10 mg/day) was effective for priapism disappearance\t\nTogul et al., 2012 [16]\tConference abstract\tTurkey\t-Male\n−30\tSchizophrenia\t-Aripiprazole at a dose of 10 mg/day.\n-The patient reported a painful erection 8 hours later.\n-Priapism disappeared after switching to olanzapine (20 mg/day).\t\nTrivedi et al., 2016 [17]\tCase report\tIndia\t-Male\n-An adolescent (age non specified)\tParanoid schizophrenia\t-Aripiprazole 10 mg/day and lorazepam 2 mg.\n-Priapism after 7 hours treated successfully with blood aspiration with saline in combination to local adrenaline\t\n\n\nOur patient case differs from the rare reports published mainly by the nature of the underlying psychiatric disease. On the other hand, other common points are present. The repeated occurrence of priapism under different antipsychotics could refer to a predisposition to this adverse event [18,19]. The use of psychoactive substances would also increase the risk of occurrence of priapism [20]. This was the case of our patient who is a chronic user of tobacco, cannabis and occasional cocaine. So far, the occurrence of priapism in our case does not appear to be dose related. In fact, our clinical case must attract the attention of practitioners to several key points. First, the systematic search for a history of priapism before administration of an antipsychotic should be performed because the literature raises cases of repeated priapism in these patients. Furthermore, a careful follow up of patients treated with antipsychotics especially those who have unstable psychiatric diseases should be implemented. And finally, the use of antipsychotics with weak or absent alpha1-adrenergic affinity should be recommended along with psychoeducation. During follow up, our patient was very satisfied with our management despite the stress experienced during his hospitalization for priapism.\n\n3 Conclusion\nPriapism is a serious urological emergency that requires a rapid and an adequate management. The factors predisposing to its occurrence after aripiprazole use or other antipsychotics need to be evaluated in well conducted robust studies. This will be essential to identify patients at risk to develop priapism. Patients under treatments using antipsychotics should be informed of the risk of this adverse event.\n\nConflict of interest\nNone declared.\n\nSources of funding\nNone.\n\nEthical approval\nN/a.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\nDr Salah-Eddine El Jabiry collected data and wrote the manuscript. Dr Atif Mansour participated in the patient management. Professors Mohammed Barrimi, Bouchra Oneib, and Fatima El Ghazouani supervised the article writing. All the authors approved the final version.\n\nResearch registration\nN/a.\n\nGuarantor\nDr Salah-Eddine El Jabiry.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n\nAppendix A Supplementary data\nThe following is the supplementary data related to this article:Multimedia component 1\nMultimedia component 1 \n\nAppendix A Supplementary data related to this article can be found at https://doi.org/10.1016/j.amsu.2021.01.015.\n==== Refs\nReferences\n1 Ben jelloun S. El Mirin M. Aboutaib R. Bennami S. Joual A. Le priapisme à propos de 10 cas J. Urol. 1993 9991 9993 \n2 Brichart N. Delavierre D. Peneau M. Priapism associated with antipsychotic medications: a series of four patients Prog. Urol. 18 2008 669—73 18971111 \n3 Penaskovic K.M. Haq F. Raza S. Priapism during treatment with olanzapine, quetiapine, and risperidone in a patient with schizophrenia: a case report J. Clin. Psychiatr. 12 5 2010 PCC.09l00939 \n4 Wang C.S. Kao W.T. Chen C.D. Priapism associated with typical and atypical antipsychotic medications Int. Clin. Psychopharmacol. 21 2006 245 248 16687997 \n5 Riley D.S. Barber M.S. Kienle G.S. Aronson J.K. von Schoen-Angerer T. Tugwell P. Kiene H. Helfand M. Altman D.G. Sox H. Werthmann P.G. Moher D. Rison R.A. Shamseer L. Koch C.A. Sun G.H. Hanaway P. Sudak N.L. Kaszkin-Bettag M. Carpenter J.E. Gagnier J.J. CARE guidelines for case reports: explanation and elaboration document J. Clin. Epidemiol. 89 2017 Sep 218 235 10.1016/j.jclinepi.2017.04.026 28529185 \n6 Andersohn F. Schmedt N. Weinmann S. Priapism associated with antipsychotics: role of alpha1-adrenoceptor affinity J. Clin. Psychopharmacol. 30 1 2010 68 71 20075651 \n7 Sood S. James W. Bailon M.J. Priapism associated with atypical antipsychotic medications: a review Int. Clin. Psychopharmacol. 23 1 2008 9 17 18090503 \n8 Razali Salleh M, Mohamad H, Zainol J. Unpredictable neuroleptics induced priapism: a case report. Eur. Psychiatr.;11(8):419-420.\n9 Kaufman K.R. Stern L. Mohebati A. Ziprasidone-induced priapism requiring surgical treatment Eur. Psychiatr. 21 2006 48 50 \n10 Lidow M.S. General overview of contemporary antipsychotic medications Neurotransmitter Receptors in Actions of Antipsychotic Medications 2000 CRC Boca Raton 27 \n11 Goodnick P.J. Jerry J.M. Aripiprazole: profile on efficacy and safety Expet Opin. Pharmacother. 3 2002 1773 1781 \n12 Hsu W.Y. Chiu N.Y. Wang C.H. Lin C.Y. High dosage of aripiprazole induced priapism: a case report CNS Spectr. 16 2011 177 24725558 \n13 Aguilar-Shea A.L. Palomero-Juan I. Sierra Santos L. Gallardo-Mayo C. Aripiprazole and priapism Atención Primaria 41 2009 228 229 19324466 \n14 Mago R. Anolik R. Johnson R.A. Kunkel E.J. Recurrent priapism associated with use of aripiprazole J. Clin. Psychiatr. 67 2006 1471 1472 \n15 Negin B. Murphy T.K. Priapism associated with oxcarbazepine, aripiprazole, and lithium J. Am. Acad. Child Adolesc. Psychiatry 44 2005 1223 1224 \n16 Toğul H. Budak A.A. Algül A. Balibey H. Ebrinç S. Aripiprazole induced priapism Bull. Clin. Psychopharmacol. 22 Suppl 1 2012 S149 \n17 Trivedi S.K. Mangot A.G. Sinha S. Aripiprazole-induced priapism Ind. Psychiatr. J. 25 1 2016 119 121 10.4103/0972-6748.196044 \n18 Sinkeviciute I. Kroken R.A. Johnsen E. Priapism in antipsychotic drug use: a rare but important side effect Case Rep Psychiatry 2012 2012 496364 22934218 \n19 Hosseini S.H. Bajoghli H. Ghaeli P. Effects of cigarette smoking on priapism induced by quetiapine: a case report DARU.J PharmSci 20 2012 55 \n20 Giuliano F. Droupy S. La iatrogénie médicamenteuse en médecine sexuelle Prog. Urol. 23 9 2013 804 810 23830275\n\n",
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"abstract": "We present a 21-year-old woman diagnosed with Philadelphia (Ph) chromosome-like CD20 positive B-cell acute lymphoblastic leukaemia (ALL). She was a Jehovah's Witness (JW) and declined all blood product transfusion support. She was initiated on the CALGB 10403 chemotherapy protocol for her ALL. She received darbepoetin alfa and romiplostim as supportive therapies for her disease/chemotherapy-associated anaemia and thrombocytopaenia. A complete remission was achieved with negative minimal residual disease and she remains in remission 18 months after diagnosis. This case report describes the successful treatment of an adult JW with Ph-like CD20 +B cell ALL, in the absence of blood product transfusions, using growth factor support.",
"affiliations": "Department of Internal Medicine, University of Texas Southwestern, Dallas, Texas, USA.;Department of Internal Medicine, University of Texas Southwestern, Dallas, Texas, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern, Dallas, Texas, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern, Dallas, Texas, USA.",
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"abstract": "To compare the incidence of diabetic ketoacidosis (DKA) among patients with type 2 diabetes mellitus (T2DM) who were new users of sodium glucose co-transporter 2 inhibitors (SGLT2i) versus other classes of antihyperglycemic agents (AHAs).\n\n\n\nPatients were identified from four large US claims databases using broad (all T2DM patients) and narrow (intended to exclude patients with type 1 diabetes or secondary diabetes misclassified as T2DM) definitions of T2DM. New users of SGLT2i and seven groups of comparator AHAs were matched (1:1) on exposure propensity scores to adjust for imbalances in baseline covariates. Cox proportional hazards regression models, conditioned on propensity score-matched pairs, were used to estimate hazard ratios (HRs) of DKA for new users of SGLT2i versus other AHAs. When I2 <40%, a combined HR across the four databases was estimated.\n\n\n\nUsing the broad definition of T2DM, new users of SGLT2i had an increased risk of DKA versus sulfonylureas (HR [95% CI]: 1.53 [1.31-1.79]), DPP-4i (1.28 [1.11-1.47]), GLP-1 receptor agonists (1.34 [1.12-1.60]), metformin (1.31 [1.11-1.54]), and insulinotropic AHAs (1.38 [1.15-1.66]). Using the narrow definition of T2DM, new users of SGLT2i had an increased risk of DKA versus sulfonylureas (1.43 [1.01-2.01]). New users of SGLT2i had a lower risk of DKA versus insulin and a similar risk as thiazolidinediones, regardless of T2DM definition.\n\n\n\nIncreased risk of DKA was observed for new users of SGLT2i versus several non-SGLT2i AHAs when T2DM was defined broadly. When T2DM was defined narrowly to exclude possible misclassified patients, an increased risk of DKA with SGLT2i was observed compared with sulfonylureas.",
"affiliations": "Janssen Research & Development, LLC, Titusville, New Jersey.;Janssen Research & Development, LLC, Raritan, New Jersey.;Janssen Research & Development, LLC, Titusville, New Jersey.;Janssen Research & Development, LLC, Titusville, New Jersey.;Janssen Research & Development, LLC, Titusville, New Jersey.;Janssen Research & Development, LLC, Raritan, New Jersey.;Janssen Research & Development, LLC, Titusville, New Jersey.;Janssen Research & Development, LLC, Titusville, New Jersey.;Janssen Research & Development, LLC, Titusville, New Jersey.;Janssen Research & Development, LLC, Titusville, New Jersey.;Janssen Research & Development, LLC, Raritan, New Jersey.;Janssen Research & Development, LLC, Raritan, New Jersey.;Janssen Research & Development, LLC, Raritan, New Jersey.;Johnson & Johnson, Titusville, New Jersey.;Janssen Research & Development, LLC, Raritan, New Jersey.",
"authors": "Wang|Lu|L|0000-0001-7225-9407;Voss|Erica A|EA|;Weaver|James|J|;Hester|Laura|L|;Yuan|Zhong|Z|0000-0002-5824-2040;DeFalco|Frank|F|;Schuemie|Martijn J|MJ|;Ryan|Patrick B|PB|;Sun|Don|D|;Freedman|Amy|A|;Alba|Maria|M|;Lind|Joan|J|;Meininger|Gary|G|;Berlin|Jesse A|JA|;Rosenthal|Norman|N|",
"chemical_list": "D001786:Blood Glucose; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013453:Sulfonylurea Compounds; D008687:Metformin",
"country": "England",
"delete": false,
"doi": "10.1002/pds.4887",
"fulltext": "\n==== Front\nPharmacoepidemiol Drug SafPharmacoepidemiol Drug Saf10.1002/(ISSN)1099-1557PDSPharmacoepidemiology and Drug Safety1053-85691099-1557John Wiley and Sons Inc. Hoboken 10.1002/pds.4887PDS4887PDS-19-0129.R1Original ReportOriginal ReportsDiabetic ketoacidosis in patients with type 2 diabetes treated with sodium glucose co‐transporter 2 inhibitors versus other antihyperglycemic agents: An observational study of four US administrative claims databases Wang et al.Wang Lu https://orcid.org/0000-0001-7225-9407\n1\nlwang284@its.jnj.com Voss Erica A. \n2\nWeaver James \n1\nHester Laura \n1\nYuan Zhong https://orcid.org/0000-0002-5824-2040\n1\nDeFalco Frank \n2\nSchuemie Martijn J. \n1\nRyan Patrick B. \n1\nSun Don \n1\nFreedman Amy \n1\nAlba Maria \n2\nLind Joan \n2\nMeininger Gary \n2\nBerlin Jesse A. \n3\nRosenthal Norman \n2\n\n1 \nJanssen Research & Development, LLC\nTitusville\nNew Jersey\n\n2 \nJanssen Research & Development, LLC\nRaritan\nNew Jersey\n\n3 \nJohnson & Johnson\nTitusville\nNew Jersey\n* Correspondence\n\nLu Wang, Janssen Research & Development, LLC, 1125 Trenton‐Harbourton Road, Titusville, NJ 08560.\n\nEmail: lwang284@its.jnj.com\n27 8 2019 12 2019 28 12 10.1002/pds.v28.121620 1628 26 3 2019 01 7 2019 25 7 2019 © 2019 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nPurpose\nTo compare the incidence of diabetic ketoacidosis (DKA) among patients with type 2 diabetes mellitus (T2DM) who were new users of sodium glucose co‐transporter 2 inhibitors (SGLT2i) versus other classes of antihyperglycemic agents (AHAs).\n\nMethods\nPatients were identified from four large US claims databases using broad (all T2DM patients) and narrow (intended to exclude patients with type 1 diabetes or secondary diabetes misclassified as T2DM) definitions of T2DM. New users of SGLT2i and seven groups of comparator AHAs were matched (1:1) on exposure propensity scores to adjust for imbalances in baseline covariates. Cox proportional hazards regression models, conditioned on propensity score‐matched pairs, were used to estimate hazard ratios (HRs) of DKA for new users of SGLT2i versus other AHAs. When I2 <40%, a combined HR across the four databases was estimated.\n\nResults\nUsing the broad definition of T2DM, new users of SGLT2i had an increased risk of DKA versus sulfonylureas (HR [95% CI]: 1.53 [1.31‐1.79]), DPP‐4i (1.28 [1.11‐1.47]), GLP‐1 receptor agonists (1.34 [1.12‐1.60]), metformin (1.31 [1.11‐1.54]), and insulinotropic AHAs (1.38 [1.15‐1.66]). Using the narrow definition of T2DM, new users of SGLT2i had an increased risk of DKA versus sulfonylureas (1.43 [1.01‐2.01]). New users of SGLT2i had a lower risk of DKA versus insulin and a similar risk as thiazolidinediones, regardless of T2DM definition.\n\nConclusions\nIncreased risk of DKA was observed for new users of SGLT2i versus several non‐SGLT2i AHAs when T2DM was defined broadly. When T2DM was defined narrowly to exclude possible misclassified patients, an increased risk of DKA with SGLT2i was observed compared with sulfonylureas.\n\ndiabetic ketoacidosisSGLT2 inhibitortype 2 diabetesJanssen Research & Development, LLC 10.13039/100005205 source-schema-version-number2.0cover-dateDecember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.3 mode:remove_FC converted:17.12.2019\n\n\nWang \nL \n, \nVoss \nEA \n, \nWeaver \nJ \n, et al. Diabetic ketoacidosis in patients with type 2 diabetes treated with sodium glucose co‐transporter 2 inhibitors versus other antihyperglycemic agents: An observational study of four US administrative claims databases . Pharmacoepidemiol Drug Saf . 2019 ;28 :1620 –1628 . 10.1002/pds.4887 \n31456304 \n\n\n\nPrior presentations: These data were presented, in part, at the Scientific Sessions of the Quality of Care and Outcomes Research (QCOR), April 5 to 6, 2019; Arlington, Virginia. This study was supported by Janssen Research & Development, LLC.\n\nThe copyright line for this article was changed on 28 August 2019 after original online publication.\n==== Body\nKEY POINTS:\n\nIn this observational study, new use of SGLT2 inhibitors was associated with an increased risk of diabetic ketoacidosis (DKA) compared with new use of sulfonylureas, DPP‐4 inhibitors, GLP‐1 receptor agonists, metformin, and insulinotropic antihyperglycemic agents using a broad definition of type 2 diabetes mellitus (T2DM).\n\nWhen a more restrictive definition of T2DM was used to exclude possible misdiagnosed T1DM patients, an increased risk of DKA was observed in new users of SGLT2 inhibitors when compared with new users of sulfonylureas.\n\nUsing both definitions of T2DM, new use of SGLT2 inhibitors was associated with a reduced risk of DKA compared with new use of insulin.\n\n\n\n\n1 INTRODUCTION\nDiabetic ketoacidosis (DKA) is a serious acute metabolic complication of diabetes, characterized by hyperglycemia, ketosis, and metabolic acidosis.1 The underlying pathophysiology of DKA is an absolute or relative insulin deficiency, increased insulin counter‐regulatory hormones, and peripheral insulin resistance.1 DKA is often precipitated by stressful conditions such as trauma, surgery, or infection and is more common in patients with type 1 diabetes mellitus (T1DM) than in patients with type 2 diabetes mellitus (T2DM).2, 3 The incidence of DKA among patients with T1DM ranged from 8 to 56 per 1000 patient‐years in larger studies in the United States, Canada, Europe, and Israel.4 In comparison, a much lower DKA incidence of <2 per 1000 patient‐years was reported in cohort studies of adults with T2DM in clinical practice.5, 6, 7\n\n\nSodium glucose co‐transporter 2 (SGLT2) inhibitors are oral antihyperglycemic agents (AHAs) that lower blood glucose by increasing urinary glucose excretion.8 Currently, four SGLT2 inhibitors are approved in the United States and Europe for the treatment of T2DM: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin.9, 10, 11, 12, 13, 14, 15, 16 In 2015, the US Food and Drug Administration (FDA) issued a Drug Safety Communication about the risk of ketoacidosis with SGLT2 inhibitors based on postmarketing adverse event reporting, and a warning was subsequently added to the label of all SGLT2 inhibitors.17 In 2016, on the recommendation of the Pharmacovigilance Risk Assessment Committee (PRAC), the European Medicines Agency (EMA) listed DKA as a rare adverse reaction in the product information of SGLT2 inhibitors and implemented risk management measures to minimize this risk.18 Of note, patients taking SGLT2 inhibitors may present with atypical DKA (no marked hyperglycemia) because of SGLT2 inhibitors' glycosuria effect, which can delay diagnosis and treatment.18\n\n\nMost clinical development programs of SGLT2 inhibitors, including canagliflozin, dapagliflozin, empagliflozin, as well as meta‐analyses of randomized controlled trials, have reported a low frequency of DKA events in patients with T2DM, with a numerically higher rate for SGLT2 inhibitors as a class or individual agent relative to placebo and active controls.19, 20, 21, 22, 23, 24, 25, 26 Real‐world studies of DKA among new users of SGLT2 inhibitors are limited, particularly in patients with T2DM. An increased risk of DKA with SGLT2 inhibitor treatment was observed in some, but not all, studies.6, 7, 27, 28 Limitations of prior studies include small sample size and number of events, specific patient population, and select treatment comparators.\n\nThe current study sought to estimate the incidence rate and further evaluate the comparative risk of DKA among patients with T2DM in routine clinical practice who were new users of SGLT2 inhibitors versus new users of other classes of AHAs using data from four large US claims databases.\n\n2 METHODS\n2.1 Study design\nThis was a retrospective, observational, comparative cohort study. The study protocol has been reviewed and approved by the EMA PRAC as a postauthorization safety study (PASS) and is available at https://github.com/OHDSI/StudyProtocols/tree/master/Sglt2iDka/documents.\n\n2.2 Data source\nEligible patients were identified from four large US administrative claims databases (IBM® MarketScan® Commercial Database [CCAE], IBM® MarketScan® Multi‐State Medicaid Database [MDCD], IBM® MarketScan® Medicare Supplemental Database [MDCR], and Optum© De‐identified Clinformatics® Data Mart Database [Optum]; see Supplemental Description of Data Sources for additional details). Data from health insurance claims were used to characterize patient demographics and identify all drug exposure, medical conditions, and procedures that occurred during the enrollment period. The study period started on 1 April 2013, which coincides with the approval of the first SGLT2 inhibitor in the United States (canagliflozin was approved 29 March 2013), in all databases and ended on the last date of data availability for each database (CCAE: 31 October 2017; MDCD: 31 December 2016; MDCR: 31 December 2017; Optum: 30 September 2017).\n\nTo enable consistent analyses across multiple data sources, all four databases were converted to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) 5.0. The OMOP CDM accommodates different data domains typically found within observational data and transforms data from diverse databases into a common data format with a standardized vocabulary for coding of health care information (such as drug utilization and condition occurrence),29 which then allows performance of analyses across multiple, disparate databases in a consistent manner.\n\n2.3 New‐user cohort categorization\nEligible patients were required to have ≥1 diagnosis of T2DM on or before the AHA exposure index date, ≥1 prescription dispensing record for a new pre‐specified SGLT2 inhibitor or non‐SGLT2 inhibitor AHA (ie, no prior use of the respective AHA ever recorded in the database), and ≥365 days of continuous enrollment prior to the first dispensing record of the new AHA.\n\nSGLT2 inhibitors were evaluated as a class and as individual agents (canagliflozin, dapagliflozin, and empagliflozin). Seven classes of non‐SGLT2 inhibitor AHAs were prespecified as primary comparators (sulfonylureas [SU], dipeptidyl peptidase‐4 [DPP‐4] inhibitors, glucagon‐like peptide‐1 [GLP‐1] receptor agonists, thiazolidinediones [TZD], insulin, metformin, and insulinotropic AHAs [including DPP‐4 inhibitors, GLP‐1 receptor agonists, SU, nateglinide, and repaglinide]). Since the category of insulinotropic AHAs includes several AHAs that were also evaluated separately, the results are presented mainly in the Supplemental Materials. A category of “other AHAs” (acarbose, miglitol, nateglinide, and repaglinide) was included as a secondary comparator to capture less common AHAs. Patients were categorized into a new‐user cohort at the first prescription claim recorded in the database. For those who met the new user definition for >1 AHA, patients were categorized into a new‐user cohort on the date of the first prescription of each AHA, with a different index date and different baseline characteristics for each respective AHA.\n\nPatients with T2DM were defined by broad and narrow definitions. The broad definition required that patients had ≥1 diagnosis of T2DM and no diagnosis of T1DM or secondary diabetes mellitus (DM) on or before the AHA exposure index date. The narrow definition of T2DM additionally required that patients had no diagnosis of T1DM or secondary DM after the exposure index date, had no insulin monotherapy before the index date, and were aged ≥40 years on the index date; this definition was intended to exclude patients with T1DM or secondary DM who may have been misdiagnosed with T2DM.\n\n2.4 Outcomes\nThe primary outcome of this study was the first DKA event that occurred after the index date of an AHA therapy, identified from a diagnosis code recorded in inpatient or emergency room claims. To be considered an incident event, DKA occurring after exposure to a new AHA had to occur ≥30 days after any pre‐index DKA event. Fatal DKA was defined as death at discharge from the hospitalized DKA event, whereas this information could not be assessed in the Optum database. As laboratory tests were not systematically collected in the databases used for this study, DKA cases could not be validated using lab tests or categorized as typical or atypical DKA.\n\n2.5 Statistical analyses\nAnalyses were performed in SQL and R.30\n\n\n2.6 Descriptive analyses\nThe unadjusted incidence rates of DKA were expressed as number of incident events per 1000 patient‐years and were also stratified by subgroups of age, sex, history of DKA, and history of insulin use. Distribution of the DKA risk factors and prespecified preceding events were characterized in each cohort. The mean and standard deviation (SD) are presented for continuous variables, and frequencies/proportions are presented for categorical variables. For the primary cohort follow‐up, time‐at‐risk started on the day after the first AHA exposure (index date) and ended at the first incident DKA diagnosis, disenrollment, or the end of the database coverage, whichever came first. Change of AHA treatment during follow‐up was considered in the sensitivity analyses described below.\n\n2.7 Comparative analyses\nEach new user of an SGLT2 inhibitor (class and individual agents) was matched 1:1 to a new user of a comparator AHA based on the exposure propensity score (PS). Large‐scale PS were estimated using regularized logistic regression models including all baseline covariates available from 365 days prior to the exposure index date (ie, demographics, history of all diagnoses and conditions, procedures, observations, medications, frequency of health care encounters, Charlson Comorbidity Score, and Diabetes Complication Severity Index) as candidate predictors.31 The model used a cyclic coordinate descending method with least absolute shrinkage and selection operator (LASSO), and the regularization hyperparameter was selected by optimizing the likelihood in a 10‐fold cross validation.32, 33 Conventional greedy algorithms with nearest neighbor that minimize the absolute difference between the PS were used for matching.34 The maximum matching caliper was 20% of the SD of the logit of the PS.35\n\n\nEvaluations of the history of DKA and prior AHA therapies considered all available claims records prior to the exposure index date. Conditional Cox proportional hazards models were used to estimate the hazard ratio (HR) of DKA in the SGLT2 inhibitor cohort versus the comparator cohort, with each PS‐matched set treated as a separate stratum in the model. For each comparison, the P value was calibrated against an empirical null distribution estimated using 43 negative control outcomes to address potential systematic bias (Supplemental Table\n\n1\n).36 HRs were estimated in each database separately. When the I2 was <40%, a pooled HR across the four databases was generated using a random effects approach,37 in which the standard errors of the database‐specific estimates were adjusted to incorporate variation of effects across databases, the across‐database variance was estimated by comparing the result of each database with the result of an inverse‐variance fixed‐effects meta‐analysis.\n\n2.8 Sensitivity analyses\nFirst, a modified DKA definition was used where cases were identified by inpatient claims only. Second, change of AHA treatment was considered for cohort follow‐up, in which censoring was applied to the time‐at‐risk at the initiation of non‐index AHAs as well as at the discontinuation of the index AHA (defined as refill gap of ≥90 days from the day the index AHA supply from the previous prescription was expected to run out).\n\n3 RESULTS\nAll results have been made publicly available through an interactive web‐based application at http://data.ohdsi.org/Sglt2iDka/. This section summarizes the key findings across these results.\n\n3.1 Study population\nOf the four claims databases, CCAE provided the largest sample size for all AHA new‐user cohorts, and MDCD provided the smallest sample size for most cohorts (Supplemental Table\n\n2\n). Canagliflozin had the largest number of new‐users in the SGLT2 inhibitor class. Using the broad definition of T2DM, the number of new users ranged from 11 141 in MDCD to 152 728 in CCAE for SGLT2 inhibitors, and from 5687 TZD users in MDCR to 329 839 metformin users in CCAE for comparator AHAs. The corresponding numbers were fewer when using the narrow definition of T2DM, ranging from 7779 users in MDCD to 130 708 users in CCAE for SGLT2 inhibitors and from 3982 TZD users in MDCD to 271 723 metformin users in CCAE for comparator AHAs. Across databases, the mean age of all new‐user cohorts ranged from 47.9 to 75.5 years and the percentage of female patients ranged from 41.0% to 72.1%.\n\n3.2 Incidence of DKA\nUsing the broad definition of T2DM, the unadjusted incidence rates of DKA ranged from 2.75 to 8.84 per 1000 patient‐years among new users of all SGLT2 inhibitors and from 1.38 to 15.82 per 1000 patient‐years among new users of comparator AHAs (Table\n1 and Supplemental Table\n\n3\n). The corresponding incidence rates using the narrow definition of T2DM ranged from 1.15 to 3.91 per 1000 patient‐years in the all SGLT2 inhibitor cohorts and from 0.75 to 7.94 per 1000 patient‐years in the comparator cohorts. In general, the incidence rates were highest in MDCD, followed by Optum, and lowest in CCAE and MDCR.\n\nTable 1 Unadjusted incidence rate of DKA in prespecified AHA new‐user cohorts\n\n\tDatabase\tBroad T2DM Definition\tNarrow T2DM Definition\t\nN of Events\tTime‐at‐Risk (PY)\tIncidence Rate (per 1000 PY)\tN of Events\tTime‐at‐Risk (PY)\tIncidence Rate (per 1000 PY)\t\nSGLT2 inhibitor\tCCAE\t638\t227 079\t2.81\t218\t189 129\t1.15\t\nMDCD\t107\t12 106\t8.84\t32\t8180\t3.91\t\nMDCR\t74\t26 944\t2.75\t37\t22 187\t1.67\t\nOptum\t324\t98 642\t3.28\t131\t82 051\t1.60\t\nCanagliflozin\tCCAE\t423\t140 041\t3.02\t144\t115 704\t1.24\t\nMDCD\t98\t10 351\t9.47\t29\t6995\t4.15\t\nMDCR\t53\t20 688\t2.56\t25\t16 879\t1.48\t\nOptum\t240\t72 659\t3.30\t97\t60 110\t1.61\t\nDapagliflozin\tCCAE\t168\t72 030\t2.33\t58\t60 923\t0.95\t\nMDCD\t10\t1525\t6.56\t2\t1019\t1.96\t\nMDCR\t18\t4632\t3.89\t9\t3864\t2.33\t\nOptum\t57\t16 815\t3.39\t19\t13 955\t1.36\t\nEmpagliflozin\tCCAE\t123\t44 572\t2.76\t48\t38 471\t1.25\t\nMDCD\t5\t625\t8.01\t1\t441\t2.27\t\nMDCR\t9\t3380\t2.66\t5\t2991\t1.67\t\nOptum\t49\t16 319\t3.00\t25\t14 246\t1.75\t\nSU\tCCAE\t542\t231 396\t2.34\t193\t190 197\t1.01\t\nMDCD\t299\t40 760\t7.34\t102\t26 348\t3.87\t\nMDCR\t108\t59 518\t1.81\t56\t50 826\t1.10\t\nOptum\t470\t180 646\t2.60\t225\t151 094\t1.49\t\nDPP‐4 inhibitor\tCCAE\t468\t214 243\t2.18\t171\t178 003\t0.96\t\nMDCD\t209\t28 941\t7.22\t76\t19 578\t3.88\t\nMDCR\t121\t60 529\t2.00\t57\t50 533\t1.13\t\nOptum\t425\t151 705\t2.80\t180\t125 001\t1.44\t\nGLP‐1 receptor agonist\tCCAE\t300\t133 250\t2.25\t111\t105 848\t1.05\t\nMDCD\t126\t13 558\t9.29\t45\t8019\t5.61\t\nMDCR\t31\t17 271\t1.79\t12\t13 375\t0.90\t\nOptum\t196\t67 369\t2.91\t73\t53 047\t1.38\t\nTZD\tCCAE\t138\t51 441\t2.68\t53\t43 015\t1.23\t\nMDCD\t63\t7287\t8.65\t24\t4892\t4.91\t\nMDCR\t29\t11 871\t2.44\t16\t10 168\t1.57\t\nOptum\t137\t48 123\t2.85\t58\t40 731\t1.42\t\nInsulin\tCCAE\t857\t166 653\t5.14\t255\t118 292\t2.16\t\nMDCD\t741\t46 830\t15.82\t212\t26 693\t7.94\t\nMDCR\t205\t53 219\t3.85\t98\t35 975\t2.72\t\nOptum\t739\t133 720\t5.53\t328\t97 800\t3.35\t\nMetformin\tCCAE\t1069\t497 877\t2.15\t327\t404 839\t0.81\t\nMDCD\t627\t81 106\t7.73\t143\t49 317\t2.90\t\nMDCR\t144\t104 142\t1.38\t68\t90 540\t0.75\t\nOptum\t713\t353 587\t2.02\t273\t294 680\t0.93\t\nOther AHAsa\n\tCCAE\t25\t14 156\t1.77\t12\t11 313\t1.06\t\nMDCD\t12\t1335\t8.99\t3\t843\t3.56\t\nMDCR\t25\t7160\t3.49\t12\t5471\t2.19\t\nOptum\t52\t14 162\t3.67\t20\t11 270\t1.77\t\nAbbreviations: AHA, antihyperglycemic agent; CCAE, IBM® MarketScan® Commercial Database; DKA, diabetic ketoacidosis; DPP‐4, dipeptidyl peptidase‐4; GLP‐1, glucagon‐like peptide‐1; MDCD, IBM® MarketScan® Multi‐State Medicaid Database; MDCR, IBM® MarketScan® Medicare Supplemental Database; Optum, Optum© De‐identified Clinformatics® Data Mart Database; PY, patient‐years; SGLT2, sodium glucose co‐transporter 2; SU, sulfonylurea; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione.\n\na Includes acarbose, miglitol, nateglinide, and repaglinide.\n\nOverall, the proportion of fatal DKA events was low, although it varied across databases and AHA cohorts (Supplemental Table\n\n4\n). In general, the case fatality is higher in MDCR and MDCD than in CCAE. Among new users of SGLT2 inhibitors, the highest fatality was observed in MDCD (1.9% and 3.1% using the broad and narrow definitions of T2DM, respectively). Among new users of comparator AHAs, the highest fatality was observed in MDCR (6.3% and 8.9% using the broad and narrow definitions of T2DM, respectively).\n\n3.3 Risk factors and preceding events\nThe unadjusted incidence rates of DKA were higher in patients with prior use of insulin and history of DKA (data not shown). A higher proportion of new users of SGLT2 inhibitors who had incident DKA events received a prescription for insulin prior to the index date compared with new users of comparator AHAs who had incident DKA events, except for GLP‐1 receptor agonists (Supplemental Table\n\n5\n). Other risk factors for DKA and events that occurred prior to DKA (eg, hospitalization, surgery, and infections) were similarly distributed across the AHA new‐user cohorts.\n\n3.4 Risk of DKA in the PS‐matched cohorts\nBaseline characteristics prior to the AHA exposure index date, including demographics, comorbidities, and medications, were well balanced after PS matching for all matched cohorts (data not shown).\n\nUsing the broad definition of T2DM, a significantly increased risk of DKA was observed in new users of SGLT2 inhibitors compared with SU, DPP‐4 inhibitors, GLP‐1 receptor agonists, metformin, and insulinotropic AHAs in select individual databases and the meta‐analysis (Figure 1 and Supplemental Figure\n\n1\n\nA). Meta‐analytic estimates of the HR (95% confidence interval [CI]) for DKA with SGLT2 inhibitors were 1.53 (1.31‐1.79) versus SU, 1.28 (1.11‐1.47) versus DPP‐4 inhibitors, 1.34 (1.12‐1.60) versus GLP‐1 receptor agonists, and 1.31 (1.11‐1.54) versus metformin.\n\nFigure 1 Hazard ratio of DKA for new users of SGLT2 inhibitors versus comparator AHAs.\n\nAbbreviations: AHA, antihyperglycemic agent; CCAE, IBM® MarketScan® Commercial Database; CI, confidence interval; DKA, diabetic ketoacidosis; DPP‐4, dipeptidyl peptidase‐4; GLP‐1, glucagon‐like peptide‐1; HR, hazard ratio; MDCD, IBM® MarketScan® Multi‐State Medicaid Database; MDCR, IBM® MarketScan® Medicare Supplemental Database; Optum, Optum© De‐identified Clinformatics® Data Mart Database; SGLT2, sodium glucose co‐transporter 2; SU, sulfonylurea; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione\n\nWhen using the narrow definition of T2DM to exclude patients with T1DM or secondary DM who may have been misclassified as T2DM, the risk of DKA was not significantly increased among new users of SGLT2 inhibitors compared with DPP‐4 inhibitors, GLP‐1 receptor agonists, or metformin in individual databases or the meta‐analysis. However, new users of SGLT2 inhibitors had an increased risk of DKA compared with SU in the meta‐analysis (HR [95% CI]: 1.43 [1.01‐2.01]). In all comparative analyses using the narrow T2DM definition, the associations observed in MDCD were less consistent compared with the other databases, which may reflect fewer events observed and/or unique patient characteristics captured by the database (eg, patients with a disability or low socioeconomic status).\n\nIn the meta‐analysis, with both the broad and narrow definitions of T2DM, new users of SGLT2 inhibitors had a significantly lower risk of DKA compared with insulin. Across the four databases and with both definitions of T2DM, the risk of DKA was similar for new users of SGLT2 inhibitors and TZD.\n\nThe risk of DKA for new users of individual SGLT2 inhibitor agents versus comparator AHAs was generally similar to that for the SGLT2 inhibitor class but with greater variation in HRs across databases (Supplemental Figures\n\n2‐4\n).\n\n3.5 Sensitivity analyses\nIn sensitivity analyses identifying DKA events from inpatient diagnoses only (Supplemental Table\n\n6\n) and censoring time‐at‐risk at the regimen change (Figure 2 and Supplemental Figure\n\n1\n\nB), the HRs of DKA for new users of SGLT2 inhibitors versus comparator AHAs were generally consistent with the main analyses, although with fewer cases and less precision.\n\nFigure 2 Hazard ratio of DKA for new users of SGLT2 inhibitors versus comparator AHAs with censoring at the initiation of non‐index AHAs and discontinuation of the index AHA.\n\nAbbreviations: AHA, antihyperglycemic agent; CCAE, IBM® MarketScan® Commercial Database; CI, confidence interval; DKA, diabetic ketoacidosis; DPP‐4, dipeptidyl peptidase‐4; GLP‐1, glucagon‐like peptide‐1; HR, hazard ratio; MDCD, IBM® MarketScan® Multi‐State Medicaid Database; MDCR, IBM® MarketScan® Medicare Supplemental Database; Optum, Optum© De‐identified Clinformatics® Data Mart Database; SGLT2, sodium glucose co‐transporter 2; SU, sulfonylurea; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione.\n\n\n*Either no cases in the target and/or comparator cohort or number of cases were too few for the model to converge\n\n4 DISCUSSION\nThis observational, retrospective cohort study compared the risk of DKA among new users of SGLT2 inhibitors and other classes of AHAs in four US administrative claims databases. Using the broad definition of T2DM, a moderate, but statistically significant, increased risk of DKA was observed among new users of SGLT2 inhibitors compared with SU, DPP‐4 inhibitors, GLP‐1 receptor agonists, and metformin in the meta‐analysis combining four databases. Using the narrow definition of T2DM to remove younger patients and those with prior insulin monotherapy, the risk of DKA remained significantly increased among new users of SGLT2 inhibitors when compared with SU in the meta‐analysis. A trend for a higher risk of DKA for new users of SGLT2 inhibitors compared with insulinotropic AHAs (including SU, DPP‐4 inhibitors, and GLP‐1 receptor agonists) was observed in three of four databases; this trend appears to be largely driven by SU. Using both definitions of T2DM, the risk of DKA with SGLT2 inhibitors was lower compared with insulin and not significantly different compared with TZD. The association with the risk of DKA appeared generally similar for individual SGLT2 inhibitor agents; however, for the individual agent comparisons, there was more variability in HRs and 95% CIs, and the results were largely inconsistent across databases.\n\nThe different associations using the broad versus the narrow T2DM definitions suggest that the observation of an increased risk of DKA in new users of SGLT2 inhibitors might be attributed in part to use of SGLT2 inhibitors in patients who were misdiagnosed as having T2DM, such as those with T1DM or latent autoimmune diabetes. Clinical development programs of SGLT2 inhibitors and clinical observations have identified cases of DKA in patients who were diagnosed with T2DM, but presented with biochemical evidence for autoimmune diabetes.19, 38, 39, 40 In our study, the narrow definition for T2DM aimed to remove potential late‐onset autoimmune diabetes, even at the expense of excluding some true T2DM patients. However, because our definition of T2DM was based on algorithms of diagnosis codes and prescription claims, we cannot completely rule out all potential misdiagnoses.\n\nThe unadjusted incidence rates of DKA were several‐fold higher in patients with prior use of insulin and those with a history of DKA. A greater proportion of new users of SGLT2 inhibitors who had incident DKA events already had an insulin prescription before the index date compared with new users of comparator AHAs who had incident DKA events, except for GLP‐1 receptor agonists. This observation suggests that new users of SGLT2 inhibitors who subsequently developed DKA likely had more advanced diabetes with both insulin resistance and insulin deficiency at index. In our comparative analyses, the risk of DKA among new users of SGLT2 inhibitors was increased compared with new users of one AHA class that stimulates insulin release from β‐cells, but decreased compared with the new users of insulin. Together, these findings support the hypothesis that in SGLT2 inhibitor users, diminished β‐cell function could fail to suppress hepatic ketogenesis and peripheral lipolysis, subsequently leading to DKA development, particularly in the presence of acute conditions that increase insulin demand (eg, infection, surgery).\n\nReal‐world evidence on the occurrence of DKA among patients treated with SGLT2 inhibitors remains largely in case studies and adverse event reports with limited comparative analyses. One study that used the Danish National Patient Registry found no increase in the incidence of DKA with SGLT2 inhibitors when used as monotherapy or combination therapy compared with no pharmacological therapy.6 Two retrospective cohort studies using population‐based claims databases to compare the risk of DKA with SGLT2 inhibitors and DPP‐4 inhibitors found an increased risk of DKA (HR [95% CI]: 2.2 [1.4‐3.6]) among new users of SGLT2 inhibitors in the United States,28 but not in South Korea.7 Another previous study using the CCAE claims database, which was also used in the current study, compared the incidence of DKA among over 30 000 new users of canagliflozin versus new users of non‐SGLT2 inhibitor AHAs who were 1:1 matched on PS, and showed that the HR (95% CI) of DKA were 1.91 (0.94‐4.11) and 1.13 (0.43‐3.00) using the broad and narrow definitions of T2DM, respectively.27\n\n\nThe current study strengthens the real‐world evidence by its use of four large claims databases, which are likely representative of routine clinical practice for US patients with insurance coverage, and comprehensive analyses comparing SGLT2 inhibitors as a class, as well as by individual agent, with multiple comparators. Nevertheless, this study is subject to the limitations of all claims database research. First, as claims data are collected for administrative purposes, no standardized methodology was implemented in the source record to validate exposures, outcomes, or baseline covariates. In particular, due to limited availability and likely biased collection of laboratory data, DKA cases identified from claims diagnoses could not be verified using lab test results, nor categorized into typical or atypical DKA. Thus, it is possible that closer scrutiny of DKA by clinicians concerned about this risk in patients taking SGLT2 inhibitors could lead to observation of more clinical diagnoses of DKA in SGLT2 inhibitor users. Second, bias due to missing data and unmeasured confounding is possible, although the use of negative control outcomes suggested little to no systematic error. Finally, sample sizes for several pairwise comparisons were relatively small; thus, the HR estimates should be interpreted with caution.\n\nIn this claims database study, an increased risk of DKA was observed for new users of SGLT2 inhibitors compared with new users of other classes of AHAs when T2DM was defined broadly. When T2DM was defined narrowly to exclude possible misdiagnosed patients, an increased risk of DKA with SGLT2 inhibitors was observed compared with SU.\n\nSupporting information\n\nSupplemental Table 1. Negative control outcomes\n\n\nSupplemental Table 2. Baseline demographics in pre‐specified AHA new‐user cohorts\n\n\nSupplemental Table 3. Unadjusted incidence rate of DKA in new users of insulinotropic AHAs†\n\n\nSupplemental Table 4. Proportion of fatal DKA events across databases†\n\n\nSupplemental Table 5. Selected risk factors and preceding events among patients who developed DKA after index\n\n\nSupplemental Table 6. Hazard ratio of DKA identified from diagnoses in inpatient claims only for new users of SGLT2 inhibitors versus comparator AHAs\n\n\nSupplemental Figure 1. Hazard ratio of DKA for new users of SGLT2 inhibitors versus insulinotropic AHAs† (A) over the entire observation period and (B) with censoring at the initiation of nonindex AHAs and discontinuation of the index AHA.\n\n\nSupplemental Figure 2. Hazard ratio of DKA for new users of canagliflozin versus comparator AHAs.\n\n\nSupplemental Figure 3. Hazard ratio of DKA for new users of dapagliflozin versus comparator AHAs.\n\n\nSupplemental Figure 4. Hazard ratio of DKA for new users of empagliflozin versus comparator AHAs.\n\nClick here for additional data file.\n\n ACKNOWLEDGEMENTS\nThis study was supported by Janssen Research & Development, LLC. Medical writing support was provided by Dana Tabor, PhD, of MedErgy, and was funded by Janssen Global Services, LLC.\n\nCanagliflozin has been developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation.\n==== Refs\nREFERENCES\n1 \n\nGosmanov \nAR \n, \nGosmanova \nEO \n, \nDillard‐Cannon \nE \n. Management of adult diabetic ketoacidosis . Diabetes Metab Syndr Obes . 2014 ;7 :255 ‐264 .25061324 \n2 \n\nKitabchi \nAE \n, \nUmpierrez \nGE \n, \nMiles \nJM \n, \nFisher \nJN \n. Hyperglycemic crises in adult patients with diabetes . Diabetes Care . 2009 ;32 (7 ):1335 ‐1343 .19564476 \n3 \nInternational Diabetes Federation \n. IDF Diabetes Atlas . 8th ed. \nBrussels, Belgium : International Diabetes Federation ; 2017 .\n4 \n\nFazeli Farsani \nS \n, \nBrodovicz \nK \n, \nSoleymanlou \nN \n, \nMarquard \nJ \n, \nWissinger \nE \n, \nMaiese \nBA \n. 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Diabetes Obes Metab . 2018 ;20 (8 ):1852 ‐1858 .29569427 \n8 \n\nLam \nKS \n, \nChow \nCC \n, \nTan \nKC \n, et al. Practical considerations for the use of sodium‐glucose co‐transporter type 2 inhibitors in treating hyperglycemia in type 2 diabetes . Curr Med Res Opin . 2016 ;32 (6 ):1097 ‐1108 .26933918 \n9 \nINVOKANA® (canagliflozin) tablets, for oral use [package insert] . Titusville, NJ : Janssen Pharmaceuticals ; 2018 .\n10 \nInvokana (canagliflozin hemihydrate) [package insert] . Italy : Janssen‐Cilag SpA ; n.d.\n11 FARXIGA® (dapagliflozin) [package insert]. Wilmington, DE AstraZeneca Pharmaceuticals; October 2017 .\n12 \nForxiga (dapagliflozin) [package insert] . Germany : AstraZeneca GmbH ; n.d.\n13 JARDIANCE® (empagliflozin) [package insert]. Ridgefield, CT; Boehringer Ingelheim Pharmaceuticals; December 2017 .\n14 \nJardiance (empagliflozin) [package insert] . Germany : Boehringer Ingelheim Pharma GmbH & Co. KG ; n.d.\n15 \nSTEGLATRO™ (ertugliflozin) [package insert] . Whitehouse Station, NJ : Merck Sharp & Dohme Corp ; December 2017 .\n16 \nSteglatro (ertugliflozin) [packet insert] . Belgium : Schering‐Plough Labo NV ; n.d.\n17 \nFood and Drug Administration \n. FDA drug safety communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood . Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM446954.pdf. Accessed March 22, 2018 .\n18 \nEuropean Medicines Agency \n. EMA confirms recommendations to minimise ketoacidosis risk with SGLT2 inhibitors for diabetes. Healthcare professionals should be aware of possible atypical cases . Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/SGLT2_inhibitors__20/European_Commission_final_decision/WC500202393.pdf. Accessed June 19, 2017 .\n19 \n\nErondu \nN \n, \nDesai \nM \n, \nWays \nK \n, \nMeininger \nG \n. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program . 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J Royal Statistical Soc, Series B (Methodological) . 1996 ;58 (1 ):267 ‐228 .\n33 \n\nSuchard \nMA \n, \nSimpson \nSE \n, \nZorych \nI \n, \nRyan \nP \n, \nMadigan \nD \n. Massive parallelization of serial inference algorithms for a complex generalized linear model . ACM Trans Model Comput Simul . 2013 ;23 (1 ):1 ‐17 .\n34 \n\nRassen \nJA \n, \nShelat \nAA \n, \nMyers \nJ \n, \nGlynn \nRJ \n, \nRothman \nKJ \n, \nSchneeweiss \nS \n. One‐to‐many propensity score matching in cohort studies . Pharmacoepidemiol Drug Saf . 2012 ;21 (Suppl 2 ):69 ‐80 .22552982 \n35 \n\nAustin \nPC \n. Optimal caliper widths for propensity‐score matching when estimating differences in means and differences in proportions in observational studies . Pharm Stat . 2011 ;10 (2 ):150 ‐161 .20925139 \n36 \n\nSchuemie \nMJ \n, \nRyan \nPB \n, \nDuMouchel \nW \n, \nSuchard \nMA \n, \nMadigan \nD \n. Interpreting observational studies: why empirical calibration is needed to correct p‐values . Stat Med . 2014 ;33 (2 ):209 ‐218 .23900808 \n37 \n\nDerSimonian \nR \n, \nLaird \nN \n. Meta‐analysis in clinical trials . Control Clin Trials . 1986 ;7 (3 ):177 ‐188 .3802833 \n38 \n\nHine \nJ \n, \nPaterson \nH \n, \nAbrol \nE \n, \nRussell‐Jones \nD \n, \nHerring \nR \n. SGLT inhibition and euglycaemic diabetic ketoacidosis . Lancet Diabetes Endocrinol . 2015 ;3 (7 ):503 ‐504 .\n39 \n\nAhmed \nM \n, \nMcKenna \nMJ \n, \nCrowley \nRK \n. Diabetic ketoacidosis in patients with type 2 diabetes recently commenced on Sglt‐2 inhibitors: an ongoing concern . Endocr Pract . 2017 ;23 (4 ):506 ‐508 .28437153 \n40 \n\nBell \nDSH \n. Re: diabetic ketoacidosis in patients with type 2 diabetes on Sglt‐2 inhibitors: an ongoing concern . Endocr Pract . 2018 ;24 (1 ):126 .29368970\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1053-8569",
"issue": "28(12)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": "SGLT2 inhibitor; diabetic ketoacidosis; type 2 diabetes",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D000067575:Administrative Claims, Healthcare; D000368:Aged; D001786:Blood Glucose; D016208:Databases, Factual; D003924:Diabetes Mellitus, Type 2; D016883:Diabetic Ketoacidosis; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D015994:Incidence; D007328:Insulin; D008297:Male; D008687:Metformin; D008875:Middle Aged; D012307:Risk Factors; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013453:Sulfonylurea Compounds; D014481:United States",
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"pages": "1620-1628",
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"pubdate": "2019-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "28437153;30415602;29368970;25670757;28591538;28950419;28448895;28605608;18644074;28765134;28283564;31456304;29569427;22552982;25061324;19564476;28631216;20925139;3802833;26203064;26378978;23900808;27311492;26933918;25328363;26025388;28570924",
"title": "Diabetic ketoacidosis in patients with type 2 diabetes treated with sodium glucose co-transporter 2 inhibitors versus other antihyperglycemic agents: An observational study of four US administrative claims databases.",
"title_normalized": "diabetic ketoacidosis in patients with type 2 diabetes treated with sodium glucose co transporter 2 inhibitors versus other antihyperglycemic agents an observational study of four us administrative claims databases"
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"abstract": "Patients with malignancy are often profoundly immunocompromised due to chemotherapy, placing them at potential increased risk for periprosthetic joint infection (PJI). However, there is little information regarding PJI management in these patients. We describe 4 patients with a history of primary total knee arthroplasty followed by diagnosis of multiple myeloma or Waldenström macroglobulinemia who received chemotherapy within 4 months prior to PJI. The Musculoskeletal Infection Society major and minor criteria and either debridement, antibiotics, and implant retention or a 2-stage approach appear to be effective for acute or chronic PJI, respectively. We recommend an anticoagulant be administered concomitantly with antineoplastics that significantly increase deep vein thrombosis risk, and we recommend long-term oral suppressive antibiotics postoperatively, especially if chemotherapy will be resumed. Additional studies are needed to investigate risks and benefits of PJI prophylaxis during chemotherapy and long-term suppressive antibiotics after PJI treatment.",
"affiliations": "College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA.",
"authors": "Bloom|G Barnes|GB|;Mears|Simon C|SC|;Edwards|Paul K|PK|;Barnes|C Lowry|CL|;Stambough|Jeffrey B|JB|",
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"doi": "10.1016/j.artd.2020.04.002",
"fulltext": "\n==== Front\nArthroplast Today\nArthroplast Today\nArthroplasty Today\n2352-3441 Elsevier \n\nS2352-3441(20)30066-2\n10.1016/j.artd.2020.04.002\nCase Report\nTotal Knee Periprosthetic Joint Infection in the Setting of Hematologic Malignancy: Considerations for Management\nBloom G. Barnes BSCEa Mears Simon C. MD, PhDb Edwards Paul K. MDb Barnes C. Lowry MDb Stambough Jeffrey B. MDJStambough@uams.edub∗ a College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA\nb Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA\n∗ Corresponding author. Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 531, Little Rock, AR 72205, USA. Tel.: +1 501 256 8600. JStambough@uams.edu\n02 6 2020 \n9 2020 \n02 6 2020 \n6 3 309 315\n19 2 2020 31 3 2020 2 4 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/).Patients with malignancy are often profoundly immunocompromised due to chemotherapy, placing them at potential increased risk for periprosthetic joint infection (PJI). However, there is little information regarding PJI management in these patients. We describe 4 patients with a history of primary total knee arthroplasty followed by diagnosis of multiple myeloma or Waldenström macroglobulinemia who received chemotherapy within 4 months prior to PJI. The Musculoskeletal Infection Society major and minor criteria and either debridement, antibiotics, and implant retention or a 2-stage approach appear to be effective for acute or chronic PJI, respectively. We recommend an anticoagulant be administered concomitantly with antineoplastics that significantly increase deep vein thrombosis risk, and we recommend long-term oral suppressive antibiotics postoperatively, especially if chemotherapy will be resumed. Additional studies are needed to investigate risks and benefits of PJI prophylaxis during chemotherapy and long-term suppressive antibiotics after PJI treatment.\n\nKeywords\nChemotherapyMultiple myelomaTotal knee arthroplastyPeriprosthetic joint infectionDAIRTwo stage\n==== Body\nIntroduction\nPeriprosthetic joint infection (PJI) is a growing cause of knee and hip arthroplasty failure and is difficult and expensive to treat. There are 2 main type of PJIs based on the timing and duration of symptoms: acute and chronic. Chronic infections are found when the hip or knee has symptoms for a duration greater than 4 weeks. Oftentimes, the clinical presentation is unremarkable other than pain and swelling. In cases of acute infection, the patient’s joint often becomes painful, red, and/or swollen. This can be accompanied by systemic symptoms such as fever, malaise, or even sepsis. Acute joint infections usually stem from inoculation of newly implanted hardware or, in later spontaneous cases, hematogenous spread of bacteria with seeding to the foreign implant material. The diagnosis of PJI remains imprecise, but the Musculoskeletal Infection Society (MSIS) major and minor criteria have helped increase the sensitivity and specificity of diagnosing a PJI event. If acute infections are diagnosed within 3-4 weeks of symptom onset, it is possible to retain the fixed components and only replace the modular bearing after performing a thorough debridement. Similar to a 2-stage approach, patients are treated postoperatively with a 6-week course of intravenous (IV) antibiotics tailored to the infectious organism. This protocol, known as debridement, antibiotics, and implant retention (DAIR), has shown promising results when treating infections that are truly acute. The 2-stage procedure involves initial removal of prosthesis and placement of an articulating antibiotic spacer followed by delayed reconstruction [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10]].\n\nImmunocompromised patients are thought to be at higher risk for hematogenous spread of infections. Patients who are undergoing acute cancer treatment fall into this category [11]. The presentation of PJI when a patient has pancytopenia due to malignancy or chemotherapy presents the surgeon and oncologist with challenges. In some cases, patients may not be able to undergo surgery until they improve from the side effects of their cancer treatment. In addition, patients receiving certain chemotherapies may be at higher risk of deep vein thrombosis (DVT) in the perioperative and postoperative periods. The rates of hematologic malignancies are increasing as the general population ages, and newer chemotherapy agents with immunosuppressive side effects are now available for use by oncologists. With an increasing number of joint replacements being performed and increasing numbers of patients undergoing treatment for multiple myeloma (MM) and other hematologic cancers, PJI after chemotherapy is likely to become more prevalent in the future [11].\n\nKao et al [12] recently reported data for a cohort of patients with and without a history of cancer who then underwent total knee arthroplasty (TKA), showing similar 1-year PJI rates between the 2 groups; however, the management of postoperative PJI was not discussed. Although much has been studied regarding PJI treatment strategies, there is a paucity of information regarding PJI management and outcomes in patients being treated for concomitant cancer. Arguments could be made for or against treatment with either debridement with component retention or 2-stage implant removal in this patient population. We describe 4 cases in which patients with previously well-functioning TKA developed PJI within 4 months of receiving chemotherapy for a hematologic malignancy. We hypothesize that acute or chronic PJI in immunocompromised patients can be successfully treated with either DAIR or a 2-stage approach, respectively.\n\nCase histories\nCase 1\nCase 1 involves a 74-year-old woman who underwent primary right TKA 12 years before developing PJI. She was diagnosed with IgA kappa MM 4 years before presentation and had begun a chemotherapy regimen of bortezomib (Velcade [Takeda Oncology; Cambridge, MA, USA]) 1 mg/m2 subcutaneously (subQ) weekly, lenalidomide (Revlimid [Celgene; Summit, NJ, USA]) 10 mg by mouth (PO) daily (days 1-21, every 28 days), and dexamethasone 12 mg PO weekly (VRd protocol) 2 months before presentation.\n\nShe presented with pancytopenia secondary to chemotherapy, acute kidney injury, pneumonia of the left lower lung, sepsis, gram-positive bacteremia, and a 3-day history of right knee pain. Her blood work showed an erythrocyte sedimentation rate (ESR) of 90 mm/hr (0-30 normal), C-reactive protein (CRP) of 372 mg/L (0-10 normal), red blood cell (RBC) count of 2,340,000/μL (4,000,000-5,200,000 normal), platelet count of 63,000/μL (150,000-450,000 normal), white blood cell (WBC) count of 1710/μL (3600-9500 normal), and neutrophil count of 920/μL (1400-6000 normal) [53.7%]. She was admitted and started on empiric vancomycin 750 mg IV daily, ceftazidime 500 mg IV twice daily (bid), and acyclovir 200 mg PO daily. Ceftazidime was switched to meropenem 500 mg IV bid the next day for aspiration pneumonia coverage.\n\nOrthopaedic surgery was consulted the day after admission, and examination of the right knee showed an effusion and limited active and passive range of motion (ROM) because of pain. Right knee aspiration revealed a synovial fluid WBC count of 365,200/μL and a neutrophil percentage of 98%, consistent with an acute PJI diagnosis. Synovial fluid culture grew pansensitive Streptococcus pneumoniae.\n\nSeveral surgical options, including DAIR and removal of implants with placement of an antibiotic spacer, were considered. Given the acuity of presentation, she chose to pursue DAIR and was taken to the operating room (OR) 3 days after presentation and 6 days after the onset of knee symptoms. Perioperative findings included gross purulence in the joint capsule and well-fixed tibial and femoral components. Postoperatively, she was switched to vancomycin and ceftriaxone 2 g IV daily and began aspirin 81 mg PO daily for DVT prophylaxis for 6 weeks. She was immediately mobilized, and her sepsis and pneumonia improved. She was discharged on postoperative day (POD) 5 with plans for 6 weeks of ceftriaxone 2 g IV daily. Her blood work at this time showed a CRP of 86.60 mg/L and improvement of her pancytopenia with a hemoglobin level of 8.0 g/dL (12.0-15.0 g/dL normal), platelet count of 75,000/μL, WBC count of 7270/μL, and neutrophil count of 5570/μL (76.6%).\n\nShe began antibiotic suppression with penicillin V potassium 500 mg PO bid after completing 6 weeks of ceftriaxone as recommended by the infectious disease specialist. She experienced no surgical complications within 90 days of PJI treatment. Four months after DAIR, she began a new chemotherapy regimen of daratumumab 900 mg IV weekly. At 14-month follow-up, she reported intermittent pain in her right knee but denied drainage or redness. Examination of the right knee showed a stable joint without edema or erythema and ROM 0°-100°. She remained on long-term suppressive antibiotics after the most recent follow-up.\n\nCase 2\nCase 2 involves a 73-year-old man with a past medical history of unilateral renal agenesis, chronic kidney disease, DVT, hypertension, cytomegalovirus infection, prostatectomy, and peripheral neuropathy at presentation. He underwent primary left TKA 5 years before presentation and was diagnosed with IgG lambda MM 2 years before presentation. He was treated for MM and achieved complete remission 13 months prior to presentation. He then began a maintenance chemotherapy protocol of Velcade 1 mg/m2 subQ weekly and dexamethasone 12 mg PO weekly (Vd protocol). Four months before presentation, he was diagnosed with pancytopenia with severe thrombocytopenia, L4-L5/L5-S1 discitis, and Streptococcus infantarius osteomyelitis of the spine and received 6 weeks of ceftriaxone 2 g IV daily, followed by 6 weeks of levofloxacin 750 mg PO every other day. He discontinued his maintenance chemotherapy protocol at the onset of infection. At follow-up, blood cultures were negative, and magnetic resonance imaging showed continuous improvement of his osteomyelitis and discitis.\n\nHe presented with improving back pain, pancytopenia of unknown etiology, several weeks of intermittent left knee swelling, and a 2-week history of a painful left knee. His most recent bone marrow biopsy showed normocellular marrow with trilineage maturation and was morphologically negative for plasma cell myeloma. His blood work showed an ESR of 44 mm/hr, CRP of 87.1 mg/L, platelet count of 101,000/μL, WBC count of 2710/μL, and neutrophil count of 1440/μL (53.2%). Antibiotics were held on admission. His peripheral blood culture result was negative.\n\nOrthopaedic surgery was consulted the day after admission, and examination showed a visible and palpable effusion about the left knee. Left knee aspiration revealed turbid synovial fluid with a WBC count of 23,870/μL and a neutrophil percentage of 86%. The synovial fluid culture result was negative; however, alpha-defensin testing was positive.\n\nOwing to concerns for chronic knee infection based on symptom recurrence and aspirate findings, the patient opted to pursue resection and placement of an articulating antibiotic spacer with plans for 2-stage reconstruction. Perioperative findings included gross purulence, a thick rind of inflamed synovial tissue surrounding the joint, good remaining bone stock, and intact medial and lateral collateral ligaments. Postoperatively, he began ceftriaxone 2 g IV daily and vancomycin 1 g IV daily. Enoxaparin 40 mg subQ daily and aspirin 81 mg PO bid were given for DVT prophylaxis. While soft-tissue culture results were negative, blood cultures grew Enterobacter. As a result, he was switched to meropenem 1gIV bid. Before discharge, he developed left proximal femoral DVT, which was treated with enoxaparin 30 mg subQ daily for 2 days followed by 70 mg (1 mg/kg) subQ bid. He was discharged on ertapenem 1 g IV daily, with plans for discontinuation of the antibiotic after 6 weeks.\n\nOn POD 23, he was admitted to our facility with acute altered mental status, acute kidney injury, acute swelling and hemarthrosis of the left knee, and an acute retroperitoneal hematoma after an unwitnessed fall that required multiple blood transfusions. The cause of the fall was unclear because of his altered mental status at the time of the fall, and it was thought that the acute left knee swelling was secondary to trauma with the fall. Enoxaparin was decreased to 30 mg subQ daily because of the hematoma, and he underwent inferior vena cava filter placement for his chronic left lower extremity DVT. He then received enoxaparin 40 mg subQ daily after his hemoglobin and hematocrit levels stabilized, and his dose was later increased to 110 mg subQ daily for therapeutic treatment. The infectious disease team changed his antibiotic regimen to daptomycin 450 mg (6 mg/kg) and ertapenem 1 g IV daily for an additional 6 weeks.\n\nFour months after knee resection, inflammatory markers had normalized. The articulating knee spacer was painful, and he wished to undergo stage 2 reimplantation. Revision knee replacement was performed with a constrained polycomponent and short-cemented stems. All intraoperative culture results were negative. He was discharged on rivaroxaban 10 mg PO daily for 6 weeks for DVT prophylaxis and doxycycline 100 mg PO bid for 10 days as per our infectious disease colleagues. Six months after stage 2 reimplantation, he presented to the orthopaedic clinic for his most recent follow-up. Examination of the left knee showed a well-healed incision with no signs of infection and ROM 0°-70°. He resumed chemotherapy 10 months after reimplantation.\n\nCase 3\nCase 3 involves a 75-year-old woman with a history of anemia, kidney disease, chronic femoral and popliteal DVT, congestive heart failure, myocardial infarction, pacemaker implantation, chronic obstructive pulmonary disease, and type 2 diabetes mellitus at presentation. She underwent primary right TKA 5 years before presentation and was diagnosed with IgG kappa MM 3 years before presentation. She was initially treated with Revlimid IV and dexamethasone PO (Rd protocol). Six months before presentation she began lenalidomide 25 mg IV weekly, and her last dose was administered at an outside facility 3 months before presentation.\n\nWhen she transferred care for her MM to our institution, a right posterior iliac crest bone marrow biopsy was performed for staging. Her blood work that day showed an ESR of 36 mm/hr, CRP of <5.0 mg/L, platelet count of 100,000/μL, WBC count of 4700/μL, and neutrophil count of 3130/μL (66.6%). Two days later she presented with complaints of a painful, hot, and swollen right knee that began immediately after her bone marrow biopsy. Her blood work showed a CRP of 155.3 mg/L and WBC count of 10,150/μL. Arthrocentesis of the right knee revealed turbid synovial fluid with a WBC count of 172,760/μL and 95% neutrophils, and cultures grew oxacillin-resistant Staphylococcus aureus.\n\nOrthopaedic surgery was consulted, and examination in the emergency department showed a warm, swollen, and erythematous right knee that was very painful with any ROM. She was diagnosed with acute PJI and admitted for further treatment. The patient chose to pursue a DAIR approach and underwent surgery 1 day after presentation and 3 days after the onset of symptoms. Perioperative findings included gross purulence but no evidence of loosening. Vancomycin 1250 mg IV daily and rifampin 300 mg IV bid were administered postoperatively for 6 weeks. She began aspirin 81 mg PO bid on POD 1 for DVT prophylaxis for 6 weeks and was discharged on POD 3. After completion of 6 weeks of IV antibiotics, she began long-term suppressive doxycycline 100 mg PO bid.\n\nTwo months after DAIR, she was diagnosed with right ankle cellulitis, right femoral and popliteal DVT, and left distal popliteal DVT. This was treated acutely with a course of IV antibiotics and therapeutic enoxaparin. Owing to worsening of her MM, she began a combination chemotherapy regimen of Velcade 2.1 mg (1 mg/m2) subQ weekly, Revlimid 15 mg PO daily (days 1-21, every 28 days), and dexamethasone 20 mg IV weekly (VRd protocol). She had several further admissions for leg swelling and cellulitis.\n\nEight months after her DAIR procedure, she presented to our institution with a 7-day history of worsening right knee pain and swelling. Her blood work at this time showed a CRP of 59.8 mg/L, WBC count of 5650/μL, and neutrophil count of 4200/μL (74.3%). On examination, the right knee was edematous with significant effusion and warmth; active and passive ROM was limited owing to pain. Her radiographs showed a well-fixed, well-aligned cemented right TKA with significant soft-tissue fullness in the prepatellar and suprapatellar regions. Right knee aspiration revealed purulent synovial fluid with a WBC count of 190,300/μL and 83% neutrophils. Synovial fluid and peripheral blood culture results were negative. She was diagnosed with chronic PJI and started on empiric vancomycin 1250 mg IV daily and ceftriaxone 2 g IV daily. She elected for removal of right TKA and placement of an articulating antibiotic spacer 3 days after the onset of symptoms. Perioperative findings included signs of chronic PJI and lateral distal femoral bone loss. OR cultures again grew oxacillin-resistant S. aureus. Postoperatively, she was treated with vancomycin 1250 mg IV daily for 6 weeks and enoxaparin 40 mg subQ daily for DVT prophylaxis. She was discharged 3 weeks after surgery after resolution of a postoperative partial bowel obstruction.\n\nShe began Bactrim (Hoffmann-La Roche Inc.; Litte Falls, NJ, USA) 800-160 mg PO bid for 6 months after her IV antibiotic regimen. Sixteen months after DAIR and 8 months after stage 1 resection and spacer placement, she presented to the orthopaedic clinic for her most recent follow-up. She was ambulating with a walker and reported minor pain in her right knee at full flexion. The Knee Injury and Osteoarthritis Outcome Score was 65.99, and she had ROM 0-90°. Due to her satisfaction with the function of her articulating spacer, the necessity for ongoing chemotherapy treatment, and her chronic medical conditions, she opted to keep the spacer and not pursue stage 2 reimplantation.\n\nCase 4\nCase 4 involves a 64-year-old man with a history of depression, seizures, vertigo, and right bundle branch block at presentation. He underwent primary right TKA 19 years before presentation and was also diagnosed with stable MYD88-positive Waldenström macroglobulinemia 19 years before presentation. He developed fatigue, low-grade fever, and unintentional weight loss and subsequently began a chemotherapy protocol of ibrutinib (Imbruvica [Pharmacyclics LLC; Sunnyvale, CA,USA]) 560 mg PO daily 3 months before presentation.\n\nHe initially presented with a 12-day history of a traumatic right knee pain and swelling. His blood work revealed an ESR of 86 mm/hr, CRP of 95.7 mg/L, platelet count of 176,000/μL, WBC count of 3180/μL, and neutrophil count of 1530/μL (48.2%). Imbruvica was discontinued at this time. Orthopaedic surgery was consulted later that day. Right knee aspiration revealed purulent synovial fluid with a WBC count of 20,220/μL and a neutrophil percentage of 45%. Synovial fluid and peripheral blood culture results were negative. Acute PJI was diagnosed, and aztreonam 2 g IV 3 times daily and vancomycin 1500 mg IV bid were started. He elected for a DAIR approach and underwent surgery 2 days after presentation and 14 days after onset of symptoms. Perioperative findings included gross purulence, a mobile, noninflamed synovium, and well-fixed tibial and femoral components. The OR culture results were negative, and ceftriaxone 2 g IV daily and vancomycin 1750 mg IV bid were started postoperatively. On POD 6, the infectious disease team discontinued vancomycin and replaced it with daptomycin 6 mg/kg IV daily. He spiked a fever on POD 8, and ceftriaxone was switched to cefepime 2 g IV bid. He was discharged on POD 10 with plans for 6 weeks of IV antibiotic treatment.\n\nHe was started on long-term suppressive doxycycline 100 mg PO bid after completing IV antibiotics. Three months after DAIR, he began an 8-week chemotherapy protocol of rituximab 900 mg weekly. Six months after DAIR, he switched to a protocol of venetoclax 400 mg PO daily. His Knee Injury and Osteoarthritis Outcome Score Jr. 6 months after DAIR was 100. One year after DAIR, he had a well-healed incision, no effusion or joint line tenderness, and active and passive ROM 0°-110°.\n\nDiscussion\nWe presented a series of patients who were undergoing hematologic cancer treatment and developed TKA PJI (Table 1). While each patient’s surgical management was dictated by the timing of his or her PJI diagnosis (acute vs chronic), all 4 patients completed 6 weeks of intravenous antibiotics, and 3 were placed on long-term suppressive antibiotics. No recurrence of infection was noted at the most recent follow-up. We believe it is important for orthopaedic surgeons to be aware of certain immunosuppressive medications used in hematologic malignancies that may place a patient at higher risk for PJI.Table 1 Summary.\n\n\tCase 1\tCase 2\tCase 3\tCase 4\t\nPast medical history\t\t\t\t\t\n Primary TKA\t\t\t\t\t\n Laterality\tRight\tLeft\tRight\tRight\t\n Year\t2004\t2011\t2011\t1998\t\n Malignancy\t\t\t\t\t\n Type\tMultiple myeloma\tMultiple myeloma\tMultiple myeloma\tWaldenström macroglobulinemia\t\n Diagnosis year\t2012\t2014\t2014\t1998\t\n Chemotherapy drugs\tVRd, ixazomib, IRd, VRda, daratumumab\tVda\tRd, Ra, VRd\tIbrutiniba, rituximab, venetoclax\t\n Prophylaxis given\tAntiviral, none, none, none, none\tNone\tUnknown, unknown, ASA\tAntiviral, antiviral, antiviral\t\n DVT\tNo\tYes\tYes\tNo\t\n Recent separate-site infection\tYes\tYes\tYes\tNo\t\nPJI\t\t\t\t\t\n Index TJA to diagnosis, y\t12\t5\t5\t19\t\n Last chemotherapy to diagnosis, d\t56\t73\t99\t1\t\n WBC count at diagnosis, #/μL\t1710\t2710\t4700\t2440\t\n Joint fluid cell count\t365,000 WBC\t23,870 WBC\t172,760 WBC\t22,220 WBC\t\n Culture results\tStreptococcus pneumonia\tCulture negative\tMethicillin-resistant Staphylococcus aureus\tCulture negative\t\n MSIS major or minor criteria met\tYes\tYes\tYes\tYes\t\n Surgical treatment\tDAIR\tTwo-stage Revision\tDAIR (failed); Stage 1 only\tDAIR\t\n Onset of symptoms to treatment interval\t6 d\t3 mo\t3 d\t14 d\t\nPostoperative period\t\t\t\t\t\n Initial postoperative antibiotic treatment\tCeftriaxone\tErtapenem; daptomycin + ertapenem\tDAIR: vancomycin, rifampin; stage 1: vancomycin\tCeftriaxone + daptomycin\t\n Suppressive antibiotic treatment\tPenicillin V\t-\tDAIR: doxycycline, Bactrim; stage 1: Bactrim\tDoxycycline\t\n DVT\tNo\tYes\tYes\tNo\t\n Reinfection\tNo\tNo\tYes; no\tNo\t\n PJI surgery to resuming chemo, mo\t4\t10\t2.5; 3.5\t4\t\n PJI diagnosis to most recent follow-up, mo\t13.5\t11.6\t16.6\t12.6\t\nASA, low-dose aspirin; Bactrim, sulfamethoxazole + trimethoprim; DAIR, debridement, antibiotics, and implant retention; IRd, ixazomib + Revlimid + dexamethasone; PJI, periprosthetic joint infection; R, Revlimid; Rd, Revlimid + dexamethasone; Vd, Velcade + dexamethasone; VRd, Velcade + Revlimid + dexamethasone; TKA, total knee arthroplasty; WBC, white blood cell.\n\na Denotes chemotherapy regimen received immediately before PJI.\n\n\n\nChemotherapy agents used before PJI\nThe patients in this study were treated with chemotherapy agents that may be unfamiliar to the orthopaedic surgeon. Three patients with MM received varying combinations of antineoplastic agents before development of PJI, and 1 patient with Waldenström macroglobulinemia received ibrutinib immediately before development of PJI (Table 2).Table 2 Chemotherapy agents used for hemotologic malignancies before PJI.\n\n\tBortezomib (Velcade)\tLenalidomide (Revlimid)\tIbrutinib (Imbruvica)\t\nPharmacologic category\tAntineoplastic, proteasome inhibitor\tAntineoplastic, angiogenesis inhibitor; immunomodulator\tAntineoplastic agent; Bruton’s tyrosine kinase inhibitor\t\nMechanism(s) of action\tReversibly inhibits chymotrypsin-like activity at the 26S proteasome, leading to activation of signaling cascades, cell cycle arrest, and apoptosis\tSelectively inhibits secretion of proinflammatory cytokines; enhances cell-mediated immunity by stimulating proliferation of anti-CD3 stimulated T cells; inhibits trophic signals to angiogenic factors in cells; inhibits the growth of myeloma, myelodysplastic, and lymphoma tumor cells by inducing cell cycle arrest and cell death\tPotent and irreversible inhibitor of Bruton's tyrosine kinase resulting in decreased malignant B cell proliferation and survival.\t\nAntineoplastic uses\tLabeled: mantle cell lymphoma, multiple myeloma; off-label: cutaneous T-cell lymphomas, follicular lymphoma, peripheral T-cell lymphoma, Waldenström macroglobulinemia\tLabeled: follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplastic syndromes; off-label: chronic lymphocytic leukemia, diffuse large B-cell lymphoma, multiple myeloma (newly diagnosed), myelodysplastic syndrome without deletion 5q\tLabeled: chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia\t\nRelevant adverse reactions\tPeripheral neuropathy, neuralgia, paresthesia, dizziness, infection (herpes zoster reactivation, urinary tract, bacteremia, listeriosis, toxoplasmosis, pneumonia, and sepsis), thrombocytopenia, neutropenia, anemia, leukopenia, asthenia, dyspnea, fever\tThrombocytopenia [US boxed warning], neutropenia [US boxed warning], thromboembolic events (thromboprophylaxis recommended) [US boxed warning], teratogenic [US boxed warning], infection (urinary tract, upper respiratory tract, sepsis, bacteremia, fungal, influenza, and renal), leukopenia, anemia, muscle spasm, asthenia, arthralgia, back pain, muscle cramps, limb pain\tNeutropenia, thrombocytopenia, anemia, serious infection (fungal, pneumonia, sepsis, upper respiratory tract, pleural, skin, cellulitis, sinusitis, Streptococcal endocarditis, subcutaneous abscess, and urinary tract), peripheral edema, decreased hemoglobin, petechiae, second primary malignant neoplasm, tendinitis, tenosynovitis, arthralgia, musculoskeletal pain, muscle spasm, asthenia, arthropathy, falls, fever, atrial fibrillation, atrial flutter, ventricular tachycardia, postprocedural hemorrhage, abnormal platelet aggregation, peripheral neuropathy, reactivation of HBV, renal failure syndrome, Stevens-Johnson syndrome, tumor lysis syndrome\t\nMonitoring parameters\tObtain CBC with differential and platelets, liver function tests (dosage adjustments may be needed), and blood glucose levels. Monitor tumor response to therapy. Watch for signs of tumor lysis syndrome (elevated uric acid, potassium, phosphate, hypocalcemia, or acute renal failure) or worsening cardiac function, particularly heart failure. Monitor for peripheral neuropathy, postural hypotension, dehydration, and infections. Monitor for visual or neurologic symptoms and consider MRI if they develop. Be alert to the potential for reactivation of herpes.\tObtain CBC with differential, serum creatinine, liver function test, and thyroid function tests. Dosage adjustment may be needed in patients with renal impairment. Obtain ECG when clinically needed. Screen patients for lactose intolerance before therapy. Assess other drugs the patient may be taking; alternate therapy or dosage adjustments may be needed. Assess for signs and symptoms of adverse effects.\tObtain CBC (monthly), renal function tests, liver function tests, and uric acid. Obtain ECG before initiation in patients with cardiac risk factors. Assess other medicines the patient may be taking; alternate therapy or dosage adjustments may be needed. Assess for signs and symptoms of bleeding, infections, progressive multifocal encephalopathy, tumor lysis syndrome, atrial fibrillation, and secondary malignancies.\t\nCBC, complete blood count; MRI, magnetic resonance imaging; ECG, echocardiogram.\n\n\n\nBortezomib (Velcade) is a proteasome inhibitor that has been known to inhibit osteoclasts and induces osteoblast differentiation [13]. Adverse effects of bortezomib include peripheral neuropathy, infection (urinary tract, bacteremia, listeriosis, toxoplasmosis, pneumonia, and sepsis), and less commonly neutropenia and thrombocytopenia [[14], [15], [16], [17]]. Lenalidomide (Revlimid) is an immunomodulatory drug derived from thalidomide that induces B cell ubiquitination leading to cell death [18]. Lenalidomide administration poses a significant risk for neutropenia, thrombocytopenia, anemia, infection (urinary tract, upper respiratory tract, sepsis, bacteremia, fungal, and renal), and DVT (especially with coadministration of dexamethasone) [16,[19], [20], [21], [22]]. It is recommended that standard-risk patients receive prophylactic low-dose aspirin, and high-risk patients receive low-molecular-weight heparin or vitamin K antagonists during lenalidomide treatment [16]. Dexamethasone is used in combination with bortezomib and/or lenalidomide in the treatment of refractory MM (Vd, Rd, or VRd protocols). It is thought that in this role, dexamethasone aids in the apoptosis of MM cells. However, high-dose dexamethasone when administered with lenalidomide has shown to lead to an increase in incidence of DVT, pulmonary embolus, infection, pneumonia, and mortality when compared with low-dose dexamethasone [23].\n\nIbrutinib is an orally administered chemotherapeutic agent that leads to apoptosis of Waldenström macroglobulinemia cells that have high expressivity of the MYD88L265P cell surface protein. Adverse effects include neutropenia, thrombocytopenia, anemia, serious infection (fungal, pneumonia, sepsis, pleural, skin, cellulitis, sinusitis, Streptococcal endocarditis, subcutaneous abscess, and urinary tract), tenosynovitis, and arthralgias. Owing to the increased risk of bleeding, it is recommended that patients with a history of bleeding diathesis be tested for von Willebrand activity before initiation, and ibrutinib should be held 3-7 days before and after surgery. Ibrutinib should not be administered to patients already receiving anticoagulation therapy for comorbidity. Antimicrobial prophylaxis should be considered in patients receiving ibrutinib who are at risk for opportunistic infection [[24], [25], [26], [27], [28], [29]].\n\nKnowledge of the increased risks of pancytopenia, DVT, and infection is important to both the treating cancer physician and the consulting orthopaedic surgeon. Given the propensity of these drugs to cause neutropenia or pancytopenia, the suspicion for infection must remain high during and after chemotherapy treatment.\n\nDiagnosis, treatment, and postoperative complications\nObtaining a thorough history of prior total joint arthroplasty will give clues to clinical oncologists to potential at-risk sites for infection. It is critical for patients and clinicians to act quickly if the knee or hip suddenly becomes swollen and/or painful. All 4 patients presented with at least 1 of the well-established signs and symptoms of PJI. All 4 had elevated synovial WBC counts and met either the MSIS major or minor criteria for PJI diagnosis. Two patients had pancytopenia and 3 patients had low or low-to-normal serum neutrophil levels at the time of PJI diagnosis. The cases of neutropenia and pancytopenia were thought to be secondary to chemotherapy, but it is difficult to know whether the cause was a result of the chemotherapy, the hematologic malignancy, or a side effect of the PJI. Although neutropenia and pancytopenia may pose potential challenges to the orthopaedic surgeon when diagnosing PJI, the standard MSIS criteria appears to be an effective diagnostic tool in this patient population based on our small sample size.\n\nIn these cases, we used an operative treatment algorithm for PJI similar to that for patients who have not recently received chemotherapy. The 1 patient who initially presented with signs and symptoms of chronic PJI was successfully treated with a 2-stage approach. Of the 3 patients diagnosed with acute PJI, 2 were successfully treated with DAIR. The patient who failed DAIR (case 3) subsequently underwent removal of implants and placement of a well-functioning articulating spacer. Owing to being considered a class C host, the decision was made to forgo stage 2 reimplantation. The articulating spacer has so far survived and functions well for this patient. Patients with sudden onset of symptoms and acute infection are thought to be candidates for implant retention, and this seemed to be a reasonable approach in our population despite perioperative immunosuppression and the necessity for additional chemotherapy after surgery. However, the exact DAIR methodology that provides the greatest success for immunosuppressed patients remains unclear. Irrigation with Betadine (Avrio Health L.P.; Stamford, CT, USA) and chlorhexidine seems to be the most effective approach in preventing infection recurrence [30,31]. A 2-stage DAIR approach with the use of antibiotic-eluting beads may help improve results in this patient population [32]. DAIR should remain contraindicated in the setting of chronic PJI in patients with malignancy.\n\nNone of the patients in this study developed surgical complications such as hematoma or delayed wound healing because of pancytopenia. However, postoperative DVT occurred in 2 (50%) of our cases. The patient in case 2 had a history of DVT and had a recent history of infection at a separate site. He did not develop DVT during chemotherapy but developed DVT after PJI treatment. The patient in case 3 had a history of DVT, had a recent history of infection at a separate site, and had taken lenalidomide before PJI development. She also did not develop DVT during chemotherapy but developed DVT after PJI treatment. More aggressive postoperative anti-DVT agents may be warranted in patients who have recently received chemotherapy for hematologic malignancies and subsequently develop PJI—especially in those who also have a recent history of or active infection at a separate site, a history of DVT, and/or have recently received lenalidomide.\n\nBased on the results of these cases, DAIR and 2-stage revision TKA are indeed viable surgical treatment options for immunosuppressed patients with hematologic malignancies. Early detection, early referral, and timely treatment of acute PJI with DAIR can potentially alleviate the need for 2-stage revision, reduce cost, and decrease comorbidity in this patient population.\n\nPJI prophylaxis\nThe American Society of Clinical Oncology and the Infectious Diseases Society of America currently recommend antifungal and antibiotic prophylaxis with a fluoroquinolone for patients who are at high risk for febrile neutropenia or profound, protracted neutropenia (<100 neutrophils/μL for >7 days), which includes most patients with myelodysplastic syndromes [33]. Long-term suppressive antibiotic therapy has been used in cases of vascular graft and cardiovascular implantable electronic device infections; however, data on treatment success and long-term survival are limited [34].\n\nAll 4 patients received at least 6 weeks of empiric or organism-specific antibiotics after surgical treatment for PJI. Three patients then received subsequent long-term suppressive antibiotics; however, 1 of the 3 patients (case 3) discontinued antibiotics (owing to adverse effects) for approximately 4 months after definitive surgical treatment. All 4 of our patients remained free of recurrent PJI at the most recent follow-up.\n\nThe role of long-term suppressive antibiotics after PJI treatment in patients who require further chemotherapy is undefined. In addition, given the propensity for certain chemotherapy agents discussed to cause neutropenia and infection, the current practice of recommending antimicrobial prophylaxis concomitantly during chemotherapy treatment for some blood cancers but not others is intriguing. Large multicenter studies are needed to further investigate the risks and benefits of long-term suppressive antibiotics after PJI treatment. Studies on the incidence and risk of PJI after chemotherapy treatment for hematologic malignancies would also be useful to determine if and when antimicrobial prophylaxis is warranted to prevent PJI during certain periods of a chemotherapy cycle or with particular combination of chemotherapeutic agents.\n\nSummary\nThis study reviews 4 patients treated with chemotherapy for a hematologic malignancy who subsequently developed TKA PJI. Chemotherapy agents taken before PJI development included bortezomib and/or lenalidomide with or without dexamethasone, and ibrutinib. Routine clinical and laboratory evaluation for evidence of joint infection appears to be effective in diagnosing acute PJI, even in patients with pancytopenia secondary to chemotherapy. Patients with previous TKA who subsequently require chemotherapy for hematologic malignancies can benefit from either DAIR for acute PJI or a 2-stage approach for chronic PJI. Rates of failure in this small study did not seem to vary significantly from the literature. Patients who receive chemotherapy agents that increase the risk of DVT, including lenalidomide, should receive appropriate thrombolytic prophylaxis for the duration of their chemotherapy treatment. We recommend that all patients treated for PJI after receiving chemotherapy for a hematologic malignancy receive long-term suppressive antibiotics targeted against the culprit organism if identified, especially if chemotherapy will be resumed postoperatively.\n\nConflict of interest\nG. Bloom: None; S. Mears: Delta Ortho LLC: Stock or stock Options, Fragility Fracture Network: Board or committee member, International Geriatric Fracture Society: Board or committee member, Journal of the American Geriatrics Society: Editorial or governing board, SAGE: Editorial or governing board; P. Edwards: DJ Orthopaedics: IP royalties and Paid consultant; C. Barnes: American Association of Hip and Knee Surgeons: Board or committee member, ConforMIS: Research support, DJO: IP royalties, HealthTrust: Paid consultant, HipKnee Arkansas Foundation: Board or committee member, Journal of Arthroplasty: Editorial or governing board, JSOA: Editorial or governing board, Medtronic: IP royalties and Paid consultant, Mid American Orthopaedic Association: Board or committee member, Responsive Risk Solutions: Paid consultant and Stock or stock Options, Southern Orthopaedic Association: Board or committee member, Zimmer: IP royalties; J. Stambough: American Association of Hip and Knee Surgeons: Board or committee member.\n\nSupplementary data\nConflict of Interest Statement for Barnes\n Conflict of Interest Statement for Bloom\n Conflict of Interest Statement for Stambough\n Conflict of Interest Statement for Edwards\n Conflict of Interest Statement for Mears\n \n\nAcknowledgments\nWe would like to recognize the Translational Research Institute and the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences for their roles in data acquisition and organization.\n==== Refs\nReferences\n1 Ottesen C.S. Troelsen A. Sandholdt H. Jacobsen S. Husted H. Gromov K. Acceptable success rate in patients with periprosthetic knee joint infection treated with debridement, antibiotics, and implant retention J Arthroplasty 34 2 2019 365 30401558 \n2 Zhu Y. Zhang F. Chen W. Liu S. Zhang Q. Zhang Y. Risk factors for periprosthetic joint infection after total joint arthroplasty: a systematic review and meta-analysis J Hosp Infect 89 2 2015 82 25575769 \n3 Kuiper J.W. Willink R.T. Moojen D.J.F. van den Bekerom M.P. Colen S. Treatment of acute periprosthetic infections with prosthesis retention: review of current concepts World J Orthop 5 5 2014 667 25405096 \n4 Lidgren L. Chronic inflammation, joint replacement and malignant lymphoma J Bone Joint Surg Br 90-B 1 2008 7 \n5 Morrison T.A. Figgie M. Miller A.O. Goodman S.M. Periprosthetic joint infection in patients with inflammatory joint disease: a review of risk factors and current approaches to diagnosis and management HSS J 9 2 2013 183 24426866 \n6 Ji B. Zhang X. Xu B. The fate of immunocompromised patients in the treatment of chronic periprosthetic joint infection: a single-centre experience Int Orthop 42 3 2018 487 29344701 \n7 George M.D. Baker J.F. Hsu J.Y. Perioperative timing of infliximab and the risk of serious infection after elective hip and knee arthroplasty Arthritis Care Res (Hoboken) 69 12 2017 1845 28129484 \n8 Berbari E.F. Osmon D.R. Lahr B. The Mayo prosthetic joint infection risk Score: implication for surgical site infection reporting and risk stratification Infect Control Hosp Epidemiol 33 8 2012 774 22759544 \n9 Diaz-Ledezma C. Baker J. Parvizi J. “Warning signs” of primary immunodeficiency among patients with periprosthetic joint infection J Appl Biomater Funct Mater 12 2 2014 65 25191844 \n10 Parvizi J. Zmistowski B. Berbari E.F. New definition for periprosthetic joint infection: from the workgroup of the musculoskeletal infection society Clin Orthop Relat Res 469 11 2011 2992 21938532 \n11 Safdar A. Armstrong D. Infections in patients with hematologic neoplasms and hematopoietic stem cell transplantation: neutropenia, humoral, and splenic defects Clin Infect Dis 53 8 2011 798 21890754 \n12 Kao F.C. Hsu Y.C. Lai P.Y. Wang C.B. Tu Y.K. Chen W.K. One-year mortality and Periprosthetic infection rates after Total knee Arthroplasty in Cancer patients: a population-based cohort study BMC Cancer 18 1 2018 1 29291726 \n13 Accardi F. Toscani D. Bolzoni M. Dalla Palma B. Aversa F. Giuliani N. Mechanism of action of bortezomib and the new proteasome inhibitors on myeloma cells and the bone microenvironment: impact on myeloma-induced alterations of bone remodeling Biomed Res Int 2015 2015 172458 26579531 \n14 Lonial S. Waller E.K. Richardson P.G. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma Blood 106 2005 3777 16099887 \n15 Wu K.L. Heule F. Lam K. Sonneveld P. Pleomorphic presentation of cutaneous lesions associated with the proteasome inhibitor bortezomib in patients with multiple myeloma J Am Acad Dermatol 55 5 2006 897 17052502 \n16 Bringhen S. De Wit E. Dimopoulos M.A. New agents in multiple myeloma: an examination of safety profiles Clin Lymphoma Myeloma Leuk 17 7 2017 391.e5 28601492 \n17 Bortezomib Lexi-drugs online, Hudson 2019 Wolters Kluwer Clinical Drug Information, Inc. Ohio http://online.lexi.com Subscription required to view \n18 Fink E.C. Ebert B.L. The novel mechanism of lenalidomide activity Blood 126 21 2015 2366 26438514 \n19 Dimopoulos M.A. Richardson P.G. Brandenburg N. A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide Blood 119 12 2012 2764 22323483 \n20 Qiao S.K. Guo X.N. Ren J.H. Ren H.Y. Efficacy and safety of lenalidomide in the treatment of multiple myeloma: a systematic review and meta-analysis of randomized controlled trials Chin Med J (Engl) 128 9 2015 1215 25947406 \n21 Ying L. YinHui T. Yunliang Z. Sun H. Lenalidomide and the risk of serious infection in patients with multiple myeloma: a systematic review and meta-analysis Oncotarget 8 28 2017 46593 28423741 \n22 Lenalidomide Lexi-drugs online 2019 Wolters Kluwer Clinical Drug Information, Inc. Hudson, Ohio http://online.lexi.com Subscription required to view \n23 Rajkumar S.V. Jacobus S. Callander N.S. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial [published correction appears in Lancet Oncol. 2010 Jan;11(1):14] Lancet Oncol 11 1 2010 29 19853510 \n24 Treon S.P. Gustine J. Meid K. Ibrutinib monotherapy in symptomatic, treatment-Naïve patients with Waldenström macroglobulinemia J Clin Oncol 36 27 2018 2755 30044692 \n25 Treon S.P. Tripsas C.K. Meid K. Ibrutinib in previously treated Waldenström's macroglobulinemia N Engl J Med 372 15 2015 1430 25853747 \n26 Abeykoon J.P. Zanwar S. Ansell S.M. Ibrutinib monotherapy outside of clinical trial setting in Waldenström macroglobulinaemia: practice patterns, toxicities and outcomes Br J Haematol 188 3 2020 394 403 31468508 \n27 Papanota A.M. Ntanasis-Stathopoulos I. Kastritis E. Dimopoulos M.A. Gavriatopoulou M. Evaluating ibrutinib in the treatment of symptomatic Waldenstrom's macroglobulinemia J Blood Med 10 2019 291 31695539 \n28 Varughese T. Taur Y. Cohen N. Serious infections in patients receiving ibrutinib for treatment of lymphoid cancer Clin Infect Dis 67 5 2018 687 29509845 \n29 Ibrutinib Lexi-drugs online 2019 Wolters Kluwer Clinical Drug Information, Inc. Hudson, Ohio http://online.lexi.com Subscription required to view \n30 Kavolus J.J. Schwarzkopf R. Rajaee S.S. Chen A.F. Irrigation fluids used for the prevention and treatment of orthopaedic infections J Bone Joint Surg Am 102 1 2020 76 31596810 \n31 Blom A. Cho J. Fleischman A. General assembly, prevention, antiseptic irrigation solution: proceedings of international consensus on orthopedic infections [published correction appears in J arthroplasty. 2019 Jun;34(6):1299] J Arthroplasty 34 2S 2019 S131 30348567 \n32 Chung A.S. Niesen M.C. Graber T.J. Two-stage debridement with prosthesis retention for acute periprosthetic joint infections J Arthroplasty 34 6 2019 1207 30872035 \n33 Taplitz R.A. Kennedy E.B. Bow E.J. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update J Clin Oncol 36 30 2018 3043 30179565 \n34 Lau J.S.Y. Korman T.M. Woolley I. Life-long antimicrobial therapy: where is the evidence? J Antimicrob Chemother 73 10 2018 2601 29873746\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-3441",
"issue": "6(3)",
"journal": "Arthroplasty today",
"keywords": "Chemotherapy; DAIR; Multiple myeloma; Periprosthetic joint infection; Total knee arthroplasty; Two stage",
"medline_ta": "Arthroplast Today",
"mesh_terms": null,
"nlm_unique_id": "101681808",
"other_id": null,
"pages": "309-315",
"pmc": null,
"pmid": "32514420",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": "29344701;25853747;25191844;28601492;30348567;30401558;17052502;24426866;22759544;30872035;19853510;30044692;16099887;26438514;25405096;25947406;22323483;31695539;18160491;26579531;28423741;30179565;31596810;28129484;31468508;29509845;25575769;29866058;21890754;29873746;21938532",
"title": "Total Knee Periprosthetic Joint Infection in the Setting of Hematologic Malignancy: Considerations for Management.",
"title_normalized": "total knee periprosthetic joint infection in the setting of hematologic malignancy considerations for management"
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"abstract": "BACKGROUND\nDrug-induced parkinsonism is a well-known complication of several different drugs--the most common being neuroleptic-induced parkinsonism. However, very few autopsies have been reported in such cases.\n\n\nMETHODS\nPatients assessed at Movement Disorders Clinic Saskatchewan are offered brain autopsy. Detailed clinical records are kept.\n\n\nRESULTS\nBrains were obtained from 7 drug-induced parkinsonism patients with parkinsonian symptom onset coinciding with use of drugs known to produce parkinsonism. Six were on antipsychotics and 1 was on metoclopramide. Three cases were treated with levodopa for parkinsonism. In two cases, parkinsonian features reversed after stopping the offending agent. Both had autopsy evidence of preclinical PD. In 4 of the remaining 5, dopamine-blocking drugs were continued until death. In 4 of those 5, brain histology revealed no cause for the parkinsonism, but 1 had mild SN neuronal loss without Lewy bodies.\n\n\nCONCLUSIONS\nThis study shows that reversal of parkinsonism after discontinuing offending drugs does not indicate absence of underlying pathology. Neuroleptics can unmask preclinical PD in patients with insufficient SN damage for the disease to manifest clinically. Though the mechanism of sustained parkinsonian features after discontinuing neuroleptics remains to be established, it is unlikely that dopamine receptor block leads to retrograde SN neuronal degeneration. Furthermore, L-dopa does not appear to be toxic to SN.",
"affiliations": "Saskatchewan Movement Disorders Program, Royal University Hospital, Saskatoon, Saskatchewan, Canada.;Division of Neurology, Saskatchewan Movement Disorders Program, University of Saskatchewan, Saskatoon Health Region, Saskatoon, Saskatchewan, Canada.;Neuropathology, Department of Pathology, University of Saskatchewan, Saskatoon Health Region, Saskatoon, Saskatchewan, Canada.;Division of Neurology, Saskatchewan Movement Disorders Program, University of Saskatchewan, Saskatoon Health Region, Saskatoon, Saskatchewan, Canada.",
"authors": "Shuaib|Umar A|UA|;Rajput|Ali H|AH|;Robinson|Christopher A|CA|;Rajput|Alex|A|",
"chemical_list": "D014150:Antipsychotic Agents; D015259:Dopamine Agents; D007980:Levodopa",
"country": "United States",
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"doi": "10.1002/mds.26467",
"fulltext": "\n==== Front\nMov DisordMov. Disord10.1002/(ISSN)1531-8257MDSMovement Disorders0885-31851531-8257John Wiley and Sons Inc. Hoboken 10.1002/mds.26467MDS26467Research ArticleResearch ArticlesNeuroleptic‐induced Parkinsonism: Clinicopathological study Neuroleptic‐induced ParkinsonismShuaib et alShuaib Umar A. MBBS\n1\nRajput Ali H. MBBS, FRCPC\n2\nRobinson Christopher A. MD, FRCPC\n3\nRajput Alex MD, FRCPC\n2\n1 Saskatchewan Movement Disorders ProgramRoyal University HospitalSaskatoonSaskatchewanCanada2 Division of Neurology, Saskatchewan Movement Disorders ProgramUniversity of Saskatchewan, Saskatoon Health RegionSaskatoonSaskatchewanCanada3 Neuropathology, Department of PathologyUniversity of Saskatchewan, Saskatoon Health RegionSaskatoonSaskatchewanCanadaCorrespondence to: Dr. Ali H. Rajput, Royal University Hospital, Room 1663, Saskatoon, Saskatchewan, Canada, S7N 0W8; ali.rajput@saskatoonhealthregion.ca11 12 2015 3 2016 31 3 10.1002/mds.v31.3360 365 25 6 2015 29 9 2015 05 10 2015 © 2015 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.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\nBackground\nDrug‐induced parkinsonism is a well‐known complication of several different drugs—the most common being neuroleptic‐induced parkinsonism. However, very few autopsies have been reported in such cases.\n\nMethods\nPatients assessed at Movement Disorders Clinic Saskatchewan are offered brain autopsy. Detailed clinical records are kept.\n\nResults\nBrains were obtained from 7 drug‐induced parkinsonism patients with parkinsonian symptom onset coinciding with use of drugs known to produce parkinsonism. Six were on antipsychotics and 1 was on metoclopramide. Three cases were treated with levodopa for parkinsonism. In two cases, parkinsonian features reversed after stopping the offending agent. Both had autopsy evidence of preclinical PD. In 4 of the remaining 5, dopamine‐blocking drugs were continued until death. In 4 of those 5, brain histology revealed no cause for the parkinsonism, but 1 had mild SN neuronal loss without Lewy bodies.\n\nConclusion\nThis study shows that reversal of parkinsonism after discontinuing offending drugs does not indicate absence of underlying pathology. Neuroleptics can unmask preclinical PD in patients with insufficient SN damage for the disease to manifest clinically. Though the mechanism of sustained parkinsonian features after discontinuing neuroleptics remains to be established, it is unlikely that dopamine receptor block leads to retrograde SN neuronal degeneration. Furthermore, l‐dopa does not appear to be toxic to SN. © 2015 International Parkinson and Movement Disorder Society\n\nparkinsonismdrug inducedpathologysubstantia nigraneuroleptic‐induced source-schema-version-number2.0component-idmds26467cover-dateMarch 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:14.10.2016\nRelevant conflicts of interest/financial disclosures: Nothing to report.\n\nFull financial disclosures and author roles may be found in the online version of this article.\n==== Body\nDrug‐induced parkinsonism (DIP) is defined as the appearance of parkinsonism on treatment with pharmaceutical agents. Most of those drugs impair dopamine (DA) function.1 DIP was first recognized in the early 1950s as a common complication of neuroleptic therapy—neuroleptic‐induced parkinsonism (NIP).1 Other drugs that produce DA receptor block or deplete DA1, 2 also produce parkinsonism. Initially, it was considered to be an exclusive side effect of first‐generation neuroleptics that block D2 receptors. Other agents, such as calcium channel blockers, gastrointestinal prokinetics, antiarrhythmics, and antidepressants, have also been implicated in DIP.1 The mechanisms of how these other drugs produce parkinsonism is not known.1\n\n\nOlder literature indicates that DIP is the second‐most common cause of parkinsonism.3, 4 The incidence of DIP may have declined with widespread use of atypical antipsychotics, but conclusive evidence is not available so far. In most cases, DIP is reversible after discontinuing the offending agent. However, in up to 25% of cases, symptoms persist after cessation of the drug.5, 6 Symptoms of parkinsonism are typically bilateral and symmetric without prominent resting tremor. They may manifest within a few days after initiation of neuroleptic therapy and 90% of cases emerge by 3 months.2, 7 The risk of DIP with different agents varies widely.2, 8 Postsynaptic D2 receptor block by neuroleptics is closely linked to antipsychotic effect.2, 9 Production of extrapyramidal symptoms (EPS) is a requirement to classify conventional neuroleptics.9 More recent studies indicate that D2 receptor affinity is not necessary for the antipsychotic effect and the production of EPS is not necessary for that benefit. Antipsychotic drugs with low D2 receptor affinity became known as “atypical” antipsychotics, of which clozapine is an example.9 With more widespread use of atypical antipsychotic drugs, it is anticipated that the incidence of DIP would decline, though definite evidence for that is not available so far.\n\nAfter discontinuing the causal agent, persistence, worsening, or symptom resolution followed by reemergence of parkinsonian symptoms is each interpreted as evidence of underlying preclinical Parkinson's disease (PD) being unmasked by DA blockers. Old age, dementia and family history of PD are reported as risk factors for DIP.1, 8 Autopsy studies have confirmed that some patients who recover from DIP after discontinuing the offending drug have pathological findings characteristic of preclinical PD.10, 11 The motor features of DIP and PD are similar,8 and clinical distinction is not always possible. Single‐photon emission computed tomography (SPECT) imaging with FP‐CIT has been a useful tool to identify preclinical PD, which may be unmasked by drugs. There is reduced dopamine transporter (DAT) uptake in PD and in preclinical degenerative PD, but the uptake is normal in pure DIP.12, 13\n\n\nIn spite of the large number of DIP cases observed in clinical practice, very few autopsies have been reported in such cases.10, 11 We report on a detailed clinical and pathologic study in 7 DIP patients.\n\nPatients and Methods\nThe Movement Disorders Clinic Saskatchewan (MDCS) has operated continuously since 1968. Details have been reported previously.14 All MDCS patients are offered brain autopsy at no cost to the family. Patients are followed by movement disorders specialists (A.H.R., A.R.) at the MDCS at 6‐ to 12‐month intervals. Information on sex, age of symptom onset, past history, use of neuroleptics and other drugs, family history, use of antiparkinson drugs, medication benefits, and adverse effects is obtained from patients/caregivers prospectively. Severity of bradykinesia, rigidity, and tremor as per the Webster scale15 and, more recently, by the UPDRS16 and global disability using the H & Y scale are assessed at each clinic visit.14, 16, 17 Between clinic visits, the neurologists are available for patient management.\n\nAutopsy is performed after written consent from the next of kin. Autopsy consent is approved by the Saskatoon Health Region, and approval for research on the autopsied brains is granted by the University of Saskatchewan Ethics Board. Immediately after autopsy, the brain is divided at midline. One half of the brain is fixed in formalin and examined histologically by a neuropathologist. The other half is frozen at −80°C for future studies. Contemporary protocols for PD pathology were followed—using the commercially available stains at our institution, including silver stain, ubiquitin, tau, and alpha‐synuclein (α‐Syn) immunostains. A complete neuropathology report is issued on each case and shared with the family.\n\nResults\nOnly those cases of DIP who came to autopsy between 1970 ando 2014 were considered for this study. Of the total of 505 autopsies on patients observed in the MDCS, 7 such cases were identified.\n\nReport of Cases\nCase 1\nA 65‐year‐old man with a long history of bipolar disorder (BPD) was treated with chlorpromazine 75 mg three times daily (TID) since age 41 and lithium 300 mg TID since around age 50. At age 60, he noticed resting tremor in the left upper limb (UL), which worsened over the next 5 years and involved the right side. A trial on benztropine by the family physician produced confusion and hallucinations. Examination at the MDCS at age 65 revealed bilateral UL action tremor, more pronounced on the left, bilateral UL rigidity and bradykinesia. Diagnosis of parkinsonism, stage 2,16, 17 secondary to neuroleptic use was made. Because of asymmetrical parkinsonism findings, it was considered that he may have underlying PD pathology unmasked by neuroleptics, he was started on selegiline 5 mg once‐daily. It made his “stomach sour” and was therefore discontinued. He was switched to trihexyphenidyl 2 mg TID 2 weeks before his next visit 6 months later when his parkinsonism was essentially unchanged at stage 2 disability.17 He continued with chlorpromazine (though at a reduced dose of 50 mg TID), lithium, and trihexyphenidyl and was followed at the MDCS for 5 years. At age 69, orofacial tardive dyskinesias were noted and his wife noted that his memory was not good—he was on trihexyphenidyl 2 mg four times daily (QID), and it was recommended that the dose be reduced. At his last visit to the MDCS at age 70, his parkinsonism was at H & Y stage 2.16, 17 Toward the end, he was in a nursing home and his medications included quetiapine and lithium; he was no longer on trihexyphenidyl or chlorpromazine. He died at age 85.\n\nOn autopsy, the brain weighed 1,410 g and was grossly normal. There were neurofibrillary tangles throughout the brain and amyloid deposits in the hippocampus. There was no loss of pigmented neurons in the SN or in the locus ceruleus (LC). α‐Syn staining was negative. The final pathological diagnosis was mild Alzheimer's disease and mild cortical amyloid angiopathy.\n\nCase 2\nHe had been on long‐term treatment with metoclopramide 10 mg twice‐daily (BID) for reflux owing to a large hiatus hernia. He had onset of gait difficulty at age 78 followed by gait initiation failure, gait freezing, and bilateral UL resting tremor. The metoclopramide dose was reduced to once‐daily. He was started on levodopa/carbidopa 100/25 mg 1 tablet BID 6 weeks before first evaluation at the MDCS, with reported improvement in tremor. On examination at age 83, he had bilateral UL rigidity, right side worse, definite bradykinesia in all four limbs, and UL postural and kinetic tremors. He had mild orofacial chewing movements intermittently. He had a flexed posture and was unable to stand from sitting position without assistance; gait was wide based and shuffling with minimal arm swing. He was diagnosed with PD, H & Y stage 4,16, 17 and the l‐dopa/carbidopa 100/25 mg was increased to 1 tablet QID, with a final maintenance dose of 2 tablets five times daily. There was some improvement of symptoms, though he remained at H & Y stage 4. Metoclopramide was continued by the family physician and the dose increased to 10 mg TID before his death at age 85.\n\nAt autopsy, the brain weighed 1,680 g and was grossly normal except for a hemorrhagic infarct in the right posterior angular gyrus. There were rare cerebral neurofibrillary tangles, but no loss of pigmented neurons in the SN or LC. There were no pathological findings consistent with clinical features of parkinsonism. α‐Syn staining was negative.\n\nCase 3\nAt age 69, he was admitted to local hospital for confusion and treated with lorazepam 0.5 to 1.0 mg up to six times daily as needed (PRN) and risperidone 0.5 mg TID. He was discharged to a nursing home on those drugs. One month later, he was admitted to the Royal University Hospital Saskatoon for confusion and personality change. Clinical diagnosis was encephalopathy. He was investigated extensively. The peripheral blood counts and electrolytes were normal. Multiple electroencephalograms were normal and nerve conduction study was normal. Cerebral angiograms were normal; notably, there was no evidence of vessel occlusion, aneurysm, malformation, or other evidence of vasculitis. Carotid doppler was normal. CT of the brain revealed mild cerebral atrophy and an ill‐defined hypodensity in the left corona radiata. MRI of the brain, MR diffusion study, and MRA of the head revealed diffuse cerebral and cerebellar atrophy and periventricular and subcortical foci of T2 hyperintensity and patchy T2 signal in the left pons. Regional cerebral blood perfusion SPECT study revealed no abnormality.\n\nCerebrospinal fluid (CSF) was normal for proteins, glucose, and white cell count. Polymerase chain reaction for herpes simplex was negative. CSF culture revealed no organisms. CSF was faintly positive for 14‐3‐3 proteins by immunoblotting. Definite diagnosis for the cause of encephalopathy was not made. He was discharged to the nursing home and was continued on risperidone 0.5 mg TID. Four months later, his wife noted that he was tremulous, had shuffling gait, and visual hallucinations. He could walk less than half a block alone, provided somebody was with him, but after that he needed active support. Examination at that time revealed, mild but definite bradykinesia in all four limbs, bilateral UL mild resting tremor, bilateral kinetic and postural tremor, bilateral mild rigidity, and flexed posture with slow shuffling gait. His Mini–Mental Status Examination (MMSE) score was 21/30. He was diagnosed as having parkinsonism and dementia, likely Lewy body dementia given his visual hallucinations and variable cognition and behavior. His disability was rated at stage 4.0 H & Y.17 He was treated with rivastigmine 1.5 mg once‐daily (OD) for 1 week and then increased to BID. It was recommended that the risperidone be changed to quetiapine; however, that was not pursued by the family physician and he was continued on risperidone. There was no symptomatic improvement on rivastigmine. He was reevaluated at the MDCS 6 months later. His MMSE was 18/30 and H & Y stage was 5. He was incontinent of urine and sometimes stool. His tremor had become worse and hallucinations were “too bad” to describe. l‐dopa/carbidopa 100/25 mg OD was initiated. It was increased over 1 week to 1 tablet TID and rivastigmine dose was recommended to increase to 3 mg TID. At his final visit to the MDCS nearly 8 months later on his 71st birthday, his condition had declined further. By then, rivastigmine had been stopped. At that time, he was recommended to increase the l‐dopa/carbidopa 100/25 mg to 1.5 tablets TID. There was no symptomatic benefit. He continued to decline over the next 5 years while in a nursing home. The risperidone was continued until his death at age 75.\n\nAt autopsy, the brain weighed 1,380 g. Microscopically there was a moderate loss of pigmented neurons in the LC and a mild loss in the SN. α‐Syn immunostaining was negative, as was that for ubiquitin, TDP‐43, and FUS, thus ruling out common forms of tau‐negative degenerations. Tau immunostaining revealed changes consistent with an Alzheimer's disease neuropathological score of “low” according to 2012 National Institute on Aging‐Alzheimer's Association guidelines.18 Thus, although not ruled out, a definite diagnosis of Alzheimer's disease could not be made, and the cause for his dementia could not be established.\n\nCase 4\nHe was seen at age 55 years in our clinic in May 1974. He had a long history of depression, anxiety, and insomnia. He was hospitalized under psychiatry at age 42 and was noted to have obvious tremor. He received electroconvulsive treatment and was started on chlorpromazine and benztropine. Chlorpromazine was continued until his death. He had onset of UL tremor at age 23, and at age 50, was diagnosed as PD by the family physician and treated with l‐dopa. That was discontinued because of severe nausea, but had no symptomatic benefit. Examination at the MDCS at age 55 revealed a slow head tremor with both vertical and horizontal components, moderate bilateral UL resting tremor and more pronounced action tremor, and mild bradykinesia and rigidity in both ULs and unstable posture—stage 3 H & Y.17 He was diagnosed as having essential tremor and parkinsonism, secondary to antipsychotics. He was not willing to try antiparkinson drugs. He died of myocardial infarction at age 58.\n\nOn autopsy, the brain weighed 1,400 g and was grossly normal. There was no loss of pigmentation of SN or other pathology consistent with parkinsonism noted grossly or microscopically. Brain histology otherwise was normal.\n\nCase 5\nAt age 61, he had noticed bilateral UL tremor during writing, which became worse at age 65 subsequent to the death of his wife. He was hospitalized for depression and was treated with electroconvulsive therapy and started on phenothiazine at age 66. Examination at the MDCS 2 months later revealed moderate bilateral UL postural and action tremor; the right side was worse. In addition, there was right UL resting tremor mostly at the thumb, and mild bradykinesia and rigidity in the left UL. Because his primary problem was tremor, he was started on propranolol. Three months later, propranolol was discontinued because he did not think it was effective (though objectively the tremor appeared improved). At that visit, he had UL postural, action, and resting tremor and questionable rigidity, but no definite bradykinesia. Diagnosis of PD was made. He died at age 67 of myocardial infarction.\n\nOn autopsy, the brain weighed 1,350 g. There was marked cerebral arteriosclerosis and enlarged perivascular spaces, in the basal ganglia. The brain was otherwise grossly and microscopically normal. There was no loss of SN or LC neurons.\n\nCase 6\nHe was hospitalized at age 69 with a 2‐week history of confusion, agitation, and combative tendencies after he had hit his head against the stairs. He was treated with intramuscular chlorpromazine 50 mg TID, with additional doses given as necessary. Six days later, he was noted to have bilateral, small‐amplitude resting tremor in the upper limbs and moderate generalized rigidity and bradykinesia. A diagnosis of NIP was made. The following day, he received chlorpromazine 75 mg intramuscular and 2 mg of benztropine orally. Both drugs were discontinued the next day. The parkinsonian manifestations subsided completely during the next 7 days. He developed respiratory symptoms and he died 1 month later.\n\nAt autopsy, pulmonary embolism and bronchopneumonia were confirmed as the cause of death. The brain weighed 1,500 g and was grossly normal. Moderate loss of SN pigmented nerve cells, gliosis, and frequent intracytoplasmic Lewy bodies were found. Lewy bodies were also observed in the LC. DA and homovanillic acid levels were moderately reduced in the caudate and the putamen. The final diagnosis was preclinical PD unmasked by neuroleptics.10\n\n\nCase 7\nHe was known to have bipolar disorder and was treated with haloperidol 2 mg TID and benztropine for 3 months, before his hospitalization in May 1977 at age 59. On examination, he had moderate generalized rigidity, bradykinesia, and resting tremor in both ULs. The neuroleptics and benztropine were discontinued. The parkinsonian features resolved over the next 2 weeks. He died suddenly 2 months later at age 59.\n\nAt autopsy, acute pulmonary edema was detected. Histological examination of the brain revealed slight loss of SN pigmented cells and numerous intracytoplasmic Lewy bodies (LB). Biochemical assay of the striatum showed no measurable reduction of DA levels.10\n\n\nDiscussion\nStriatal DA deficiency is well recognized as the primary biochemical abnormality in PD.19 Histologically, marked SN neuronal loss is characteristic of PD.20, 21 DIP shares clinical features with PD,2 but there are no known histological changes in the DIP brains. PET studies show that blockage of 75% to 80% postsynaptic D2 receptors results in motor features of parkinsonism.22 Whereas hundreds of autopsied cases of PD have been reported in the literature, fewer than 20 DIP autopsies have been reported thus far.10, 11\n\n\nDIP is produced by several different classes of drugs. Whereas the D2 receptor blockage is known in the NIP,2, 23 the mechanism of DIP owing to other drugs is not fully understood.1 By definition, the older neuroleptics always produce EPS.9, 23 Other drugs with no significant D2 receptor affinity also produce DIP, indicating that DA receptor blockage is not the sole mechanism of DIP.\n\nA “double hit” hypothesis has been proposed, with DA‐blocking agents also producing neurotoxicity and pathological changes of PD, though this has not been proven.23 Our data do not support neuroleptic‐induced SN neurotoxicity as measured by standard neuropathology. It is possible that there are some changes with chronic neuroleptic use, which compromise SN neuronal function without causing neuronal death, resulting in persistent parkinsonism.\n\nNonmotor functions were not specifically identified in our cases; however, recent work suggests that nonmotor features, such as disordered olfaction and cardiac denervation, may predict those who will go on to develop persistent PS.24, 25, 26 Autopsy verification has, however, not been performed in these cases.\n\nOur cases broadly represent three subgroups: Cases 6 and 7 had underlying PD pathology and were previously reported on in detail.10 Cases 1, 2, 4, and 5 had no pathological changes that may produce parkinsonism or predispose to neuroleptic‐induced Parkinson syndrome (PS). Case 3 had mild SN neuronal loss, but no LB inclusions. Some SN loss is observed with normal aging,27, 28 but the subregional pattern of neuronal loss is different than in the PD.28 The exact threshold of SN neuronal loss to manifest parkinsonian motor features has not been established. However, slight to moderate loss on standard neuropathology study, as observed in our cases 6 and 7, does not produce clinical features of parkinsonism. Autopsy studies report between 65% and 80% SN neuronal loss in PD cases.29 The mild neuronal loss in case 3, we believe, is not the basis of parkinsonism, though it could have predisposed this patient to NIP.\n\nIn addition to the clinical features of PS, two of our cases (1 and 2) had tardive dyskinesia (TD). That combination is common in patients on DA receptor‐blocking agents.1 It is estimated that there is a 2‐fold higher risk of TD in DIP cases.30 Concurrent use of anticholinergics in neuroleptic‐treated cases is believed to increase the risk of TD.30 Case 1 was concurrently on anticholinergic medication.\n\nBower and colleagues11 reported on eight cases with clinical diagnosis of DIP. In three of those, the PS resolved after discontinuing neuroleptics. One of those three had LB pathology and one had vascular pathology. These cases resemble our cases 3, 6, and 7. In five of their cases that were continued on the neuroleptics until death, four had other identifiable pathology.11 Thus, two cases in that series—one with reversible DIP and one with DIP on continued neuroleptic use—had no identifiable pathological process, as in four of our cases (1, 2, 4, and 5).\n\nTogether, these observations indicate that even after prolonged use of neuroleptics, there are no histological changes including no SN neuronal loss. This supports the observations that DIP in such cases is primarily the result of DA receptor blockage. Cessation of PS features on discontinuing the offending drug indicates that the DA receptor blockage is reversible. Given that all DIP cases do not resolve after discontinuing the DA‐blocking drugs, DA receptor change may be irreversible in some cases or there are other as yet unknown changes that account for the ongoing parkinsonism. Further studies are needed to identify the pathophysiology in such cases.\n\nGiven that the D2 receptor block on the neuroleptics occurs bilaterally, it is expected that NIP would have symmetrical clinical features. Asymmetrical parkinsonism manifestations favor a PD diagnosis,20 and imaging studies indicate that DIP cases with asymmetrical clinical features are more likely to have underlying degenerative PD.13 Up to 44% of DIP cases have functional imaging findings indicative of underlying degenerative PD.23 However, those have not been verified pathologically. None of our patients had DAT or PET scan. In one study,7 54% and in another study31 30% of the DIP cases had asymmetrical clinical features. Three of our cases had asymmetrical findings, but none had underlying SN or other pathology. On the other hand, the two preclinical PD cases (6 and 7) unmasked by neuroleptics had a symmetrical parkinsonian finding. These observations indicate that asymmetrical parkinsonism is a part of DIP spectrum.\n\nRest tremor, which is a characteristic of PD, but is considered uncommon in DIP, was observed in all seven of our NIP cases at some time during the course.\n\nOur data do not permit detailed comments on treatment of DIP cases. It has been a common practice to use anticholinergic prophylaxis with the prescription of neuroleptics.8 Anticholinergics are not without risk, especially so in the elderly. They can produce memory loss, confusion, dry mouth, urinary retention, and aggravate glaucoma. Prophylactic use of anticholinergic drugs may also increase the risk of TD.30 A large proportion of individuals on neuroleptics do not develop PS.8 Therefore, prophylactic use of anticholinergics in all cases treated with neuroleptic is not justified.\n\nThe effective symptomatic drugs for DIP reported in the literature are the anticholinergics32 and amantadine.33 Though the efficacy is similar, the adverse effects profile favors amantadine.33 Some symptomatic benefit has been reported on l‐dopa, but compared to PD cases, the response is inconsistent and modest at best.7\n\n\nAuthor Roles\n(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.\n\nU.A.S.: 1A, 1B, 3A, 3B\n\nA.H.R.: 1A, 1B, 1C, 3A\n\nC.A.R.: 1C, 3B\n\nA.R.: 1B, 1C, 3A, 3B\n\nFinancial Disclosures\nA.H.R. received an honorarium from Parkinson Society Canada. A.R. received research support from the Regina Curling Classic, Greystone Classic for Parkinson's, Inc. and the Dr. Ali Rajput Endowment for Parkinson's Disease and Movement Disorders.\n==== Refs\nReferences\n1 \n\nLopez‐Sendon \nJ \n, \n\nMena \nMA \n, \n\nde Yebenes \nJG \n. Drug‐induced parkinsonism . Expert Opin Drug Saf \n2013 ;12 :487 ‐496 .\n23540800 \n2 \n\nFriedman \nJH \n. Drug‐Induced parkinsonism In: Lang AE , Weiner WJ , eds. Drug‐Induced Movement Disorders . 1st ed. Mount Kisco, NY : Futura ; 1992 :41 ‐83 .\n\n3 \n\nBarbosa \nMT \n, \n\nCaramelli \nP \n, \n\nMaia \nDP \n, et al. Parkinsonism and Parkinson's disease in the elderly: a community‐based survey in Brazil (the Bambuí Study) . Mov Disord \n2006 ;21 :800 ‐808 .\n16482566 \n4 \n\nRajput \nAH \n, \n\nOfford \nKP \n, \n\nBeard \nCM \n, \n\nKurland \nLT \n. Epidemiology of parkinsonism: incidence, classification, and mortality . Ann Neurol \n1984 ;16 :278 ‐282 .\n6333204 \n5 \n\nMarti Masso \nJF \n, \n\nPoza \nJJ \n. Drug‐induced or aggravated parkinsonism: clinical signs and the changing pattern of implicated drugs . Neurologia \n1996 ;11 :10 ‐15 .\n8714170 \n6 \n\nLlau \nME \n, \n\nNguyen \nL \n, \n\nSenard \nJM \n, et al. Drug‐induced parkinsonian syndromes: a 10‐year experience at a regional center of pharmaco‐vigilance . Rev Neurol (Paris) \n1994 ;150 :757 ‐762 .\n7597368 \n7 \n\nHardie \nRJ \n, \n\nLees \nAJ \n. Neuroleptic‐induced Parkinson's syndrome: clinical features and results of treatment with levodopa . J Neurol Neurosurg Psychiatry \n1988 ;51 :850 ‐854 .\n2900293 \n8 \n\nFriedman \nJH \n, \n\nTrieschmann \nME \n, \n\nFernandez \nHH \n. Drug‐induced parkinsonism In: Factor SA , Lang AE , Weiner WJ , eds. Drug Induced Movement Disorders . 2nd ed. Blackwell Futura ; 2005 :103–139.\n\n9 \n\nRemington \nG \n, \n\nKapur \nS \n. The pharmacology of typical and atypical antipsychotics In: Factor SA , Lang AE , Weiner WJ , eds. Drug Induced Movement Disorders . 2nd ed. Blackwell Futura ; 2005 :55 ‐71 .\n\n10 \n\nRajput \nAH \n, \n\nRozdilsky \nB \n, \n\nHornykiewicz \nO \n, \n\nShannak \nK \n, \n\nLee \nT \n, \n\nSeeman \nP \n. Reversible drug‐induced parkinsonism: clinicopathologic study of two cases . Arch Neurol \n1982 ;39 :644 ‐646 .\n6127066 \n11 \n\nBower \nJH \n, \n\nDickson \nDW \n, \n\nTaylor \nL \n, \n\nMaraganore \nDM \n, \n\nRocca \nWA \n. Clinical correlates of the pathology underlying parkinsonism: a population perspective . Mov Disord \n2002 ;17 :910 ‐916 .\n12360539 \n12 \n\nLorberboym \nM \n, \n\nTreves \nTA \n, \n\nMelamed \nE \n, \n\nLampl \nY \n, \n\nHellmann \nM \n, \n\nDjaldetti \nR \n. [23I]‐FP/CIT SPECT imaging for distinguishing drug‐induced parkinsonism from Parkinson's disease . Mov Disord \n2006 ;21 :510 ‐514 .\n16250023 \n13 \n\nTinazzi \nM \n, \n\nMargante \nF \n, \n\nMatinella \nA \n, et al. Imaging of the dopamine transporter predicts pattern of disease progression and response to levodopa in patients with schizophrenia and parkinsonism: a 2‐year follow‐up multicenter study . Schizophr Res \n2014 ;152 :344 ‐349 .\n24369987 \n14 \n\nRajput \nAH \n, \n\nVoll \nA \n, \n\nRajput \nML \n, \n\nRobinson \nCA \n, \n\nRajput \nA \n. Course in Parkinson's disease subtypes: a 39‐year clinicopathological study . Neurology \n2009 ;73 :206 ‐212 .\n19620608 \n15 \n\nWebster \nDD \n. Critical analysis of disability in Parkinson's disease . Mod Treat \n1968 ;5 :257 ‐282 .\n5655944 \n16 \n\nFahn \nS \n, \n\nElton \nRL \n, UPDRS Development Committee. Unified Parkinson's disease rating scale In: Fahn S , Marsden CD , Calne D , Goldstein M , eds. Recent Developments in Parkinson's Disease , 2 ed. Florham Park, NJ : Macmillan Healthcare Information ; 1987 :153 ‐305 .\n\n17 \n\nHoehn \nMM \n, \n\nYahr \nMD \n. Parkinsonism: onset, progression, and mortality . Neurology \n1967 ;17 :427 ‐442 .\n6067254 \n18 \n\nMontine \nTJ \n, \n\nPhelps \nCH \n, \n\nBeach \nTG \n, et al. National Institute on Aging‐Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach . Acta Neuropathol \n2012 ;123 :1 ‐11 .\n22101365 \n19 \n\nEhringer \nH \n, \n\nHornykiewicz \nO \n. Distribution of noradrenaline and dopamine (3‐hydroxytyramine) in human brain: their behaviour in extrapyramidal system diseases . Klin Wochenschr \n1960 ;38 :1236 ‐1239 .\n13726012 \n20 \n\nGelb \nDJ \n, \n\nOliver \nE \n, \n\nGilman \nS \n. Diagnostic criteria for Parkinson disease . Arch Neurol \n1999 ;56 :33 ‐39 .\n9923759 \n21 \n\nJellinger \nK \n. The pathology of parkinsonism In: Marsden CD , Fahn S , eds. Movement Disorders 2 . London : Butterworths ; 1987 :124 ‐165 .\n\n22 \n\nFarde \nL \n, \n\nNordstrom \nAL \n, \n\nWiesel \nFA \n, \n\nPauli \nS \n, \n\nHalldin \nC \n, \n\nSedvall \nG \n. Positron emission tomogrphic analysis of central D1 and D2 receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects . Arch Gen Psychiatry \n1992 ;49 :538 ‐544 .\n1352677 \n23 \n\nErro \nR \n, \n\nBhatia \nKP \n, \n\nTinazzi \nM \n. Parkinsonism following neuroleptic exposure: a double‐hit hypothesis? \nMov Disord \n2015 ;30 :780 ‐785 .\n25801826 \n24 \n\nMorley \nJ \n, \n\nPawlowski \nS \n, \n\nPantelyat \nA \n, \n\nKesari \nA \n, \n\nMaina \nI \n, \n\nDuda \nJ \n. Olfactory impairment and other features of Parkinson disease that predict persistent drug‐induced parkinsonism . Neurology \n2014 ;82 :P3.080 .\n\n25 \n\nKim \nJS \n, \n\nOh \nYS \n, \n\nKim \nYI \n, et al. Combined use of 123l‐metaiodobenzylguanidine (MIBG) scintigraphy and dopamine transporter (DAT) positron emission tomography (PET) predicts prognosis in drug‐induced Parkinsonism (DIP): a 2‐year follow‐up study . Arch Gerontol Geriatr \n2013 ;56 :124 ‐128 .\n22633343 \n26 \n\nBrigo \nF \n, \n\nError \nR \n, \n\nMarangi \nA \n, \n\nBhatia \nK \n, \n\nTinazzi \nM \n. Differentiating drug‐induced parkinsonism from Parkinson's disease: an update on non‐motor symptoms and investigations . Parkinsonism Relat Disord \n2014 ;20 :808 ‐814 .\n24935237 \n27 \n\nAlvord \nEC , Jr.\n, \n\nForno \nLS \n, \n\nKusske \nJA \n, \n\nKauffman \nRJ \n, \n\nRhodes \nJS \n, \n\nGoetowski \nCR \n. The pathology of parkinsonism: a comparison of degenerations in cerebral cortex and brainstem In: McDowell FH , Barbeau A , eds. Advances in Neurology , Vol. 5 \nNew York : Raven ; 1974 :175 ‐193 .\n\n28 \n\nFearnley \nJM \n, \n\nLees \nAJ \n. Ageing and Parkinson's disease: substantia nigra regional selectivity . Brain \n1991 ;114 :2283 ‐2301 .\n1933245 \n29 \n\nPakkenberg \nB \n, \n\nMoller \nA \n, \n\nGundersen \nHJ \n, \n\nMouritzen Dam \nA \n, \n\nPakkenberg \nH \n. The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method . J Neurol Neurosurg Psychiatry \n1991 ;54 :30 ‐33 .\n2010756 \n30 \n\nKhot \nV \n, \n\nEgan \nMF \n, \n\nHyde \nTM \n, \n\nWyatt \nRJ \n. Neuroleptics and classic tardive dyskinesia In: Factor SA , Lang AE , Weiner WJ , eds. Drug Induced Movement Disorders . 2nd ed. Blackwell Futura ; 2005 :121 ‐166 .\n\n31 \n\nSethi \nKD \n, \n\nZamrini \nEY \n. Asymmetry in clinical featurse of drug‐induced parkinsonism . J Neuropsychiatry Clin Neurosci \n1990 ;2 :64 ‐66 .\n1983774 \n32 \n\nMagnus \nRV \n. A comparison of biperiden hydrochloride (Akineton) benzhexol (Artane) in the treatment of drug‐induced parkinsonism . J Int Med Res \n1980 ;8 :343 ‐346 .\n7418951 \n33 \n\nFann \nWE \n, \n\nLake \nCR \n. Amantadine vs trihexyphenidyl in the treatment of neuroleptic‐induced parkinsonism . Am J Psychiatry \n1976 ;133 :940 ‐943 .\n782262\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0885-3185",
"issue": "31(3)",
"journal": "Movement disorders : official journal of the Movement Disorder Society",
"keywords": "drug induced; neuroleptic-induced; parkinsonism; pathology; substantia nigra",
"medline_ta": "Mov Disord",
"mesh_terms": "D000368:Aged; D014150:Antipsychotic Agents; D015259:Dopamine Agents; D006801:Humans; D007980:Levodopa; D016631:Lewy Bodies; D008297:Male; D008875:Middle Aged; D010302:Parkinson Disease, Secondary; D013378:Substantia Nigra",
"nlm_unique_id": "8610688",
"other_id": null,
"pages": "360-5",
"pmc": null,
"pmid": "26660063",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article",
"references": "24369987;19620608;6067254;24935237;6127066;25801826;1352677;22633343;7418951;7597368;6333204;13726012;16482566;22101365;23540800;9923759;4374061;12360539;16250023;2900293;5655944;1933245;1983774;782262;2010756;8714170",
"title": "Neuroleptic-induced Parkinsonism: Clinicopathological study.",
"title_normalized": "neuroleptic induced parkinsonism clinicopathological study"
} | [
{
"companynumb": "CA-WATSON-2016-09176",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
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... |
{
"abstract": "BACKGROUND\nThough insulin has no upper limit in dosage, we do not encounter very high dose requirements too often. The reported case is the first in Bangladesh to require more than 1000 international units (IU) of subcutaneous insulin per day.\n\n\nMETHODS\nA 44-year old male diabetic patient from Bangladesh presented with unusually uncontrolled diabetes mellitus due to extreme insulin resistance. Despite dramatic increase in insulin step by step up to 1110 IU of concomitant short and intermediate acting insulin per day by subcutaneous route, his blood glucose remained over 12 mmol/L persistently, in all the fasting, pre-prandial, postprandial and random samples. He was also treated with several oral hypoglycemic agents including metformin, vildagliptin, glimepiride, pioglitazone and miglitol along with insulin but blood glucose levels remained almost unchanged. However, intravenous infusion of insulin over 4 hours caused a plummet in the glucose level. His blood test for insulin autoantibody was negative.\n\n\nCONCLUSIONS\nThis paper provides a scope to review literatures on extreme subcutaneous insulin resistance and its management. It also reveals the limitations of management due to lack of facilities in an underdeveloped country, which hinders proper exploration to many medical issues.",
"affiliations": "Department of Endocrinology, Dhaka Medical College Hospital, Dhaka, Bangladesh.;Department of Endocrinology, Dhaka Medical College Hospital, Dhaka, Bangladesh.;Department of Endocrinology, Dhaka Medical College Hospital, Dhaka, Bangladesh.;Department of Endocrinology, Dhaka Medical College Hospital, Dhaka, Bangladesh.;Department of Endocrinology, Dhaka Medical College Hospital, Dhaka, Bangladesh.",
"authors": "Ahmed|Zuhayer|Z|;Prasad|Indrajit|I|;Rahman|Hafizur|H|;Ansari|Jalil|J|;Hassan|Khaled|K|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": "10.1515/rjdnmd-2016-0025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2068-8245",
"issue": "23(2)",
"journal": "Romanian journal of diabetes, nutrition, & metabolic diseases",
"keywords": "Diabetes Mellitus; Insulin Resistance; Subcutaneous Injection",
"medline_ta": "Rom J Diabetes Nutr Metab Dis",
"mesh_terms": null,
"nlm_unique_id": "101540593",
"other_id": null,
"pages": "209-213",
"pmc": null,
"pmid": "27917299",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article",
"references": "6183163;7983790;11723102;17065692;7671097;26855961;19328577;20724017;109340;23424687;18308674",
"title": "A Male with Extreme Subcutaneous Insulin Resistance: A Case Report.",
"title_normalized": "a male with extreme subcutaneous insulin resistance a case report"
} | [
{
"companynumb": "BD-IMPAX LABORATORIES, INC-2017-IPXL-01265",
"fulfillexpeditecriteria": "1",
"occurcountry": "BD",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "INSULIN NOS"
},
"drugadditi... |
{
"abstract": "OBJECTIVE\nSkin metastases from gastric cancer are rare and usually occur very late in the course of the disease. The most common metastatic sites liver, the peritoneal surfaces, and the non regional or distant lymph nodes.\n\n\nMETHODS\nIn this case we report the short-term survival of a 67-year-old man complined of multiple nodular lesions in various part of his skin. Histology showed a metastatic signet ring cell adenocarsinoma. Esophagogastroduodenoscopy was performed and a crater- like ulcer, about 3 cm in diameter, was observed on the anterior part of the stomach corpus distal. A biopsy specimen was obtained, and histopathological findings were consistent with gastric signet-ring cell carcinoma. XELOX chemotherapy regimen was initiated for the patient.\n\n\nCONCLUSIONS\nSkin metastasis of gastric adenocarcinoma is a rare condition with a poor prognosis. It may be the first manifestation of a clinically silent visceral cancer or may represent a recurrence of an internal malignancy.",
"affiliations": "Trakya University School of Medicine, Edirne, Turkey.;Department of Pathology, Trakya University School of Medicine, Edirne, Turkey.;Department of Pathology, Trakya University School of Medicine, Edirne, Turkey.;Department of Dermatology, Çanakkale 18 Mart School of Medicine, Çanakkale, Turkey.;Division of Medical Oncology, Department of Internal Medicine, Trakya University School of Medicine, Edirne, Turkey. aligkyer@hotmail.com.",
"authors": "Bulut|Ezgi|E|;Taştekin|Ebru|E|;Topuz|Canberk|C|;Öztürk|Sevgi|S|;Gökyer|Ali|A|http://orcid.org/0000-0002-1653-6155",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12029-021-00747-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": null,
"journal": "Journal of gastrointestinal cancer",
"keywords": "Nodular lesion; Signet-ring cell gastric carcinoma; Skin metastasis",
"medline_ta": "J Gastrointest Cancer",
"mesh_terms": null,
"nlm_unique_id": "101479627",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34786642",
"pubdate": "2021-11-16",
"publication_types": "D016428:Journal Article",
"references": "22927530;12914385;19538484",
"title": "Exceptional Variant with Distant Cutaneous Metastasis as the First Clinical Sign in Gastric Signet-Ring Carcinoma.",
"title_normalized": "exceptional variant with distant cutaneous metastasis as the first clinical sign in gastric signet ring carcinoma"
} | [
{
"companynumb": "TR-ROCHE-2968969",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "4",
"dru... |
{
"abstract": "Plasmablastic lymphoma (PBL) is a rare and aggressive CD20-negative lymphoma. Despite improvements of the biology behind PBL, it still represents a challenge from the diagnostic and therapeutic perspectives for pathologists and clinicians. PBL is characterized by high rates of relapse and short median survival with standard approaches. Here, we report the use of the combination of bortezomib and infusional etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (V-EPOCH) in three patients with PBL; two were HIV-positive and one was HIV-negative. All three patients obtained a durable complete response to V-EPOCH with survival times of 24, 18 and 12 months respectively.",
"affiliations": "Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.",
"authors": "Castillo|Jorge J|JJ|;Reagan|John L|JL|;Sikov|William M|WM|;Winer|Eric S|ES|",
"chemical_list": "D015415:Biomarkers; D001897:Boronic Acids; D011719:Pyrazines; D019788:Fluorodeoxyglucose F18; D014750:Vincristine; D000069286:Bortezomib; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.13300",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "169(3)",
"journal": "British journal of haematology",
"keywords": "EPOCH; Plasmablastic lymphoma; bortezomib",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D001897:Boronic Acids; D000069286:Bortezomib; D003520:Cyclophosphamide; D004317:Doxorubicin; D005047:Etoposide; D019788:Fluorodeoxyglucose F18; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D049268:Positron-Emission Tomography; D011241:Prednisone; D011719:Pyrazines; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "352-5",
"pmc": null,
"pmid": "25612847",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bortezomib in combination with infusional dose-adjusted EPOCH for the treatment of plasmablastic lymphoma.",
"title_normalized": "bortezomib in combination with infusional dose adjusted epoch for the treatment of plasmablastic lymphoma"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-98193",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drug... |
{
"abstract": "Therapeutic plasma exchange is a procedure used to remove pathologic substances from a patient's blood that has proven useful in some cases of drug overdose. Overdose by calcium channel blocker antihypertensive agents has been shown to be a cause of significant morbidity and can often times prove fatal. These agents cause systemic hypotension by inhibiting cell membrane calcium channels, which leads to a slowing of intracardiac electric conduction with consequent impairment of myocardial function and widespread vasodilation. Shock and metabolic acidosis result from the persistent hypotension. In high doses, calcium channel blocking agents cause insulin resistance. We describe the case of a previously healthy young woman who ingested a massive dose of amlodipine and was treated by therapeutic plasma exchange after non-responsiveness to conventional therapy. The case illustrates the need for utilization of therapeutic plasma exchange in the emergency management of certain cases of severe amlodipine overdose.",
"affiliations": "Department of Pathology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.",
"authors": "Ezidiegwu|Christian|C|;Spektor|Zhanna|Z|;Nasr|Michel R|MR|;Kelly|Karen C|KC|;Rosales|Lazaro G|LG|",
"chemical_list": "D002121:Calcium Channel Blockers; D017311:Amlodipine",
"country": "Australia",
"delete": false,
"doi": "10.1111/j.1744-9987.2008.00567.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1744-9979",
"issue": "12(2)",
"journal": "Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy",
"keywords": null,
"medline_ta": "Ther Apher Dial",
"mesh_terms": "D000328:Adult; D017311:Amlodipine; D002121:Calcium Channel Blockers; D062787:Drug Overdose; D005260:Female; D006801:Humans; D010951:Plasma Exchange; D013406:Suicide, Attempted; D016896:Treatment Outcome",
"nlm_unique_id": "101181252",
"other_id": null,
"pages": "180-4",
"pmc": null,
"pmid": "18387170",
"pubdate": "2008-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case report on the role of plasma exchange in the management of a massive amlodipine besylate intoxication.",
"title_normalized": "a case report on the role of plasma exchange in the management of a massive amlodipine besylate intoxication"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2022-00722",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
... |
{
"abstract": "OBJECTIVE\nTo report a case of hepatotoxicity when niacin was used by a patient with HIV to pass a drug test.\n\n\nMETHODS\nNiacin is a soluble pyridine derivative widely used in the management of dyslipidemia. Common adverse effects include flushing, nausea, gastrointestinal discomfort, and hepatotoxicity. The use of niacin for nonmedical purposes has been increasing in prevalence in recent years, particularly in attempts to alter or mask results of urine drug tests. Although there is no scientific evidence that niacin can alter a urine drug screen result, easily retrievable information exists on the Internet touting niacin as a potential way to prevent detection of tetrahydrocannabinol (THC). The following report describes a case of hepatotoxicity in an HIV-infected adult who reported using niacin to mask THC in urine drug screen results.\n\n\nRESULTS\nThe patient developed marked elevations in his liver enzymes (aspartate aminotransferase greater than 25 times the upper limit of normal and alanine aminotransferase greater than 3 times the upper limit of normal) that resolved after discontinuation of the drug. Because of the patient's self-reported use and discontinuation of niacin, the Naranjo Adverse Drug Reaction Probability Scale demonstrated a \"definite\" relationship between the development of hepatotoxicity and the ingestion of over-the-counter sustained-release niacin. The patient did not develop further clinical abnormalities proposed to be secondary to niacin toxicity in previously published case reports, including glucose abnormalities, coagulopathies, metabolic acidosis, QTc prolongation, and myalgias.\n\n\nCONCLUSIONS\nHealth care providers should be aware of this nonmedical use of niacin to alter or mask a drug test, especially when discerning the cause of hepatotoxicity. In addition, pharmacists in the community setting should be aware of this use of niacin when encountering patients purchasing over-the-counter niacin, particularly in patients who may be more likely to use illicit substances.",
"affiliations": null,
"authors": "Durham|Spencer H|SH|;Covington|Elizabeth W|EW|;Clemmons|Kimberley J|KJ|",
"chemical_list": "D009525:Niacin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.japh.2018.04.033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1086-5802",
"issue": "58(5)",
"journal": "Journal of the American Pharmacists Association : JAPhA",
"keywords": null,
"medline_ta": "J Am Pharm Assoc (2003)",
"mesh_terms": "D000328:Adult; D056486:Chemical and Drug Induced Liver Injury; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008297:Male; D009525:Niacin; D015813:Substance Abuse Detection",
"nlm_unique_id": "101176252",
"other_id": null,
"pages": "564-567",
"pmc": null,
"pmid": "29941333",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatotoxicity upon using niacin to pass a drug test: A case report.",
"title_normalized": "hepatotoxicity upon using niacin to pass a drug test a case report"
} | [
{
"companynumb": "US-TEVA-2018-US-961730",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": null,
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthoriz... |
{
"abstract": "Lactic acidosis is a common complication of status asthmaticus in adults. However, data is sparse in children. The aim of this study was to describe the prevalence and risk factors for lactic acidosis in children hospitalised for acute moderate or severe asthma. A total of 154 children 2-17 years of age were enrolled in a prospective observational study conducted in a tertiary hospital. All had capillary blood gas assessment 4 h after the first dose of salbutamol in hospital. The primary endpoint was the prevalence of lactic acidosis. Potential contributing factors such as age, sex, BMI, initial degree of asthma severity, type of salbutamol administration (nebuliser or inhaler), steroids, ipratropium bromide, and glucose-containing maintenance fluid represented secondary endpoints. All in all, 87% of patients had hyperlactatemia (lactate concentration > 2.2 mmol/l). Lactic acidosis (lactate concentration > 5 mmol/l and anion gap ≥ 16 mmol/l) was observed in 26%. In multivariate analysis, age more than 6 years (OR = 2.8, 95% CI 1.2-6.6), glycemia above 11 mmol/l (OR = 3.2 95% CI 1.4-7.4), and salbutamol administered by nebuliser (OR = 10, 95% CI 2.7-47) were identified as risk factors for lactic acidosis in children with moderate or severe asthma.Conclusion: Lactic acidosis is a frequent and early complication of acute moderate or severe asthma in children. What is Known: • Lactic acidosis during acute asthma is associated with b2-mimetics administration. • Salbutamol-related lactic acidosis is self-limited but important to recognise, as compensatory hyperventilation of lactic acidosis can be mistaken for respiratory worsening and lead to inappropriate supplemental bronchodilator administration. What is New: • Lactic acidosis is a frequent complication of acute asthma in the paediatric population. • Age older than 6 years, hyperglycaemia, and nebulised salbutamol are risk factors for lactic acidosis during asthma.",
"affiliations": "Children's Hospital, Service of Paediatrics, Department of Woman, Mother, Child, Lausanne University Hospital, University of Lausanne, Chemin de Montétan 16, 1004, Lausanne, Switzerland.;Respiratory Unit, Service of Paediatrics, Department of Woman, Mother, Child, Lausanne University Hospital, University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland.;Service of Pharmacy, Lausanne University Hospital, University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland.;Children's Hospital, Service of Paediatrics, Department of Woman, Mother, Child, Lausanne University Hospital, University of Lausanne, Chemin de Montétan 16, 1004, Lausanne, Switzerland.;Children's Hospital, Service of Paediatrics, Department of Woman, Mother, Child, Lausanne University Hospital, University of Lausanne, Chemin de Montétan 16, 1004, Lausanne, Switzerland. jean-yves.pauchard@chuv.ch.",
"authors": "Ruman-Colombier|Marta|M|http://orcid.org/0000-0003-2841-5956;Rochat Guignard|Isabelle|I|;Di Paolo|Ermindo R|ER|;Gehri|Mario|M|;Pauchard|Jean-Yves|JY|",
"chemical_list": "D000420:Albuterol",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00431-020-03834-x",
"fulltext": "\n==== Front\nEur J Pediatr\nEur J Pediatr\nEuropean Journal of Pediatrics\n0340-6199\n1432-1076\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n33089387\n3834\n10.1007/s00431-020-03834-x\nOriginal Article\nPrevalence and risk factors of lactic acidosis in children with acute moderate and severe asthma, a prospective observational study\nhttp://orcid.org/0000-0003-2841-5956\nRuman-Colombier Marta marta.ruman@hotmail.fr\n\n1\nRochat Guignard Isabelle isabelle.rochat@chuv.ch\n\n2\nDi Paolo Ermindo R. ermindo.di-paolo@chuv.ch\n\n3\nGehri Mario mario.gehri@chuv.ch\n\n1\nPauchard Jean-Yves jean-yves.pauchard@chuv.ch\n\n1\n1 grid.9851.5 0000 0001 2165 4204 Children’s Hospital, Service of Paediatrics, Department of Woman, Mother, Child, Lausanne University Hospital, University of Lausanne, Chemin de Montétan 16, 1004 Lausanne, Switzerland\n2 grid.9851.5 0000 0001 2165 4204 Respiratory Unit, Service of Paediatrics, Department of Woman, Mother, Child, Lausanne University Hospital, University of Lausanne, Rue du Bugnon 46, 1011 Lausanne, Switzerland\n3 grid.9851.5 0000 0001 2165 4204 Service of Pharmacy, Lausanne University Hospital, University of Lausanne, Rue du Bugnon 46, 1011 Lausanne, Switzerland\nCommunicated by Peter de Winter\n\n22 10 2020\n22 10 2020\n2021\n180 4 11251131\n27 8 2020\n28 9 2020\n9 10 2020\n© The Author(s) 2020, corrected publication 2020\nOpen 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nLactic acidosis is a common complication of status asthmaticus in adults. However, data is sparse in children. The aim of this study was to describe the prevalence and risk factors for lactic acidosis in children hospitalised for acute moderate or severe asthma. A total of 154 children 2–17 years of age were enrolled in a prospective observational study conducted in a tertiary hospital. All had capillary blood gas assessment 4 h after the first dose of salbutamol in hospital. The primary endpoint was the prevalence of lactic acidosis. Potential contributing factors such as age, sex, BMI, initial degree of asthma severity, type of salbutamol administration (nebuliser or inhaler), steroids, ipratropium bromide, and glucose-containing maintenance fluid represented secondary endpoints. All in all, 87% of patients had hyperlactatemia (lactate concentration > 2.2 mmol/l). Lactic acidosis (lactate concentration > 5 mmol/l and anion gap ≥ 16 mmol/l) was observed in 26%. In multivariate analysis, age more than 6 years (OR = 2.8, 95% CI 1.2–6.6), glycemia above 11 mmol/l (OR = 3.2 95% CI 1.4–7.4), and salbutamol administered by nebuliser (OR = 10, 95% CI 2.7–47) were identified as risk factors for lactic acidosis in children with moderate or severe asthma.\n\nConclusion: Lactic acidosis is a frequent and early complication of acute moderate or severe asthma in children.What is Known:\n\n• Lactic acidosis during acute asthma is associated with b2-mimetics administration.\n\n• Salbutamol-related lactic acidosis is self-limited but important to recognise, as compensatory hyperventilation of lactic acidosis can be mistaken for respiratory worsening and lead to inappropriate supplemental bronchodilator administration.\n\nWhat is New:\n\n• Lactic acidosis is a frequent complication of acute asthma in the paediatric population.\n\n• Age older than 6 years, hyperglycaemia, and nebulised salbutamol are risk factors for lactic acidosis during asthma.\n\n\t\n\nKeywords\n\nLactic acidosis\nSalbutamol\nAsthma\nPaediatrics\nUniversity of LausanneOpen access funding provided by University of Lausanne\n\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2021\n==== Body\nIntroduction\n\nAsthma is characterised by chronic airway inflammation and hyperresponsiveness. During an acute exacerbation, inhomogeneous airway narrowing and obstruction lead to hypoxemia. Compensatory hyperventilation mediated by pulmonary mechanoreceptors conducts to respiratory alkalosis, the most frequent acid-base disturbance observed in acute asthma. If not treated properly, progressive respiratory insufficiency may occur with hypercapnia and respiratory acidosis [1].\n\nLactic acidosis is another blood gas alteration observed during moderate or severe asthma. Multiple mechanisms have been proposed. Some have evoked reduced tissue perfusion or overuse of respiratory muscles under hypoxic conditions [2]. Others have suggested that b2-adrenergic agents like bronchodilators used to treat asthma lead to increased gluconeogenesis, glycogenolysis, glycolysis, and lipolysis, cumulating in lactic acid production [3–6]. Depending on the mechanism of lactate formation, two types of lactic acidosis exist that can be distinguished calculating the lactate to pyruvate ratio (L/P). Type A (L/P ratio < 25/1) is related to impaired oxygenation, and type B (L/P > 25/1) is caused by excessive b2-receptor stimulation [6].\n\nLactic acidosis is now a well-known complication of status asthmaticus in adults. Case reports and some retrospective and rare prospective studies describe a transient lactic acidosis as a side effect of high doses b2-agonists used in acute asthma treatment. However, data is rare in children [7].\n\nEven if lactic acidosis during asthma is a self-limited condition, it has an impact on assessment and management of respiratory distress. Compensatory hyperventilation of lactic acidosis is often mistaken as a sign of respiratory worsening and leads to inappropriate escalation of bronchodilator therapy, increasing morbidity and mortality [8, 9].\n\nThe aim of our study is to describe the prevalence and risk factors contributing to lactic acidosis in children treated with salbutamol for moderate or severe acute asthma.\n\nMaterials and methods\n\nStudy design\n\nThis prospective observational monocentric prevalence study was conducted from May 01, 2017, to April 30, 2019, in a tertiary care children’s hospital.\n\nPatients\n\nChildren and adolescents 2 to 17 years of age hospitalised for acute moderate or severe asthma were eligible for the study. At our institution, patients requiring inhaled b2-agonists minimum every 2 h fill the indications to be admitted, and an initial degree of asthma severity based on PRAM score is part of the clinical evaluation [10]. Exclusion criteria were as follows: parent’s refusal, metabolic disorder, shock, sepsis, renal or hepatic insufficiency, diabetes mellitus, and cancer.\n\nData collection\n\nBasic clinical data included age; body mass index (BMI); sex; initial degree of asthma severity; dose and type of salbutamol administration, of oral or intravenous steroids, and of inhaled ipratropium bromide; and type of maintenance intravenous fluid. Hypoxemia (defined as SpO2 < 92%) was rigorously assessed and treated. Salbutamol was administered by using a metered dose inhaler (pMDI) (through a valved holding chamber with a mouthpiece or a mask, when necessary, AeroChamber Plus Flow Vu®, 1push = 100 cmg of salbutamol) or nebuliser (aerosol solution of 5 mg of salbutamol in 5 ml of normal saline solution NaCl 0.9%). Three types of maintenance fluid were used: 91% of G10% and 9% of NaCl 10% mix, 91% of G5% and 9% of NaCl 10% mix, or normal saline solution (NaCl 0.9%). Capillary blood sample was drawn 4 h after the first administration of salbutamol in hospital, or in case of secondary appearance of tachypnoea or worsening of the respiratory status during hospitalisation. Oxygen saturation was measured by pulse oximetry before blood extraction. Blood gas assessment including the measurement of pH, pCO2, HCO3, base excess (BE), and glucose and lactate concentrations was performed on a RAPIDPoint500, Siemens, gasometer. One millilitre of blood was used for analysis. Hyperlactatemia was defined as lactate concentration > 2.2 mmol/l. Lactic acidosis was defined as lactate > 5 mmol/l and anion gap (AG) ≥ 16mmol/l (AG = Na + K-HC03-Cl), non-compensated lactic acidosis as pH < 7.35, and lactate concentration as > 5 mmol/l. Compensated lactic acidosis represented lactate concentration > 5 mmol/l, pH ≥ 7.35, and pCO2 < 35 mmHg. Hyperglycaemia was characterised as glucose > 11 mmol/l.\n\nOutcomes\n\nThe primary outcome was the prevalence of lactic acidosis. Secondary outcomes included other contributing factors like age, sex, BMI, initial degree of severity, salbutamol administered by inhaler or by nebuliser, steroids, ipratropium bromide, and glucose-containing maintenance fluid.\n\nEthical considerations\n\nPatients older than 11 years and parents or legal guardians were informed orally and in writing about the research project by one of the doctors working in the paediatric emergency room during admission to the hospital. Adolescents ≥ 14 years and their parents or legal guardians provided informed consent. The study was approved by the institutional ethics committee (Swiss Ethics, protocol number 2016-01320).\n\nStatistical analysis\n\nCategorical data were described as absolute counts. Percentages and continuous data we described as means and standard deviations (SD). The Mann–Whitney U test was used to compare the means. We firstly realised simple logistic regression and calculated odd ratio for all potential risk factors. All variables potentially able to influence lactic acidosis (p < 0.2) were used as covariates in multiple logistic regression. Pearson’s correlation coefficient was used to measure statistical relationship between the levels of lactates and doses of salbutamol. All statistical analysis was performed with the Epi Info version 7.2.3.1 software (Centres for Disease Control and Prevention).\n\nResults\n\nAmong 627 patients from 2 to 17 years of age hospitalised for moderate or severe asthma, 174 received information about the study. Eleven did not provided informed consent, and 9 did not have blood sample for technical problem. Finally, 154 patients were included in the study (Fig. 1)Fig. 1 Flow chart of study population\n\nAmong 154 patients, 99 (64%) were aged from 2 to 6 years and 55 (36%) were more than 6. A total of 13% were obese (P > 97‰). Sex ratio was 1.92 male to female. Forty-three percent of episodes were categorised as severe (PRAM > 8) and 57% as moderate (PRAM 4–8). Salbutamol was administered by pMDI with holding chamber alone in 30% of cases (46/154) or by nebuliser (alone or associated with pMDI administration) in 70% (108/154) (Table 1). Mean overall dose of salbutamol administered during the first 4 h after hospital admission was 12 ± 10 mg. The mean dose was similar in older (> 6 years of age) and younger groups (≤ 6 years of age), 12.3 ± 10.5 mg and 11.8 ± 9.8 mg respectively (p = 0.59). Patients with severe asthma received higher doses of salbutamol (mean 19 ± 10.1 mg) compared to patients with moderate asthma (mean 6.67 ± 5.7 mg), p < 0.0005. When delivered by nebulisation (1 nebulisation = 5 mg of salbutamol), the mean dose of salbutamol was 16 ± 9.3 mg versus 2.4 ± 1.2 mg when delivered by inhaler (1 push = 100 cmg), p < 0.0005.Table 1 Characteristics of study population\n\nCharacteristics\tn = 154\t%\t\nAge ≥ 6 years of age\t55\t36\t\nFemale sex\t51\t33\t\nSevere asthma (PRAM 8–12)\t66\t43\t\nModerate asthma (PRAM 4–7)\t88\t57\t\nPICU admission\t0\t0\t\nObesity\t20\t13\t\nSalbutamol administered by inhaler\t46\t30\t\nSalbutamol administered by nebuliser\t108\t70\t\nIntravenous salbutamol\t0\t0\t\nAminophylline\t0\t0\t\nCorticoids\t146\t95\t\nIpratropium bromide\t23\t15\t\nGlucose-containing maintenance fluid\t30\t19\t\nHyperlactatemia > 2.2 mmol/l\t134\t87\t\nHyperlactatemia > 5 mmol/l\t40\t26\t\nNon-compensated lactic acidosis (lactate > 5 mmol/l and pH < 7.35 mmHg)\t6\t4\t\nCompensated lactic acidosis (lactate > 5, pH > 7.35, pCO2 < 35 mmHg)\t34\t22\t\nHyperglycaemia\t56\t36\t\n\nAlmost all patients (95%) received corticosteroids with a mean dose of 1.85 ± 0.75 mg/kg. Corticosteroids were mainly administered orally (88%). Twenty-three of 154 patients (15%) received ipratropium bromide. Nineteen percent were perfused with glucose-containing maintenance fluid (91% of G10% and 9% of NaCl 10% mix or 91% of G5% and 9% of NaCl 10%) (Table 1).\n\nAll patients had capillary blood gas analysis 4 h after the first dose of salbutamol administration. Secondary appearance of tachypnoea or worsening of the respiratory status motivated a second blood gas analysis in 13 patients.\n\nMost of the patients (87%) had mild hyperlactatemia (lactate > 2.2 mmol/l). All of patients with lactate concentration > 5 mmol/l (26%) had lactic acidosis (lactate > 5 mmol/l and augmented anion gap AG ≥ 16 mmol/l). Thirty-four (22%) presented compensated lactic acidosis (lactate > 5 mmol/l, pH ≥ 7.35, and pCO2 < 35 mmHg). Only 6 (4%) had pH < 7.35. None had hypercapnia (pCO2 > 40 mmHg) (Table 1).\n\nIn univariate analyses, a significant correlation was found between lactic acidosis and female sex (OR = 2, 95% CI 1–4.2), as well as between lactic acidosis and severe asthma (OR = 4, 95% CI 1.9–8.6). When adjusted on potential confusing factors in multivariate analysis, salbutamol administered by nebuliser (aOR = 10, 95% CI 2.7–47), age older than 6 years (aOR = 2.8, 95% CI 1.2–6.6), and hyperglycaemia (aOR = 3.2 95% CI 1.4–7.4) were related to increased risk of lactic acidosis (Table 2).Table 2 Risk factors of lactic acidosis\n\nRisk factors of lactic acidosis\tNumber of patients (%)\tUnivariate analysis unadjusted OR [95% CI]\tMultivariate analysis adjusted OR [95% CI]\t\nLactic acidosis (yes/non)\tn = 40\tn = 114\t\t\t\nFemale sex\t18 (45)\t33 (29)\t2 [1–4.2]\t1.9 [0.8–4.4]\t\nAge ≥ 6 years of age\t19 (48)\t36 (32)\t1.9 [1–4.1]\t2.8* [1.2–6.6]\t\nSevere asthma\t27 (68)\t39 (34)\t4 [1.9–8.6]\t2 [0.8–5.2]\t\nObesity\t8 (20)\t12 (11)\t2.1 [0.8–5.7]\t2.5 [0.8–8.1]\t\nHyperglycemia (> 11 mmol/l)\t24 (60)\t32 (28)\t3.8 [1.8–8.2]\t3.2* [1.4–7.4]\t\nGlucose-containing maintenance fluid\t8 (20)\t22 (19)\t1.05 [0.4–2.6]\t\t\nCorticoids\t41 (100)\t106 (95)\t\t\t\nIpratropium bromure\t8 (20)\t15 (13)\t1.7 [0.6–4.3]\t\t\nSalbutamol administered by nebulisation\t38 (95)\t70 (61)\t11.9 [2.7–52]\t10* [2.3–47]\t\nOR, odds ratio; CI, confidence interval\n\nNumber of patients was expressed in absolute number and in percentage (%)\n\nAll variables associated with p < 0.2 were included in the multivariate analysis\n\nSignificative findings were marked with an asterisk (*p < 0.05)\n\nLactic acidosis was observed even with low doses of salbutamol (< 0.5 mg/kg). No correlation was found between lactate levels and salbutamol doses (Pearson’s r = 0.17 (SE = 0.24)) (Fig. 2).Fig. 2 Relation between lactate levels and doses of salbutamol\n\nDiscussion\n\nAlthough lactic acidosis is a well-known metabolic disturbance of asthma in adults, data are rare in the paediatric population. To our knowledge, this is the first large prospective study describing prevalence and risk factors for lactic acidosis in children with acute moderate or severe asthma.\n\nA total of 87% (134/154) of our patients had increased blood lactate concentration (lactate > 2.2 mmol/l) 4 h after the first salbutamol dose in hospital. Our findings compare to those of Meert who recorded 83% (62/105) of children with mild hyperlactatemia (lactate> 2.2 mmol/l) during status asthmaticus [5]. Lower prevalence (71%) was found in a retrospective study of 75 children, but the time of lactatemia assessment was not specified [11]. In adults, the prevalence of mild hyperlactatemia (lactate > 2 mmol/l) ranges from 59 in 29 patients with severe asthma 4 to 6 h after therapy beginning [12] to 69.2% at an earlier time point for lactate measurement (about 1 h 25 min after albuterol treatment beginning) [13].\n\nIn paediatric case reports, lactate concentration in asthma-related lactic acidosis ranged from 5.9 to 9.2 mmol/l [8]. Koul documented lactic acidosis with a peak lactate range (5.2–13 mmol/l) 2–8 h after the beginning of aerosol therapy in 4 children 11 to 17 years of age. In our study, lactatemia varied from 1.4 to 9.66 mmol/l 4 h after salbutamol administration, with 26% of patients presenting respiratory-compensated lactic acidosis (lactate > 5 mmol/l and AG ≥ 16 mmol/l, pCO2 < 35 mmHg), consistent with other observations [14]. In a retrospective study of 75 children with acute asthma, metabolic acidosis (pH < 7.35 and BE < − 7) was found in 21% of patients [11]. Available lactate level was > 5 mmol/l in 22% of children. Likewise, Meert identified 28% of 53 patients with metabolic acidosis (pH < 7.35, PCO2 < 35 mmHg, and BE < − 7 mmol/l) during acute asthma, with lactate assessment from 7.2 to 9.3 mmol/l 8 to 24 h after admission [4]. Lastly, lactic acidosis with or without respiratory compensation was identified in 47 of 105 (45%) children with acute asthma [5].\n\nIn critically ill paediatric patients with asthma, acidosis (pH < 7.35) was found in 45% of patients admitted to the intensive care unit (ICU). Only one had metabolic acidosis with hyperlactatemia (4.6 mmol/l 6 h after ICU admission). All the others had acidosis from respiratory origin. However, in these patients, the blood gas determination was realised quite early, within 2 h after emergency room admission, and the dose of salbutamol received was not specified. Yousef did not find metabolic acidosis in eight other episodes of severe respiratory failure attributable to asthma and suggested that lactic acidosis during asthma is not underestimated and children may be more resistant than adults to the development of this complication. He implied that metabolic acidosis reported in previous studies could be rather related to ketosis following suboptimal hydration and caloric management [15]. We cannot support this hypothesis because all our patients unable to feed or to drink received intravenous glucose perfusion.\n\nLactic acidosis implies two mechanisms. Type A is associated with impaired oxygen delivery and/or hypotension. Type B implies underlying disease (liver or renal insufficiency, diabetes mellitus, or cancer), drugs (such as b2-agonists), or inborn errors of metabolism [16]. None of our patients had known chronic underlying disease. Many authors thought lactic acidosis during asthma to be type B [4–6]. Exposition to high doses of bronchodilator-type salbutamol induces hyperadrenergic state and leads to increased lactate production. Presence of lactic acidosis in patients receiving b-2 agonist therapy under optimal oxygenation or artificial ventilation supports this hypothesis [17]. On the biological level, types A and B can be distinguished by the L/P ratio (L/P < 25/1 versus L/ P> 25/1, respectively). Meert calculated the L/P ratio and concluded that type B lactic acidosis is the most frequent in asthma [5]. Even if hyperlactatemia has been described as a marker of mortality in critically ill patients [18], type B lactic acidosis is a self-limiting condition, and no fatal case has been described in children. The spontaneous resolution with decreasing doses or discontinuation of bronchodilator therapy is a rule [4, 5]. In our study, we did not perform pyruvate assessment for technical reasons and thus could not ascertain the mechanism of lactic acidosis precisely, but we highly suggest type B because none was hypoxemic at the time of lactate assessment and a favourable evolution was observed for all.\n\nIn our patients, mean total dose of salbutamol delivered by nebulisation (16 ± 9.3 mg) was almost seven times higher compared to the mean dose delivered by inhalator (2.4 ± 1.2 mg). Higher doses could explain the greater risk of lactic acidosis if salbutamol is administered by nebulisation (RR = 10, 95% CI 2.3–47). According the Cochrane database, other side effects of salbutamol such as increased pulse rate were lower for pMDI in children (mean difference − 5% baseline, 95% CI − 8 to − 2%), as was the risk of developing tremor (RR = 0.64; 95% CI 0.44 to 0.95) [19]. On the other hand, in the paediatric population, only 1–10% nebulised salbutamol reaches the inferior respiratory tract [20–23]. Previous study by Wildhaber has shown equivalent percentages of total lung deposition of radiolabeled salbutamol aerosolised by using either a nebuliser or a pMDI with holding chamber (9.6% and 11% for inhaled and nebulised respectively in children > 4 years of age and 5.4% for both in children < 4 years of age) [22]. In a more recent study, it was shown that the amount of drug delivered from pMDI was higher, ranging from 18.1 to 22.5% in young children (3–5 years of age) [22, 23] and from 35.4 to 54.9% in older children (5–17 years of age) [24]. The authors concluded that most children from 5 years of age could obtain lung deposition of more than 30% using a tidal breathing technique with a pMDI. All our patients receiving salbutamol by inhaler via pMDI used this inhalation technique. We did not find a correlation between lactate levels and doses of salbutamol. The statistical power of a dose correlation would be probably reduced by a large proportion of children with mild hyperlactatemia (2.2–5 mmol/l).\n\nIntravenous, oral, and inhaled salbutamol raise glycogenolysis resulting in hyperglycaemia. Concurrent use of corticosteroids may exacerbate blood glucose level [6]. In our study, almost all patients received concomitant steroids (95%), and 36% of them had hyperglycaemia (glucose > 11 mmol/l). b2-agonist drugs have two main actions. Firstly, b2-adrenergic receptor stimulation increases glycogenolysis, neoglucogenesis, and glycolysis leading to transformation of glucose to glucose 6-phosphate and then to pyruvate. Secondly, b2-agonists enhance lipolysis. Free acids inhibit pyruvate dehydrogenase, an enzyme which normally allows pyruvate to enter the Krebs cycle. In this way, pyruvate to lactate formation is promoted [25]. In our study, we show that hyperglycaemia raises the risk of lactic acidosis during asthma (aOR = 3.2 95% CI 1.4–7.4). On the intracellular level, the rise in glucose blood level via bronchodilator-mediated glycolysis provides more substrate for lactate production. In patients with severe asthma in ICU, serum glucose was measured. Even if 88% of them had hyperglycaemia (> 6.8 mmol/l), the relationship between hyperglycaemia and lactate concentration could not be proved [4]. Our study showed that children aged more than 6 have almost three times more risk to develop lactic acidosis during asthma (aOR = 2.8, 95% CI 1.2–6.6), despite the fact that the mean dose of salbutamol was the same in both age groups (mean of 11.8 mg, SD 9.8 for < 6 years versus 12.3 mg, SD 10.5 for > 6 years). It could be related to the fact that younger children dispose less glucose resources and in consequence less substrate for lactate production.\n\nWe identified other parameters like female sex, severe asthma, and obesity as independent risk factors for lactic acidosis. Even if they could not be confirmed in multivariate analysis, they need to be put forward as our study is the first one to try to identify potential risk factors of lactic acidosis in children with asthma.\n\nOur study has some limits. Firstly, only 25% of potential patients with moderate or severe asthma seen in the emergency room were included, which is a major selection bias. Secondly, we performed only capillary lactate assessment. However, prior research suggests that capillary lactate value accurately reflects arterial lactate [26]. Moreover, this technique is quicker and easier to perform, especially in children. Another limitation is the lack of initial lactate level. It would be interesting to compare the lactate level upon arrival and 4 h later. Finally, the relationship between steroid therapy and lactic acidosis could not be investigated because almost all patient received corticosteroids.\n\nConclusion\n\nLactic acidosis is a frequent and early (H4) complication of asthma observed in children treated with high doses of bronchodilators. Salbutamol administered by nebuliser, age more than 6 years, and hyperglycaemia were identified as risk factors of lactic acidosis during asthma. Even if self-limited, this condition is important to recognise to avoid unnecessary and harmful therapeutic intensification.\n\nAbbreviations\n\nAG Anion gap\n\naOR Adjusted odds ratio\n\nBE Base excess\n\nBMI Body mass index\n\nCI Confidence interval\n\nL/P Lactate to pyruvate ratio\n\nOR Odds ratio\n\npMDI Pressurised metered dose inhaler\n\nSD Standard deviations\n\nAuthors’ contributions\n\nJYP conceived the original idea and supervised the work. .\n\nMR collected and analysed the data, and took the lead in writing the manuscript as well.\n\nIRG provided critical feedback and contributed to the final manuscript.\n\nEDP supervised the pharmacological aspect of the study.\n\nMG was in charge of overall direction.\n\nFunding\n\nOpen access funding provided by University of Lausanne.\n\nCompliance with ethical standards\n\nConflict of interest\n\nThe authors declare that they have no conflict of interest.\n\nEthical approval\n\nThis article does not contain any studies with human participants or animals performed by any of the authors.\n\nInformed consent\n\nInformed consent was obtained from all individual participants included in the study.\n\nThe original online version of this article was revised: The name of the first author of the above mentioned published article has a double last name. The family name should have been “Ruman-Colombier” instead of “Ruman”.\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nChange history\n\n3/8/2021\n\nA Correction to this paper has been published: 10.1007/s00431-020-03863-6\n==== Refs\nReferences\n\n1. Boulet LP Reddel HK Brightling C Brusselle G GINA fosters World Asthma Day 2020 to prevent asthma deaths Am J Physiol Lung Cell Mol Physiol 2020 318 5 L998 L1000 10.1152/ajplung.00075.2020 32191118\n2. Roncoroni AJ Adrougué HJ De Obrutsky CW Marchisio ML Herrera MR Metabolic acidosis in status asthmaticus Respiration 1976 33 2 85 94 10.1159/000193721 778959\n3. Rodrigo GJ Rodrigo C Elevated plasma lactate level associated with high dose inhaled albuterol therapy in acute severe asthma Emerg Med J 2005 22 6 404 408 10.1136/emj.2003.012039 15911945\n4. Meert KL Clark J Sarnaik AP Metabolic acidosis as an underlying mechanism of respiratory distress in children with severe acute asthma Pediatr Crit Care Med 2007 8 6 519 523 10.1097/01.PCC.0000288673.82916.9D 17906597\n5. Meert KL McCaulley L Sarnaik AP Mechanism of lactic acidosis in children with acute severe asthma Pediatr Crit Care Med 2012 13 1 28 31 10.1097/PCC.0b013e3182196aa2 21460758\n6. Vernon C Letourneau JL Lactic acidosis: recognition, kinetics, and associated prognosis Crit Care Clin 2010 26 2 255 283 10.1016/j.ccc.2009.12.007 20381719\n7. Liedtke AG Lava S Milani GP Agostoni C Gilardi V Bianchetti MG Treglia G Faré PB Selective ß2-adrenoceptor agonists and relevant hyperlactatemia: systematic review and meta-analysis J Clin Med 2019 9 1 71 10.3390/jcm9010071\n8. Sharif Z Al-Alawi M Beware of beta! A case of salbutamol-induced lactic acidosis in severe asthma BMJ Case Rep 2018 2018 bcr2017224090 10.1136/bcr-2017-224090\n9. Saxena R Marais G Salbutamol: beware of the paradox! BMJ Case Rep 2010 2010 bcr0120102665 10.1136/bcr.01.2010.2665 22778368\n10. Ducharme FM, Chalut D, Plotnick L, Savdie C, Kudirka D, Zhang X, Meng L, McGillivray D (2008) The pediatric respiratory assessment measure: a valid clinical score for assessing acute asthma severity from toddlers to teenagers. J Pediatr (4):152, 476–480.e1. 10.1016/j.jpeds.2007.08.034\n11. Walsh SA Paget RI Ramnarayan P Salbutamol usage and lactic acidosis in acute severe asthma Pediatr Crit Care Med 2013 14 1 116 117 10.1097/PCC.0b013e31825b8635 23295850\n12. Rabbat A Laaban JP Boussairi A Rochemaure J Hyperlactatemia during acute severe asthma Intensive Care Med 1998 24 4 304 312 10.1007/s001340050572 9609407\n13. Lewis LM Ferguson I House SL Aubuchon K Schneider J Johnson K Matsuda K Albuterol administration is commonly associated with increases in serum lactate in patients with asthma treated for acute exacerbation of asthma Chest 2014 145 1 53 59 10.1378/chest.13-0930 23949578\n14. Koul PB Minarik M Totapally BR Lactic acidosis in children with acute exacerbation of severe asthma Eur J Emerg Med 2007 14 1 56 58 10.1097/01.mej.0000224430.59246.cf 17198331\n15. Yousef E McGeady SJ Lactic acidosis and status asthmaticus: how common in pediatrics? Ann Allergy Asthma Immunol 2002 89 6 585 588 10.1016/S1081-1206(10)62106-0 12487224\n16. Vernon C Letourneau JL Lactic acidosis: recognition, kinetics, and associated prognosis Crit Care Clin 2010 26 2 255 283 10.1016/j.ccc.2009.12.007 20381719\n17. Liem EB Mnookin SC Mahla ME Albuterol-induced lactic acidosis Anesthesiology 2003 99 2 505 506 10.1097/00000542-200308000-00036 12883427\n18. Haas SA Lange T Saugel B Petzoldt M Fuhrmann V Metschke M Kluge S Severe hyperlactatemia, lactate clearance and mortality in unselected critically ill patients Intensive Care Med 2016 42 202 210 10.1007/s00134-015-4127-0 26556617\n19. Cates CJ Welsh EJ Rowe BH Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma Cochrane Database Syst Rev 2013 2013 9 CD000052 10.1002/14651858.CD000052.pub3\n20. Amirav I Luder A Chleechel A Newhouse MT Gorenberg M Lung aerosol deposition in suckling infants Arch Dis Child 2012 97 6 497 501 10.1136/archdischild-2011-301236 22362720\n21. Ditcham W Murdzoska J Zhang G Roller C von Hollen D Nikander K Devadason SG Lung deposition of 99mTc-radiolabeled albuterol delivered through a pressurized metered dose inhaler and spacer with facemask or mouthpiece in children with asthma J Aerosol Med Pulm Drug Deliv 2014 27 Suppl 1 S63 S75 10.1089/jamp.2014.1139 25054483\n22. Wildhaber JH Dore ND Wilson JM Devadason SG Le Souef PN Inhalation therapy in asthma: nebulizer or pressurized metered-dose inhaler with holding chamber? In vivo comparison of lung deposition in children J Pediatr 1999 135 1 28 33 10.1016/S0022-3476(99)70323-9 10393600\n23. Zar HJ Weinberg EG Binns HJ Gallie F Mann MD Lung deposition of aerosol-a comparison of different spacers Arch Dis Child 2000 82 6 495 498 10.1136/adc.82.6.495 10833188\n24. Roller CM Zhang G Troedson RG Leach CL Le Souëf PN Devadason SG Spacer inhalation technique and deposition of extrafine aerosol in asthmatic children Eur Respir J 2007 29 2 299 306 10.1183/09031936.00051106 17005581\n25. Tobin AE Pellizzer AM Santamaria JD Mechanisms by which systemic salbutamol increases ventilation Respirology 2006 11 182 187 10.1111/j.1440-1843.2006.00832.x 16548904\n26. Fauchère JC Bauschatz AS Arlettaz R Zimmermann-Bar U Bucher HU Agreement between capillary and arterial lactate in the newborn Acta Paediatr 2002 91 78 81 10.1111/j.1651-2227.2002.tb01645.x 11883824\n\n",
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"journal": "European journal of pediatrics",
"keywords": "Asthma; Lactic acidosis; Paediatrics; Salbutamol",
"medline_ta": "Eur J Pediatr",
"mesh_terms": "D000140:Acidosis, Lactic; D000293:Adolescent; D000420:Albuterol; D001249:Asthma; D002648:Child; D002675:Child, Preschool; D006801:Humans; D015995:Prevalence; D012307:Risk Factors",
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"title": "Prevalence and risk factors of lactic acidosis in children with acute moderate and severe asthma, a prospective observational study.",
"title_normalized": "prevalence and risk factors of lactic acidosis in children with acute moderate and severe asthma a prospective observational study"
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"abstract": "OBJECTIVE\nRheumatoid arthritis (RA) is a chronic, autoimmune disease characterized by joint destruction. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. This post hoc analysis assessed the safety of tofacitinib in Latin American (LA) patients with RA versus the Rest of World (RoW) population.\n\n\nMETHODS\nData were pooled from 14 clinical studies of tofacitinib: six Phase 2, six Phase 3 and two long-term extension studies. Incidence rates (IRs; patients with events/100 patient-years of treatment exposure) were calculated for safety events of special interest combined across tofacitinib doses. 95% confidence intervals (CI) for IRs were calculated using the maximum likelihood method. Descriptive comparisons were made between LA and RoW (excluding LA) populations.\n\n\nRESULTS\nThis analysis included data from 984 LA patients and 4687 RoW patients. IRs for safety events of special interest were generally similar between LA and RoW populations, with overlapping 95% CIs. IRs for discontinuation due to adverse events, serious infections, tuberculosis, all herpes zoster (HZ), serious HZ, malignancies (excluding non-melanoma skin cancer) and major adverse cardiovascular events were numerically lower for LA versus RoW patients; IR for mortality was numerically higher. No lymphoma was reported in the LA population versus eight cases in the RoW population. Exposure (extent and length) was lower in the LA population (2148.33 patient-years [mean = 2.18 years]) versus RoW (10515.68 patient-years [mean = 2.24 years]).\n\n\nCONCLUSIONS\nThis analysis of pooled data from clinical studies of tofacitinib in patients with RA demonstrates that tofacitinib has a consistent safety profile across LA and RoW patient populations.",
"affiliations": "From the *Clínica Angloamericana, Lima, Peru; †Instituto Peruano del Hueso y la Articulación, Lima, Peru; ‡Hospital Nacional Alberto Sabogal, Bellavista, Callao, Peru; §Instituto de Rehabilitación Psicofísica, Buenos Aires, Argentina; ∥Organización Médica de Investigación, Buenos Aires, Argentina; ¶Section of Rheumatology, Department of Medicine, Hospital Dr I Pirovano, Ciudad Autónoma de Buenos Aires, Argentina; #Universidade Federal do Paraná, Curitiba, Brazil; **Centro de Investigación Clínica de Morelia, Morelia, México; ††Centro de Reumatología y Ortopedia, Barranquilla, Colombia; ‡‡Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia; §§Pfizer Inc., Lima, Peru; ∥∥Pfizer Inc., Buenos Aires, Argentina; ¶¶Pfizer Inc., Collegeville, PA, USA; ##Pfizer Inc., New York, NY, USA; and ***Pfizer Inc., Groton, CT, USA.",
"authors": "Castañeda|Oswaldo M|OM|;Romero|Felix J|FJ|;Salinas|Ariel|A|;Citera|Gustavo|G|;Mysler|Eduardo|E|;Rillo|Oscar|O|;Radominski|Sebastiao C|SC|;Cardiel|Mario H|MH|;Jaller|Juan J|JJ|;Alvarez-Moreno|Carlos|C|;Ponce de Leon|Dario|D|;Castelli|Graciela|G|;García|Erika G|EG|;Kwok|Kenneth|K|;Rojo|Ricardo|R|",
"chemical_list": "D000075242:Janus Kinase Inhibitors; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib",
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"journal": "Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases",
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"mesh_terms": "D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D015994:Incidence; D000075242:Janus Kinase Inhibitors; D007843:Latin America; D000069451:Long Term Adverse Effects; D008297:Male; D008875:Middle Aged; D061214:Patient Safety; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D016896:Treatment Outcome",
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"title": "Safety of Tofacitinib in the Treatment of Rheumatoid Arthritis in Latin America Compared With the Rest of the World Population.",
"title_normalized": "safety of tofacitinib in the treatment of rheumatoid arthritis in latin america compared with the rest of the world population"
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"abstract": "A complex mix of inflammatory and microbial associations underscores the chronic inflammatory condition chronic rhinosinusitis (CRS), and the etiology remains poorly understood. Recent work has begun to delineate between variants (endotypes) of CRS on the basis of inflammatory biomarkers. This study aimed to assess inflammatory patterns in CRS phenotypes, identify putative endotypes of CRS, and to assess inflammatory associations with the sinonasal microbiota. Ten cytokines and six inflammatory cell types were assessed in mucosal biopsies from 93 CRS subjects and 17 controls via cytometric bead array and immunohistochemical techniques. Putative endotypes were identified via cluster analysis of subjects on the basis of inflammatory markers and comorbidities including polyposis, asthma, and aspirin sensitivity. Finally, previously published bacterial data for this cohort were reanalyzed to evaluate associations with inflammatory markers and CRS subtypes. Inflammatory patterns were highly variable within standard CRS phenotypes. Cluster analysis identified eight subject clusters, with strong delineation on the basis of polyposis and asthma, but also subtle distinctions in inflammatory markers. An association was also identified between depletion of several \"health-associated\" bacterial taxa, reduced bacterial diversity and increased overall bacterial load, with markers of inflammation and clinical severity. This study contributes to ongoing efforts to define distinct endotypes of CRS on the basis of underlying inflammatory processes, and also offers compelling evidence of a link between bacterial community dysbiosis and inflammation in CRS. Further resolving the heterogeneity of CRS is vital to inform clinical management and personalized treatment approaches.",
"affiliations": "School of Biological Sciences, The University of Auckland, Auckland, New Zealand.;School of Medicine, The University of Auckland, Auckland, New Zealand.;School of Medicine, The University of Auckland, Auckland, New Zealand.;Department of Statistics, Statistical Consulting Centre, The University of Auckland, Auckland, New Zealand.;School of Medical Sciences, The University of Auckland, Auckland, New Zealand.;School of Medicine, The University of Auckland, Auckland, New Zealand.;School of Medicine, The University of Auckland, Auckland, New Zealand.;School of Medicine, The University of Auckland, Auckland, New Zealand.;School of Biological Sciences, The University of Auckland, Auckland, New Zealand.",
"authors": "Hoggard|Michael|M|;Waldvogel-Thurlow|Sharon|S|;Zoing|Melissa|M|;Chang|Kevin|K|;Radcliff|Fiona J|FJ|;Wagner Mackenzie|Brett|B|;Biswas|Kristi|K|;Douglas|Richard G|RG|;Taylor|Michael W|MW|",
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"fulltext": "\n==== Front\nFront ImmunolFront ImmunolFront. Immunol.Frontiers in Immunology1664-3224Frontiers Media S.A. 10.3389/fimmu.2018.02065ImmunologyOriginal ResearchInflammatory Endotypes and Microbial Associations in Chronic Rhinosinusitis Hoggard Michael 1Waldvogel-Thurlow Sharon 2Zoing Melissa 2Chang Kevin 3Radcliff Fiona J. 4Wagner Mackenzie Brett 2Biswas Kristi 2Douglas Richard G. 2*Taylor Michael W. 151School of Biological Sciences, The University of Auckland, Auckland, New Zealand2School of Medicine, The University of Auckland, Auckland, New Zealand3Department of Statistics, Statistical Consulting Centre, The University of Auckland, Auckland, New Zealand4School of Medical Sciences, The University of Auckland, Auckland, New Zealand5Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New ZealandEdited by: Miriam Wittmann, University of Leeds, United Kingdom\n\nReviewed by: Alejandra Pera, Universidad de Córdoba, Spain; Catherine Maree Burke, University of Technology Sydney, Australia\n\n*Correspondence: Richard G. Douglas richard.douglas@auckland.ac.nzThis article was submitted to Inflammation, a section of the journal Frontiers in Immunology\n\n19 9 2018 2018 9 206523 4 2018 21 8 2018 Copyright © 2018 Hoggard, Waldvogel-Thurlow, Zoing, Chang, Radcliff, Wagner Mackenzie, Biswas, Douglas and Taylor.2018Hoggard, Waldvogel-Thurlow, Zoing, Chang, Radcliff, Wagner Mackenzie, Biswas, Douglas and TaylorThis 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.A complex mix of inflammatory and microbial associations underscores the chronic inflammatory condition chronic rhinosinusitis (CRS), and the etiology remains poorly understood. Recent work has begun to delineate between variants (endotypes) of CRS on the basis of inflammatory biomarkers. This study aimed to assess inflammatory patterns in CRS phenotypes, identify putative endotypes of CRS, and to assess inflammatory associations with the sinonasal microbiota. Ten cytokines and six inflammatory cell types were assessed in mucosal biopsies from 93 CRS subjects and 17 controls via cytometric bead array and immunohistochemical techniques. Putative endotypes were identified via cluster analysis of subjects on the basis of inflammatory markers and comorbidities including polyposis, asthma, and aspirin sensitivity. Finally, previously published bacterial data for this cohort were reanalyzed to evaluate associations with inflammatory markers and CRS subtypes. Inflammatory patterns were highly variable within standard CRS phenotypes. Cluster analysis identified eight subject clusters, with strong delineation on the basis of polyposis and asthma, but also subtle distinctions in inflammatory markers. An association was also identified between depletion of several “health-associated” bacterial taxa, reduced bacterial diversity and increased overall bacterial load, with markers of inflammation and clinical severity. This study contributes to ongoing efforts to define distinct endotypes of CRS on the basis of underlying inflammatory processes, and also offers compelling evidence of a link between bacterial community dysbiosis and inflammation in CRS. Further resolving the heterogeneity of CRS is vital to inform clinical management and personalized treatment approaches.\n\ninflammationphenotypesendotypescluster analysismicrobiotadysbiosischronic rhinosinusitisGarnett Passe and Rodney Williams Memorial Foundation10.13039/501100003354Green Lane Research and Educational Fund10.13039/501100003449\n==== Body\nIntroduction\nChronic rhinosinusitis (CRS) is a group of debilitating chronic inflammatory conditions affecting the upper airways in up to 5% of the population (1, 2). It represents a considerable burden on patient quality of life and healthcare systems alike (1–3). As with previous developments in the understanding of lower respiratory inflammatory conditions such as asthma (4, 5), CRS is increasingly understood as an umbrella term covering a diverse array of chronic inflammatory subtypes (6–9).\n\nRecent studies have made initial steps in characterizing CRS in terms of variants of the underlying inflammatory processes. One study identified 10 putative subtypes of CRS on the basis of a suite of inflammatory markers in a large cohort of 262 subjects (173 CRS subjects compared against results from 89 control subjects) (10). Inflammatory markers included the cytokines interleukin- (IL-)1β, IL-5, IL-6, IL-8, IL-17A, tumor necrosis factor- (TNF-)α, interferon- (IFN-)γ, and transforming growth factor- (TGF-)β1, as well as other inflammatory biomarkers such as myeloperoxidase, eosinophilic cationic protein, IgE, and Staphylococcus aureus enterotoxin-specific (SE)-IgE. While standard phenotypic divisions (on the basis of associated nasal polyposis) fell largely into separate inflammatory groups, multiple inflammatory subtypes were identified. A study of large-scale gene expression patterns in CRS similarly illustrated the heterogeneous nature of inflammation within CRS phenotypic subtypes (11). Most recently, an early indication of a link between the inflammatory heterogeneity of CRS and the associated sinonasal bacterial community patterns was also observed (12).\n\nThis study builds on the aforementioned work, assessing an array of inflammatory cells and signaling markers (CD3+ T cells, CD20+ B cells, CD68+ macrophages, plasma cells, eosinophils, neutrophils, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-17A, IFN-γ, and TNF), together with the presence of comorbidities (including polyposis, asthma, and a history of aspirin sensitivity), in a cohort of 110 subjects, to delineate between inflammatory variants that might be suggestive of endotypes in this condition. Additionally, a reanalysis of previously published bacterial microbiota data (13) for these subjects (collected at the same intraoperative time point) was performed. We investigated the extent to which inflammatory endotypes might better describe the observed patterns in bacterial communities when compared to traditional phenotypes based on polyposis or asthma, as well as more general associations between patterns in bacterial communities and inflammatory types underlying CRS.\n\nMaterials and methods\nPatient recruitment and sample collection\nOne hundred and ten subjects were recruited for this study, including 93 subjects undergoing endoscopic sinus surgery for extensive bilateral CRS, and 17 controls undergoing an endoscopic procedure for indications other than CRS (predominantly pituitary adenoma surgery and dacrocystorhinostomy). CRS subjects were selected as per the 2012 European Position Paper guidelines (1). Exclusion criteria for recruitment included sinonasal vasculitis, known immunodeficiency, and age less than 18 years. At the time of recruitment, patient demographics, symptom severity scores [based on a rating of five nasal symptoms, as previously described (13–15)], and Lund-Mackay scores were collected. Demographics data included age, gender, ethnicity, revision surgery for CRS, asthma status, a history of aspirin sensitivity, and antibiotic and corticosteroid administration in the 4 weeks prior to surgery. Sampling was conducted at the time of surgery, before the administration of topical mucosal vasoconstrictors.\n\nFor each subject, two tissue biopsies were collected from the bulla ethmoidalis using a Blakesley forcep, rinsed in sterile saline, placed in sterile 2 mL collection tubes on ice, and transported to the laboratory within 2 h of collection. Tissue intended for histological analysis was fixed in Carnoy's solution (60% ethanol, 30% chloroform, 10% glacial acetic acid), before being placed in 70% ethanol prior to paraffin embedding. Tissue samples intended for cytokine analysis were fixed in Ambion RNAlater (Life Technologies, Auckland, New Zealand) and stored at −20°C until the time of sample processing.\n\nThis study was approved by the New Zealand Health and Disability Ethics Committee (NTX/08/12/126), and written informed consent was obtained from all participants.\n\nHistology\nTissue sections of 4 μm thickness were prepared from paraffin-embedded tissue. Batches of sections were processed separately for each of the following: (1) Eosinophil and neutrophil cell counts (hematoxylin-eosin (H&E) staining as per routine practice); (2) Plasma cell counts [methyl green-pyronin staining as previously described (16)]; (3) CD3+ T cells [anti-CD3 monoclonal antibody (mAb)]; (4) CD20+ B cells (anti-CD20 mAb); and (5) CD68+ macrophages (anti-CD68 mAb) (Supplementary Figure 1). Immunohistochemistry to enumerate CD3+ T cells, CD20+ B cells, and CD68+ macrophages was conducted following antigen retrieval using a pressurized heat-retrieval method (2100 retriever) with citrate buffer (pH 6). Sections were incubated with either mouse anti-CD3 (clone LN10), anti-CD20 (clone L26), or anti-CD68 (clone 514H12) (Leica Biosystems, Newcastle Upon Tyne, UK) and Novocastra IHC Diluent (Leica Biosystems, Newcastle Upon Tyne, UK) at the following dilutions: 1:400; 1:200; and 1:50. Sections were then processed with the Novolink Polymer Detection System Kit (Leica Biosystems, Newcastle Upon Tyne, UK) as per the manufacturer's instructions. Negative controls (omitting the antibody) were included for all samples. Five representative high-power field images (63× magnification) were taken for each section using an epifluorescence Leica DMR upright microscope (Leica Microsystems, Wetzlar, Germany) with a SPOT camera (Diagnostic Instruments, MI) and analysis FIVE software (Olympus, Japan). Cell counts were conducted independently by two separate observers who were blinded to subject diagnoses at the time of counting. Cells were counted using ImageJ (NIH, Bethesda), with replicates for each cell type averaged for subsequent analyses.\n\nCytokines analysis\nKey human inflammatory cytokines were assessed within mucosal biopsies via Cytometric Bead Array as previously described (17). IL-2, IL-4, IL-6, IL-10, IL-17A, TNF, and IFN-γ were assessed using a Human Th1/Th2/Th17 Cytokine Kit (BD Biosciences). Flex set kits were also selected for an additional three cytokines of interest (IL-5, IL-8, and IL-13). In brief, tissue biopsies were first weighed and then added to lysis tubes with 2 mm ceramic beads and 200 μL PBS, and ruptured in a bead ruptor 24 (Omni International) at 3.55 m/s for two cycles of 10 s. The homogenate was centrifuged at 1,500 × g for 5 min, and then 25 μL of the supernatant was transferred to assay tubes. Cytokine analysis on the supernatant was conducted as per the manufacturer's instructions. Data were acquired on an LSR II with BD FACSDiva Software (version 6.1.3) and analyzed using FCAP ArrayTM (version 1.0.1) (BD Biosciences). A 5-parameter logistic model was used to produce standard curves with a fitting accuracy of >99.9% for all cytokines. Values below the threshold for the limit of detection for each cytokine were recorded as 0. IL-13 was below the limit of detection for all samples and was excluded from subsequent analyses. Final concentrations were normalized to concentration per gram of tissue based on the initial tissue weight.\n\nBacterial analyses\nPreviously published bacterial data (including 16S rRNA gene amplicon-based assessment of community structure, and quantitative (q)PCR-based estimation of total bacterial load) from sample collections conducted concurrently with sampling for this study were available for 101 subjects from this cohort (13), and were re-analyzed to assess relationships with inflammatory markers and identified subject clusters. A table of bacterial OTUs and relative sequence abundance, genus-level taxonomic assignment of OTUs, and a Bray-Curtis dissimilarity matrix (as a measure of inter-subject bacterial community dissimilarity), were generated as previously described (13). Taxonomic summary plots and non-metric multidimensional scaling plots were generated in R (version 3.3.0) (18). To assess the main patterns in community composition, the 15 bacterial OTUs with the highest relative abundance overall were identified for subsequent analyses {collectively representing, on average, over 80% of composition of the bacterial communities (median [interquartile range] = 83% [71–95%])}, with all other OTUs resolved under “other.”\n\nData analyses\nInvestigation of relationships between inflammatory variables, and clustering analysis of subjects to identify putative endotypes of CRS, were conducted as previously described (10). In brief, inflammatory variables were first analyzed using PCA and ascendant hierarchical clustering. PCA was followed by orthogonal rotation and Kaiser normalization, and variables with loadings < 0.4 were omitted. Hierarchical clustering incorporated correlation ratios and mixed PCA, with six clusters chosen as the optimal number on the basis of the Rand statistic (Supplementary Figure 2).\n\nSubject clustering to identify inflammatory variants was then conducted. A Gower dissimilarity matrix was calculated in order to incorporate both categorical and continuous variables, followed by cluster analysis of subjects via the Partitioning Around Medoids method. With the exception of IL-13, all inflammatory variables measured were included in the cluster analysis. In addition, the clinical parameters (presence/absence) of polyposis, asthma, and aspirin sensitivity status were also included due to their widely accepted clinical importance in CRS. In order to assess inflammatory profiles in CRS relative to patterns in health, both controls and CRS subjects were included together in the subject clustering analysis. As previously described (10), the optimal cluster number was selected after assessing several parameters: a scree plot of mean silhouette width, the Baker-Huber Gamma statistic, the Hubert-Levin C index, Jaccard stability after bootstrap resampling, and plotting of subjects grouping based on the top two principal components (Supplementary Figure 3). Eight subject clusters were selected as the optimal differentiation of subjects, and were used for subsequent analyses.\n\nPCA, hierarchical clustering, cluster index plots, subject clustering, and a heat map of the variables across the eight identified subject clusters were conducted and generated in R (18) using the packages cluster (19), ClustOfVar (20), clusterSim (21).\n\nDemographics, inflammatory, and bacterial variables were compared between: A. standard clinical CRS phenotypes [controls, CRS without nasal polyps (CRSsNP), CRS with nasal polyps (CRSwNP), CRS with cystic fibrosis (CRSwCF)]; and B. the eight identified subject clusters. Differences between groups were first tested using Fisher's exact test (categorical variables) and the Kruskal-Wallis test (continuous variables). Pairwise comparisons were subsequently conducted for significant variables using Fisher's exact test (categorical variables) and Dunn's test of multiple comparisons (22) (continuous variables), with Bonferroni adjustment for multiple comparisons (23). Significance tests were 2-sided with α = 0.05. To further investigate whether patterns of bacterial colonization (presence) were characteristic of distinct subject clusters, predictive probabilities of the presence or absence of bacterial OTUs in each subject cluster were generated in R via logistic regression modeling (taking the binary response of the presence or absence of OTUs as the outcome). Analyses of deviance were conducted to test for significant differences in the presence/absence of OTUs across the subject clusters.\n\nA heat map of relative sequence abundance patterns of the top 15 bacterial OTUs was generated in R. Ordering of subjects (rows) and bacterial OTUs (columns) was determined using average linkage hierarchical clustering of bacterial community similarity (based on Bray-Curtis dissimilarity), and co-occurrence patterns of bacterial OTUs, respectively.\n\nAssociations between variables were assessed via Spearman correlation analysis in R, with significance testing also conducted (α = 0.05) for each pairwise correlation test. The following variables were included in the analysis: inflammatory variables, all bacterial OTUs, bacterial community alpha diversity (Shannon index), bacterial load, symptom severity scores, and Lund-Mackay scores. A heat map of key variables identified in the Spearman correlation analysis was generated in R.\n\nData availability\nThe demographics and inflammatory data generated and analyzed during this study are provided as an online supplementary file (Supplementary Data). The bacterial data (raw sequences) analyzed during this study were previously published (13) and are publicly available in the SRA-NCBI repository (accession SRP092370).\n\nResults\nStandard clinical phenotypes\nDemographics\nCRS with nasal polyps (CRSwNP) subjects were significantly more often asthmatic than CRS without nasal polyps (CRSsNP) and control subjects (p-values < 0.04), significantly more often had aspirin sensitivity and aspirin-exacerbated respiratory disease (AERD; asthma together with concomitant aspirin sensitivity), and had higher Lund-Mackay scores than CRSsNP subjects (p-values < 0.01) (Table 1). CRS with cystic fibrosis (CRSwCF) patients were significantly more often undergoing revision surgery for CRS than CRSsNP and CRSwNP patients (Supplementary Table 1). There were no significant differences in pairwise testing with correction for multiple comparisons between any groups as to whether subjects had taken antibiotics or steroids in the 4 weeks prior to surgery (Supplementary Table 1).\n\nTable 1 Subjects' demographics.\n\n\tSubject groups\t\t\nVariablesa\tControls (n = 17)b\tCRSsNP (n = 46)b\tCRSwNP (n = 40)b\tCRSwCF (n = 7)b\tUnadjusted test p-valuec\t\nAge\t53 (23–84)\t47 (19–67)\t48 (18–71)\t31 (21–50)\t0.010\t\nEuropean\t11/17 (65%)\t37/46 (80%)\t31/38 (82%)\t6/7 (86%)\t0.514\t\nGender\t12/17 (71%)\t24/46 (52%)\t14/39 (36%)\t5/7 (71%)\t0.062\t\nAsthma\t1/17 (6%)\t18/46 (39%)\t28/40 (70%)\t1/7 (14%)\t<0.001\t\nAspirin sensitivity\t1/17 (6%)\t1/46 (2.2%)\t12/40 (30%)\t0/7 (0%)\t0.001\t\nAERD\t0/17 (0%)\t0/46 (0%)\t11/40 (28%)\t0/7 (0%)\t<0.001\t\nPreoperative antibioticsd\t1/17 (6%)\t7/46 (15%)\t4/39 (10%)\t4/7 (57%)\t0.024\t\nPreoperative corticosteroidsd\t0/17 (0%)\t7/46 (15%\t4/39 (10%)\t2/7 (29%)\t0.154\t\nRevision surgery\tNA\t17/46 (37%)\t18/39 (46%)\t7/7 (100%)\t0.006\t\nTotal symptom score\tNA\t14 (2–25)\t18 (5 to 25)\t18 (7–21)\t0.084\t\nLund-Mackay score\tNA\t14 (5–21)\t19 (5 to 24)\t19 (12–24)\t0.001\t\na Categorical variables are summarized as proportion yes/total (%), except for gender, which is given as proportion female. Continuous variables are summarized as median (range).\n\nb Total cohort numbers for each group are given. The differences in total numbers for each variable reflect missing data for some subjects.\n\nc Difference between groups tested using Fisher's exact test for categorical variables and the Kruskal-Wallis test for continuous variables. Significant p-values (α = 0.05) are expressed in bold.\n\nd Antibiotics and/or steroids in the 4 weeks prior to surgery.\n\nAERD, aspirin-exacerbated respiratory disease (asthma with concomitant aspirin hypersensitivity); CRS, chronic rhinosinusitis; CRSsNP, CRS without nasal polyps; CRSwNP, CRS with nasal polyps; CRSwCF, CRS with cystic fibrosis; NA, not applicable. Revision surgery = whether patients had previously undergone surgery for CRS prior to the current appointment.\n\nInflammatory variables\nIL-8, CD68+ macrophages, eosinophils, neutrophils, and plasma cells were significantly elevated in all CRS groups compared to controls (p-values < 0.04) [with the exception of plasma cells in CRSsNP subjects (p = 0.053)] (Figure 1). IL-8, CD68+ macrophages and neutrophils were also significantly elevated in CRSwNP and CRS with cystic fibrosis (CRSwCF) subjects compared to CRSsNP subjects (p-values < 0.05). CRSwNP subjects had significantly higher IL-5 than all other groups (p-values < 0.03), more CD20+ B cells compared to controls (p = 0.011), and more CD3+ T cells than CRSsNP subjects (p = 0.043). CRSsNP subjects had significantly higher CD20+ B cells and CD3+ T cells than controls (p-values < 0.005). Significant pairwise comparisons are given in a supplementary table available online (Supplementary Table 1).\n\nFigure 1 Boxplots of inflammatory variables grouped by CRS phenotypic subtypes [controls (n = 17), CRSsNP (n = 46), CRSwNP (n = 40), CRSwCF (n = 7)]. All data are log-transformed for visualization. Values for cell counts are log-transformations of cell numbers per high-powered field. Box center lines represent median values, whiskers outline values up to 1.5 × the interquartile range (IQR), and remaining outlier values are presented as dots. For variables where boxes and whiskers are absent, all values in the range of the box and whisker [IQR + whiskers up to 1.5 × (IQR)] were equal to zero. *represents significant differences between groups (Dunn's test of multiple comparisons with Bonferroni adjustment for multiple comparisons; α = 0.05).\n\nPrincipal components analysis (PCA) of the inflammatory variables identified six principal components that cumulatively explained 74% of the variance in the data. Principal components comprised the following: PC1. IL-17A, IFN-γ, IL-4, and TNF; PC2. CD3+ T cells, CD20+ B cells, and CD68+ macrophages; PC3. IL-5 and eosinophils; PC4. IL-6, IL-8, and neutrophils; PC5. IL-10 and IL-2; and PC6. plasma cells. Partitioning of variables in hierarchical clustering was broadly similar (Supplementary Figure 2).\n\nCRS endotypes\nPartitioning of subjects into eight subject clusters (SC1-8) gave the highest support (bootstrap means range: 0.63–0.92), and this was chosen for subsequent analyses. Control subjects were divided across SC1 and SC2 together with a number of CRS subjects (Figure 2). In general, subject clusters and traditional CRS phenotypes (CRSsNP, CRSwNP, and CRSwCF) were broadly congruent, but did not align directly, with subjects in all groups spread across a range of subject clusters.\n\nFigure 2 Heat map depicting patterns of inflammatory variables and comorbidities across the eight identified subject clusters [SC1 (n = 32), SC2 (n = 16), SC3 (n = 5), SC4 (n = 4), SC5 (n = 20), SC6 (n = 16), SC7 (n = 10), SC8 (n = 7)]. All variables in the heat map were included in the subject clustering analysis. Partitioning of subjects across clinical phenotypes (based on polyposis and cystic fibrosis), and total n for each cluster are given to the right. Variables for each cluster are color coded based on the mean value of the cluster for each variable, with intensity based on a scale of zero to maximum recorded value for each variable. Variables are arranged by principal components analysis results (PC1-6). Subject clusters are ordered based on general similarities.\n\nDemographics and inflammatory profiles\nEach subject cluster was characterized by distinct profiles of inflammatory variables (Figure 2). Patterns of inflammatory variables, bacterial community data, and characteristic elevated inflammatory patterns for subject clusters (based on significant differences with at least one other subject cluster) are presented in Figure 3. Differences were observed between some subject clusters for the variables age, Lund-Mackay score, concomitant asthma and aspirin sensitivity. There were no significant pairwise differences for any subject clusters in terms of antibiotics or corticosteroids usage in the 4 weeks prior to surgery (Supplementary Tables 2, 3).\n\nFigure 3 Inflammatory markers and bacterial communities across subject clusters [SC1 (n = 32), SC2 (n = 16), SC3 (n = 5), SC4 (n = 4), SC5 (n = 20), SC6 (n = 16), SC7 (n = 10), SC8 (n = 7)]. (A) Characteristic inflammatory patterns reflecting significantly elevated variables (α = 0.05) compared with at least one other of the eight subject clusters. Color coding above denotes subject phenotype based on polyposis and cystic fibrosis [controls (n = 17), CRSsNP (n = 46), CRSwNP (n = 40), CRSwCF (n = 7)]. (B) Heat map depicting subject profiles for each of the variables included in the subject clustering. Variables are arranged by principal components analysis results (PC1-6). (C) Taxonomic summary plot of bacterial community assemblages for each subject. (D) Bacterial community diversity (Shannon diversity index) and total bacterial load (shown on a log scale) based on data from Hoggard et al. (13), and Lund-Mackay clinical severity scores for each patient. Subjects within each cluster are arranged in descending order of the sum of the relative abundances of the eight “healthy-associated” bacterial OTUs discussed in this study. #no data available.\n\nBacterial communities\nAmong the 15 most abundant bacterial operational taxonomic units (OTUs) identified, there were few significant differences between subject clusters (Supplementary Table 3). Mean relative abundances of OTUs of Haemophilus, Pseudomonas, and Streptococcus were high in several subject clusters (Figure 3). However, most of these differences were not significant in subsequent pairwise comparisons testing (with the exception of OTU2_Streptococcus, which was significantly elevated in SC4 and SC7 compared with SC8, Supplementary Table 3). Calculation of the predictive probabilities of each OTU occurring in any given subject cluster (presence/absence) further indicated distinctions between the clusters for some OTUs. The presence/absence of OTU16_Haemophilus and OTU3_Pseudomonas were significantly different across clusters in analyses of deviance (p-values < 0.04), and were more characteristic of SC7 and SC8 (probabilities > 0.5 for these two subject clusters). The presence of several OTUs, including representatives of Staphylococcus, Corynebacterium, Peptoniphilus, Streptococcus, Propionibacterium, Anaerococcus, and Finegoldia was more characteristic of SC1, 2, 4, 5, 6, and 7 (Supplementary Table 4). Grouping subjects by the eight subject clusters in non-metric multidimensional scaling visualization (Supplementary Figure 4) or hierarchical clustering of subjects' bacterial communities (Figure 4A) did not offer additional clarity beyond traditional phenotyping (based on polyposis) or when subjects are grouped by asthma incidence (13).\n\nFigure 4 Associations within and between bacterial communities and key inflammatory variables. (A) Heat map of the top 15 bacterial OTUs by subject. Ordering of subjects (rows) and bacterial OTUs (columns) were determined using average linkage hierarchical clustering of bacterial community similarity (based on Bray-Curtis dissimilarity), and co-occurrence patterns of bacterial OTUs, respectively: the clustering of the dendrogram branches indicates subjects or bacterial OTUs that are most similar to each other. Heat map values are shaded from white to black according to increasing relative sequence abundance of bacterial OTUs within each subject (white = 0%, black = 100%). Subject color codes are for (A) the phenotypic divisions of Controls (n = 17), CRSsNP (n = 46), CRSwNP (n = 40), CRSwCF (n = 7), and (B) the eight subject clusters identified in this study [SC1 (n = 32), SC2 (n = 16), SC3 (n = 5), SC4 (n = 4), SC5 (n = 20), SC6 (n = 16), SC7 (n = 10), SC8 (n = 7)]. (B) Heat map of Spearman correlations between key bacterial and immunological variables. Color-coding represents significant positive (blue; scale 0 to 1) and negative (red; scale 0 to −1) correlations. Significance testing was based on upper tail probabilities, using the R function cor.test (α = 0.05). Non-significant pairwise associations are uncolored. The dashed box in both denotes the group of eight “health-associated” bacterial OTUs discussed in this study.\n\nSpearman correlation and hierarchical clustering analyses across the entire cohort identified an important group of eight bacterial OTUs, with significant positive correlations between OTU19_Finegoldia, OTU6_Peptoniphilus, OTU20_Anaerococcus, OTU14_Anaerococcus, OTU9_Propionibacterium, OTU130_Corynebacterium, and OTU5_Corynebacterium (Spearman rank correlation coefficients [rho] of significant pairwise associations ranging from 0.4 to 0.9), and to a lesser extent OTU1_Staphylococcus (Figure 4B). With the exception of OTU1_Staphylococcus, each of these OTUs was also significantly positively correlated with bacterial community alpha diversity (Shannon diversity index: 0.5 < rho < 0.7), and significantly negatively correlated with bacterial load (−0.4 < rho < −0.6). Alpha diversity was also significantly negatively correlated with bacterial load (rho = −0.5). This was similarly shown in hierarchical clustering of OTUs, where these OTUs clustered together reflecting co-occurrence patterns (Figure 4A). In hierarchical clustering of subjects based on bacterial community similarity, these taxa regularly occur together in subjects in the upper portion of the heat map (Figure 4A), along with fewer instances of the other bacterial OTUs assessed. Notably, a depletion of some of the diversity of these eight OTUs (as seen in subjects lower down the heat map) was associated with dominance by one of the other taxa, including several putative pathogens such as OTUs of Staphylococcus, Streptococcus, Pseudomonas, Moraxella, Haemophilus, and Fusobacterium.\n\nAssociations between bacterial OTUs and inflammatory markers\nA depletion of the aforementioned bacterial OTUs, reduced bacterial community diversity, and elevated bacterial load were each associated with several markers of inflammation, and with higher clinical severity scores. IL-6, IL-8, CD3+ T cells, CD20+ B cells, CD68+ macrophages, eosinophils, neutrophils, Lund-Mackay scores, and symptom scores [and to a lesser extent, IL-5 (−0.1 < rho < 0)] were each significantly negatively correlated with the OTUs noted above (with the exception of OTU1_Staphylococcus) as well as overall bacterial community diversity (−0.5 < rho < −0.2), and significantly positively correlated with overall bacterial load (0.1 < rho < 0.4) (Figure 4B).\n\nDiscussion\nRecent studies have begun to dissect the heterogeneity of inflammatory processes underlying CRS (10–12, 24). These studies have identified the need for more accurate demarcation of CRS variants across a multidimensional array of inflammatory axes. We assessed mucosal inflammatory profiles in 93 CRS subjects and 17 non-inflammatory controls with the aim of resolving CRS subjects on the basis of putative endotypes. In addition, we investigated bacterial associations with specific inflammatory markers, and the extent to which endotypes might better clarify observed patterns compared to previous efforts with standard phenotypes alone (13) (Figure 5).\n\nFigure 5 Schematic representation of the relationship between endotypes as sub-types of chronic inflammatory respiratory disease and associated patterns in microbial community dysbiosis (instability and disturbance). The upper panels (A,B) depict the shift from a binary (health vs. disease) approach to define and treat chronic inflammatory mucosal diseases to identifying multiple distinct endotypes (disease variants) on the basis of inflammatory biomarkers. The extent to which aberrant patterns in microbial communities (C, bottom panels) associate with or drive the underlying inflammatory heterogeneity is of increasing interest. As an example to further provide context, findings from this study of chronic rhinosinusitis subjects have been incorporated into the model: endotypes are represented by the characteristic elevated inflammatory patterns of the eight subject clusters identified in this study, including inflammatory signaling profiles and incidence of comorbidities such as asthma and polyposis. Bacterial community dysbiosis, here characterized by a loss of several “health-associated” taxa (including Staphylococcus spp., Corynebacterium spp., Propionibacterium spp., Anaerococcus spp., Peptoniphilus spp., and Finegoldia spp.) together with dominance by one of several putative pathogens (including particular members of the genera Staphylococcus, Streptococcus, Pseudomonas, Moraxella, Haemophilus, and Fusobacterium), was associated with elevated inflammatory markers and clinical severity scores. A direct relationship between particular dysbiotic bacterial community types and specific endotypes of CRS remains unclear.\n\nInflammatory patterns in CRS\nInflammatory patterns of CRS phenotypes\nCRSsNP and CRSwNP were previously described as generally characterized by Th1/neutrophilic and Th2/eosinophilic inflammation, respectively (24–26). However, reports of the proportion of eosinophilia associated with nasal polyposis in European cohorts have ranged from 54 to 90% (8, 27), and in Asian populations as low as 7.5% (27). There is increasing recognition that standard phenotypic divisions of CRS and the binary model of Th1 vs. Th2 inflammation are insufficient to describe the inflammatory heterogeneity in CRS (6–11). This was reflected in this study: inflammatory patterns were highly variable both between and within standard phenotypic variants of CRS. While there were indications of significantly elevated inflammatory markers in some phenotypes compared to others (including IL-5, IL-8, CD3+ T cells, CD68+ macrophages, and neutrophils), median values for several, including IL-5, eosinophils, and neutrophils, were zero in many cases. This highlights that, while there were increased incidences of these types of inflammation, they were absent in more than half of the subjects in these phenotypic groups. Thus, “increased incidence” of neutrophilia or eosinophilia (or elevated IL-5, etc.) is a more accurate representation of these phenotypic groups than the common description that each is “characterized” by Th1/neutrophilic or Th2/eosinophilic inflammation.\n\nClinical implications\nThese observations may explain some of the difficulties encountered in treating CRS: targeted treatment may be difficult when inflammatory processes underlying the disease are heterogeneous. While there has been increasing interest in targeted treatments such as monoclonal antibodies in chronic inflammatory conditions such as CRS (28–31), treatments aimed narrowly at specific mechanisms of inflammation may have limited efficacy or applicability across the group as a whole, where the targeted mechanism may not be relevant in sizeable proportions of subjects, or where mixed inflammatory processes might be at play in parallel within individual subjects. In contrast, the relative efficacy of corticosteroids may derive from their action of dampening inflammatory processes more broadly. For example, previous studies have identified CRSwNP as generally having elevated IL-5 (24, 26). In this study, mean IL-5 was similarly elevated for the group overall, however, the median value was zero. Thus, anti-IL-5 monoclonal antibody treatment (such as Mepolizumab) might be expected to be effective or appropriate in fewer than half of CRSwNP subjects. Monoclonal antibody trials and treatments directed by first characterizing individual patients' inflammatory patterns within the affected mucosa may better determine appropriate personalized treatment options.\n\nKey inflammatory variables in CRS\nIL-8, CD68+ macrophages, eosinophils, neutrophils and plasma cells were significantly elevated in all three CRS groups (CRSsNP, CRSwNP, CRSwCF), and IL-5 was significantly elevated in CRSwNP. IL-6 and IFN-γ (together with IL-5 and IL-8) were also important variables in identified subject clusters, and in Spearman correlation analysis of key bacterial OTUs, inflammatory variables, and clinical severity scores. Thus, these data provide further evidence for IL-5, IL-6, IL-8, IFN-γ, TNF, and comorbidities including asthma, polyposis, and aspirin sensitivity, in addition to the previously identified IL-13, albumin, myeloperoxidase, eosinophilic cationic protein, IgE, and SE-IgE (10, 11), as important variables in efforts to demarcate distinct endotypes of CRS.\n\nEndotypes of CRS\nEight subject clusters (SC1-8) were identified in this study. Overall, subject clusters were roughly divided into either low or high rates of asthma and/or polyposis incidence. This is in keeping with Tomassen and colleagues, who found that endotypes largely adhered to clinical phenotypes based on polyposis (10). In contrast to their findings, however, a clear differentiation of subject clusters into 3 subgroups on the basis of IL-5 levels (no IL-5, moderate IL-5 in all subjects, and high IL-5 in all subjects) was not seen in this cohort. Why this pattern was not reproduced in this study is unclear, but may reflect methodological differences between the studies, or genuine underlying differences between the study cohorts. Differences in CRS inflammatory profile types have been observed previously between different populations globally, including an increased association between polyposis and eosinophilia and IL-5 in European populations compared to patients studied in China (27). Patterns of association for IL-5 may similarly be less prominent in this New Zealand based cohort.\n\nNotably, controls did not fall into their own subject clusters, but instead clustered together with a number of CRSsNP subjects and a handful of CRSwNP subjects. This further highlights the complicated nature of the inflammatory patterns underlying CRS, and in particular CRSsNP, and the need to include a broad range of variables when attempting to delineate CRS endotypes.\n\nAgeing has an important influence on the immune system through the process of gradual immunosenescence, including dysregulation and reduced efficiency in managing chronic inflammation (32, 33). It is unclear whether differences in age may influence the progression and types of inflammation underlying CRS, and whether it may underpin some of the observed distinctions in inflammatory profiles across the subject clusters in this study. Significant differences in age were observed between some subject clusters in this study. However, this was in particular due to SC8, which included several CRSwCF patients. As CRSwCF also tends to be a younger patient group overall (due to the underlying congenital condition driving earlier onset of CRS), this likely confounds the observed differences in age between the subject clusters here.\n\nTo the extent that only a handful of potential inflammatory biomarkers in CRS have been examined, the results so far cannot be taken to categorically define specific endotypes of CRS, but rather provide early indications of where the inflammatory lines might be drawn and provide proof of principle. It is important to note that numbers for some subject clusters in this study were small: SC3, SC4, SC7, and SC8 only contained 5, 4, 10, and 7 subjects each. Additionally, suitable non-CRS control subjects for whom mucosal biopsies can be collected are comparably rare and difficult to recruit in large numbers, and included controls, while exhibiting no signs of CRS, are nonetheless undergoing endoscopic sinus surgery for other reasons, and may not fully represent “healthy” subjects. Observed similarities and deviations from this group when taken as a reference baseline of “normal” healthy mucosal inflammatory profiles should be viewed in light of these caveats. Furthermore, cross-sectional sampling may obscure whether some of the observed differences in subject clusters represent a temporal continuum of specific endotypes as they develop over time. Given the observed inflammatory complexity, together with other potential sources of influence in determining disease subtypes such as genetic (34) and life history factors (35, 36), many more subjects measured over more variables (or more refined variables) and at multiple time points will be necessary to clearly delineate between true endotypes of CRS and to subsequently draw robust conclusions from comparisons.\n\nImplications for hypotheses of CRS\nNumerous cases of mixed inflammatory patterns were seen within individual subjects, a phenomenon which has also been identified previously (9). This observation may lend support to a model involving loss of inflammatory regulation underlying the diverse variants of CRS, rather than a specific pro-inflammatory mechanism. Evidence suggestive of a dysfunction of T cell regulation in CRSwNP has been observed previously (25, 37, 38).\n\nA loss of mucosal integrity or predisposition toward a defective immune barrier may also be central to the pathogenesis of CRS (39). Decreased expression of tight junction proteins has been identified in CRSwNP (40, 41), and specific inflammatory molecules that are elevated in CRS have been linked to mucosal epithelial disruption. Oncostatin M, a member of the IL-6 family of cytokines, can drive increased mucosal permeability and mislocalization of tight junction proteins, together with eosinophil infiltration and the production of IL-4, IL-5, and IL-13 (42). Similar disruption has also been seen with IL-4, IFN-γ, IL-17, IL-22, and IL-26 (41, 43). In this study, IL-4, IL-5, and IL-17 were markedly elevated in certain subjects, with significantly elevated IL-4 in SC3, IL-17 in SC2 and SC3, and IL-5 in all CRSwNP subjects. Importantly, compromised mucosa would allow infiltration of diverse microbial and/or antigenic agents into the sub-mucosa, and may drive the mixed inflammatory patterns observed in CRS subjects here and elsewhere.\n\nBacterial associations with inflammation in CRS\nBacterial associations with CRS endotypes\nAttempts to identify specific, putatively pathogenic bacterial associations with phenotypic variants of CRS have remained largely unsuccessful (39, 44). We hypothesized that aberrant bacterial taxa or community types may more closely associate with inflammatory endotypic variants than with phenotypic variants of CRS. However, reanalysis of previously published bacterial community data for this cohort identified few positive associations with inflammatory variables or endotypes. Several taxa of interest, including OTUs of Haemophilus, Streptococcus, and Pseudomonas, did have high mean relative abundances in a number of subject clusters. However, these differences were not significantly different in pairwise comparisons testing. Whether this is a factor of too few subjects in some groups, or simply reflects a limited relation overall between inflammatory patterns and particular bacterial taxa, remains unclear. Notably, such associations between bacterial community types and particular inflammatory markers were observed in a recent study by Cope et al. (12), suggesting an even more specific link between the type of microbial dysbiosis and the resultant inflammatory endotype of CRS. Together with the data presented in this study, these findings provide increasing support for an association between microbial community dysbiosis and inflammation generally, as well as an indication of links between specific bacterial community types and possible endotypes of CRS.\n\nBacterial and inflammatory correlations\nA depletion of a group of bacterial taxa, including OTUs of Anaerococcus, Propionibacterium, Corynebacterium, Staphylococcus, Peptoniphilus, and Finegoldia, together with lower bacterial diversity overall and increased bacterial load, broadly associated with increased inflammatory markers and higher clinical severity scores. These taxa were previously identified within this cohort as being more typical of health-associated bacterial communities (with aberrant community types tending to occur more often in CRS) (13, 45). These data provide further evidence for the potential role of microbial dysbiosis (instability and disturbance) in CRS progression or exacerbation, where community shifts away from a normal healthy community may drive mixed inflammatory responses [such as the range of toll-like receptor (TLR) activities identified previously in CRS (17, 46, 47)], in contrast to singular pathogenic activities (such as superantigens) driving very specific inflammatory responses. Overall, aberrant microbial communities, coupled with increased mucosal damage and permeability in CRS, might further drive the heterogeneous inflammatory patterns observed.\n\nA range of key inflammatory markers were assessed in this study, providing further evidence of the inflammatory heterogeneity underlying CRS. However, the overall picture remains unclear. More comprehensive assessment of the multitude of inflammatory processes within the mucosa beyond those assessed both here and previously may better distinguish between true endotypes of CRS, as well as identify specific associations with polyposis or asthma and clarify genuine microbial associations across the spectrum of CRS.\n\nSummary and concluding remarks\nThis study contributes to ongoing efforts to further refine distinct endotypes of CRS on the basis of underlying inflammatory processes. Inflammatory patterns were highly variable within standard phenotypic variants of CRS, and mixed inflammatory profiles were often observed. In contrast, eight subject clusters, which included both control and CRS subjects, were identified with distinct patterns of inflammation and associated comorbidities. In addition to previously identified variables, the data provide further evidence for the importance of IL-2, IL-5, IL-6, IL-8, IL-10, IFN-γ, TNF, asthma, polyposis, and aspirin sensitivity, in efforts to demarcate distinct endotypes of CRS. Finally, reanalysis of previously published bacterial data for this cohort identified an important association between the depletion of a “health-associated” group of bacterial taxa, reduced bacterial diversity and increased bacterial load overall, and markers of inflammation and clinical severity. Taken together with other recent work on inflammatory endotypes and microbial community associations in CRS (10, 12), these data further establish the importance of defining distinct endotypes of CRS, as well as provide an early indication of a connection between the microbiota and the inflammatory heterogeneity of CRS.\n\nAuthor contributions\nMH contributed to study design, the acquisition of data, data analyses, and writing of the manuscript. SW-T contributed to histological processing and the acquisition of inflammatory cell data. MZ and RD contributed to subject recruitment and sampling. KC contributed to statistical analyses. FR contributed to the acquisition of inflammatory signaling data. BW contributed to data analyses. MT, RD, and KB contributed to study design, and MT, RD, KB, and FR provided laboratory space and materials. All authors contributed to editing of the manuscript.\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\nThe authors would like to acknowledge the assistance of Yannan Jiang at the Statistical Consulting Centre, University of Auckland, New Zealand, for additional guidance with statistical analyses.\n\nFunding. This work was supported by grants from the Garnett Passe and Rodney Williams Memorial Foundation and the Green Lane Research and Educational Fund.\n\nSupplementary material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2018.02065/full#supplementary-material\n\nClick here for additional data file.\n\n Click here for additional data file.\n\n Click here for additional data file.\n==== Refs\nReferences\n1. Fokkens WJ Lund VJ Mullol J Bachert C Alobid I Baroody F . EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012 . A summary for otorhinolaryngologists. Rhinology (2012 ) 50 :1 –298 . 10.4193/Rhino50E2 22469599 \n2. Orlandi RR Kingdom TT Hwang PH Smith TL Alt JA Baroody FM \nInternational consensus statement on allergy and rhinology: rhinosinusitis . Int Forum Allergy Rhinol. (2016 ) 6 :S22 –209 . 10.1002/alr.21695 26889651 \n3. Bhattacharyya N . 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Impact of cigarette smoking on the middle meatus microbiome in health and chronic rhinosinusitis . Int Forum Allergy Rhinol. (2015 ) 5 :981 –9 . 10.1002/alr.21626 26272413 \n37. Kim YM Munoz A Hwang PH Nadeau KC . Migration of regulatory T cells toward airway epithelial cells is impaired in chronic rhinosinusitis with nasal polyposis . Clin Immunol. (2010 ) 137 :111 –21 . 10.1016/j.clim.2010.05.013 20598643 \n38. Van Bruaene N Pérez-Novo CA Basinski TM Van Zele T Holtappels G De Ruyck N \nT-cell regulation in chronic paranasal sinus disease . J Allergy Clin Immunol. (2008 ) 121 :1435 –41 . 10.1016/j.jaci.2008.02.018 18423831 \n39. Lam K Schleimer R Kern RC . The etiology and pathogenesis of chronic rhinosinusitis: a review of current hypotheses . Curr Allergy Asthma Rep. (2015 ) 15 :1 –10 . 10.1007/s11882-015-0540-2 26143392 \n40. Rogers G Den Beste K Parkos CA Nusrat A DelGaudio JM Wise SK . Epithelial tight junction alterations in nasal polyposis . Int Forum Allergy Rhinol. (2011 ) 1 :50 –4 . 10.1002/alr.20014 22287308 \n41. Soyka MB Wawrzyniak P Eiwegger T Holzmann D Treis A Wanke K . Defective epithelial barrier in chronic rhinosinusitis: the regulation of tight junctions by IFN-γ and IL-4 . J Allergy Clin Immunol. (2012 ) 130 :1087 –96 . 10.1016/j.jaci.2012.05.052 22840853 \n42. Pothoven KL Norton JE Hulse KE Suh LA Carter RG Rocci E . Oncostatin M promotes mucosal epithelial barrier dysfunction, and its expression is increased in patients with eosinophilic mucosal disease . J Allergy Clin Immunol. (2015 ) 136 :737 –46 . 10.1016/j.jaci.2015.01.043 25840724 \n43. Ramezanpour M Moraitis S Smith JLP Wormald PJ Vreugde S . Th17 cytokines disrupt the airway mucosal barrier in chronic rhinosinusitis . Mediators Inflamm. (2016 ) 2016 :1 –7 . 10.1155/2016/9798206 26903715 \n44. Hoggard M Wagner Mackenzie B Jain R Taylor MW Biswas K Douglas RG . Chronic rhinosinusitis and the evolving understanding of microbial ecology in chronic inflammatory mucosal disease . Clin Microbiol Rev. (2017b ) 30 :321 –48 . 10.1128/CMR.00060-16 27903594 \n45. Wagner Mackenzie B Waite DW Hoggard M Douglas RG Taylor MW Biswas K \nBacterial community collapse: a meta-analysis of the sinonasal microbiota in chronic rhinosinusitis . Environ Microbiol. (2017 ) 19 :381 –92 . 10.1111/1462-2920.13632 27902866 \n46. Hirschberg A Szabo K Zsolt Razga B Zsolt Bella B Laszlo Tiszlavicz B Lajos Kemeny B \nDifferent activations of toll-like receptors and antimicrobial peptides in chronic rhinosinusitis with or without nasal polyposis . Eur Arch OtoRhinoLaryngol. (2016 ) 273 :1779 –88 . 10.1007/s00405-015-3816-1 26518209 \n47. Wang X Zhao C Ji W Xu Y Guo H . Relationship of TLR2, TLR4 and tissue remodeling in chronic rhinosinusitis . Int J Clin Exp Pathol. (2015 ) 8 :1199 –212 . 25973005\n\n",
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"keywords": "chronic rhinosinusitis; cluster analysis; dysbiosis; endotypes; inflammation; microbiota; phenotypes",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001419:Bacteria; D002908:Chronic Disease; D016207:Cytokines; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007249:Inflammation; D008297:Male; D064307:Microbiota; D008875:Middle Aged; D009298:Nasal Polyps; D010641:Phenotype; D012220:Rhinitis; D012852:Sinusitis; D055815:Young Adult",
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"affiliations": "Department of Medicine, Baylor College of Medicine, Houston, TX, USA.;Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Clinical Microbiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Liu|Jing|J|http://orcid.org/0000-0002-2323-6492;Mouhayar|Elie|E|;Tarrand|Jeffrey J|JJ|;Kontoyiannis|Dimitrios P|DP|http://orcid.org/0000-0002-8051-2940",
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"abstract": "In this case report an immunocompetent patient developed retinitis after implantation of an intravitreal dexamethasone implant following a primary infection with cytomegalovirus. The implant was prescribed due to a history following a central vein occlusion with macular oedema and loss of vision. Vision improved after implantation, however, due to retinitis a vitrectomy was performed proving infection with cytomegalovirus. This case and two other recent presen-tations warrant the consideration cytomegalovirus infection in even immunocompetent individuals showing signs of retinitis following dexamethasone implantation.",
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"affiliations": "Department of Breast and Thyroid Surgery Yokohama City University Medical Center Yokohama Japan.;Department of Breast and Thyroid Surgery Yokohama City University Medical Center Yokohama Japan.;Department of Breast and Thyroid Surgery Yokohama City University Medical Center Yokohama Japan.;Department of Breast and Thyroid Surgery Yokohama City University Medical Center Yokohama Japan.;Department of Breast and Thyroid Surgery Yokohama City University Medical Center Yokohama Japan.;Department of Breast and Thyroid Surgery Yokohama City University Medical Center Yokohama Japan.;Department of Pathology Yokohama City University Medical Center Yokohama Japan.;Department of Gastroenterological Surgery Yokohama City University Graduate School of Medicine Yokohama Japan.;Department of Breast Surgery and Oncology Tokyo Medical University Shinjuku-ku Japan.;Department of Gastroenterological Surgery Yokohama City University Graduate School of Medicine Yokohama Japan.",
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"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4189\nCCR34189\nCase Report\nCase Reports\nPrimary breast lymphoma initially diagnosed as invasive ductal carcinoma: A case report\nUENAKA et al.\nUenaka Natsuki https://orcid.org/0000-0002-8974-9231\n1 2\nYamamoto Shinya https://orcid.org/0000-0002-8083-5387\n1 shinya@rf.catv.ne.jp\n\nSato Seiya 1\nKudo Takamichi 1\nAdachi Shoko 1\nNarui Kazutaka 1\nTanabe Mikiko 3\nYamada Akimitsu 4\nIshikawa Takashi 2\nEndo Itaru 4\n1 Department of Breast and Thyroid Surgery Yokohama City University Medical Center Yokohama Japan\n2 Department of Breast Surgery and Oncology Tokyo Medical University Shinjuku‐ku Japan\n3 Department of Pathology Yokohama City University Medical Center Yokohama Japan\n4 Department of Gastroenterological Surgery Yokohama City University Graduate School of Medicine Yokohama Japan\n* Correspondence\nShinya Yamamoto, Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, 4‐57 Urafune‐cho, Minami‐ku, Yokohama, Kanagawa 232‐0024, Japan.\nEmail: shinya@rf.catv.ne.jp\n\n05 5 2021\n6 2021\n9 6 10.1002/ccr3.v9.6 e0418926 3 2021\n24 2 2021\n31 3 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nA malignant tumor in the breast may not be conclusive of breast cancer. It is important to keep the possibility of primary breast lymphoma in rare scenarios. For the diagnosis of primary breast lymphoma, immunohistochemical staining is necessary.\n\nA malignant tumor in the breast may not be conclusive of breast cancer. It is important to keep the possibility of primary breast lymphoma in rare scenarios. For the diagnosis of primary breast lymphoma, immunohistochemical staining is necessary.\n\nbreast\nimmunohistochemical staining\nlymphoma\nsource-schema-version-number2.0\ncover-dateJune 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:24.06.2021\nUenaka N , Yamamoto S , Sato S , et al. Primary breast lymphoma initially diagnosed as invasive ductal carcinoma: A case report. Clin Case Rep. 2021;9 :e04189. 10.1002/ccr3.4189\n==== Body\n1 INTRODUCTION\n\nA 73‐year‐old woman presented with a right breast mass. Radiological findings were consistent with breast cancer. Pathological analysis of the core needle biopsy specimen indicated triple‐negative invasive ductal carcinoma. However, additional immunohistochemical studies indicated primary breast diffuse large B‐cell lymphoma, which is difficult to diagnose by imaging and pathological findings.\n\nPrimary breast lymphoma (PBL) is very rare, accounting for 0.04%‐0.5% of all malignant breast tumors. 1 PBL has the following characteristics: (a) a tumor in the breast, (b) no history of lymphoma, (c) lymphoma has a close association with the breast tissue in the pathological specimen, and (d) no lymphadenopathy except for in the ipsilateral axillary lymph node. 2 Most PBLs are diffuse large B‐cell lymphoma (DLBCL), which accounts for approximately 40%‐70% of all PBL cases. 3\n\nWe report a case of DLBCL in the breast initially treated as breast cancer.\n\n2 CASE HISTORY/EXAMINATION\n\nA 73‐year‐old woman visited the hospital with complaints of a painless palpable mass more than 1‐month duration in her right breast. She was diagnosed with a malignant lesion after fine‐needle aspiration, and she was transferred to our hospital. She had no B symptoms (unexplained weight loss, fever, or night sweats). She had no family history of breast cancer.\n\nPhysical examination showed a hard mass in the upper to lower outer quadrant of the right breast measuring 50 mm, and there were no palpable axillary lymph nodes. Mammography showed a high‐density mass with microlobulated margins (Figure 1). Ultrasonography revealed a 47‐mm irregular hypoechoic mass with a heterogeneous internal echo and blood flow (Figure 2). Contrast‐enhanced computed tomography showed a mass in the right breast and no metastatic lesions (Figure 3A). Magnetic resonance imaging (MRI) revealed that the edge of the mass was isointense on T1‐weighted imaging (Figure 4A) and hyperintense on T2‐weighted imaging (Figure 4B). The time‐intensity curve of contrast‐enhanced T1‐weighed imaging showed a slow plateau pattern (Figure 4C and D).\n\nFIGURE 1 Mammography in the mediolateral oblique position. A high‐density mass with microlobulated margins in the middle area (arrowhead)\n\nFIGURE 2 Ultrasonography. A 47‐mm irregular hypoechoic mass with heterogeneous internal echo (arrowhead) and blood flow in the mass (arrow)\n\nFIGURE 3 Contrast‐enhanced computed tomography (CT). A, CT before chemotherapy showing the mass in the right breast (arrowhead). B, CT after chemotherapy showing remarkable mass shrinkage (arrowhead)\n\nFIGURE 4 Magnetic resonance imaging. A, T1‐weighted images. The edge of mass is isointense (arrowhead). B, T2‐weighted images. The edge of mass is hyperintense (arrowhead). C, Contrast‐enhanced T1‐weighted images in the early phase (arrowhead). D, Contrast‐enhanced T1‐weighted images in the late phase (arrowhead)\n\nLevels of all tumor markers, including carcinoembryonic antigen and carbohydrate antigen 15‐3, were within the normal ranges. Her lactate dehydrogenase level was 207 IU/L.\n\nAnalysis of a core needle biopsy (CNB) specimen revealed solid proliferation of atypical cells with rounded nuclei (Figure 5A). Therefore, the lesion was identified as invasive ductal carcinoma, solid type, nuclear grade 3 (nuclear atypia: 3, mitotic count: 3). Immunohistochemical (IHC) staining showed that the tumor was negative for estrogen receptor, progesterone receptor, and human epidermal growth factor 2. The Ki67 labeling index was 80%.\n\nFIGURE 5 Pathological and immunohistochemical analysis. A, Hematoxylin‐eosin staining of the core needle biopsy specimen indicating solid proliferation of atypical cells with rounded nuclei (×400). B, Hematoxylin‐eosin staining of the surgical specimen indicating no residual tumor (×400). C, The resected specimen is positive for CD20 (×400)\n\n3 DIFFERENTIAL DIAGNOSIS, INVESTIGATIONS, AND TREATMENT\n\nA diagnosis of triple‐negative breast cancer (cT2N0M0) was made based on the pathological and imaging findings. Because the patient had atrial fibrillation, anthracycline‐containing regimens were avoided. Therefore, 12 weeks of neoadjuvant weekly paclitaxel (80 mg/m2) were scheduled. However, due to cerebral infarction, chemotherapy was ended after eight cycles. The mass had shrunk remarkably after only eight cycles (Figure 3B), so she underwent total mastectomy and sentinel lymph node biopsy.\n\nPathological examination of the resected specimen revealed no tumor cells; hence, we made a diagnosis of a pathological complete response (pCR) (Figure 5B). However, a pathologist reexamined the CNB specimen, and a diagnosis of PBL was considered. IHC staining indicated positivity for leukocyte common antigen (LCA), CD20 (Figure 5C), Bcl‐6, and MUM‐1, with borderline positivity for CD10. Therefore, the diagnosis was corrected to DLBCL, nongerminal center type. The Ann Arbor stage was 1E because there was one extralympatic site.\n\n4 OUTCOME AND FOLLOW‐UP\n\nThe patient received R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy based on the suggestion of a hematologist. She was scheduled to receive six cycles, but R‐CHOP administration was terminated after five cycles due to hematologic toxicity requiring blood transfusion. No recurrence has been observed 2 years after chemotherapy.\n\n5 DISCUSSION\n\nWe experienced a case of PBL initially treated as invasive ductal carcinoma. PBL is difficult to diagnose based on both imaging and pathological findings.\n\nThere are few imaging features that distinguish PBL and breast cancer. However, PBL shows characteristic features on MRI. 2 PBL is hyperintense on T2‐weighted images and isointense on T1‐weighted images. With regard to time‐intensity curves, most PBLs display type 2 kinetic curves (slow or rapid enhancement and plateau in the delayed phase). Type 1 (enhancing pattern) and type 3 (rapid enhancement and washout in the delayed phase) kinetic curves are less common. In our case, the MRI findings were consistent with the diagnosis of PBL. However, as 33.6% of breast cancers also have type 2 kinetic curves, 4 it can be difficult to differentiate PBL from breast cancer based solely on MRI findings.\n\nIt is also difficult to distinguish PBL and breast cancer based solely on pathological findings. 5 In a study by Lin et al 6 7 of 41 (17%) hematologic malignant lesions in the breast were misdiagnosed as breast cancer. PBL and breast cancer cells are often morphologically similar; therefore, it may be difficult to distinguish them by hematoxylin‐eosin staining alone. DLBCL, which was the histological type in our case, is characterized by a diffuse proliferation of large lymphocytes with large nuclei. 7 These features can mimic invasive breast cancer, solid type, or invasive lobular carcinoma. When diffuse proliferation of cells is observed in breast tumors, the epithelial or hematologic origin should be confirmed by IHC staining, especially if the tumor shows other findings, such as hormone receptor negativity, no intraductal lesions, and a high N/C ratio, that do not actively support breast cancer. Guilbert et al reported a similar proposal. 8 Yoneyama et al reported a similar case, and they highlighted several characteristics, including conspicuous apoptosis, marked nuclear rays due to crushing, and polymorphism in tumor cells, that distinguish breast cancer from PBL. 5 Lin et al also identified several characteristics as findings suspicious of lymphoma, such as lack of in situ lesions, frequent individual karyorrhectic cells, lymphoepithelial lesions, and cellular discohesiveness. 6 On the other hand, on hematoxylin and eosin staining, the shape of the cells, the lack of similar glandular shape, the uniform appearance of the tumor tissue, and the lack of invasiveness into the mammary ducts may have been findings that would have raised suspicion of lymphoma.\n\nA malignant tumor in the breast may not be conclusive of breast cancer. Other possible malignancies in the breast area, such as lymphoma, should be considered as a differential diagnosis by clinicians and pathologists. In cases where the findings are not typical of breast cancer, examining a larger tissue sample using biopsy may help make an accurate diagnosis.\n\nImmunohistochemical staining is useful to confirm that a breast lesion is lymphoma and is required to determine the histological type. LCA is a specific leukocyte marker used to identify lymphoid neoplasms. 9 CD20 is used to determine whether a neoplasm originated from B cells. 7 Other B‐cell markers include CD19, CD22, CD79, and CD45. 7 DLBCL is classified into two types, namely germinal center B cell–like type and nongerminal center B cell–like type, depending on the expression patterns of CD10, Bcl‐6, and MUM‐1. 10\n\nBecause of the low frequency of PBL, there is no standard treatment. Chemotherapy for PBL is generally administered based on the recommendation for systemic lymphoma of the same histological type. 11 Our patient achieved pCR after 8 weeks of weekly paclitaxel. The standard treatment for DLBCL is R‐CHOP, and paclitaxel‐based regimens are rarely administered. Rizzieri et al reported the effectiveness of weekly paclitaxel for recurrent or refractory aggressive non‐Hodgkin lymphoma. In their study, 26% of patients achieved pCR. 12 Casasnovas et al also reported a Phase II study of paclitaxel in patients with refractory and relapsed aggressive non‐Hodgkin lymphoma, in which 4.4% of patients achieved CR. 13 Therefore, the response to paclitaxel need not indicate that the tumor was not DLBCL.\n\nAccording to previous reports, surgery does not improve the prognosis in PBL, 5 , 14 and surgery is recommended only for diagnostic purposes. Therefore, in our case, surgery was deemed to be unnecessary. A proper initial diagnosis is important to avoid overtreatment. In addition, administering paclitaxel as neoadjuvant chemotherapy might have also been an overtreatment. Although the patients achieved pCR while taking paclitaxel, additional chemotherapeutic agents were still administered.\n\nSozzi et al 15 reported a multicenter analysis on PBL. In their study, the 5‐year overall survival, disease‐free survival, and local control rates were 53%, 41%, and 87%, respectively. They concluded that local control is good, but systemic recurrence occurs frequently. No recurrence has been observed within 2 years after chemotherapy in our presented case; however, a longer follow‐up is necessary.\n\nIn conclusion, we reported a case of PBL initially treated as breast cancer. It can be difficult to distinguish between primary breast lymphoma and breast cancer based on pathological findings. For the accurate diagnosis of PBL, IHC staining is necessary, particularly when the tumor is hormone receptor‐negative, has no intraductal lesions and no high N/C ratio. A malignant tumor in the breast may not be conclusive of breast cancer. It is important for both clinicians and pathologists to keep the possibility of PBL in rare scenarios.\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHOR CONTRIBUTIONS\n\nNU: acquired the data, analyzed, and interpreted the data; wrote the manuscript; approved the final manuscript. SY: analyzed and interpreted the data; wrote the manuscript; approved the final manuscript. MT: wrote the manuscript; approved the final manuscript. SS, TK, SA, KN, AY, TI, and IE: analyzed and interpreted the data; approved the final manuscript.\n\nACKNOWLEDGMENTS\n\nThe authors received no specific funding for the publication of this case report. The patient provided informed consent for the publication of her medical information in the case report. This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal.\n\nDATA AVAILABILITY STATEMENT\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n\n1 Mouna B , Saber B , el Tijani H , Hind M , Amina T , Hassan E . Primary malignant non‐Hodgkin's lymphoma of the breast: a study of seven cases and literature review. World J Surg Oncol. 2012;10 :151.22800119\n2 Raj SD , Shurafa M , Shah Z , Raj KM , Fishman MDC , Dialani VM . Primary and secondary breast lymphoma: clinical, pathologic, and multimodality imaging review. Radiographics. 2019;39 (3 ):610‐625.30924754\n3 Luo H , Yi P , Wang W , et al. Clinicopathological features, treatment, and prognosis in primary diffuse large B cell lymphoma of the breast: a retrospective study of 46 patients. Med Sci Monit. 2019;25 :8671‐8682.31734687\n4 Kuhl CK , Mielcareck P , Klaschik S , et al. Dynamic breast MR imaging: are signal intensity time course data useful for differential diagnosis of enhancing lesions. Radiology. 1999;211 (1 ):101‐110.10189459\n5 Yoneyama K , Nakagawa M , Hara A . Primary lymphoma of the breast: A case report and review of the literature. Radiol Case Rep. 2021;16 (1 ):55‐61.33193929\n6 Lin Y , Govindan R , Hess JL . Malignant hematopoietic breast tumors. Am J Clin Pathol. 1997;107 (2 ):177‐186.9024066\n7 Liu Y , Barta SK . Diffuse large B‐cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2019;94 (5 ):604‐616.30859597\n8 Guilbert MC , Hornick JL , Chikarmane SA , Lester SC . Hematologic malignancies of the breast: a contemporary series investigating incidence, presentation, accuracy of diagnosis on core needle biopsy, and hormone receptor expression. Breast Cancer (Auckl). 2019;13 :1178223419830982.30814841\n9 Cartun RW , Coles FB , Pastuszak WT . Utilization of monoclonal antibody L26 in the identification and confirmation of B‐cell lymphomas. A sensitive and specific marker applicable to formalin‐and B5‐fixed, paraffin‐embedded tissues. Am J Pathol. 1987;129 (3 ):415‐421.3322020\n10 Hans CP , Weisenburger DD , Greiner TC , et al. Confirmation of the molecular classification of diffuse large B‐cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103 (1 ):275‐282.14504078\n11 Jung SP , Kim M , Han KM , et al. Primary breast lymphoma: a single institution's experience. J Korean Surg Soc. 2013;84 (5 ):267‐272.23646311\n12 Rizzieri DA , Sand GJ , McGaughey D , et al. Low‐dose weekly paclitaxel for recurrent or refractory aggressive non‐Hodgkin lymphoma. Cancer. 2004;100 (11 ):2408‐2414.15160345\n13 Casasnovas RO , Haioun C , Dumontet C , et al. Phase II study of 3‐hour infusion of high dose paclitaxel in refractory and relapsed aggressive non‐Hodgkin's lymphomas. Groupe d'Etude des Lymphomes de l'Adulte. Haematologica. 2000;85 (5 ):502‐507.10800167\n14 Shao YB , Sun XF , He YN , Liu CJ , Liu H . Clinicopathological features of thirty patients with primary breast lymphoma and review of the literature. Med Oncol. 2015;32 (2 ):448.25572809\n15 Jeanneret‐Sozzi W , Taghian A , Epelbaum R , et al. Primary breast lymphoma: patient profile, outcome and prognostic factors. A multicentre Rare Cancer Network study. BMC Cancer. 2008;8 (1 ):86.18380889\n\n",
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"title": "Primary breast lymphoma initially diagnosed as invasive ductal carcinoma: A case report.",
"title_normalized": "primary breast lymphoma initially diagnosed as invasive ductal carcinoma a case report"
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"abstract": "Arterial occlusive events (AOEs) such as cerebrovascular, cardiovascular and peripheral arterial events are known side effects of ponatinib, assumed due to the rapid development and increase of arteriosclerosis, while the definitive pathomechanisms therefore are still unclear. We present a case of clinically apparent large vessel vasculitis and discuss this phenomenon as a possible mechanism of AOEs beside arteriosclerosis.",
"affiliations": "Department of Hematology and Oncology, Universitaetsklinikum Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany.;Department of Hematology and Oncology, Universitaetsklinikum Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany.;Department of Hematology and Oncology, Universitaetsklinikum Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany.;Institute of Pathology, Universitaetsklinikum Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany.;Department of Radiology, Universitaetsklinikum Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany.;Internistische Gemeinschaftspraxis am Vincentinum, Franziskanergasse 14, 86152 Augsburg, Germany.;Department of Visceral Surgery, Universitaetsklinikum Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany.;Department of Hematology and Oncology, Universitaetsklinikum Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany.;Department of Hematology and Oncology, Universitaetsklinikum Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany.",
"authors": "Hirschbuehl|Klaus|K|;Rank|Andreas|A|;Pfeiffer|Tim|T|;Schaller|Tina|T|;Haeckel|Thomas|T|;Roeling|Joerg|J|;Vlasenko|Dmytro|D|;Trepel|Martin|M|;Schmid|Christoph|C|",
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"fulltext": "\n==== Front\nJ Hematol\nJ Hematol\nElmer Press\nJournal of Hematology\n1927-1212 1927-1220 Elmer Press \n\n32300450\n10.14740/jh519\nCase Report\nLarge Vessel Vasculitis as a Possible Mechanism of Vascular Side Effects of Ponatinib: A Case Report\nPonatinib-Induced VasculitisHirschbuehl Klaus af Rank Andreas a Pfeiffer Tim a Schaller Tina b Haeckel Thomas c Roeling Joerg d Vlasenko Dmytro e Trepel Martin a Schmid Christoph a a Department of Hematology and Oncology, Universitaetsklinikum Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany\nb Institute of Pathology, Universitaetsklinikum Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany\nc Department of Radiology, Universitaetsklinikum Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany\nd Internistische Gemeinschaftspraxis am Vincentinum, Franziskanergasse 14, 86152 Augsburg, Germany\ne Department of Visceral Surgery, Universitaetsklinikum Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany\nf Corresponding Author: Klaus Hirschbuehl, Department of Hematology and Oncology, Universitaetsklinikum Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany. Email: klaus.hirschbuehl@uk-augsburg.de\n6 2019 \n30 6 2019 \n8 2 83 85\n13 5 2019 7 6 2019 Copyright 2019, Hirschbuehl et al.2019This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Arterial occlusive events (AOEs) such as cerebrovascular, cardiovascular and peripheral arterial events are known side effects of ponatinib, assumed due to the rapid development and increase of arteriosclerosis, while the definitive pathomechanisms therefore are still unclear. We present a case of clinically apparent large vessel vasculitis and discuss this phenomenon as a possible mechanism of AOEs beside arteriosclerosis.\n\nPonatinibArterial occlusive eventsVasculitis\n==== Body\nIntroduction\nTyrosine kinase inhibitors (TKIs) represent the standard treatment for chronic myeloid leukemia (CML) and, in addition to chemotherapy, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The third-generation TKI ponatinib has been shown to be effective in advanced diseases, including patients with T315I mutation and with relapse after allogeneic stem cell transplantation (alloSCT) [1-4]. However, arterial occlusive events (AOEs) such as cerebrovascular, cardiovascular and peripheral arterial events are known side effects of this drug, assumed due to the rapid development and increase of arteriosclerosis, while the definitive pathomechanisms therefore are still unclear [1, 5, 6]. We here present a case report of clinically apparent large vessel vasculitis and discuss this phenomenon also as a possible mechanism of AOEs beside arteriosclerosis.\n\nCase Report\nA 56-year-old woman underwent alloSCT for Ph+ ALL from a matched unrelated donor in March 2011 in first complete molecular remission (CMR). Due to molecular relapse 5 months from alloSCT, she was put on dasatinib and again achieved CMR. After hematological relapse 18 months from alloSCT and re-induction chemotherapy, a second alloSCT from a haplo-identical family donor was performed in November 2012. Again, CMR was achieved. Despite a transient chronic graft-versus-host disease of the skin, a second hematological relapse was diagnosed 2 years later, with detection of a T315I mutation within the bcr/abl fusion transcript. Therefore, the patient was put on ponatinib at a dose of 45 mg/day, upon which she responded rapidly and achieved again CMR. Due to increased liver enzymes (gamma glutamyltransferase 10 times the upper limit of normal range (ULN), alkaline phosphatase two times ULN) and dry, flaky skin, the ponatinib dose was reduced to 30 mg/day after 3 months of treatment, resulting in improvement of both side effects within 4 weeks. After 5 months on ponatinib, the patient developed rapidly increasing symptoms of intermittent claudication, with a final maximum walking distance of just a few meters. Extended vascular workup revealed long-segment stenosis of bilateral femoro-iliacal and subclavian arteries. Ultrasound showed a typical pattern for large vessel vasculitis with low-echo thickened vascular wall and no signs for arteriosclerosis (Fig. 1). After stop of ponatinib and initiation of therapy with steroids, claudication symptoms improved within 4 weeks. Within this time, ultrasound signs of vasculitis decreased as well. Due to a meningeal relapse of the ALL 16 months later, ponatinib was restarted in lack of available treatment alternatives. A dose of 15 mg/day was applied in combination with intrathecal chemotherapy (cytarabin, methotrexate and dexamethasone). This resulted in a CMR in the cerebrospinal fluid, but symptoms of intermittent claudication recurred. Therefore, steroids were administered again, while ponatinib was continued at 15 mg/day, resulting in slight improvement of leg pain and walking distance. Three months later, the patient was admitted to the emergency department with severe abdominal pain of acute onset. The computed tomography (CT) scan showed a distended cecum (7 cm) with no more clear delineation of the bowel wall, and a complete occlusion of the superior mesenteric artery (SMA; Fig. 2). The presence of collaterals suggested a chronic stenosis or occlusion of SMA. There were no signs of intestinal arteriosclerosis on the CT scan. Further, there was no evidence of atrial fibrillation in the patient’s history and the current electro-cardiogram that might have suggested a thromboembolic event. Immediate ileocecal surgical resection was performed. However, the patient died due to septic complications shortly thereafter. The histopathological evaluation of the resected compartment showed an infarction of the bowel wall but only minimal signs of both arteriosclerosis and inflammation.\n\nFigure 1 Typical pattern for large vessel vasculitis with low-echo thickened vascular wall (arrows).\n\nFigure 2 Occlusion of superior mesenteric artery (arrows).\n\nDiscussion\nLarge vessel vasculitis as a possible mechanism for vascular events following ponatinib has been described in a patient with cerebral ischemia [7]. In accordance with this report, the present case suggests this pathomechanism by typical symptoms of claudication and ultrasound signs of vasculitis, as well as by rapid clinical improvement after cessation of ponatinib and steroid treatment. After re-exposition to ponatinib, claudication clinically re-appeared, and the patient finally died from an otherwise unexplained ischemic bowel disease. In the lack of other obvious reasons, intestinal vasculitis in the context of re-exposition to ponatinib was suspected as a trigger for the occlusion of the SMA. The missing clear proof of inflammation in histology in our case may be explained by the prior restart of steroids.\n\nPathogenesis of ponatinib-related vascular events might be mediated by vascular endothelial growth factor receptor 2 (VEGFR2) inhibition, leading to an increase in apoptosis as well as inhibition of viability and functional capacity of human umbilical vein endothelial cells (HUVECs) and endothelial progenitor cells (EPCs) in vitro [8, 9]. Further, exposition of HUVECs to serum of patients with thromboangiitis obliterans confers a diminished sprouting capacity [10]. Thus, one might speculate that there is a link between ponatinib, VEGFR2 inhibition and vasculitis.\n\nConclusion\nAs suggested previously [7], this case supports large vessel vasculitis as a possible mechanism for vascular complications of ponatinib beside arteriosclerosis. Therefore, we propose to consider vasculitis as a potential pathobiological factor in patients with perfusion deficits under ponatinib treatment. In addition, the drug should be used with great caution, once clinical signs of vasculitis are observed or pre-existent.\n\nNone.\n\nFinancial Disclosure\nThis work was not supported by any sponsorship (e.g. university, charity, commercial organization) or sources of material (e.g. novel drugs) not available commercially.\n\nConflict of Interest\nThe authors declare no conflict of interest.\n\nInformed Consent\nNot applicable.\n\nAuthor Contributions\nKlaus Hirschbuehl: writing manuscript. Andreas Rank: treating patient. Tim Pfeiffer: treating patient. Tina Schaller: doing histology. Thomas Haeckel: doing CT scan and providing image. Joerg Roeling: doing ultrasound and providing image. Dmytro Vlasenko: doing surgery. Martin Trepel: lector of the manuscript. Christoph Schmid: writing manuscript.\n==== Refs\nReferences\n1 Cortes JE Kim DW Pinilla-Ibarz J le Coutre PD Paquette R Chuah C Nicolini FE et al Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial Blood 2018 132 4 393 404 10.1182/blood-2016-09-739086 29567798 \n2 Cortes JE Kim DW Pinilla-Ibarz J le Coutre P Paquette R Chuah C Nicolini FE et al A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias N Engl J Med 2013 369 19 1783 1796 10.1056/NEJMoa1306494 24180494 \n3 Cortes JE Kantarjian H Shah NP Bixby D Mauro MJ Flinn I O'Hare T et al Ponatinib in refractory Philadelphia chromosome-positive leukemias N Engl J Med 2012 367 22 2075 2088 10.1056/NEJMoa1205127 23190221 \n4 Hirschbuehl K Rank A Pfeiffer T Slawik HR Schlimok G Kolb HJ Schmid C Ponatinib given for advanced leukemia relapse after allo-SCT Bone Marrow Transplant 2015 50 4 599 600 10.1038/bmt.2014.301 25581405 \n5 Caldemeyer L Dugan M Edwards J Akard L Long-term side effects of tyrosine kinase inhibitors in chronic myeloid leukemia Curr Hematol Malig Rep 2016 11 2 71 79 10.1007/s11899-016-0309-2 26922746 \n6 Valent P Hadzijusufovic E Schernthaner GH Wolf D Rea D le Coutre P Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors Blood 2015 125 6 901 906 10.1182/blood-2014-09-594432 25525119 \n7 Mayer K Gielen GH Willinek W Muller MC Wolf D Fatal progressive cerebral ischemia in CML under third-line treatment with ponatinib Leukemia 2014 28 4 976 977 10.1038/leu.2013.320 24170029 \n8 Gover-Proaktor A Granot G Shapira S Raz O Pasvolsky O Nagler A Lev DL et al Ponatinib reduces viability, migration, and functionality of human endothelial cells Leuk Lymphoma 2017 58 6 1455 1467 10.1080/10428194.2016.1239258 27733071 \n9 Gover-Proaktor A Granot G Pasmanik-Chor M Pasvolsky O Shapira S Raz O Raanani P et al Bosutinib, dasatinib, imatinib, nilotinib, and ponatinib differentially affect the vascular molecular pathways and functionality of human endothelial cells Leuk Lymphoma 2019 60 1 189 199 10.1080/10428194.2018.1466294 29741440 \n10 Hewing B Stangl V Stangl K Enke-Melzer K Baumann G Ludwig A Circulating angiogenic factors in patients with thromboangiitis obliterans PLoS One 2012 7 4 e34717 10.1371/journal.pone.0034717 22506045\n\n",
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"issn_linking": "1927-1212",
"issue": "8(2)",
"journal": "Journal of hematology",
"keywords": "Arterial occlusive events; Ponatinib; Vasculitis",
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"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "25525119;27733071;29567798;25581405;24180494;24170029;22506045;23190221;26922746;29741440",
"title": "Large Vessel Vasculitis as a Possible Mechanism of Vascular Side Effects of Ponatinib: A Case Report.",
"title_normalized": "large vessel vasculitis as a possible mechanism of vascular side effects of ponatinib a case report"
} | [
{
"companynumb": "DE-TAKEDA-2020TUS019497",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
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"activesubstancename": "PONATINIB"
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{
"abstract": "BACKGROUND\nThe standard of care for CNS lymphoma typically includes high dose methotrexate followed by whole brain radiation therapy, but there is an increased risk of neurotoxicity with this regimen. In our institution, we offered stereotactic radiosurgery (SRS) for disease refractory to HD-MTX in a subset of patients. A search of the literature on this modality for CNS lymphoma was also conducted.\n\n\nMETHODS\nMedical records of six patients who received partial brain radiation therapy for persistent CNS lymphoma were reviewed. SRS was given via 1-3 fractions to doses of 21 or 24 Gy. PubMed, SCOPUS, and Cochrane Library databases were systematically searched for articles reporting on outcomes for CNS lymphoma treated with SRS.\n\n\nRESULTS\nSix patients (eleven lesions) were treated with SRS for CNS lymphomas. Median follow up was 15.6 months (range 3.3-37.8). Median RT dose per lesion was 21 Gy and median time to progression was 12.7 months. Median overall survival was not reached. Four patients had distant intracranial failure with two developing local recurrence. The search strategy yielded 16 studies of which only one was prospective and included a control group. 183 out of 256 evaluated lesions (69%) responded completely to treatment and 13 of 204 patients (6%) recurred within the treatment area at last follow-up. Overall, the treatment was well tolerated.\n\n\nCONCLUSIONS\nSRS may provide favorable local control in patients with refractory CNS lymphomas. A prospective trial is warranted to validate the efficacy of such an approach.",
"affiliations": "Department of Radiation Oncology, The James Cancer Hospital and Solove Research Institute, Ohio State University Wexner Medical Center, 460 W 10th Avenue, Columbus, OH, 43210, USA. Joshua.palmer@osumc.edu.;Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, USA.;Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, USA.;Department of Internal Medicine, Division of Hematology, The James Cancer Hospital and Solove Research Institute, Ohio State University Wexner Medical Center, Columbus, USA.;Department of Neurosurgery, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, USA.;Department of Neurosurgery, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, USA.;Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, USA.",
"authors": "Palmer|Joshua D|JD|;Bhamidipati|Deepak|D|;Shukla|Gaurav|G|;Epperla|Narendranath|N|;Glass|Jon|J|;Kim|Lyndon|L|;Shi|Wenyin|W|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s11060-020-03444-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-594X",
"issue": "147(2)",
"journal": "Journal of neuro-oncology",
"keywords": "CNS; Central nervous system lymphoma; Gamma knife; Lymphoma; SRS; Stereotactic radiosurgery",
"medline_ta": "J Neurooncol",
"mesh_terms": "D000368:Aged; D016543:Central Nervous System Neoplasms; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016634:Radiosurgery; D015996:Survival Rate",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "465-476",
"pmc": null,
"pmid": "32108296",
"pubdate": "2020-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "3241537;28427529;27132696;25568347;28434043;27458945;27570717;25868718;25911295;28602418;18948725;17483078;18503346;16283435;19621072;22656234;17325700;21383331;22179954;24481997;19801201;27022122",
"title": "Outcomes after stereotactic radiosurgery for CNS lymphoma.",
"title_normalized": "outcomes after stereotactic radiosurgery for cns lymphoma"
} | [
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"activesubstancename": "TEMOZOLOMIDE"
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"abstract": "Despite the extensive information regarding hemophilia's hemorrhagic complications, the literature on cancer in hemophilia is scarce, especially in pediatric patients. Many uncertainties remain concerning diagnosis and workup. We report a rare case of two severe diseases (neuroblastoma and hemophilia A (HA)) concomitantly present in the same pediatric patient. We highlight that the diagnosis of severe HA did not have a negative impact on the patient's oncologic course. This case also illustrates the significance of the cooperation among different specialties and hospitals when caring for the same patient.",
"affiliations": "Centro de Coagulopatias Congénitas, Centro Hospitalar Universitário do Porto (CHUP), 4050-342 Porto, Portugal.;Serviço de Onco-Hematologia, Instituto Português de Oncologia do Porto (IPO-Porto), 4200-072 Porto, Portugal.;Serviço de Imuno-Hemoterapia, Instituto Português de Oncolologia do Porto (IPO-Porto), 4200-072 Porto, Portugal.;Serviço de Pediatria, Instituto Português de Oncolologia do Porto (IPO-Porto), 4200-072 Porto, Portugal.;Unidade de Hematologia Pediátrica, Centro Materno-Infantil do Norte (CMIN), Centro Hospitalar Universitário do Porto (CHUP), 4050-651 Porto, Portugal.;Serviço de Terapia Celular, Instituto Português de Oncolologia do Porto (IPO-Porto), 4200-072 Porto, Portugal.;Serviço de Imuno-Hemoterapia, Instituto Português de Oncolologia do Porto (IPO-Porto), 4200-072 Porto, Portugal.;Centro de Coagulopatias Congénitas, Centro Hospitalar Universitário do Porto (CHUP), 4050-342 Porto, Portugal.;Centro de Coagulopatias Congénitas, Centro Hospitalar Universitário do Porto (CHUP), 4050-342 Porto, Portugal.",
"authors": "Costa|Lidia|L|0000-0001-8109-2098;Couto|Maria Eduarda|ME|0000-0003-2092-0325;Moutinho|Juliana|J|;Ferreira|Ana Maia|AM|;Costa|Emilia|E|;Roncon|Susana|S|;Santos|Luisa Lopes|LL|;Cruz|Eugenia|E|;Morais|Sara|S|0000-0003-4266-4457",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/pediatric13010018",
"fulltext": "\n==== Front\nPediatr Rep\nPediatr Rep\npediatrrep\nPediatric Reports\n2036-749X\n2036-7503\nMDPI\n\n10.3390/pediatric13010018\npediatrrep-13-00018\nCase Report\nAggressive Neuroblastoma in a Pediatric Patient with Severe Hemophilia A\nhttps://orcid.org/0000-0001-8109-2098\nCosta Lidia 1\nhttps://orcid.org/0000-0003-2092-0325\nCouto Maria Eduarda 2\nMoutinho Juliana 3\nFerreira Ana Maia 4\nCosta Emilia 5\nRoncon Susana 6\nSantos Luisa Lopes 3\nCruz Eugenia 17\nhttps://orcid.org/0000-0003-4266-4457\nMorais Sara 18*\n1 Centro de Coagulopatias Congénitas, Centro Hospitalar Universitário do Porto (CHUP), 4050-342 Porto, Portugal; u12084@chporto.min-saude.pt (L.C.); ecruz@ibmc.up.pt (E.C.)\n2 Serviço de Onco-Hematologia, Instituto Português de Oncologia do Porto (IPO-Porto), 4200-072 Porto, Portugal; eduarda.scouto@gmail.com\n3 Serviço de Imuno-Hemoterapia, Instituto Português de Oncolologia do Porto (IPO-Porto), 4200-072 Porto, Portugal; juliana.moutinho@gmail.com (J.M.); mlsantos@ipoporto.min-saude.pt (L.L.S.)\n4 Serviço de Pediatria, Instituto Português de Oncolologia do Porto (IPO-Porto), 4200-072 Porto, Portugal; ana.ferreira@ipoporto.min-saude.pt\n5 Unidade de Hematologia Pediátrica, Centro Materno-Infantil do Norte (CMIN), Centro Hospitalar Universitário do Porto (CHUP), 4050-651 Porto, Portugal; emvcosta@hotmail.com\n6 Serviço de Terapia Celular, Instituto Português de Oncolologia do Porto (IPO-Porto), 4200-072 Porto, Portugal; sroncon@ipoporto.min-saude.pt\n7 i3S-Basic&Clinical Research on Iron Biology (BCRIB), Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal\n8 Unidade Multidisciplinar de Investigação Biomédica, Instituto de Ciências Biomédicas, Universidade do Porto (UMIB/ICBAS/UP), 4050-313 Porto, Portugal\n* Correspondence: centro.coagulopatias@chporto.min-saude.pt; Tel.: +351-222-077-500 (ext. 4208)\n08 3 2021\n3 2021\n13 1 125130\n10 11 2020\n26 2 2021\n© 2021 by the authors.\n2021\nLicensee 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/).\nDespite the extensive information regarding hemophilia’s hemorrhagic complications, the literature on cancer in hemophilia is scarce, especially in pediatric patients. Many uncertainties remain concerning diagnosis and workup. We report a rare case of two severe diseases (neuroblastoma and hemophilia A (HA)) concomitantly present in the same pediatric patient. We highlight that the diagnosis of severe HA did not have a negative impact on the patient’s oncologic course. This case also illustrates the significance of the cooperation among different specialties and hospitals when caring for the same patient.\n\nhemophilia A\nneuroblastoma\nperipheral blood stem cell transplantation\nprophylaxis\n==== Body\n1. Introduction\n\nHemophilia A (HA) is a rare X-linked inherited bleeding disorder characterized by deficiency of FVIII with an estimated incidence of 1 in 5000 male births [1,2]. In patients with severe disease (FVIII levels < 0.01 IU/mL), spontaneous bleeding or hemorrhage after minimal trauma in joints or muscles are common. Replacement therapy with FVIII concentrates (prophylaxis) is the mainstay of treatment in hemophilia, mainly to prevent bleeding.\n\nNeuroblastoma is the most common extracranial solid tumor in childhood [3], with a median age at diagnosis of 18 months [4] and having a heterogeneous clinical presentation. It is still unclear if hemophilia A (HA) is a predisposing condition to malignancy or if it conditions a worse prognosis in HA patients with neoplastic disorders.\n\nHere, we describe a case of severe HA in a child with aggressive neuroblastoma, the first report in the literature to the best of our knowledge, which makes these findings rare and valuable.\n\n2. Results\n\nThe patient was a black, male, full-term neonate from an uneventful pregnancy, unremarkable family history, unrelated parents, and born from routine eutocic delivery. At day 2 of life, several hematomas (extensive subgaleal hematoma, subdural small volume deposits, and subarachnoid blood without intraventricular bleeding) and severe secondary anemia (hemoglobin [Hb]: 6.6 g/dL) were diagnosed and he was admitted to the neonatal intensive care unit. Severe HA was diagnosed on day 3 of life [5]. Replacement therapy with recombinant FVIII concentrate (rFVIII) was started at a dose of 65 IU/kg every 8 h the first day, every 12 h the second and third days, and daily from the 6th day onward. On day 11 of life, he was discharged and FVIII infusion was stopped. He maintained slow reabsorption left parietal cephalohematoma. No inhibitors were detected.\n\nThe patient started regular follow-up at a hemophilia center. Genetic studies revealed point mutation c4969C > T p.(Gln1657*) on exon 14 of the F8 gene in the child. The infant presented normal development without relevant incidents. During the first 18 months of life, he underwent three on-demand treatments with rFVIII due to minor or moderate bleedings (no hemarthrosis).\n\nAt 19 months of age, the child was admitted at the emergency department due to loss of weight (15% of body weight in 43 days), lethargy, somnolence, anorexia, and discomfort. Physical exam showed pallor and right paravertebral mass, suggesting paravertebral muscle hematoma (confirmed with ultrasound). The initial laboratorial workup unveiled mild anemia (Hb: 9.7 g/dL, age-adjusted reference range (RR): 10.5–13.5 g/dL), mild reactive thrombocytosis (platelets: 445 × 109/L, RR: 150–400 × 109/L), and increased lactate dehydrogenase (LDH; 1481 IU/L, RR: 130–350 IU/L) and uric acid (8.9 mg/dL, RR: 2.0–5.5 mg/dL). The thoracoabdominal–pelvic CT scan (Figure 1) showed a large retroperitoneal solid mass in the left quadrants (larger diameter of 12.8 × 10.8 × 8 cm) with areas of necrosis and calcification involving the left kidney. It also presented hydronephrosis. The right kidney had two solid masses measuring 3 and 5 cm each, probable metastatic lesions. No adenopathies were found. The paravertebral muscles were bilaterally thick (approximately 57 × 7 mm), suggesting hemorrhagic infiltration. Due to the patient’s age, location, clinical presentation, and imaging findings, it was assumed that neuroblastoma would be a likely diagnosis.\n\nThe patient was admitted to the pediatric ward (day 0). He immediately started replacement therapy with rFVIII (50 IU/kg) due to paravertebral hematomas with good response. This was followed by the initiation of prophylaxis with rFVIII 25 IU/kg, three times per week. He had developed spontaneous tumor lysis syndrome secondary to a disseminated neuroblastoma de novo, with left hydronephrosis.\n\nThe infant was transferred into the pediatric intensive care unit (ICU). As relevant complications, he developed mild hypertension after surgical biopsy (at day + 6), promptly corrected, anemia (Hb: 7.3 g/dL) with the need for packed red blood cells transfusion, and low-grade fever paired with elevated C reactive protein. Despite no pathogenic agents being isolated, he completed one cycle of empiric antibiotic therapy (piperacillin/tazobactam).\n\nThe laboratory workup (urinary catecholamines, histology of the fragment, immunophenotyped, and genetic profile) confirmed neuroblastoma diagnosis. The genetic tests demonstrated relative loss of 1p36 and relative gain of MYCN. The patient was diagnosed with undifferentiated large cells neuroblastoma, stage IV International Neuroblastoma Staging System (INSS), due to ganglionic regions, bone marrow, and both kidneys’ involvement.\n\nAt day + 15, the patient was directly referred to an oncologic facility. He began chemotherapy: the rapid-COJEC protocol (cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide). The first cycle was complicated by mild hypertension (needing a three-drug scheduled regimen to achieve blood pressure control) and Clostridium difficile infection (treated with metronidazole).\n\nA metaiodobenzylguanidine (MIBG) and CT scan carried out four months later showed only partial response of the primary tumor, with persistence of the smaller metastatic renal lesions. Therefore, he started second line therapy. The treatment consisted of five courses of chemotherapy (TVD: topotecan, vincristine, and doxorubicin). Peripheral blood mobilized stem cells were collected for an autologous stem cell transplant (ASCT) to obtain a tandem transplant after myeloablative therapy (MAT) was planned, following the protocol of Park et al. [2]. Surgery was performed between the third and fourth TVD courses, allowing macroscopic complete removal of a left adrenal mass and biopsy of a small right kidney nodule (later histologically confirmed as metastatic). At this point, although the disease persisted, bone marrow aspiration and biopsy were both negative. A central venous catheter (CVC) was placed for the apheresis procedures.\n\nThe patient was subjected to third line therapy with the MATIN protocol (131I-mIBG (metaiodobenzylguanidine)/topotecan). The first ASCT was accomplished 10 months after diagnosis. The conditioning regimen consisted of busulfan plus melphalan. The second ASCT was performed two months later. Thirteen months after diagnosis, the MIBG scan was negative, urinary catecholamines were normal (dopamine, vanillylmandelic acid, and homovanillic acid), bone marrow aspirate and biopsy maintained negative, but the CT scan showed two persistent residual lesions in the right kidney (the same location as the previous metastasis).\n\nHe completed treatment with external beam radiation therapy toward the primary site and metastasis, followed by five courses of dinutuximab-beta alternated with six courses of oral isotretinoin.\n\nThe two residual renal nodules remained stable and there was no further evidence of neuroblastoma persistence. Presently, the patient is engaged in a clinical trial with oral difluoromethylornithine (DFMO).\n\nSince the oncologic disease diagnosis, the patient remained on prophylaxis with rFVIII three times per week (25 IU/kg). Prophylaxis was adjusted to the different tumor treatment procedures, adapting FVIII doses to the procedures’ hemorrhagic risk (Table 1). During the aplasia period, he underwent daily prophylaxis. The patient did not experience major bleeding events, adverse reactions, increased use of packed red blood cells, or the development of FVIII inhibitors.\n\nCurrently, the child is under prophylaxis with an extended half-life (EHL) rFVIII factor, 25 IU/kg, twice per week.\n\n3. Discussion\n\nIn infancy, abdominal masses should raise suspicion of four solid tumors: neuroblastoma, Wilms tumor, germ cells tumor, or soft tissue sarcoma [6].\n\nHemophilia A is currently not associated with oncologic diseases in childhood, except in immunocompromised patients [7], which was not the case here. There are few reports of oncologic diseases parallel to congenital hemophilia diagnosis [7], so clinical expertise in this setting is scarce. To date, there are no reports in the literature of neuroblastoma in a severe HA patient.\n\nOur patient presented at cancer diagnosis without any previous hemarthrosis and a moderate bleeding phenotype (since the subgaleal hemorrhage at birth). The finding of the paravertebral muscle hematoma at the time of neuroblastoma detection motivated the beginning of primary prophylaxis.\n\nIn patients with severe HA, the differential diagnosis between hematomas in the retroperitoneal location and oncologic diseases is not always clear. In this case, signs of severe disease were promptly recognized at admission, namely in the blood chemistry, already suggesting an underlying aggressive disorder. A high clinical suspicion index was important for diagnosis as well as complete body imaging with a CT scan, which provided the distinction between oncologic disease and hematoma.\n\nBeyond the differential diagnostic problems, enormous challenges are faced in the care of a cancer patient with an underlying severe bleeding disease. As highlighted by Franchini [8] whether patients with hemophilia and cancer present treatment limitations resulting in worse prognosis, such as therapy-related thrombocytopenia or mucosal bleeding, is unclear [8]. Thus, it is still unknown if they present a higher incidence of adverse hemorrhagic events due to their condition [8].\n\nHigh-risk neuroblastoma can be refractory to conventional treatment approaches, requiring more aggressive strategies to achieve disease remission and improve outcome [3,4]. These include high-dose chemotherapy protocols that exceed bone marrow tolerance (MAT) followed by autologous peripheral blood stem cells (PBSC) collection and infusion [3,4,9], as described. Tandem ASCT presents an increased hemorrhagic risk [9], thus adding an additional complication to the patient’s management.\n\nSo, if managing a patient with severe HA initially appears to be a challenge, it only increases when associated with such an aggressive tumor. Severe HA presents with an augmented risk of spontaneous bleeding per se. Nevertheless, multiple therapies with high bleeding risk by themselves are also needed in the oncologic setting. Therefore, in our patient, these two concurrent entities were handled together, even though they both presented high bleeding risk. Hence, the patient was always successfully managed from the hematologists’ criteria with on-demand treatment or prophylaxis with rFVIII, without any impairment of the cancer treatment (Table 1).\n\n4. Conclusions\n\nAn accurate hemorrhagic prophylaxis allowed the accomplishment of the entire oncologic therapeutic protocol with success. Hemophilia was neither a worse prognosis determinant nor an obstacle to the clinical approach. Our pediatric patient neither experienced severe bleeding events, adverse reactions, nor increased need for transfusion support. Despite having severe HA, this patient’s oncologic prognosis was not negatively affected.\n\nNeuroblastoma is an aggressive disease, especially if metastases are already present at diagnosis. This is the first case reported in the literature of a neuroblastoma, a severe oncologic disease, along with severe HA. Close work between physicians from different hospitals dedicated to bleeding disorders and pediatric oncology was required for the successful management of the patient.\n\nAuthor Contributions\n\nL.C. acquired, analyzed, and interpreted data, drafted the initial manuscript and reviewed and revised it. M.E.C., J.M., and A.M.F. contributed to the analysis and interpretation of the data, contributed to drafting the manuscript, and reviewed and revised the manuscript. E.C. (Emilia Costa), L.L.S., S.R., and E.C. (Eugenia Cruz) substantially contributed to the analysis and interpretation of the data, critically reviewed the manuscript and revised it. S.M. conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed and revised the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nNo funding was secured for this study.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nNot applicable.\n\nConflicts of Interest\n\nThe authors have no conflict of interest relevant to this article to declare.\n\nAbbreviations\n\nASCT\tAutologous stem cell transplantion\t\nCOJEC\tCisplatin, vincristine, carboplatin, etoposide, cyclophosphamide\t\nCT\tComputed tomography\t\nCVC\tCentral venous catheter\t\nDMFO\tDifluoromethylornithine\t\nEHL\tExtended half-life\t\nFVIII\tFactor VIII of the coagulation\t\nG-CSF\tGranulocyte colony stimulating factor\t\nHA\tHemophilia A\t\nHb\tHemoglobin\t\nICU\tIntensive care unit\t\n131I-mIBG\tMetaiodobenzylguanidine\t\nINSS\tInternational Neuroblastoma Staging System\t\nLDH\tLactate dehydrogenase\t\nMATIN\tMetaiodobenzylguanidine, topotecan\t\nPBSC\tPeripheral blood stem cells\t\nrFVIII\tRecombinant FVIII concentrate\t\nRR\tReference range\t\nTVD\tTopotecan, vincristine, doxorubicin\t\n\nFigure 1 Thoracic, abdominal, and pelvic CT scan performed at diagnosis: (A) large described mass over left kidney (arrow); (B) metastatic lesion on right kidney (arrow); (C) hemorrhagic infiltration of the paravertebral muscles (arrowhead).\n\npediatrrep-13-00018-t001_Table 1 Table 1 Hematological patient management (rFVIII regimen) during oncologic treatment (according to the protocol of Park et al. (2019).\n\nFVIII Replacement Scheme\tMajor Hemorrhagic Procedures\tImmediately Before\t1st Day\t2nd Day\t8 Following Days\t\n(by Chronologic Order)\t\nChemotherapy and invasive maneuvers\tStandard chemotherapy\t25 IU/kg 3×/week\t\n(Rapid COJEC protocol + TVD cycles)\t\nRetroperitoneal tumor excision\t50 IU/kg\t40 IU/kg\t40 IU/lg\nq12 h\t\nq8 h\t\n131I-mIBG + Topotecan\t25 IU/kg 3×/week\t\nInsertion/replacement\t50 IU/kg\t40 IU/kg\t40 IU/kg q12 h\t25 IU/kg 3×/week\t\nof CVC\tq8 h\t\nPBSC collection\t50 IU/kg\t50 IU/kg 1st dose + 40 UI/kg q8 h\t25 IU/kg 3×/week\t\n(5 day mobilization with G-CSF 12 µg/kg/day + leukapheresis) *\t\nDouble autologous hematopoietic transplant\tHigh-dose chemotherapy (busulfan + melphalan)\t25 IU/kg 3×/week\t\nPBSC infusion\t25 IU/kg 3×/week\t40 IU/kg\nq8 h\t25 IU/kg\nq24 h **\t\n(3.5 × 106 CD34 + cells/kg per transplant)\t\nCaption: * Platelet count > 50 × 109/L in all conditions, except in leukapheresis (platelet count > 100 × 109/L); ** 25 IU/kg daily during the aplasia period; COJEC: cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide; TVD: topotecan, vincristine, and doxorubicin; CVC: central venous catheter; G-CSF: granulocyte colony stimulating factor; 131I-mIBG: metaiodobenzylguanidine; PBSC: peripheral blood stem cells; rFVIII: recombinant factor FVIII.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Mannucci P.M. Tuddenham E.G.D. The Hemophilias—From Royal Genes to Gene Therapy N. Engl. J. Med. 2001 344 1773 1779 10.1056/NEJM200106073442307 11396445\n2. Srivastava A. Brewer A.K. Mauser-Bunschoten E.P. Key N.S. Kitchen S. Llinas A. Ludlam C.A. Mahlangu J.N. Mulder K. Poon M.C. Guidelines for the management of hemophilia Haemophilia 2013 19 e1 e47 10.1111/j.1365-2516.2012.02909.x 22776238\n3. Barrett D. Fish J.D. Grupp S.A. Autologous and allogeneic cellular therapies for high-risk pediatric solid tumors Pediatr. Clin. N. Am. 2010 57 47 66 10.1016/j.pcl.2010.01.001 20307711\n4. Tolbert V.P. Matthay K.K. Neuroblastoma: Clinical and biological approach to risk stratification and treatment Cell Tissue Res. 2018 372 195 209 10.1007/s00441-018-2821-2 29572647\n5. Ferreira N. Proenca E. Godinho C. Oliveira D. Guedes A. Morais S. Carvalho C. Neonatal Hemophilia: A Rare Presentation Pediatr. Rep. 2015 7 79 80 10.4081/pr.2015.6338 26734126\n6. Allen-Rhoades W. Whittle S.B. Rainusso N. Pediatric Solid Tumors of Infancy: An Overview Pediatr Rev. 2018 39 57 67 10.1542/pir.2017-0057 29437125\n7. Lu G. Qiao L. Li D. Liu Z. Zhao F. Yu D. Concurrent lymphoma and hemophilia B in a pediatric patient Medicine 2019 98 e15474 10.1097/MD.0000000000015474 31083180\n8. Franchini M. Haemophilia and cancer: A personal perspective Blood Transfus. 2013 11 26 31 10.2450/2012.0149-11 22790273\n9. Park J.R. Kreissman S.G. London W.B. Naranjo A. Cohn S.L. Hogarty M.D. Tenney S.C. Haas-Kogan D. Shaw P.J. Kraveka J.M. Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma: A Randomized Clinical Trial JAMA 2019 322 746 755 10.1001/jama.2019.11642 31454045\n\n",
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"title": "Aggressive Neuroblastoma in a Pediatric Patient with Severe Hemophilia A.",
"title_normalized": "aggressive neuroblastoma in a pediatric patient with severe hemophilia a"
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"abstract": "Monitoring the potential for abuse and dependence of psychoactive substances falls within the scope of international conventions on narcotic drugs. At the European level, this monitoring is based on activities controlled by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) for substance abuse in general and by the European Medicines Agency (EMA) for marketed drugs, in the context of pharmacovigilance. If France has set up in the early 1990s an original system to assess potential for abuse of psychoactive substances, with specific tools combining both the evaluation of the use of these substances (illicit substances or diverted drugs), and the consequences of that use in terms of morbidity and mortality, there is no equivalent in other European countries. Indeed, unlike the USA, who, for several decades, organized this type of surveillance, with a multisource approach (sentinel systems, databases, medical and administrative data, databases for seeking care in relation abuse), we have not found in other European countries integrated system for identifying a signal of drug abuse, or to assess the impact of measures for minimizing the risk of abuse. However, some recent examples show a growing concern about drug addiction, based on a pharmacoepidemiological approach using pharmacovigilance databases or medical administrative data. These examples illustrate the interest of these approaches in the field of drug of abuse.",
"affiliations": "CEIP-Addictovigilance de Toulouse, Service de Pharmacologie Médicale et Clinique, CHU de Toulouse, Toulouse, France.;CEIP-Addictovigilance de Toulouse, Service de Pharmacologie Médicale et Clinique, CHU de Toulouse, Toulouse, France.",
"authors": "Lapeyre-Mestre|Maryse|M|;Dupui|Mathilde|M|",
"chemical_list": "D013287:Illicit Drugs; D011619:Psychotropic Drugs",
"country": "France",
"delete": false,
"doi": "10.2515/therapie/2015010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-5957",
"issue": "70(2)",
"journal": "Therapie",
"keywords": null,
"medline_ta": "Therapie",
"mesh_terms": "D016208:Databases, Factual; D005060:Europe; D005602:France; D006801:Humans; D013287:Illicit Drugs; D017891:Pharmacoepidemiology; D060735:Pharmacovigilance; D011619:Psychotropic Drugs; D019966:Substance-Related Disorders",
"nlm_unique_id": "0420544",
"other_id": null,
"pages": "147-65",
"pmc": null,
"pmid": "25858571",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Drug abuse monitoring: which pharmacoepidemiological resources at the European level?",
"title_normalized": "drug abuse monitoring which pharmacoepidemiological resources at the european level"
} | [
{
"companynumb": "DK-ALKEM LABORATORIES LIMITED-DK-ALKEM-2018-11556",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DULOXETINE HYDROCHLORIDE"
},
... |
{
"abstract": "OBJECTIVE\nA prednisone and calcineurin inhibitor (CNI)-free protocol was compared with a sirolimus, cyclosporine A (CsA), and prednisone-based immunosuppressive regimen for simultaneous pancreas-kidney transplantation (SPK).\n\n\nMETHODS\nA nonrandomized, single-center, sequential study enrolled low-immune responder SPK transplant recipients. The prednisone/CNI-free (minimization) group of 22 patients received thymoglobulin followed by sirolimus and reduced-dose CsA. Prednisone was withdrawn on day 5, and recipients were converted from CsA to mycophenolic acid at 6 months posttransplantation. The sirolimus/CsA group of 20 consecutive recipients transplanted immediately before this series received thymoglobulin followed by sirolimus, reduced-dose CsA, and prednisone.\n\n\nRESULTS\nDonor and recipient demographic variables were equivalent between groups. The 24-month actual patient, kidney, and pancreas survivals for the minimization group were 100%, 100%, and 91% vs. 100%, 95%, and 95% for the sirolimus/CsA group (P=not significant [NS] for patient, kidney, and pancreas survivals). One acute rejection occurred in the minimization group and none in the sirolimus/CsA group. After withdrawal of CsA at 6 months, the minimization group showed an increase in mean estimated glomerular filtration rate, resulting in a significant improvement in renal function compared with the sirolimus/CsA group. At 24 months, the mean glomerular filtration rate of the minimization and sirolimus/CsA groups was 71.6+/-11.2 mL/min/1.73 m and 60.1+/-13.4 mL/min/1.73 m, respectively (P<0.05). Mean fasting blood glucose levels were equivalent between groups at all time points studied.\n\n\nCONCLUSIONS\nLow-immune responder SPK recipients receiving a prednisone/CNI-free protocol achieved similar 2-year graft survivals and improved renal function compared with those treated with a sirolimus, CsA, and prednisone regimen.",
"affiliations": "Department of Surgery, The Methodist Hospital, Houston, TX 77030, USA. RJKnight@tmhs.org",
"authors": "Knight|Richard J|RJ|;Podder|Hemangshu|H|;Kerman|Ronald H|RH|;Lawless|Amy|A|;Katz|Stephen M|SM|;Van Buren|Charles T|CT|;Gaber|A Osama|AO|;Kahan|Barry D|BD|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D001786:Blood Glucose; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C512542:thymoglobulin; D009173:Mycophenolic Acid; D011241:Prednisone; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0b013e3181c9dc9b",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "89(6)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000208:Acute Disease; D000305:Adrenal Cortex Hormones; D000328:Adult; D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D001786:Blood Glucose; D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005919:Glomerular Filtration Rate; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D016035:Pancreas Transplantation; D011241:Prednisone; D020123:Sirolimus; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "727-32",
"pmc": null,
"pmid": "20195219",
"pubdate": "2010-03-27",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Comparing an early corticosteroid/late calcineurin-free immunosuppression protocol to a sirolimus-, cyclosporine A-, and prednisone-based regimen for pancreas-kidney transplantation.",
"title_normalized": "comparing an early corticosteroid late calcineurin free immunosuppression protocol to a sirolimus cyclosporine a and prednisone based regimen for pancreas kidney transplantation"
} | [
{
"companynumb": "NVSC2019US075426",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThis observational study investigates the effectiveness and safety of dabrafenib/trametinib combination in patients with metastatic melanoma.\n\n\nMETHODS\nSeventy-six patients treated with dabrafenib/trametinib (150 mg twice daily/2 mg once daily) were included.\n\n\nRESULTS\nMedian progression-free survival was 9 months (95% CI: 7-11) and median overall survival was 14 months (11-16); disease control rate was 72%. Nine patients (12%) experienced a complete response. Of these, seven presented one metastatic site, none had lung or CNS metastasis, and none had elevated baseline lactate dehydrogenase (LDH) levels. Overall, subgroup analysis for patients with adverse prognostic features led to similar results. No new safety signals were reported.\n\n\nCONCLUSIONS\nDabrafenib/trametinib combination can be effective and well-tolerated also in a heterogeneous 'real life' population comprising patients with adverse prognostic features.",
"affiliations": "Division of Oncology, Department of Oncology & Hematology, University of Modena & Reggio Emilia, Modena, Italy.;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy.;Division of Oncology, Department of Oncology & Hematology, University of Modena & Reggio Emilia, Modena, Italy.;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy.;Department of Dermatology, University of Modena & Reggio Emilia, Modena, Italy.;Department of Diagnostic, Clinical Medicine & Public Health, Clinical Pathology Unit, University of Modena & Reggio Emilia, Modena, Italy.;Division of Oncology, Department of Oncology & Hematology, University of Modena & Reggio Emilia, Modena, Italy.;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy.",
"authors": "Depenni|Roberta|R|;De Rosa|Francesco|F|;Greco|Stefano|S|;Ridolfi|Laura|L|;Pellacani|Giovanni|G|;Ponti|Giovanni|G|;Cascinu|Stefano|S|;Guidoboni|Massimo|M|",
"chemical_list": "D007093:Imidazoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C561627:dabrafenib",
"country": "England",
"delete": false,
"doi": "10.2217/fon-2017-0714",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1479-6694",
"issue": "14(20)",
"journal": "Future oncology (London, England)",
"keywords": "LDH baseline level; dabrafenib/trametinib; metastatic melanoma; number of metastasis; prognosis; real-life setting",
"medline_ta": "Future Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles; D007558:Italy; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms; D010091:Oximes; D011379:Prognosis; D011728:Pyridones; D011744:Pyrimidinones; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101256629",
"other_id": null,
"pages": "2045-2052",
"pmc": null,
"pmid": "30081673",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Dabrafenib-trametinib combination in 'field-practice': an Italian experience.",
"title_normalized": "dabrafenib trametinib combination in field practice an italian experience"
} | [
{
"companynumb": "PHHY2018IT095035",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABRAFENIB"
},
"drugadditional": "3",
"druga... |
{
"abstract": "OBJECTIVE\nTo determine the extent of QTc prolongation following administration of an atypical antipsychotic in critically ill patients diagnosed with delirium and to conduct an assessment of risk factors to identify the presence of specific risk factors associated with QTc prolongation in this patient population.\n\n\nMETHODS\nPatients were included if they were at least 18 years of age, admitted to an Intensive Care Unit (ICU) at the study institution from July 1, 2013 through January 30, 2014, had a documented diagnosis of delirium within their electronic medical record, and received an atypical antipsychotic for delirium during their hospital admission. Excluded patients were those who received an atypical antipsychotic for an indication other than delirium, received fewer than two doses of the atypical antipsychotic, had an atypical antipsychotic documented as a home medication, or demonstrated a lack of EKG data at baseline or post administration of their atypical antipsychotic dose.\n\n\nRESULTS\nOf the 360 patient charts screened, 118 subjects met inclusion criteria. For the study's primary outcome, the proportion of change from baseline EKG to the first EKG following atypical antipsychotic administration, 72 (61.0%) patients had a decrease in their QTc interval, 1 (0.85%) patient stayed the same, and 45 (38.1%) patients had an increase in their QTc interval. The median change in QTc interval was a decrease of 12.5 msec. Of the 45 (38%) subjects who had an increase in their QTc interval, the mean change from baseline to the first EKG post atypical antipsychotic administration was an increase of 30 msec. Sixty-six (56%) subjects reached steady state while on their first atypical antipsychotic. With respect to the secondary outcome, 40 of 66 (60.1%) had a decrease in their QTc interval, while 26 (39.4%) subjects had an increase in their QTc interval. The median change in QTc interval was a decrease of 10.5 msec. Receipt of a pro-arrhthymic medication was used concomitantly among 25 (21.2%) of patients at baseline. Antibiotics were the most commonly observed class used concomitantly in 39 (21.7%) of the 180 observed total instances of concomitant QTc prolonging agent use, followed by antidepressants (18.9%). Amiodarone was the single most commonly observed agent utilized (10%).\n\n\nCONCLUSIONS\nThis retrospective analysis of a mixed ICU population demonstrates that following initiation of an atypical antipsychotic, QTc interval increase occurred less frequently then a QTc interval decrease from baseline. Providers should correct modifiable risk factors and minimize concomitant QTc prolonging medications as much as possible.",
"affiliations": "P.O. Box 3089 - Pharmacy, Durham, NC 27710,. United States.",
"authors": "Palazzolo|Nicole|N|;Kram|Bridgette|B|;Muzyk|Andrew J|AJ|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886311666160815110801",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": "12(1)",
"journal": "Current drug safety",
"keywords": "Agitation; ICU; QTc; atypical antipsychotic; critically ill; delirium",
"medline_ta": "Curr Drug Saf",
"mesh_terms": "D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents; D001145:Arrhythmias, Cardiac; D016638:Critical Illness; D003693:Delirium; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "101270895",
"other_id": null,
"pages": "32-38",
"pmc": null,
"pmid": "27527528",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Examination of QTc Values in Critically Ill Patients Diagnosed with Delirium and Prescribed Atypical Antipsychotics.",
"title_normalized": "examination of qtc values in critically ill patients diagnosed with delirium and prescribed atypical antipsychotics"
} | [
{
"companynumb": "US-JNJFOC-20170220655",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "3",
... |
{
"abstract": "Some rare cases of erysipelas-like or pseudocellulitis have been reported in relation to gemcitabine. This rare adverse event is more frequent in the presence of edema. Here, we report a case of pseudocellulitis after adjuvant treatment for pancreatic cancer. Oncologists should be aware of this infrequent and non-well understood adverse event. They should be especially careful when administering gemcitabine in the presence of lymphedema.",
"affiliations": "Department of Medical Oncology, Hospital Universitario Puerta de Hierro, Majadahonda, Spain.",
"authors": "Ruiz-Casado|Ana|A|;Gutiérrez|David|D|;Juez|Ignacio|I|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine",
"country": "India",
"delete": false,
"doi": "10.4103/0973-1482.148711",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "11(4)",
"journal": "Journal of cancer research and therapeutics",
"keywords": null,
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D003841:Deoxycytidine; D004887:Erysipeloid; D005076:Exanthema; D005260:Female; D006801:Humans; D010190:Pancreatic Neoplasms; D011379:Prognosis; D035583:Rare Diseases",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "1024",
"pmc": null,
"pmid": "26881588",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Erysipeloid rash: A rare adverse event induced by gemcitabine.",
"title_normalized": "erysipeloid rash a rare adverse event induced by gemcitabine"
} | [
{
"companynumb": "ES-FRESENIUS KABI-FK201601993",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
... |
{
"abstract": "Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD) is a life-threatening complication following allogeneic hematopoietic stem cell transplantation (HSCT). Monitoring of EBV DNA in high-risk patients with subsequent pre-emptive rituximab treatment is highly effective, and can prevent EBV-associated disease following HSCT. Here, we report a 10-year-old girl with aplastic anemia who developed CD20 negative EBV-PTLD after unrelated bone marrow transplantation that was refractory to rituximab treatment. Similar to other types of lymphoma, the absence of CD20 antigen is likely to be characteristic of rituximab-refractory EBV-PTLD.",
"affiliations": "Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, Aichi, 466-8650, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, Aichi, 466-8650, Japan.;Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Aichi, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, Aichi, 466-8650, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, Aichi, 466-8650, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, Aichi, 466-8650, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, Aichi, 466-8650, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, Aichi, 466-8650, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, Aichi, 466-8650, Japan.;Department of Pathology, Japanese Red Cross Nagoya First Hospital, Aichi, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, Aichi, 466-8650, Japan. kojimas@med.nagoya-u.ac.jp.",
"authors": "Muramatsu|Hideki|H|;Takahashi|Yoshiyuki|Y|;Shimoyama|Yoshie|Y|;Doisaki|Sayoko|S|;Nishio|Nobuhiro|N|;Ito|Yoshinori|Y|;Hama|Asahito|A|;Shimada|Akira|A|;Yagasaki|Hiroshi|H|;Ito|Masafumi|M|;Kojima|Seiji|S|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D004279:DNA, Viral; D000069283:Rituximab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-011-0870-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "93(6)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000741:Anemia, Aplastic; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D016026:Bone Marrow Transplantation; D002648:Child; D056915:DNA Copy Number Variations; D004279:DNA, Viral; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007668:Kidney; D008232:Lymphoproliferative Disorders; D010614:Pharynx; D049268:Positron-Emission Tomography; D000069283:Rituximab; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "779-781",
"pmc": null,
"pmid": "21559814",
"pubdate": "2011-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17511690;19558376;14576843;8093146;19246561;12036863;10666232;11722420",
"title": "CD20-negative Epstein-Barr virus-associated post-transplant lymphoproliferative disease refractory to rituximab in a patient with severe aplastic anemia.",
"title_normalized": "cd20 negative epstein barr virus associated post transplant lymphoproliferative disease refractory to rituximab in a patient with severe aplastic anemia"
} | [
{
"companynumb": "JP-ROCHE-1916017",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Topiramate, presumably through antagonism of excitatory glutaminergic pathways and facilitation of inhibitory gamma-aminobutyric acid neurons in the cortico-mesolimbic system, might reduce cocaine's abuse liability. We tested whether topiramate (100 mg twice daily) would reduce the euphoria, subjective mood, craving and preference for cocaine over money induced by low and high doses (0.325 and 0.65 mg/kg i.v., respectively) of experimentally administered cocaine in 24 male and female, cocaine-dependent, non-treatment-seeking research volunteers in a university in-patient laboratory. We utilized a randomized, double-blind, placebo-controlled, within-subject, Latin-square cross-over design in which three experimental challenge doses of low-dose cocaine, high-dose cocaine and placebo were administered in counterbalanced order after 5 days of topiramate or matching placebo pre-treatments separated by a 1-week washout period (2006-2009). After placebo pre-treatments, cocaine produced dose-related increases in euphoria, stimulant effects, craving for more cocaine and monetary value of cocaine in a behavioral preference test of cocaine versus money choice. Topiramate pre-treatment reduced the cocaine-related craving and monetary value of high-dose cocaine while increasing the monetary value, euphoria and stimulant effects of low-dose cocaine. Validated and standardized human experimental methods evaluating the potential for topiramate to alter cocaine's abuse liability suggest that topiramate may reduce the reinforcing effects and craving induced by higher cocaine doses. Low-dose cocaine might appear to have some enhancement of its stimulant properties in the presence of topiramate's prominent sedative effects.",
"affiliations": "Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, USA. bankolejohnson@virginia.edu",
"authors": "Johnson|Bankole A|BA|;Roache|John D|JD|;Ait-Daoud|Nassima|N|;Gunderson|Erik W|EW|;Haughey|Heather M|HM|;Wang|Xin-Qun|XQ|;Liu|Lei|L|",
"chemical_list": "D018765:Dopamine Uptake Inhibitors; D018696:Neuroprotective Agents; D000077236:Topiramate; D005632:Fructose; D003042:Cocaine",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1369-1600.2012.00499.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-6215",
"issue": "18(3)",
"journal": "Addiction biology",
"keywords": null,
"medline_ta": "Addict Biol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000339:Affect; D003042:Cocaine; D019970:Cocaine-Related Disorders; D018592:Cross-Over Studies; D018765:Dopamine Uptake Inhibitors; D004311:Double-Blind Method; D005059:Euphoria; D005260:Female; D005632:Fructose; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents; D057240:Patient Preference; D012054:Reinforcement, Psychology; D000077236:Topiramate; D055815:Young Adult",
"nlm_unique_id": "9604935",
"other_id": null,
"pages": "405-16",
"pmc": null,
"pmid": "23039088",
"pubdate": "2013-05",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "20402706;10025774;12726795;18470406;19777216;3960276;17925516;9438676;2893392;8033763;15206666;11224414;11440351;7606438;7508582;12073170;7965077;7484980;18283437;9097399;9536451;7886626;7616389;9706732;11475940;2019989;9559930;8923575;17895405;10768300;8019704;1602388;11224166;11746717;7853170;9670779;20482511;108042;21481843;9600578;9749793;16366762;7902523;16448579;9610948;11002911;2594898;8593597;1786488;9152375;1604710;19041336;15283944;9332882;9560846;1385603;10435398;14054658;15510234;8786528;10768293",
"title": "Topiramate's effects on cocaine-induced subjective mood, craving and preference for money over drug taking.",
"title_normalized": "topiramate s effects on cocaine induced subjective mood craving and preference for money over drug taking"
} | [
{
"companynumb": "US-JNJFOC-20130410312",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "Overexpression and cellular mis-localization of aurora kinase A (AURKA) in gastrointestinal cancers results in chromosomal instability, activation of multiple oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 leading to cell death. Our preclinical data showed cooperative activity with the AURKA inhibitor alisertib and platinum agents in cell lines and xenografts, and suggested an optimal treatment window. Therefore, this study was designed to determine the maximum-tolerated dose (MTD) of alisertib in combination with modified FOLFOX (mFOLFOX), as this is a standard platinum-based therapy for gastrointestinal cancers. Standard 3 + 3 dose escalation was used, where the starting dose of alisertib was 10 mg twice daily (Days 1-3), with leucovorin (400 mg/m2) and oxaliplatin (85 mg/m2) on Day 2 followed by continuous 46-h 5-FU (2400 mg/m2) infusion on Days 2-4 in 14-day cycles. Fourteen patients with advanced gastrointestinal cancers were enrolled and two doses explored; two patients were not evaluable for dose-limiting toxicity (DLT) and replaced. Two patients experienced DLTs at 20 mg of alisertib (Grade 3 fatigue (n = 2); Grade 3 nausea, vomiting, dehydration with hospitalization (n = 1)). MTD was 10 mg alisertib with 85 mg/m2 oxaliplatin and 2400 mg/m2 5-FU. Most frequent toxicities were nausea (57%), diarrhea, fatigue, neuropathy, and vomiting (43%), and anorexia and anemia (36%); most were Grade 1-2. One patient with colorectal cancer had a partial response of 12 evaluable patients, and four patients had stable disease. Alisertib in combination with mFOLFOX did not demonstrate unexpected side effects, but the regimen was only tolerable at the lowest dose investigated.",
"affiliations": "Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Vanderbilt University, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA. laura.goff@vumc.org.;Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.;Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.;Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Vanderbilt University, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA.;Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Vanderbilt University, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA.;Karmanos Cancer Institute, Detroit, MI, USA.;Rutgers Canter Institute, New Brunswick, NJ, USA.;Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.;Karmanos Cancer Institute, Detroit, MI, USA.;Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.;Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Vanderbilt University, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA.;University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA.;Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Vanderbilt University, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA.",
"authors": "Goff|Laura W|LW|;Azad|Nilofer S|NS|;Stein|Stacey|S|;Whisenant|Jennifer G|JG|;Koyama|Tatsuki|T|;Vaishampayan|Ulka|U|;Hochster|Howard|H|;Connolly|Roisin|R|;Weise|Amy|A|;LoRusso|Patricia M|PM|;Salaria|Safia N|SN|;El-Rifai|Wael|W|;Berlin|Jordan D|JD|",
"chemical_list": "D001381:Azepines; C550258:MLN 8237; D009944:Organoplatinum Compounds; D011743:Pyrimidines; C576917:AURKA protein, human; D064096:Aurora Kinase A; D002955:Leucovorin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-018-0663-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6997",
"issue": "37(2)",
"journal": "Investigational new drugs",
"keywords": "Alisertib; Aurora kinase a inhibition; Gastrointestinal cancers; Modified FOLFOX",
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D064096:Aurora Kinase A; D001381:Azepines; D005260:Female; D005472:Fluorouracil; D005770:Gastrointestinal Neoplasms; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D002955:Leucovorin; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009944:Organoplatinum Compounds; D011379:Prognosis; D011743:Pyrimidines; D015996:Survival Rate; D014018:Tissue Distribution",
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "315-322",
"pmc": null,
"pmid": "30191522",
"pubdate": "2019-04",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "19060929;19111882;22016509;27192055;19075002;16715125;22939930;17438137;15182704;28055103;26884555;15078988;17360485;22302096;22753585;18801727;24240108;11748251;19786657;12631597;22772063;20460511;21291867;17457043;15289843;7720077;23993973;11551964;18311783;27385211;17390048;13678582;10523496;15041727;14523000;21091633;18974145;19412426;9771714;19684075;25728526;9606188",
"title": "Phase I study combining the aurora kinase a inhibitor alisertib with mFOLFOX in gastrointestinal cancer.",
"title_normalized": "phase i study combining the aurora kinase a inhibitor alisertib with mfolfox in gastrointestinal cancer"
} | [
{
"companynumb": "US-CIPLA LTD.-2019US03025",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALISERTIB"
},
"drugadditional": null,
... |
{
"abstract": "Methylene blue (MB) is a medication commonly used to treat methemoglobinemia, reducing methemoglobin to hemoglobin. A novel use of MB, as detailed here, is in the treatment of refractory hypotension. A number of reports have detailed use of MB for this purpose in adults, but few data in pediatrics. A 22-month-old girl with Noonan syndrome, biventricular hypertrophic cardiomyopathy, and chronic positive pressure ventilation developed shock with tachycardia, hypotension, and fever after 3 days of diarrhea. She was critically ill, with warm extremities, bounding pulses, and brisk capillary refill. Laboratory tests revealed metabolic acidosis, low mixed venous oxygen saturation, and leukocytosis with bandemia. Treatment of severe septic shock was initiated with fluid resuscitation, inotropic support, sedation, and paralysis. She remained hypotensive despite norepinephrine at 0.7 μg/kg per minute, dopamine at 20 μg/kg per minute, and vasopressin at 0.04 U/kg per hour. Her vasoplegic shock worsened, despite aggressive conventional therapy. Intravenous MB was initiated, with a loading dose of 1 mg/kg followed by a continuous infusion at 0.25 mg/kg per hour. Upon initiation of MB, her systolic blood pressure increased by 33 points (40% increase), and diastolic blood pressure increased by 20 points (46% increase). She was able to wean off all inotropes quickly after initiation of MB. MB should be considered in the setting of refractory vasoplegic shock in the PICU.",
"affiliations": "Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama; crutledge@peds.uab.edu.;Department of Pharmacy, Children's of Alabama, Birmingham, Alabama; and.;McWhorter School of Pharmacy, Samford University, Birmingham, Alabama.;Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama;;Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama;",
"authors": "Rutledge|Chrystal|C|;Brown|Brian|B|;Benner|Kimberley|K|;Prabhakaran|Priya|P|;Hayes|Leslie|L|",
"chemical_list": "D004791:Enzyme Inhibitors; D008751:Methylene Blue",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2014-3722",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "136(4)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D003131:Combined Modality Therapy; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D007022:Hypotension; D007223:Infant; D008751:Methylene Blue; D012772:Shock, Septic; D056987:Vasoplegia",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "e1030-4",
"pmc": null,
"pmid": "26347436",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Novel Use of Methylene Blue in the Pediatric ICU.",
"title_normalized": "a novel use of methylene blue in the pediatric icu"
} | [
{
"companynumb": "US-PAR PHARMACEUTICAL COMPANIES-2015SCPR014439",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CALCIUM GLUBIONATE"
},
... |
{
"abstract": "OBJECTIVE\nThe interaction between valproic acid (VPA) and carbapenem antibiotics is well described with previous reports suggesting a reduction in VPA half-life between 47% and 90%. As described in this case, this interaction might be beneficial in the setting of toxic VPA ingestion.\n\n\nMETHODS\nAn intubated, unresponsive patient arrived via emergency medical services after toxic VPA ingestion. Meropenem was prescribed for a suspected pneumonia and to take advantage of the VPA interaction. We observed a 56% decline in half-life with short-term meropenem dosing and an improvement in mental status shortly after administration.\n\n\nCONCLUSIONS\nOur findings suggest a potential role for short-term carbapenem therapy for VPA overdose.",
"affiliations": "Department of Pharmacy Practice & Science, College of Pharmacy, The University of Arizona, Tucson, AZ, USA.;Arizona Poison & Drug Information Center, College of Pharmacy, The University of Arizona, Tucson, AZ, USA.;Department of Pharmacy Services, Banner University Medical Center - Tucson, Tucson, AZ, USA.;Department of Pharmacy Services, Banner University Medical Center - Tucson, Tucson, AZ, USA.;Department of Pharmacy Services, Froedtert Hospital, Milwaukee, WI, USA.;Arizona Poison & Drug Information Center, College of Pharmacy, The University of Arizona, Tucson, AZ, USA.;Arizona Poison & Drug Information Center, College of Pharmacy, The University of Arizona, Tucson, AZ, USA.;Department of Pharmacy Practice & Science, College of Pharmacy, The University of Arizona, Tucson, AZ, USA.",
"authors": "Khobrani|M A|MA|;Dudley|S W|SW|;Huckleberry|Y C|YC|;Kopp|B J|BJ|;Biggs|A D|AD|;French|R N E|RNE|;Shirazi|F M|FM|;Erstad|B L|BL|",
"chemical_list": "D000927:Anticonvulsants; D015780:Carbapenems; D014635:Valproic Acid; D000077731:Meropenem",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12705",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "43(5)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "carbapenem interaction; valproic acid interaction; valproic acid overdose; valproic acid toxicity",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000927:Anticonvulsants; D015780:Carbapenems; D004347:Drug Interactions; D006801:Humans; D008297:Male; D000077731:Meropenem; D008875:Middle Aged; D014635:Valproic Acid",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "723-725",
"pmc": null,
"pmid": "29733112",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Intentional use of carbapenem antibiotics for valproic acid toxicity: A case report.",
"title_normalized": "intentional use of carbapenem antibiotics for valproic acid toxicity a case report"
} | [
{
"companynumb": "US-IMPAX LABORATORIES, INC-2016-IPXL-02391",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditiona... |
{
"abstract": "Relapse is the main cause of treatment failure after allogeneic stem cell transplant (alloSCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Injectable azacitidine can improve post-transplant outcomes but presents challenges with exposure and compliance. Oral CC-486 allows extended dosing to prolong azacitidine activity. We investigated use of CC-486 maintenance therapy after alloSCT. Adults with MDS or AML in morphologic complete remission at CC-486 initiation (42 to 84 days after alloSCT) were included. Patients received 1 of 4 CC-486 dosing schedules per 28-day cycle for up to 12 cycles. Endpoints included safety, pharmacokinetics, graft-versus-host disease (GVHD) incidence, relapse/progression rate, and survival. Of 30 patients, 7 received CC-486 once daily for 7 days per cycle (200 mg, n = 3; 300 mg, n = 4) and 23 for 14 days per cycle (150 mg, n = 4; 200 mg, n = 19 [expansion cohort]). Grades 3 to 4 adverse events were infrequent and occurred with similar frequency across regimens. Standard concomitant medications did not alter CC-486 pharmacokinetic parameters. Three patients (10%) experienced grade III acute GVHD and 9 experienced chronic GVHD. Of 28 evaluable patients, 6 (21%) relapsed or had progressive disease: 3 of 7 patients (43%) who had received 7-day dosing and 3 of 23 (13%) who had received 14-day dosing. Transplant-related mortality was 3%. At 19 months of follow-up, median overall survival was not reached. Estimated 1-year survival rates were 86% and 81% in the 7-day and 14-day dosing cohorts, respectively. CC-486 maintenance was generally well tolerated, with low rates of relapse, disease progression, and GVHD. CC-486 maintenance may permit epigenetic manipulation of the alloreactive response postallograft. Findings require confirmation in randomized trials. (ClinicalTrials.gov NCT01835587.).",
"affiliations": "University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio. Electronic address: Marcos.deLima@UHhospitals.org.;Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Transplantation Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.;Division of Hematology, The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio.;Celgene Corporation, Summit, New Jersey.;Celgene Corporation, Summit, New Jersey.;Celgene Corporation, Summit, New Jersey.;Celgene Corporation, Summit, New Jersey.;Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom.",
"authors": "de Lima|Marcos|M|;Oran|Betul|B|;Champlin|Richard E|RE|;Papadopoulos|Esperanza B|EB|;Giralt|Sergio A|SA|;Scott|Bart L|BL|;William|Basem M|BM|;Hetzer|Joel|J|;Laille|Eric|E|;Hubbell|Becky|B|;Skikne|Barry S|BS|;Craddock|Charles|C|",
"chemical_list": "D001374:Azacitidine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2018.06.016",
"fulltext": "\n==== Front\n9600628\n20830\nBiol Blood Marrow Transplant\nBiol Blood Marrow Transplant\nBiology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation\n1083-8791\n1523-6536\n\n29933073\n10.1016/j.bbmt.2018.06.016\nnihpa1685196\nArticle\nCC-486 Maintenance after Stem Cell Transplantation in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes\nde Lima Marcos 1*\nOran Betul 2\nChamplin Richard E. 2\nPapadopoulos Esperanza B. 3\nGiralt Sergio A. 3\nScott Bart L. 4\nWilliam Basem M. 5\nHetzer Joel 6\nLaille Eric 6\nHubbell Becky 6\nSkikne Barry S. 6\nCraddock Charles 7\n1 University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio\n2 Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas\n3 Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York\n4 Transplantation Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington\n5 Division of Hematology, The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio\n6 Celgene Corporation, Summit, New Jersey\n7 Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom\nAuthorship statement: All authors contributed to, revised, and approved manuscript content and gave approval for submission to the journal.\n\n* Correspondence and reprint requests: Marcos de Lima, MD, University Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106. Marcos.deLima@UHhospitals.org (M. de Lima).\n4 4 2021\n20 6 2018\n10 2018\n21 4 2021\n24 10 20172024\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)\nRelapse is the main cause of treatment failure after allogeneic stem cell transplant (alloSCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Injectable azacitidine can improve post-transplant outcomes but presents challenges with exposure and compliance. Oral CC-486 allows extended dosing to prolong azacitidine activity. We investigated use of CC-486 maintenance therapy after alloSCT.\n\nAdults with MDS or AML in morphologic complete remission at CC-486 initiation (42 to 84 days after alloSCT) were included. Patients received 1 of 4 CC-486 dosing schedules per 28-day cycle for up to 12 cycles. Endpoints included safety, pharmacokinetics, graft-versus-host disease (GVHD) incidence, relapse/progression rate, and survival.\n\nOf 30 patients, 7 received CC-486 once daily for 7 days per cycle (200 mg, n = 3; 300 mg, n = 4) and 23 for 14 days per cycle (150 mg, n = 4; 200 mg, n = 19 [expansion cohort]). Grades 3 to 4 adverse events were infrequent and occurred with similar frequency across regimens. Standard concomitant medications did not alter CC-486 pharmacokinetic parameters. Three patients (10%) experienced grade III acute GVHD and 9 experienced chronic GVHD. Of 28 evaluable patients, 6 (21%) relapsed or had progressive disease: 3 of 7 patients (43%) who had received 7-day dosing and 3 of 23 (13%) who had received 14-day dosing. Transplant-related mortality was 3%. At 19 months of follow-up, median overall survival was not reached. Estimated 1-year survival rates were 86% and 81% in the 7-day and 14-day dosing cohorts, respectively.\n\nCC-486 maintenance was generally well tolerated, with low rates of relapse, disease progression, and GVHD. CC-486 maintenance may permit epigenetic manipulation of the alloreactive response postallograft. Findings require confirmation in randomized trials. (ClinicalTrials.gov NCT01835587.)\n\nCC-486\nAcute myeloid leukemia\nMyelodysplastic syndromes\nAllogeneic stem cell\ntransplantation\nMaintenance therapy\n==== Body\nINTRODUCTION\n\nAllogeneic stem cell transplantation (alloSCT) is a potentially curative therapeutic option for patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Disease relapse occurs in 35% to 45% of patients after alloSCT and is the most frequent cause of treatment failure and mortality [1–4]. Moreover, relapse after alloSCT is associated with poor prognosis despite salvage chemotherapy, donor lymphocyte infusions, and/or second transplants [4].\n\nDuration of remission is a key determinant of patient outcomes after alloSCT [5]. A longer interval from transplant to relapse is associated with reduced risk of death [5]. Therefore, maximizing the duration of remission is an important treatment goal [6], and novel therapeutic strategies are needed to provide long-term disease control and extend remission in the post-transplant setting.\n\nAcute and chronic graft-versus-host disease (GVHD) are major causes of non-relapse mortality after alloSCT [7]. Post-transplant maintenance therapy should be well tolerated, with acceptable myelotoxicity and limited drug–drug interactions, and should reduce the incidence or severity of GVHD without impeding graft-versus-leukemia effects [8].\n\nThe DNA methyltransferase inhibitor, azacitidine, is a well-established treatment option for higher-risk MDS and AML [9–11], shown to increase expression of epigenetically silenced leukemia antigens and to induce a CD8+ T cell response to tumor antigens post-transplant, potentially augmenting a graft-versus-leukemia effect [12–14]. Studies further suggest azacitidine may accelerate reconstitution of immunomodulatory regulatory T cells, which may reduce GVHD risk [12,15,16]. The dual activity of azacitidine as an antileukemic agent and inhibitor of GVHD makes it a promising agent for post-transplant therapy. Encouraging preliminary data have been reported for s.c. azacitidine maintenance therapy after alloSCT in patients with MDS and AML [14,17,18], although challenges with exposure and compliance are limitations of s.c. administration. AML and MDS are associated with hypermethylation and subsequent silencing of tumor suppressor genes [19]. With the recommended dosing schedule of s.c. azacitidine (75 mg/m2/day given on days 1 to 7 in 28-day treatment cycles), global DNA reduction is maximal at mid-cycle, whereupon remethylation begins and methylation returns to pre-treatment levels by cycle end [20].\n\nCC-486 is a novel oral formulation of azacitidine that allows for prolonged azacitidine exposure and sustained DNA hypomethylation over the entire 28-day treatment cycle by using extended dosing schedules [21,22]. Here, we report final results of a prospective phase I/II dose-finding study of CC-486 maintenance treatment after alloSCT in patients with AML or MDS.\n\nMETHODS\n\nStudy Design\n\nThis multicenter, open-label study was conducted in accordance with Good Clinical Practice, per the International Conference on Harmonization Guideline E6, and with ethical principles outlined in the Declaration of Helsinki. The protocol was approved by the institutional review boards of all participating centers. All patients provided written informed consent. This study is registered at ClinicalTrials.gov (NCT01835587).\n\nPatients\n\nPatients aged ≥18 years with a diagnosis of MDS or AML according to World Health Organization criteria [23] who had undergone alloSCT with myeloablative or reduced-intensity conditioning regimens were eligible. Related and unrelated donors were permitted. Stem cells could be from peripheral blood or bone marrow. Donors could have a single mismatch at the HLA-A, -B, -C, -DRB1, or -DQB1 loci. Patients must have had Eastern Cooperative Oncology Group performance status score ≤2 and were to be in morphologic complete remission (CR; ie, ≤5% bone marrow blasts) with absolute neutrophil counts ≥1.0 × 109/L and platelets ≥ 75 × 109/L before CC-486 treatment initiation, which was to occur 42 to 84 days after alloSCT. This post-alloSCT interval was to allow for adequate marrow recovery before starting CC-486 treatment, based on our previous experience with parenteral azacitidine [17].\n\nKey exclusion criteria were use of hypomethylating agents, lenalidomide, thalidomide, pomalidomide, chemotherapy, or any other investigational agent after alloSCT; grade ≥II acute GVHD or evidence of gastrointestinal GVHD at screening; or malignancies other than MDS or AML, unless diseasefree for ≥1 year.\n\nEndpoints\n\nThe primary objectives were to determine a safe and effective CC-486 dosing regimen and the maximum tolerated dose (MTD) of CC-486 in patients with MDS or AML in the post-alloSCT setting. Secondary endpoints included overall survival (OS), cumulative 1-year relapse- and progression-free survival (RPFS), time to relapse, relapse rate, incidence of acute and chronic GVHD, time to treatment discontinuation, and pharmacokinetic parameters. The safety population included all patients who received ≥ 1 CC-486 dose. The efficacy population included all patients who received ≥ 1 CC-486 dose and had ≥ 1 post-baseline efficacy assessment. The pharmacokinetic population comprised a subset of study patients.\n\nDetermination of CC-486 Dose\n\nA standard 3+3 dose-escalation design was followed to evaluate 4 CC-486 dosing schedules in repeated 28-day cycles: CC-486 200 mg (Cohort 1) or 300 mg (Cohort 2) once daily (QD) for 7 days per cycle or CC-486 150 mg (Cohort 3) or 200 mg (Cohort 4) QD for 14 days per cycle. Patients received enough CC-486 doses at a site visit on day 1 of each cycle to complete dosing for that cycle. The MTD was established if 2 dose-limiting toxicities (DLTs) occurred in a cohort during the first 2 treatment cycles. At the MTD, or if the MTD was not reached, a cohort could be expanded with an additional 10 to 12 patients to further evaluate that dosing regimen.\n\nA DLT was defined as any of the following treatment-emergent adverse events (TEAEs), considered by the investigator to be related to CC-486: a clinically significant grade ≥3 nonhematologic toxicity, including nausea, diarrhea, or vomiting despite adequate medical intervention; absolute neutrophil counts < .5×109/L lasting >1 week despite myeloid growth factor support; platelets < 10× 109/L lasting > 1 week despite transfusion support; failure to reach absolute neutrophil counts ≥ 1.0×109/L and/or platelets ≥ 25×109/L in the presence of a hypocellular bone marrow (< 10%) within 56 days after the start of a treatment cycle; inability to initiate a subsequent cycle of CC-486 within 28 days of the anticipated start because of any treatment-related, non-hematologic TEAEs; and any toxic effect requiring dose reduction or treatment interruption.\n\nCC-486 treatment continued until unacceptable toxicity, disease relapse or progression, development of grades III to IV acute or severe chronic GVHD, consent withdrawal, death, or until a maximum of 12 CC-486 cycles had been administered.\n\nEfficacy and Safety\n\nEfficacy and safety measurements were based on complete blood counts monitored weekly for the first 2 cycles (8 weeks) and then on days 1, 15, and 22 of each cycle thereafter. Bone marrow aspirates and cytogenetic studies were performed every 6 months or more frequently if clinically indicated.\n\nOS was defined as the time from transplantation to death by any cause. RPFS was the time from transplantation to relapse, progressive disease, or death, whichever occurred first. Relapse and progressive disease were defined as the reappearance of > 5% or > 10% bone marrow blasts, respectively, lasting more than 4 weeks. Patients without a documented relapse were censored at the date of their last assessment or study completion. All patients were followed for survival until death, loss to follow-up, withdrawal of consent, or study closure. Progression to AML was collected during follow-up for patients with MDS.\n\nSafety was assessed by TEAE reporting, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Patients were followed for TEAEs for 28 days after their last CC-486 dose.\n\nPharmacokinetic Analysis\n\nBlood samples for CC-486 pharmacokinetic analyses were collected pre- and post-dose at .5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours on day 1 of cycles 1 and 2. Plasma samples were analyzed using a validated proprietary HPLC/tandem mass spectrometric method. Pharmacokinetic parameters included maximum observed plasma concentration, time of maximum observed plasma concentration, area under the plasma concentration-time curve from zero to infinity, terminal elimination half-life, apparent total clearance, and apparent volume of distribution. Pharmacokinetic parameters were calculated using noncompartmental methods with Phoenix WinNonlin software (Pharsight Corp, Mountain View, CA). To evaluate potential drug–drug interactions, patients were alternately assigned to take their regular concomitant medications before the visit on day 1 of cycle 1 or 2 and to not to take their regular concomitant medications before the day 1 visit in the other cycle.\n\nStatistical Methods\n\nDemographic, efficacy, and safety outcomes are reported descriptively. No formal comparisons among the CC-486 dosing regimens were planned. OS was estimated using the Kaplan-Meier method. One-year cumulative RPFS rate was based on a competing risk method, in which death without documented progression or relapse is considered a competing risk for progression or relapse. Statistical analyses were conducted using SAS version 9.2 (SAS Institute, Cary, NC).\n\nRESULTS\n\nPatient Characteristics\n\nOverall, 31 patients were enrolled between July 2013 and November 2015 at 5 study sites. Thirty patients received ≥ 1 dose of CC-486 and comprised the intention-to-treat population. In the combined 7-day dosing cohorts, 3 patients received CC-486 200 mg QD (Cohort 1) and 4 received 300 mg QD (Cohort 2). In the 14-day dosing cohorts, 4 patients received CC-486 150 mg QD (Cohort 3) and 19 patients received CC-486 200 mg QD in an expansion cohort (Cohort 4).\n\nBaseline characteristics were generally comparable between the 7-day and 14-day dosing groups (Table 1). Twenty-six patients (87%) had AML and 4 (13%) had MDS, including 3 patients with International Prognostic Scoring System [24] higher-risk MDS. Patients were generally older (median age, 64.5 years [range, 28 to 80]). All patients had Eastern Cooperative Oncology Group performance status scores ≤ 1. At time of transplantation, 27 patients (90%) were in CR, 25 in first remission and 2 in second remission, and 3 patients (10%) had ≥ 5% bone marrow blasts. Eighteen patients had received a myeloablative conditioning regimen (busulfan and fludarabine, n = 14; busulfan and cyclophosphamide, n = 3; total body irradiation, cyclophosphamide, and thiotepa, n = 1) and 12 patients received a reduced-intensity conditioning regimen with fludarabine and melphalan. Twenty patients had unrelated donors, and 10 received stem cells from a sibling. Eight patients received stem cells from bone marrow and 22 patients from peripheral blood. Median time from alloSCT to start of CC-486 therapy was 81.5 days (range, 45 to 85). The median follow-up for patients in this study was 19.0 months (range, 1.0 to 41.3).\n\nThe MTD of CC-486 was not reached at doses up to 200 mg/day for 14 days per cycle. No DLT was observed in Cohorts 1 to 3. In Cohort 4 (200 mg QD × 14 days) 1 patient experienced a DLT during the first 2 treatment cycles (grade 4 neutropenia, grade 3 pneumonia), but no additional DLTs occurred and the criteria for MTD were not met. Based on observed efficacy and tolerability of the CC-486 200 mg 14-day dosing regimen, Cohort 4 was subsequently expanded to a total of 19 patients to further assess the clinical activity, safety, and tolerability of this regimen. Based on patient safety considerations with regenerating bone marrows and concern for the development of significant neutropenias or thrombocytopenia post-transplant, no higher dosing regimen was evaluated.\n\nCC-486 Exposure\n\nThe median number of CC-486 treatment cycles for all patients was 9.0 (range, 1 to 12) (Table 1). Median duration of treatment was 252.5 days (range, 3 to 371). Thirteen patients (43%) completed all 12 treatment cycles, including 1 of 7 patients (14%) in the combined 7-day dosing group and 12 of 23 patients (52%) in the combined 14-day group. Among the 17 patients (57%) who discontinued treatment before completing 12 cycles, median time to discontinuation was 283.5 days (range, 21 to 401). Reasons for discontinuation included MDS or AML relapse (n = 6, 20% of all patients), withdrawal of consent (n = 5, 17%), GVHD (n = 2, 7%), non-GVHD TEAEs (n = 2, 7%), death (n = 1, 3%), or “other” (n = 1, 3%). “Other” involved a patient in the CC-486 300-mg 7-day dosing arm who had a history of central nervous system leukemia at study entry and was receiving intrathecal methotrexate before and during CC-486 treatment. Because of presentation of central nervous system features characteristic of a transient ischemic attack and suspected central nervous system relapse at cycle 4, as well as administration of radiation therapy, the patient was discontinued because of risk of bleeding. The patient was in CR at all evaluations after discontinuing therapy, was not included in an on-study relapse rate, and was alive and in CR at the end of the study according to bone marrow aspirate samples.\n\nDisease Relapse and Survival\n\nTwo patients discontinued in the first treatment cycle and withdrew consent for further follow-up. For the 28 remaining patients, the 1-year rate of relapse or progressive disease during treatment was 21% (n = 6). Three of these 6 patients relapsed during the first treatment cycle (Figure 1). The 3 patients who had ≥ 5% bone marrow blasts at the time of transplant all relapsed on-study, 1 of whom relapsed during treatment cycle 1. The 1-year cumulative incidence of relapse was 3 of 7 (43%) in the combined 7-day dosing group and 3 of 23 (13%) in the combined 14-day dosing group. One-year RPFS rates were 54% and 72% in the 7-day and 14-day CC-486 dosing groups, respectively.\n\nMedian OS was not reached in any dosing cohort (range for all patients was 86 to 1324 days) (Figure 2), and estimated 1-year survival rates in the 7-day and 14-day dosing cohorts were 86% and 81%, respectively.\n\nAcute and Chronic GVHD\n\nOne-year cumulative incidence of acute or chronic GVHD was 50% (n = 15). Grade III acute GVHD was reported in 1 patient (3%) in the CC-486 200-mg 14-day dosing cohort. No grade IV acute GVHD was observed. Chronic GVHD was reported in 9 patients (30%) with similar frequency within 3 dosing groups (no chronic GVHD was reported in the 300-mg 7-day dosing cohort). Three of 9 patients had severe chronic GVHD, and the remaining 6 patients had mild or moderate chronic GVHD. Among patients with any GVHD, organ involvement included skin in 8 patients, the lower intestinal tract in 7 patients, and the liver in 2 patients.\n\nSafety and Tolerability\n\nThe most frequent TEAEs were gastrointestinal and hematologic events. Twenty-two patients (73%) experienced at least 1 grade 3-to-4 TEAE (Table 2; Supplementary Table 1 shows common TEAEs by CD34+ cell dose threshold at transplant). The most common (≥ 5% of patients) grades 3-to-4 TEAEs occurred at similar frequencies across all 4 dosing cohorts: diarrhea (20%), lymphopenia (20%), vomiting (17%), neutropenia (17%), nausea (13%), anemia (13%), thrombocytopenia (10%), and abdominal pain (7%). Treatment-related serious TEAEs were reported in 4 patients and included hemolysis, thrombocytopenia, neutropenia, diarrhea, nausea, vomiting, asthenia, pyrexia, pneumonia, and intracranial hemorrhage. One TEAE-related death occurred on-study (intracranial hemorrhage) in the patient who experienced the DLT at cycle 2. This patient had raised lactate dehydrogenase at baseline and subsequently developed hemolysis, progressive thrombocytopenia, and a progressive rise in lactate dehydrogenase, and was considered to have had tacrolimus-associated thrombotic thrombocytopenic purpura.\n\nPharmacokinetics\n\nPharmacokinetic data were available for patients receiving 200 mg CC-486 doses, including 4 patients with and without concomitant medications after CC-486 dose administration on day 1 of cycles 1 and 2 (per protocol), 2 patients after CC-486 administration who had not taken concomitant medications, and 9 patients after CC-486 administration who had taken concomitant medications. Thus, azacitidine pharmacokinetic data were available at the CC-486 200-mg dose for a total of 6 patients without concomitant medications and 13 patients with concomitant medications. There were too few patients in the 150-mg/day CC-486 dosing group with meaningful pharmacokinetic data to report (pharmacokinetic outcomes with 300 mg QD CC-486 have been reported elsewhere [22]).\n\nAzacitidine was rapidly absorbed, reaching mean maximum observed plasma concentration within approximately 1 hour post-dose and then decreasing in a multiphasic manner to a nonquantifiable level by the 6-hour time point (Supplementary Figure 1). After CC-486 200-mg dose administration, azacitidine plasma concentration profiles and other pharmacokinetic parameters (Figure 3) were not significantly different when taken with or without standard concomitant medications. Concomitant medications included (but were not limited to) prophylactic antibiotics, calcineurin inhibitors, antifungals, and antiviral agents; red blood cell and platelet transfusions; myeloid growth factors; antiemetics; and drugs to manage gastrointestinal complications. Moreover, pharmacokinetic parameters were within range of those reported for nontransplant patients treated with CC-486 in a different study [22].\n\nDISCUSSION\n\nDisease recurrence is a major therapeutic challenge in patients with MDS or AML undergoing alloSCT, and treatment options are limited [4,5]. Risk of disease relapse after alloSCT is a composite of many factors, including age, cytogenetic and molecular status at diagnosis, and remission status at the time of transplantation [4,25–27]. Remission duration is one of the strongest predictors of post-transplant survival [5,28,29]. This is the first prospective trial to evaluate post-transplant CC-486 therapy as a strategy to prevent or delay relapse in patients with AML or MDS. Therapy with CC-486 for 1 year was associated with a relatively low (21%) overall rate of disease relapse during treatment.\n\nIn the current study the RPFS rate was higher in the combined 14-day dosing cohort than in the 7-day dosing group, supporting the rationale for extended CC-486 dosing. The 1-year cumulative rate of relapse/disease progression with CC-486 maintenance administered for 14 days per cycle (13%) compares favorably with rates reported in studies of with 5-day dosing of low-dose s.c. azacitidine maintenance after alloSCT [14,17], although meaningful conclusions are elusive when comparing results of different studies with different patient populations and endpoints. For example, a phase I study evaluating low-dose s.c. azacitidine 8 to 40 mg/m2/day administered for 5 days per cycle after alloHSCT in patients with high-risk MDS or AML showed a 53% relapse rate at a median follow-up of 20.5 months. However, that study included a high proportion of patients with advanced disease characteristics, and most patients were not in CR at the time of transplant [17]. In any case, at-home administration of oral maintenance therapy may be more convenient for patients than making multiple daily clinic visits for parenteral drug administration. In the current study patients received enough CC-486 at the clinic on day 1 of each cycle to complete CC-486 dosing for that cycle at home.\n\nSurvival outcomes associated with CC-486 maintenance were also relatively favorable. Median OS was not reached in any dosing cohort at a median follow-up of 19 months, and estimated 1-year survival rates were above 80%.\n\nExpected rates of post-transplant serious chronic GVHD range from approximately 25% to 30% [30,31] The incidence of severe chronic GVHD in our study was low (10%), and only 2 patients discontinued the study due to a GVHD event. The generally mild presentation and low incidence of GVHD in this study support the hypothesis that CC-486 maintenance may permit epigenetic manipulation of the alloreactive response after transplantation. Two mechanisms have been proposed by which azacitidine is believed to induce tolerance and reduce the risk of GVHD: conversion of alloreactive donor T cells into suppressive regulatory T cells via hypomethylation of the FOXP3 promoter and suppression of alloreactive T cell proliferation [12,15,16,32].\n\nOnce-daily CC-486 was generally well tolerated; the MTD was not reached in this study, and there was no meaningful difference in the frequency or severity of AEs among dosing regimens. The most common TEAEs were gastrointestinal and hematologic, consistent with previous reports of low-dose s.c. azacitidine post-transplant and of front-line CC-486 in MDS and AML [17,21]. Rate of discontinuation due to TEAEs was low, with most discontinuations due to MDS or AML relapse (20% of all patients). Patients undergoing alloSCT are particularly vulnerable to myelosuppression and other toxicities [33,34]. Rates of hematologic TEAEs with CC-486 in this and other studies are lower than those seen with injectable hypomethylating agents [21,35–37]. Despite the pharmacokinetic testing protocol, investigators and patients may have been reluctant to forego the patients’ prescribed concomitant medications in the post-transplant setting. Nevertheless, these data, albeit in a small patient sample, suggest a lack of significant drug–drug interactions with CC-486 and standard concomitant medications such as antibiotics or drugs to manage gastrointestinal events.\n\nUse of maintenance therapy in hematologic disorders remains controversial [38], and whether and when to initiate maintenance treatment and how long to continue it are unresolved issues. The increasing use of next-generation sequencing may allow detection of measurable residual disease (MRD), which can be a harbinger of relapse [39], to inform whether maintenance might benefit some patients, and sustained measurable residual disease negativity may suggest maintenance therapy is unnecessary or could be discontinued. The extent of donor chimerism may also suggest whether maintenance therapy might prolong remission post-transplant [18]. Here, we somewhat arbitrarily planned for 12 CC-486 treatment cycles, with the goal of offering therapy during the period of time with higher risk of AML or MDS relapse, based on historic data [4]. One cannot underestimate the logistic challenges of prolonged maintenance therapy after allogeneic transplantation, which frequently include monitoring by different physicians and hospitals, patient and caregiver fatigue, and need for more intensive monitoring.\n\nAmong limitations of these data are that this is a phase I dose-finding study, followed by a small phase II expansion, with no placebo-control group. It is unknown whether the benefit of CC-486 maintenance correlated with improvement in quality of life, because it was not evaluated. Additionally, no information regarding the presence of MRD before or after transplant was collected, and correlations between relapse status and changes in methylation levels during CC-486 study and extent of immune reconstitution were not assessed. Nonetheless, these data support the clinical benefits and acceptable safety profile of CC-486 as maintenance treatment after alloSCT in patients with MDS or AML. Based on these data, the recommended CC-486 post-transplant maintenance dosing regimen is 200-mg daily for 14 days per 28-day cycle. Our findings warrant further study in a larger patient population.\n\nSupplementary Material\n\n1\n\nACKNOWLEDGMENTS\n\nFinancial disclosure: This study was funded by Celgene Corporation, Summit, NJ. The authors received editorial support during manuscript development from Sheila Truten and Kelly Dittmore of Medical Communication Company, Inc. (Wynnewood, PA) who were funded by Celgene Corporation. Analyses were performed by Celgene Corporation. The authors are fully responsible for all content and editorial decisions and had access to all study data.\n\nConflict of interest statement: M.d.L.: Celgene Corporation, consultancy, research funding; Pfizer, board of directors or advisory committees; Incyte, consultancy; Amgen, consultancy; Spectrum, consultancy. B.O.: Celgene Corporation, AROG, and Astex, research funding. E.B.P.: spouse has leadership roles and stock ownership at Exelixis, Regulus, and Biogen. S.A.G.: Amgen, Celgene Corporation, Jazz Pharmaceuticals, Kite Pharma, Novartis, and Sanofi, consultancy; Spectrum, consultancy, research funding. B.L.S.: Celgene Corporation, honoraria, consultancy, research funding, speakers bureau; Novartis, research funding, speakers bureau; Alexion, honoraria, speakers bureau; Incyte, honoraria, speakers bureau; Acceleron, data and safety monitoring board; Agios Pharmaceuticals, honoraria, consultancy. B.M.W.: Miragen, consultancy, honoraria. J.H., E.L., B.H., and B.S.S.: Celgene Corporation, employment, equity ownership. C.C.: Celgene Corporation, honoraria, research funding; Jazz Pharmaceuticals, Pfizer, and Janssen, honoraria.\n\nFigure 1. Patient profiles and duration of CC-486 treatment.\n\nFigure 2. OS from time of alloSCT.\n\nFigure 3. Azacitidine pharmacokinetic parameters with and without concomitant medications after 200 mg CC-486.\n\nTable 1 Baseline Characteristics and CC-486 Treatment Exposure\n\n\t200 mg QD for 7 Days (n = 3)\t300 mg QD for 7 Days (n = 4)\t150 mg QD for 14 Days (n = 4)\t200 mg QD for 14 Days (n = 19)\tTotal (N = 30)\t\n\t\nDiagnosis\t\t\t\t\t\t\n AML\t2 (67)\t4 (100)\t4 (100)\t16 (84)\t26 (87)\t\n MDS\t1 (33)\t0\t0\t3 (16)\t4 (13)\t\nMedian time from MDS/AML diagnosis to alloSCT, mo (range)\t6.2 (3.3–16.2)\t4.6 (3.4–12.8)\t3.5 (1.4–5.6)\t4.8 (2.7–75.0)\t4.8 (1.4–75.0)\t\nMedian time from initial diagnosis to CC-486, mo (range)\t8.2 (5.8–17.7)\t6.8 (6.1–15.4)\t6.2 (4.1–8.3)\t12.9 (5.3–77.7)\t7.0 (4.1–77.7)\t\nMedian time from alloSCT to CC-486, days (range)\t63.0 (45–78)\t81.5 (55–85)\t85.0 (84–85)\t81.0 (45–85)\t81.0 (45–85)\t\nMedian BM blasts before alloSCT, % (range)\t0 (0–2)\t4.0 (2–8)\t0 (0–1)\t2.0 (0–6)\t2.0 (0–8)\t\nMedian BM blasts after alloSCT, % (range)\t1.0 (1–1)\t.5 (0–2)\t1.0 (0–1)\t1.0 (0–2)\t1.0 (0–2)\t\nMedian HCT-CI score (range)\t1.0 (0–1)\t0 (0–1)\t2.0 (0–3)\t0 (0–3)\t.5 (0–3)\t\nDisease status at study entry\t\t\t\t\t\t\n CR1\t2 (67)\t2 (50)\t3 (75)\t18 (95)\t25 (83)\t\n CR2\t1 (33)\t1 (25)\t0\t0\t2 (7)\t\n Active disease\t0\t1 (25)\t1 (25)\t1 (5)\t3 (10)\t\nAML WHO classification\tn = 2\tn = 4\tn = 4\tn = 16\tn = 26\t\n Recurrent genetic abnormalities\t0\t2 (50)\t0\t7 (44)\t9 (35)\t\n Myelodysplasia-related changes\t0\t0\t1 (25)\t2 (13)\t3 (12)\t\n Therapy-related myeloid neoplasms\t0\t0\t1 (25)\t0\t1 (4)\t\n Not otherwise specified\t2 (100)\t2 (50)\t2 (50)\t7 (44)\t13 (50)\t\nMDS WHO classification\tn = 1\tn = 0\tn = 0\tn = 3\tn = 4\t\n RA / RCMD\t0\t0\t0\t2 (67)\t2 (50)\t\n MDS-U\t0\t0\t0\t1 (33)\t1 (25)\t\n del(5q)\t1 (100)\t0\t0\t0\t1 (25)\t\nMDS IPSS risk classification\tn = 1\tn = 0\tn = 0\tn = 3\tn = 4\t\n Low / Intermediate-1\t0\t0\t0\t1 (33)\t1 (25)\t\n Intermediate-2 / High\t1 (100)\t0\t0\t2 (67)\t3 (75)\t\nNCCN cytogenetic risk at AML diagnosis\tn = 2\tn = 4\tn = 4\tn = 16\tn = 26\t\n Favorable\t0\t2 (50)\t0\t1 (6)\t3 (12)\t\n Intermediate\t2 (100)\t1 (25)\t3 (75)\t12 (75)\t18 (69)\t\n Poor\t0\t0\t0\t1 (6)\t1 (4)\t\n Missing\t0\t1 (25)\t1 (25)\t2 (13)\t4 (15)\t\nMDS cytogenetic risk at diagnosis\tn = 1\tn = 0\tn = 0\tn = 3\tn = 4\t\n Good\t0\t0\t0\t1 (33)\t1 (25)\t\n Intermediate\t0\t0\t0\t1 (33)\t1 (25)\t\n Poor\t0\t0\t0\t1 (33)\t1 (25)\t\n Missing\t1 (100)\t0\t0\t0\t1 (25)\t\nMolecular abnormalities\t\t\t\t\t\t\n NPM1\t0\t0\t0\t2 (11)\t2 (7)\t\n CEBPA\t0\t0\t1 (25)\t3 (16)\t4 (13)\t\n FLT3-ITD\t1 (33)\t1 (25)\t0\t3 (16)\t5 (17)\t\nECOG performance status\t\t\t\t\t\t\n 0\t1 (33)\t1 (25)\t1 (25)\t8 (42)\t11 (37)\t\n 1\t2 (67)\t3 (75)\t3 (75)\t11 (58)\t19 (63)\t\n ≥2\t0\t0\t0\t0\t0\t\nPrior injectable HMA use\t1 (33)\t0\t1 (25)\t7 (37)\t9 (30)\t\nMedian CC-486 treatment cycles (range)\t7 (6–12)\t5.5 (1–7)\t11.5 (4–12)\t12 (1–12)\t9 (1–12)\t\nValues are n (%) unless otherwise defined. BM indicates bone marrow; CR, complete remission; CR1, first CR; CR2, second CR; ECOG, Eastern Cooperative Oncology Group; HCT-CI, hematopoietic cell transplantation–specific comorbidity index; HMA, hypomethylating agent; IPSS, International Prognostic Scoring System; MDS-U, MDS-undefined; NCCN, National Comprehensive Cancer Network; RA, refractory anemia; RCMD, refractory cytopenia with multilineage dysplasia; WHO, World Health Organization.\n\nTable 2 Most Common (≥5% of All Patients) Grades 3–4 TEAEs\n\nAE\tCC-486 200 mg QD for 7 Days (n = 3)\tCC-486 300 mg QD for 7 Days (n = 4)\tCC-486 150 mg QD for 14 Days (n = 4)\tCC-486 200 mg QD for 14 Days (n = 19)\tTotal (N = 30)\t\n\t\nPatients with ≥1 grade 3–4 TEAE\t2 (67)\t3 (75)\t3 (75)\t14 (74)\t22 (73)\t\nHematologic\t\t\t\t\t\t\n Lymphopenia\t0\t0\t3 (75)\t3 (16)\t6 (20)\t\n Neutropenia\t0\t0\t1 (25)\t4 (21)\t5 (17)\t\n Anemia\t0\t0\t1 (25)\t3 (16)\t4 (13)\t\n Thrombocytopenia\t1 (33)\t0\t0\t2 (11)\t3 (10)\t\ngastrointestinal\t\t\t\t\t\t\n Diarrhea\t1 (33)\t0\t2 (50)\t3 (16)\t6 (20)\t\n Vomiting\t1 (33)\t1 (25)\t1 (25)\t2 (11)\t5 (17)\t\n Nausea\t1 (33)\t0\t0\t3 (16)\t4 (13)\t\n GI GVHD*\t0\t0\t0\t3 (16)\t3 (10)\t\n Abdominal pain\t0\t0\t0\t2 (11)\t2 (7)\t\nOther\t\t\t\t\t\t\n Device-related infection\t0\t1 (25)\t1 (25)\t0\t2 (7)\t\n Dehydration\t0\t0\t1 (25)\t1 (5)\t2 (7)\t\n Pneumonia\t0\t0\t1 (25)\t1 (5)\t2 (7)\t\nValues are n (%). 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Santini V , Fenaux P , Mufti GJ , Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine. Eur J Haematol. 2010;85 :130–138.20394651\n37. Kantarjian HM , Thomas XG , Dmoszynska A , Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30 :2670–2677.22689805\n38. Rashidi A , Walter RB , Tallman MS , Appelbaum FR , DiPersio JF . Maintenance therapy in acute myeloid leukemia: an evidence-based review of randomized trials. Blood. 2016;128 :763–773.27354720\n39. Schuurhuis GJ , Heuser M , Freeman S , Minimal/measurable residual disease in AML: consensus document from ELN MRD Working Party. Blood. 2018;131 :1275–1291.29330221\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1083-8791",
"issue": "24(10)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Acute myeloid leukemia; Allogeneic stem cell transplantation; CC-486; Maintenance therapy; Myelodysplastic syndromes",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D064591:Allografts; D001374:Azacitidine; D018572:Disease-Free Survival; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D015996:Survival Rate",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "2017-2024",
"pmc": null,
"pmid": "29933073",
"pubdate": "2018-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "21787195;26721801;17222760;20026804;26442612;25987659;19235255;23519388;17320953;21880629;18981462;20394651;18832655;9058730;15558037;19230772;234595;21083034;21886171;21464398;20672358;24018392;19812490;27354720;17531775;25460355;20530795;22234690;26296092;22689805;7949117;19887673;17784964;19357394;21576646;25599163;28638744;29330221",
"title": "CC-486 Maintenance after Stem Cell Transplantation in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes.",
"title_normalized": "cc 486 maintenance after stem cell transplantation in patients with acute myeloid leukemia or myelodysplastic syndromes"
} | [
{
"companynumb": "US-ASTELLAS-2018US029219",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "Pyoderma gangrenosum (PG) and hidradenitis suppurativa (HS) are rare chronic inflammatory dermatoses of unknown etiologies that often are refractory to conventional treatments. The therapeutic benefits of tumor necrosis factor a (TNF-α) inhibitors have been reported in patients with refractory PG or HS. The copresentation of these 2 diseases has previously been described in several cases in the literature and may present a therapeutic challenge. We present the case of a 51-year-old man who developed widespread inflammatory ulcers affecting approximately 50% of the body surface area and subsequent chronic debilitation from severe pain. He was ultimately diagnosed with concurrent PG and HS. Both diseases remitted in response to treatment with infliximab, which resulted in complete restoration of skin integrity and resolution of his chronic severe pain.",
"affiliations": "419 W Redwood St, Ste 240, Baltimore, MD 21201, USA. agrossberg@som.umaryland.edu.",
"authors": "Groleau|Patricia F|PF|;Grossberg|Anna L|AL|;Gaspari|Anthony A|AA|",
"chemical_list": "D000911:Antibodies, Monoclonal; D003879:Dermatologic Agents; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-4162",
"issue": "95(6)",
"journal": "Cutis",
"keywords": null,
"medline_ta": "Cutis",
"mesh_terms": "D000911:Antibodies, Monoclonal; D003879:Dermatologic Agents; D017497:Hidradenitis Suppurativa; D006801:Humans; D000069285:Infliximab; D008297:Male; D017511:Pyoderma Gangrenosum",
"nlm_unique_id": "0006440",
"other_id": null,
"pages": "337-42",
"pmc": null,
"pmid": "26125210",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hidradenitis suppurativa and concomitant pyoderma gangrenosum treated With infliximab.",
"title_normalized": "hidradenitis suppurativa and concomitant pyoderma gangrenosum treated with infliximab"
} | [
{
"companynumb": "US-JNJFOC-20150912781",
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{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
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... |
{
"abstract": "Capecitabine is an oral prodrug to 5-fluorouracil and is commonly used in the treatment of advanced breast, colon and stomach cancer. While gastrointestinal toxicity is common, enterocolitis and ischemic colitis are uncommon complications and the histologic features of capecitabine in the colonic mucosa have not been previously described. We present a case of colitis attributed to capecitabine toxicity in a 45-year-old man undergoing treatment of metastatic gastroesophageal adenocarcinoma. Possible pathophysiologic mechanisms of capecitabine toxicity are discussed and the histologic effects on the colon are described.",
"affiliations": "Saba University School of Medicine, Dutch Caribbean, Bonaire, Sint Eustatius and Saba.;Division of Gastroenterology, St. Michael's Hospital, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada.;Department of Laboratory Medicine, St. Michael's Hospital, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. Electronic address: grina@smh.ca.",
"authors": "Maggo|Gunjan|G|;Grover|Samir C|SC|;Grin|Andrea|A|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-0338",
"issue": "210(9)",
"journal": "Pathology, research and practice",
"keywords": "Adverse effects; Capecitabine; Chemotherapy; Ischemic colitis",
"medline_ta": "Pathol Res Pract",
"mesh_terms": "D000230:Adenocarcinoma; D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D003092:Colitis; D003841:Deoxycytidine; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms",
"nlm_unique_id": "7806109",
"other_id": null,
"pages": "606-8",
"pmc": null,
"pmid": "24947412",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Capecitabine induced colitis.",
"title_normalized": "capecitabine induced colitis"
} | [
{
"companynumb": "NL-TEVA-561625ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
"d... |
{
"abstract": "Members of the Cryptococcus gattii species complex are notorious causes of cryptococcosis as they often cause severe, life-threatening infections. Here we describe a case of a severe disseminated C. deuterogattii infection in a previously healthy patient who was initially treated with amphotericin B, 5-fluorocytosine and fluconazole, which led to a good neurological response, but the infection in the lungs remained unaltered and was not completely resolved until switching the antifungal therapy to isavuconazole. The infection was likely acquired during a one-month stay at the Azores Islands, Portugal. Environmental sampling did not yield any cryptococcal isolate; therefore, the source of this apparent autochthonous case could not be determined. Molecular typing showed that the cultured C. deuterogattii isolates were closely related to the Vancouver Island outbreak-genotype.",
"affiliations": "Department of Microbiology, Hospital Universitario Severo Ochoa, Avda. de Orellana S/N. 28914, Leganés, Madrid, Spain. marysolcuetara@gmail.com.;Department of Medicine, Hospital Universitario Severo Ochoa, Leganés, Madrid, Spain.;Department of Radiology, Hospital Universitario Severo Ochoa, Leganés, Madrid, Spain.;Department of Neurology, Hospital Universitario Severo Ochoa, Leganés, Madrid, Spain.;Department of Pharmacy, Hospital Universitario Severo Ochoa, Leganés, Madrid, Spain.;Department of Immunology, Hospital Materno-Infantil-CHUAC, La Coruña, Spain.;Department of Immunology, Hospital Dr. Negrín, Palmas de Gran Canaria, Spain.;Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands.;Medical Mycology Laboratory, Department of Plant Production and Microbiology, University Miguel Hernández, Campus of Sant Joan D'Alacant, 03550, Alicante, Spain. colom@goumh.umh.es.",
"authors": "Cuetara|Maria Soledad|MS|;Jusdado Ruiz-Capillas|Juan José|JJ|;Nuñez-Valentin|Maria Pilar|MP|;Rodríguez Garcia|Elena|E|;Garcia-Benayas|Elena|E|;Rojo-Amigo|Ricardo|R|;Rodriguez-Gallego|Jose Carlos|JC|;Hagen|Ferry|F|http://orcid.org/0000-0002-5622-1916;Colom|María Francisca|MF|http://orcid.org/0000-0002-8672-5429",
"chemical_list": "D000935:Antifungal Agents; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11046-021-00566-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-486X",
"issue": "186(4)",
"journal": "Mycopathologia",
"keywords": "Amplified fragment length polymorphism; Cryptococcus deuterogattii; Environmental sampling; Isavuconazole; Multi-locus sequence typing",
"medline_ta": "Mycopathologia",
"mesh_terms": "D000935:Antifungal Agents; D003453:Cryptococcosis; D056285:Cryptococcus gattii; D005838:Genotype; D006801:Humans; D009570:Nitriles; D011725:Pyridines; D016879:Salvage Therapy; D014230:Triazoles",
"nlm_unique_id": "7505689",
"other_id": null,
"pages": "507-518",
"pmc": null,
"pmid": "34115285",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20031037;20113555;15572442;24586423;25721988;30953839;27789540;23017442;26341329;20798129;29502462;21266457;24275678;29064061;28595777;30479782;19390780;19824880;21521012;22261398;28188169;22670042;10987712;30921084;19222372;30334702;20047480;23697747;30507673;25313209;27169478;30455108;20190892;23846587",
"title": "Successful Isavuconazole Salvage Therapy for a Cryptococcus deuterogattii (AFLP6/VGII) Disseminated Infection in a European Immunocompetent Patient.",
"title_normalized": "successful isavuconazole salvage therapy for a cryptococcus deuterogattii aflp6 vgii disseminated infection in a european immunocompetent patient"
} | [
{
"companynumb": "ES-AMAROX PHARMA GMBH-AMR2021ES01166",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": ... |
{
"abstract": "Brentuximab vedotin is an antibody-conjugated chemotherapy targeting CD30 indicated in treatment of several lymphomas. We report the first 3 cases of cytomegalovirus severe infections with retinitis following this treatment. Evolution was favorable, but relapse occurred after treatment rechallenge. We suggest vigilance about cytomegalovirus in patients treated with brentuximab vedotin.",
"affiliations": "Département d'Hématologie Clinique.;Département d'Hématologie Clinique.;Département de Pharmacologie Médicale et Toxicologie.;Département d'Hématologie Clinique.;Département d'Hématologie Clinique.;Département d'Ophtalmologie, and.;Département des Maladies Infectieuses et Tropicales, CHRU de Montpellier; and.;Département d'Hématologie Clinique.;Département d'Hématologie Clinique.;Département d'Hématologie Clinique.;Département d'Hématologie Clinique.;Département de Pharmacologie Médicale et Toxicologie.;Département d'Hématologie Clinique.",
"authors": "Tudesq|Jean-Jacques|JJ|;Vincent|Laure|L|;Lebrun|Julie|J|;Hicheri|Yosr|Y|;Gabellier|Ludovic|L|;Busetto|Timothé|T|;Merle|Corinne|C|;Fegueux|Nathalie|N|;Ceballos|Patrice|P|;Quittet|Philippe|P|;Navarro|Robert|R|;Hillaire-Buys|Dominique|D|;Cartron|Guillaume|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofx091",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n28638848\n10.1093/ofid/ofx091\nofx091\nBrief Report\nCytomegalovirus Infection With Retinitis After Brentuximab Vedotin Treatment for CD30+ Lymphoma\nTudesq Jean-Jacques 12 Vincent Laure 1 Lebrun Julie 3 Hicheri Yosr 1 Gabellier Ludovic 1 Busetto Timothé 4 Merle Corinne 5 Fegueux Nathalie 1 Ceballos Patrice 1 Quittet Philippe 1 Navarro Robert 1 Hillaire-Buys Dominique 3 Cartron Guillaume 123456 1 \nDépartement d’Hématologie Clinique\n\n2 \nDépartement de Réanimation Médicale et des Brûlés\n\n3 \nDépartement de Pharmacologie Médicale et Toxicologie\n\n4 \nDépartement d’Ophtalmologie, and\n5 \nDépartement des Maladies Infectieuses et Tropicales, CHRU de Montpellier; and\n6 \nCNRS UMR 5235, Université de Montpellier, France\nCorrespondence: G. Cartron, MD, PhD, Département d’Hématologie Clinique, Centre Hospitalier Régional Universitaire, 80 Avenue Augustin Fliche, 34295 Montpellier, Cedex 05, France (g-cartron@chu-montpellier.fr).\n\n\nSpring 2017 \n05 4 2017 \n05 4 2017 \n4 2 ofx09127 2 2017 03 5 2017 © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBrentuximab vedotin is an antibody-conjugated chemotherapy targeting CD30 indicated in treatment of several lymphomas. We report the first 3 cases of cytomegalovirus severe infections with retinitis following this treatment. Evolution was favorable, but relapse occurred after treatment rechallenge. We suggest vigilance about cytomegalovirus in patients treated with brentuximab vedotin.\n\nbrentuximab vedotincytomegalovirusHodgkin’s lymphomaretinitis\n==== Body\nCluster of differentiation 30 (CD30) is expressed by Hodgkin’s lymphoma (HL) and anaplastic large T-cell lymphoma (ALCL) tumor cells [1], and therefore therapies have been developed to target it. Brentuximab vedotin (BV) is a chimeric immunoglobulin G1 directed against CD30 and conjugated with a cytostatic agent (mono-methyl-auristatin E) and triggers selective CD30+ cell death [2]. After accelerated US Food and Drug Administration approval in 2011 [3], BV was registered for the treatment of relapsed/refractory ALCL and relapsed/refractory CD30+ HL. CD30 is a trans-membrane glycoprotein that belongs to the tumor necrosis factor receptor (TNFR) superfamily. It is normally expressed on activated B, T, and natural killer (NK) cells [1]. This receptor is involved in primary CD8+ T-cell expansion [4] and in terminating cytotoxic response and homing [5]. CD30–CD30 ligand (CD30L) interaction takes a critical place in the cross-talk between immature dendritic cells (iDCs) and NK cells, leading to NK-cell activation and iDC maturation [6].\n\nHere we report 3 cases of severe cytomegalovirus (CMV) infection including retinitis that occurred among 32 patients treated with BV between 2011 and June 2016.\n\nPATIENTS\nAn 83-year-old man with a history of bronchiectasis, recurrent pneumonia, and Aspergillus fumigatus epiglottitis and seropositive to CMV immunoglobulin G (IgG) was treated for a stage IV HL (mixed-cellularity type, CD30+). He successively received 1 cycle of ABVD (adriamycin, bleomycin, vinblastin, dacarbazine), stopped for toxicity (deep neutropenia and right ankle arthritis), and then completed 5 cycles of mini-CHOP (cyclophosphamide, adriamycin, vincristine, prednisone), leading to partial response. A complete response was obtained after 6 cycles of MOPP (mustargen, vincristine, procarbazine, prednisone). The patient relapsed 3 months after and received BV at 75% of standard dose (ie, 1.35 mg/kg), every 3 weeks. The patient did not receive antiviral prophylaxis and did not undergo plasma CMV polymerase chain reaction (PCR) monitoring. Thirteen days after the third cycle, he experienced left vision loss. Left eye retinitis was diagnosed, with positive CMV PCR in aqueous humor. Plasma CMV PCR was positive (threshold of <500 copies/mL). According to guidelines [7], the patient received ganciclovir treatment (10 mg/kg/d) for 2 weeks, followed by valganciclovir (1800 mg/d for 7 days and then 900 mg/d), which led to clinical remission. A fourth BV cycle was administered 4 weeks after the diagnosis of retinitis. Two days after, a vision loss occurred, and recurrent left retinitis was confirmed. This relapse was effectively treated with valganciclovir (1800 mg/d), and BV was definitively stopped.\n\nA 43-year-old man with no medical history who was seropositive for CMV IgG and who was suffering from stage IV HL (mixed-cellularity type, CD30+) received 3 cycles of VABEM (vinblastine, adriamycin, bleomycin, etoposide, methylprednisolone), leading to complete response. Relapse occurred 6.5 years later, and the patient received 2 cycles of DHAC (dexamethasone, cytarabine, carboplatine). Disease progressed, and he received successively 4 cycles of BV, followed by 5 cycles of GVD (gemcitabine, vinorelbine, doxil) plus BV, and finally 4 cycles of bendamustine plus BV, leading to complete response. The patient did not receive antiviral prophylaxis and did not undergo plasma CMV PCR monitoring. Twenty days after the fourth cycle (12 months after the first infusion of BV), he presented left vision loss. Symptoms grew progressively for 9 days until a left necrotic and hemorrhagic chorio-retinitis was diagnosed (Figure 1A). CMV DNA was found in plasma and vitreous humor. Moderate cytolysis and cholestasis (3× upper limit of the norm [ULN]) suggested hepatic involvement, but no biopsy was done. According to guidelines [7], treatment consisted of intravitreal and intravenous ganciclovir (10 mg/kg/d). Toxic neutropenia led to a switch to foscarnet (120 mg/kg/d) for 3 weeks, followed by valganciclovir (900 mg/d) at neutrophil recovery. Evolution was favorable, allowing autologous hematopoietic stem cell transplantation under foscarnet maintenance (60 mg/kg/d) without CMV reactivation. Brentuximab vedotin therapy was challenged again for an early relapse without CMV reactivation under foscarnet maintenance (follow-up: 8 weeks).\n\nFigure 1. Paraclinical investigations in patients. A, Fundus examination of patient 2’s left eye, showing inferior necrosis and hemorrhages. B, Thoracic computed tomography scan of patient 3, showing inferior bilateral ground-glass opacities.\n\nA 44-year-old man with no medical history who was seropositive for CMV IgG was treated for a stage IV peripheral CD30+ T-cell lymphoma (not otherwise specified). He received 4 cycles of CHOEP (CHOP plus etoposide) and then progressed. He successively received 2 cycles of DHAC, 3 cycles of bendamustine, and 1 cycle of CEP (cyclophosphamide, etoposide, prednisone). The patient did not receive antiviral prophylaxis and did not undergo plasma CMV PCR prophylaxis. Finally, BV therapy was started, and 2 weeks after the second cycle, a febrile dyspnea led to a diagnosis of systemic CMV disease, with blood CMV PCR strongly positive (6.03 log copies/mL); hepatitis (Alanine-Amino-Transferase: 9.5× ULN, Gamma-Glutamyl-Transferase: 33× ULN); and putative pneumonia (CMV PCR–positive on expectorations and computed tomography scan ground-glass opacities) (Figure 1B). According to guidelines [7], antiviral treatment by valganciclovir (1800 mg/d) was started, and the third course of BV was administered. Despite treatment, plasma CMV PCR remained positive after 3 weeks, leading to a switch to foscarnet. The fourth BV cycle was infused. This treatment was marked by a septic shock with multiple putative origins (colitis, pneumonia, catheter-related bacteremia). In a context of renal toxicity, a combination therapy of half of a dose of foscarnet and half of a dose of ganciclovir was then successfully administered for 6 weeks. One month later (4 months after the first diagnosis of CMV reactivation), a rapidly progressive bilateral vision loss led to a diagnosis of bilateral retinitis. Plasma CMV PCR was positive (4990 copies/mL). Cytomegalovirus genotyping showed no mutation of resistance. No vitreal sampling was collected. Bilateral intravitreal ganciclovir and intravenous ganciclovir (10 mg/kg/d for 7 days) was administered, followed by valganciclovir (1800 mg/d for 14 days and 900 mg/d after), and antitumoral therapy was definitively stopped. Retinitis relapsed on the right eye 7 weeks later and was associated with mild viremia (743 copies/mL) despite maintenance treatment with oral valganciclovir. Treatment consisted of intravenous and twice-a-week intravitreal ganciclovir.\n\nDISCUSSION\nThis is the first report describing CMV retinitis after BV therapy for CD30+ lymphoma, highlighting an unknown adverse event of this drug. Despite a similar immunosuppression profile between our patients and those recruited for the pivotal studies [8, 9], no CMV reactivation was reported in those studies. However, CMV reactivation has been reported in 5 of 25 allogeneic hematopoietic stem cells transplantation (HSCT) recipients receiving BV therapy for relapse. Only 1 of these patients presented clinically significant organ involvement [10]. Because CMV reactivation is a frequent complication of allogeneic HSCT, we can hypothesize that HSCT was the determinant factor of those viremias.\n\nThe 3 patients depicted here had individual immunosuppression factors such as lymphoma and history of cytotoxic therapy, but none of them received allogeneic HSCT. Cytomegalovirus retinitis seems to be associated with deep immunosuppression conditions. In fact, in non–human immunodeficiency virus patients, most CMV retinitis occurs in solid-organ transplant or allogeneic HSCT recipients [11]. Outside the context of transplantation, only a few case reports of CMV retinitis have been reported in cancer patients, especially in HL or B-cell lymphomas [12]. Otherwise, if steroids are associated with more CMV reactivations [13, 14], BV therapy does not imply a change in the CS therapy of lymphoma patients. To our knowledge, no case report of CMV retinitis associated with T-cell lymphoma has been published.\n\nCD30 is expressed on the surface of T cells and NK cells, and CD30L is expressed on the surface of iDC; these cells play a key role in antiviral response [15]. CD30 stimulation in activated memory T cells leads to interleukin 5 and interferon γ secretion [16]. Bekiaris et al showed that NK cells express a high level of CD30 in CMV infection [17]. CD30 seems therefore critical for anti-CMV response [18], maintaining effector and memory CD8+ T cells [4], inducing NK-cell survival, and preserving spleen white pulp architecture [17], which is required to support B-cell isotype switch and memory [19]. CD30-dependant iDC–NK cell cross-talk is involved in inflammatory cytokine secretion (tumor necrosis factor α, interferon γ, interleukin 6, interleukin 8) and T-cell proliferation [6]. Activated T cells express CD30, whose activation is involved in both terminating cytotoxicity and lymphocyte homing. Furthermore, soluble CD30 level has been associated with immune restoration inflammatory response after CMV retinitis in AIDS patients, which could underline its role in the retinal anti-CMV defense [20]. Hence, targeting CD30+ cells by BV is very likely to impair anti-CMV response also.\n\nThese cases illustrate the morbidity associated with CMV disease and especially retinal involvement in the context of BV therapy. They underline the potential role of BV therapy on anti-CMV immune response and indicate that new treatment with BV is unsafe without maintenance antiviral therapy. Ophthalmological examination and plasma CMV PCR should immediately be performed in patients suffering from visual loss in a context of BV therapy. For patients treated with BV after receiving multiple previous chemotherapies, physicians should be attentive to CMV reactivation and perform plasma PCR in respect to clinically or biologically relevant anomalies. Further studies to assess the incidence of CMV reactivation and the pertinence of prophylaxis in patients treated with BV are warranted.\n\nAcknowledgments\n\nPotential conflicts of interest. G. C. has served in a consultancy role with Roche and Celgene and has received honoraria from Gilead, Jansen, Roche, and Celgene. All other authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nChiarle R , Podda A , Prolla G et al. \nCD30 in normal and neoplastic cells\n. Clin Immunol . 1999 ;90 :157 –64\n.10080826 \n2. \nFrancisco JA , Cerveny CG , Meyer DL et al. \ncAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity\n. Blood . 2003 ;102 :1458 –65\n.12714494 \n3. \nde Claro RA , McGinn K , Kwitkowski V et al. \nU.S. Food and Drug Administration approval summary: brentuximab vedotin for the treatment of relapsed Hodgkin lymphoma or relapsed systemic anaplastic large-cell lymphoma\n. Clin Cancer Res . 2012 ;18 :5845 –9\n.22962441 \n4. \nBekiaris V , Gaspal F , Kim MY et al. \nSynergistic OX40 and CD30 signals sustain CD8+ T cells during antigenic challenge\n. Eur J Immunol . 2009 ;39 :2120 –5\n.19609980 \n5. \nMuta H , Boise LH , Fang L , Podack ER \nCD30 signals integrate expression of cytotoxic effector molecules, lymphocyte trafficking signals, and signals for proliferation and apoptosis\n. J Immunol . 2000 ;165 :5105 –11\n.11046041 \n6. \nSimhadri VL , Hansen HP , Simhadri VR et al. \nA novel role for reciprocal CD30-CD30L signaling in the cross-talk between natural killer and dendritic cells\n. Biol Chem . 2012 ;393 :101 –6\n.22628304 \n7. \nLjungman P , de la Camara R , Cordonnier C et al. ; European Conference on Infections in Leukemia \nManagement of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT\n. Bone Marrow Transplant . 2008 ;42 :227 –40\n.18587440 \n8. \nYounes A , Gopal AK , Smith SE et al. \nResults of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma\n. J Clin Oncol . 2012 ;30 :2183 –9\n.22454421 \n9. \nPro B , Advani R , Brice P et al. \nBrentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study\n. J Clin Oncol . 2012 ;30 :2190 –6\n.22614995 \n10. \nGopal AK , Ramchandren R , O’Connor OA et al. \nSafety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation\n. Blood . 2012 ;120 :560 –8\n.22510871 \n11. \nPort AD , Orlin A , Kiss S et al. \nCytomegalovirus retinitis: a review\n. J Ocul Pharmacol Ther . 2017 ;33 :224 –34\n.28355091 \n12. \nTyagi M , Ambiya V , Mathai A , Narayanan R \nAtypical cytomegalovirus retinitis in non-Hodgkin’s lymphoma\n. BMJ Case Rep . 2015 ;2015 :doi:10.1136/bcr-2015-210812 .\n13. \nNelson MR , Erskine D , Hawkins DA , Gazzard BG \nTreatment with corticosteroids—a risk factor for the development of clinical cytomegalovirus disease in AIDS\n. AIDS . 1993 ;7 :375 –8\n.8097096 \n14. \nNebbia G , Mattes FM , Sabin CA et al. \nDifferential effects of prednisolone and azathioprine on the development of human cytomegalovirus replication post liver transplantation\n. Transplantation . 2007 ;84 :605 –10\n.17876273 \n15. \nRaulet DH \nInterplay of natural killer cells and their receptors with the adaptive immune response\n. Nat Immunol . 2004 ;5 :996 –1002\n.15454923 \n16. \nBowen MA , Lee RK , Miragliotta G et al. \nStructure and expression of murine CD30 and its role in cytokine production\n. J Immunol . 1996 ;156 :442 –9\n.8543792 \n17. \nBekiaris V , Gaspal F , McConnell FM et al. \nNK cells protect secondary lymphoid tissue from cytomegalovirus via a CD30-dependent mechanism\n. Eur J Immunol . 2009 ;39 :2800 –8\n.19731363 \n18. \nBrown MG , Dokun AO , Heusel JW et al. \nVital involvement of a natural killer cell activation receptor in resistance to viral infection\n. Science . 2001 ;292 :934 –7\n.11340207 \n19. \nFu YX , Huang G , Wang Y , Chaplin DD \nLymphotoxin-alpha-dependent spleen microenvironment supports the generation of memory B cells and is required for their subsequent antigen-induced activation\n. J Immunol . 2000 ;164 :2508 –14\n.10679088 \n20. \nStone SF , Price P , Tay-Kearney ML , French MA \nCytomegalovirus (CMV) retinitis immune restoration disease occurs during highly active antiretroviral therapy-induced restoration of CMV-specific immune responses within a predominant Th2 cytokine environment\n. J Infect Dis . 2002 ;185 :1813 –7\n.12085331\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "4(2)",
"journal": "Open forum infectious diseases",
"keywords": "Hodgkin’s lymphoma; brentuximab vedotin; cytomegalovirus; retinitis.",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofx091",
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"pmid": "28638848",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "22962441;19609980;10080826;19731363;8543792;8097096;26240105;22454421;22510871;22628304;10679088;11046041;17876273;18587440;22614995;11340207;28355091;15454923;12085331;12714494",
"title": "Cytomegalovirus Infection With Retinitis After Brentuximab Vedotin Treatment for CD30+ Lymphoma.",
"title_normalized": "cytomegalovirus infection with retinitis after brentuximab vedotin treatment for cd30 lymphoma"
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"abstract": "We present the case ofa 54-year-old man who had been treated with bevacizumab-containing chemotherapy for a postoperative recurrence of lung cancer for 5 months; he had used opioids for cancer pain in his right lateral chest for 2 months. He was admitted to the hospital because his chest pain had worsened 5 days earlier and he was experiencing a dull pain in his lower abdomen. His condition was recognized as an aggravation of the cancer pain and his opioid dose was increased. He presented with intense abdominal pain 6 days after admission, and we diagnosed gastrointestinal perforations from an abdominal CT scan. Therefore, we undertook an emergency operation. Multiple perforations were seen on the transverse and descending colon; an extensive colectomy and a colostomy were performed. Histopathological findings showed that multiple ulcer perforations and normal mucosa coexisted throughout the resected specimen. Bevacizumab-induced ischemic changes were the suspected cause. When pain control becomes variable during opioid use, conditions such as bevacizumab-related gastrointestinal perforations should be considered, in addition to progression of the cancer pain itself, and the appropriate treatment should be administered.",
"affiliations": "Dept. of Surgery, Kurobe City Hospital.",
"authors": "Kurata|Toru|T|;Makita|Naoki|N|;Hagino|Shigeta|S|;Iwata|Keiko|K|;Tsuneda|Atsushi|A|;Kiriyama|Masato|M|",
"chemical_list": "D000701:Analgesics, Opioid; D000068258:Bevacizumab; D010098:Oxycodone",
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"issue": "43(1)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000701:Analgesics, Opioid; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D006801:Humans; D007416:Intestinal Perforation; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D010098:Oxycodone; D010146:Pain; D012008:Recurrence",
"nlm_unique_id": "7810034",
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"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A Case of Multiple Bevacizumab-Related Colonic Perforations during Opioid Use.",
"title_normalized": "a case of multiple bevacizumab related colonic perforations during opioid use"
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"abstract": "Phenytoin is a commonly used antiepileptic drug, especially when treating status epilepticus. Here, we present a patient who suffered from status epilepticus and developed rhabdomyolysis after being treated with phenytoin. As multiple seizures itself can induce rhabdomyolysis, it is difficult to recognize that phenytoin can be the cause of rhabdomyolysis in status epilepticus patients. Even though phenytoin is a rare cause of rhabdomyolysis, we should discern that phenytoin can be a causative drug to bring about rhabdomyolysis.",
"affiliations": "Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.",
"authors": "Kim|Hyunjin|H|;Jo|Sungyang|S|;Park|Kye Won|KW|;Han|Su-Hyun|SH|;Lee|Sang-Ahm|SA|",
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"fulltext": "\n==== Front\nJ Epilepsy ResJ Epilepsy ResJournal of Epilepsy Research2233-62492233-6257Korean Epilepsy Society 10.14581/jer.16007er-6-1-36Case ReportA Case of Phenytoin-induced Rhabdomyolysis in Status Epilepticus Kim Hyunjin Jo Sungyang Park Kye Won Han Su-Hyun Lee Sang-Ahm Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, \nKoreaCorresponding author: Sang-Ahm Lee, Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea, Tel. +82-2-3010-3445, Fax. +82-2-474-4691, E-mail; salee@amc.seoul.kr6 2016 30 6 2016 6 1 36 38 23 11 2015 04 2 2016 Copyright © 2016 Korean Epilepsy Society2016This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Phenytoin is a commonly used antiepileptic drug, especially when treating status epilepticus. Here, we present a patient who suffered from status epilepticus and developed rhabdomyolysis after being treated with phenytoin. As multiple seizures itself can induce rhabdomyolysis, it is difficult to recognize that phenytoin can be the cause of rhabdomyolysis in status epilepticus patients. Even though phenytoin is a rare cause of rhabdomyolysis, we should discern that phenytoin can be a causative drug to bring about rhabdomyolysis.\n\nPhenytoinRhabdomyolysisStatus epilepticusCreatine kinase\n==== Body\nIntroduction\nPhenytoin is one of the most commonly used anti-epileptic drugs for treating seizure disorders. The well-known adverse effects of phenytoin are nystagmus, ataxia, drowsiness as well as blood dyscrasia, nephrotoxicity, hepatotoxicity and hypersensitivity syndrome.1 Rhabdomyolysis by phenytoin was first reported at 1976 and has been rarely been reported since then.2 Here we present a patient with status epilepticus who suffered from rhabdomyolysis after being treated with intravenous (IV) phenytoin.\n\nCase\nA 37-year-old man visited the emergency center due to three events of generalized tonic-clonic seizures without recovery of consciousness between seizure from 30 minutes ago. Two-years ago the patient had left frontal intracranial hemorrhage (ICH) due to a ruptured aneurysm located at anterior communicating artery (Acom). The patients also had diabetes mellitus and liver cirrhosis due to chronic hepatitis B. The patient was receiving metformin 500 mg/day and linagliptine 5mg/day for diabetes and tenofovir 300 mg/day for hepatitis B.\n\nOn the presentation to emergency center, the blood pressure was 125/55 mmHg, the heart rate was 112/min, and the body temperature was 37.2°C. The patient was in coma with intact brainstem reflexes. There was no lateralizing sign or any other focal neurological deficit except myoclonic jerks were observed from the chest and abdominal wall continuously. The patient was intubated and IV lorazepam 4 mg was injected twice. After then, phenytoin 20 mg/kg was loaded with starting 24 hr electroencephalography (EEG) monitoring. The myoclonic jerks subsided after phenytoin loading. Brain computed tomography (CT) demonstrated an encephalomalacia at the left frontal lobe due to the prior ICH (Fig. 1). In initial laboratory tests, the creatine kinase (CK) was elevated to 727 IU/L, but the estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN) and creatinine level was in the normal range (eGFR: 70 mL/min/1.73 m2, BUN: 13 mg/dL, Creatinine 1.31 mg/dL). The patient became alert and no more clinical seizure was observed after phenytoin treatment. The 24hr EEG monitoring showed continuous medium amplitude theta to delta slowing on the left hemisphere due to the encephalomalacia without any epileptiform discharges.\n\nSince the level of CK and creatinine increased to 1,823 IU/L and 2.93 mg/dL at the second day of hospitalization, massive hydration with bicarbonate therapy initiated to treat acute kidney injury. Oral phenytoin 150 mg twice a day was maintained to control seizure. Serum CK decreased to 824 IU/L transiently after starting hydration, but it increased again at the 6th hospital day. Even though aggressive hydration was performed and no more seizures were observed, the serum CK levels peaked at 3,825 IU/L at the 7th hospital day. Considering that phenytoin might be the cause of rhabdomyolysis, phenytoin was substituted with levetiracetam at the 7th hospital day. Subsequently, the serum CK level promptly trended to decrease and was normalized at day 13 (Fig. 2). No more seizures were observed, and the patient was discharged to home at day 13.\n\nDiscussion\nIn the present case, the level of CK increased to 1,908 IU/L at the 3rd day after last seizure and decreased to 824 IU/L at the 5th day after last seizure and increased again up to 3,825 IU/L for the two consecutive days, although there were no additional seizures, immobilizations or any traumas. During hospitalization, the patient received baclofen for hiccups, tenofovir for hepatitis B and linagliptin for diabetes mellitus. But these drugs are not known to cause rhabdomyolysis. The level of CK immediately decreased after discontinuing phenytoin, and consistently decreased to 298 IU/L at the 6th day after stopping phenytoin. In the previous study about postictal CK elevation, the peak level was observed at 2–4 days after last seizure.3 Therefore, in the present case the second rise of CK level at the 7th day after last seizure could not be explained by the seizure itself and the CK level was normalized after phenytoin discontinuation. We diagnosed the cause of the second rise of the CK level as rhabdomyolysis by phenytoin. Phenytoin was not re-administrated to confirm our hypothesis due to ethical problems.\n\nIn the literature review, the classic phenytoin-induced rhabdomyolysis was associated with phenytoin hypersensitivity syndrome, which is a reaction that typically develops within three weeks to three months after initiation of phenytoin medication.4–8 Phenytoin hypersensitivity syndrome is characterized by fever, rash, lymphadenopathy, and eosinophilia. In the present case, the absolute eosinophil count was in normal range, and other presentations of phenytoin hypersensitivity syndrome were not observed. Recently, the cases of phenytoin-induced rhabdomyolysis without any distinct symptoms of hypersensitivity have been reported1,9, and those cases were very similar to our patient. They suffered from generalized tonic-clonic seizures and were treated with IV phenytoin. The serum CK level increased up to the highest level at the 5th day after last seizure and promptly decreased after stopping phenytoin. This temporal correlation provides significant evidence of phenytoin-induced rhabdomyolysis. Our patient accords with the latter type of rhabdomyolysis.\n\nConsidering the wide use of phenytoin, the reports of phenytoin-induced rhabdomyolysis are very rare. There can be several causes to explain this. First, the rhabdomyolysis can be caused by status epilepticus itself, it may be hard to distinguish the exact cause of rhabdomyolysis in certain cases, especially, when the CK level fluctuates after multiple seizures. Second, the rise of the CK level by phenytoin is mild and transient than rhabdomyolysis which is caused by multiple seizures.\n\nRhabdomyolysis is a serious complication of phenytoin and leads to acute kidney injury. So, we should consider that phenytoin can be a causative drug of rhabdomyolysis especially when the CK level increases although the seizure is well-controlled by phenytoin therapy.\n\nFigure 1. Brain computed tomography (CT) showed the encephalomalacia in the left frontal lobe due to previous intracranial hemorrhage (ICH) and clipping at the anterior communicating artery.\n\nFigure 2. Creatine kinase (CK) levels with time. The level of CK increased up to 1,908 IU/L on the 3rd day after the last seizure and it decreased to 824 IU/L on the 5th day. But, it increased again to 3,825 IU/L even though there were no more seizures. After discontinuing the phenytoin at the 7th day, the level of CK immediately decreased.\n==== Refs\nReferences\n1. Kim K Choi SA Kim GS Cho JH Lee JH A case of rhabdomyolysis associated with phenytoin loading J Korean Neurol Assoc 2006 24 630 32 \n2. Michael JR Mitch WE Reversible renal failure and myositis caused by phenytoin hypersensitivity JAMA 1976 236 2773 5 1036571 \n3. Chesson AL Kasarskis EJ Small VW Postictal elevation of serum creatine kinase level Arch Neurol 1983 40 315 7 6847427 \n4. Rapp RP Norton JA Young B Tibbs PA Cutaneous reactions in head-injured patients receiving phenytoin for seizure prophylaxis Neurosurgery 1983 13 272 5 6225961 \n5. Engel JN Mellul VG Goodman DB Phenytoin hypersensitivity: a case of severe acute rhabdomyolysis Am J Med 1986 81 928 30 3776999 \n6. Korman LB Olson MJ Phenytoin-induced hepatitis, rhabdomyolysis, and renal dysfunction Clin Pharm 1989 8 514 5 2752702 \n7. Kim YH Lee CU Kim KH Rhabdomyolysis as a manifestation of phenytoin-induced anticonvulsant hypersensitivity syndrome Korean J Asthma Allergy Clin Immunol 2007 27 66 9 \n8. Flowers FP Araujo OE Hamm KA Phenytoin hypersensitivity syndrome J Emerg Med 1987 5 103 8 3295012 \n9. Santos-Calle FJ Borras-Blasco J Navarro-Ruiz A Plaza Macias I Unsuspected rhabdomyolysis associated with phenytoin Int J Clin Pharmacol Ther 2005 43 436 40 16163896\n\n",
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"issue": "6(1)",
"journal": "Journal of epilepsy research",
"keywords": "Creatine kinase; Phenytoin; Rhabdomyolysis; Status epilepticus",
"medline_ta": "J Epilepsy Res",
"mesh_terms": null,
"nlm_unique_id": "101577886",
"other_id": null,
"pages": "36-8",
"pmc": null,
"pmid": "27390679",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports",
"references": "3776999;3295012;2752702;6847427;1036571;6225961;16163896",
"title": "A Case of Phenytoin-induced Rhabdomyolysis in Status Epilepticus.",
"title_normalized": "a case of phenytoin induced rhabdomyolysis in status epilepticus"
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"companynumb": "VISTAPHARM, INC.-VER201812-000987",
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"activesubstancename": "METFORMIN HYDROCHLORIDE"
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"abstract": "Statin-induced immune-mediated necrotizing myopathy (IMNM) is a rare subtype of idiopathic inflammatory myopathy (IIM) that distinct from other types of IIM and statin-induced muscle symptoms, regarding clinic, diagnosis and treatment. The condition, characterized by symmetrical proximal muscle weakness and significantly increased creatine kinase (CK) levels, is persistent after statin discontinuation. Muscle biopsy shows necrotic muscle fibers and regeneration fibers with minimal inflammatory infiltrates. Over the past decade, an autoantibody to hydroxymethylglutaryl coenzyme A reductase (HMGCR) has been identified for the diagnosis of statin-associated IMNM. Optimal treatment strategy is unclear, but aggressive immunosuppression has shown to be effective. This case report describes two patients with statin-induced IMNM. The patients present with proximal muscle weakness, elevated CK levels, and are subsequently positive for anti-HMGCR autoantibodies with necrosis in muscle biopsy.",
"affiliations": "ST-läkare, internmedicin, Helsingborgs lasarett.;med dr, överläkare, hjärtspecialist, Helsingborgs lasarett.",
"authors": "Safi|Tatara|T|;Wagner|Henrik|H|",
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"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Two cases of statin-induced immune-mediated necrotizing myopathy.",
"title_normalized": "two cases of statin induced immune mediated necrotizing myopathy"
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"abstract": "The N-methyl-D-aspartate receptor (NMDAR) is involved in normal physiological and pathological states in the brain. Anti-NMDAR encephalitis is characterized by memory deficits, seizures, confusion, and psychological disturbances in males and females of all ages. This type of encephalitis is often associated with ovarian teratoma in young women, but children are less likely to have tumors. Anti-NMDAR encephalitis is a neuroimmune syndrome in patients with autoantibodies recognizing extracellular epitopes of NMDAR, and the autoantibodies attenuate NMDAR function through the internalization of NMDAR. Following the initial symptoms of inflammation, the patients show the various symptoms such as memory loss, confusion, emotional disturbances, psychosis, dyskinesis, decrease in speech intelligibility, and seizures. About half of these patients improved with immunotherapy including high-dose intravenous corticosteroids and intravenous immunoglobulins is administrated to these patients, but the patients who had no improvement with these therapy require further treatments with rituximab or cyclophosphamide. It is necessary to detect anti-NMDAR antibodies at early stages, because the prognosis of these patients may be improved by early treatment. Recovery is slow, and the patients may have some disturbances in their motor function and cognition. The pathologic mechanism underlying the development of anti-NMDAR encephalitis has been elucidated gradually, but the optimal treatment has not yet been clarified. Further studies are required to clarify in detail the mechanism underlying anti-NMDA encephalitis and to develop effective treatments.",
"affiliations": "Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.;Division of Pediatrics, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka 420-8688, Japan.;Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan. Electronic address: hmori@med.u-toyama.ac.jp.",
"authors": "Miya|Kazushi|K|;Takahashi|Yukitoshi|Y|;Mori|Hisashi|H|",
"chemical_list": "D001323:Autoantibodies; D016194:Receptors, N-Methyl-D-Aspartate",
"country": "Netherlands",
"delete": false,
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"issn_linking": "0387-7604",
"issue": "36(8)",
"journal": "Brain & development",
"keywords": "Autoantibody; Encephalitis; N-Methyl-d-aspartate receptor",
"medline_ta": "Brain Dev",
"mesh_terms": "D001323:Autoantibodies; D020274:Autoimmune Diseases of the Nervous System; D002648:Child; D004660:Encephalitis; D005260:Female; D006801:Humans; D020363:Limbic Encephalitis; D008297:Male; D016194:Receptors, N-Methyl-D-Aspartate; D013724:Teratoma",
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"pages": "645-52",
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"pmid": "24211006",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Anti-NMDAR autoimmune encephalitis.",
"title_normalized": "anti nmdar autoimmune encephalitis"
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"drugadditional": n... |
{
"abstract": "Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by chromosomal fragility, progressive marrow failure, and cancer predisposition. Hematopoietic cell transplantation (HCT) is curative for FA-related marrow failure or leukemia, but both radiation exposure during transplant and graft-versus-host disease (GVHD) may increase risk of later malignancies of the head and neck and anogenital area. In this study, we tested a radiation-free conditioning regimen with a T-cell-depleted graft to eliminate radiation exposure and minimize early and late toxicities of transplant. Forty-five patients (median age, 8.2 years; range 4.3-44) with FA underwent HCT between June 2009 and May 2014. The preparative regimen included busulfan, cyclophosphamide, fludarabine, and rabbit anti-thymocyte globulin. Busulfan levels were monitored to avoid excess toxicity. All grafts were CD34-selected/T-cell-depleted using the CliniMacs CD34 columns (Miltenyi). Thirty-four patients (75.6%) with marrow failure and 11 (24.4%) with myelodysplastic syndrome underwent HCT using matched unrelated (n = 25, 55.5%), mismatched unrelated (n = 14, 31.1%), or mismatched related donors (n = 6, 13.4%). One year probabilities of overall and disease-free survival for the entire cohort, including patients with myeloid malignancy and those receiving mismatched related/haploidentical grafts, were 80% (±6%) and 77.7% (±6.2%), respectively (median follow-up 41 months). All young children (<10 years of age) undergoing HCT for marrow failure using low-dose busulfan-containing regimen survived. No patients developed acute grade 3-4 GVHD. Sequential reduction of busulfan dose was successfully achieved per study design. Our results show excellent outcomes in patients with FA undergoing alternative donor HCT without radiation exposure. The study is registered to www.clinicaltrials.gov as #NCT01082133.",
"affiliations": "Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.;Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.;Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.;Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.;Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan Kettering, New York, NY.;Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan Kettering, New York, NY.;Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan Kettering, New York, NY.;Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan Kettering, New York, NY.;Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School and Harvard Stem Cell Institute, Boston, MA.;Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School and Harvard Stem Cell Institute, Boston, MA.;Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA.;Children's Hospital of Wisconsin, Milwaukee, WI; and.;Fred Hutchinson Cancer Research Center, Seattle, WA.;Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.;Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan Kettering, New York, NY.",
"authors": "Mehta|Parinda A|PA|0000-0001-9971-8597;Davies|Stella M|SM|;Leemhuis|Thomas|T|;Myers|Kasiani|K|;Kernan|Nancy A|NA|0000-0003-1417-1823;Prockop|Susan E|SE|;Scaradavou|Andromachi|A|;O'Reilly|Richard J|RJ|;Williams|David A|DA|;Lehmann|Leslie|L|;Guinan|Eva|E|0000-0003-3874-0007;Margolis|David|D|0000-0001-5714-0002;Baker|K Scott|KS|;Lane|Adam|A|;Boulad|Farid|F|",
"chemical_list": "D000961:Antilymphocyte Serum; D019653:Myeloablative Agonists; D003520:Cyclophosphamide; C512542:thymoglobulin; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2016-09-743112",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "129(16)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000961:Antilymphocyte Serum; D001853:Bone Marrow; D002066:Busulfan; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide; D005199:Fanconi Anemia; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008212:Lymphocyte Depletion; D008297:Male; D019653:Myeloablative Agonists; D009190:Myelodysplastic Syndromes; D011446:Prospective Studies; D035781:Siblings; D016019:Survival Analysis; D013601:T-Lymphocytes; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D061349:Unrelated Donors; D014740:Vidarabine",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "2308-2315",
"pmc": null,
"pmid": "28179273",
"pubdate": "2017-04-20",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "8104617;26999465;23012326;26681308;8611687;7670120;17192508;26253028;25862235;12946993;15331448;16125637;15064687;15654354;19380833;4153799;27013026;7931488;18302713;18322251;16338616;11208840;27500492;17038525;17367413;26976241;7000153;18022575;18971419;20072151;6344915;26254775;12393516;18024375;15195080;16333862;8547667;20494932;18804044;25824692;19049661;24144640;20548092;11167755;25665042",
"title": "Radiation-free, alternative-donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study.",
"title_normalized": "radiation free alternative donor hct for fanconi anemia patients results from a prospective multi institutional study"
} | [
{
"companynumb": "US-OTSUKA-2017_020864",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
"drugaddi... |
{
"abstract": "Palliative medicine is always patient centred and promotes the principle that no unnecessary investigations are performed. The case is reported of a patient with suspected carbamazepine toxicity presenting as progression of symptoms of primary brain tumour. A comparison is made of the symptoms and signs of toxicity versus tumour, and an aid for deciding when to perform therapeutic drug level monitoring for some common drugs.",
"affiliations": "Medical, John Taylor Hospice, Birmingham, UK.;Medical, John Taylor Hospice, Birmingham, UK elizabeth.freshwater@nhs.net.",
"authors": "Bartlett|Joanne|J|;Freshwater|Elizabeth|E|http://orcid.org/0000-0001-7094-7783",
"chemical_list": "D004364:Pharmaceutical Preparations",
"country": "England",
"delete": false,
"doi": "10.1136/bmjspcare-2020-002613",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2045-435X",
"issue": "11(3)",
"journal": "BMJ supportive & palliative care",
"keywords": "brain; clinical decisions; hospice care; pharmacology",
"medline_ta": "BMJ Support Palliat Care",
"mesh_terms": "D001932:Brain Neoplasms; D017051:Hospice Care; D006801:Humans; D010166:Palliative Care; D065126:Palliative Medicine; D004364:Pharmaceutical Preparations",
"nlm_unique_id": "101565123",
"other_id": null,
"pages": "308-309",
"pmc": null,
"pmid": "33727341",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Drug level monitoring in palliative patients.",
"title_normalized": "drug level monitoring in palliative patients"
} | [
{
"companynumb": "GB-VALIDUS PHARMACEUTICALS LLC-GB-2021VAL001172",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drug... |
{
"abstract": "The choice and regimen of anticoagulation therapy in pregnant women with mechanical valve prostheses have always been a daunting task. It is a delicate balance that takes into consideration the risk of thromboembolic complications in the mother and the risk of potential Warfarin embryopathy to the foetus. Medical practice in a low socioeconomic setting also has the peculiar challenge of financial constraints on the part of the patients and difficulties in monitoring the efficacy of anticoagulation therapy. We report our experience in managing two pregnant women with mechanical valve prostheses and review the existing literature on this complex but interesting subject.",
"affiliations": "Department of Medicine, LASUTH/LASUCOM, Ikeja, Nigeria.;Department of Medicine, LASUTH/LASUCOM, Ikeja, Nigeria.;Department of Obstetrics and Gynaecology, LASUTH/LASUCOM, Ikeja, Nigeria.;Department of Obstetrics and Gynaecology, LASUTH/LASUCOM, Ikeja, Nigeria.;Department of Medicine, LUTH/CMUL, Idi-Araba, Lagos, Nigeria.;Department of Obstetrics and Gynaecology, LUTH/CMUL, Idi-Araba, Lagos, Nigeria.;Surgery, LASUTH/LASUCOM, Ikeja, Nigeria.;Surgery, LASUTH/LASUCOM, Ikeja, Nigeria.;Department of Surgery, St. Joseph Hospital, Atlanta, Georgia.",
"authors": "Adebola|Philip Alaba|PA|;Daniel|Folasade A|FA|;Oshodi|Yusuf A|YA|;Gbadegesin|Abidoye|A|;Ale|Olagoke K|OK|;Oluwole|Ayodeji O|AO|;Falase|Olabode|O|;Oludara|Mobolaji A|MA|;Nwiloh|Jonathan|J|",
"chemical_list": "D000925:Anticoagulants",
"country": "Nigeria",
"delete": false,
"doi": "10.4103/npmj.npmj_344_20",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "28(1)",
"journal": "The Nigerian postgraduate medical journal",
"keywords": "Anticoagulation therapy; Lagos State University Teaching Hospital; maternal and foetal outcomes; mechanical heart valves; pregnancy",
"medline_ta": "Niger Postgrad Med J",
"mesh_terms": "D000925:Anticoagulants; D005260:Female; D006350:Heart Valve Prosthesis; D006801:Humans; D009549:Nigeria; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D037841:Pregnant Women",
"nlm_unique_id": "9613595",
"other_id": null,
"pages": "68-70",
"pmc": null,
"pmid": "33642328",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Anticoagulation in pregnant women with mechanical heart valve prostheses: Case reports and a literature review.",
"title_normalized": "anticoagulation in pregnant women with mechanical heart valve prostheses case reports and a literature review"
} | [
{
"companynumb": "NG-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-033615",
"fulfillexpeditecriteria": "1",
"occurcountry": "NG",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"dr... |
{
"abstract": "BACKGROUND\nExtrahepatic metastatic spread of hepatocellular carcinoma is present at the time of diagnosis in 5-15% of hepatocellular carcinoma patients. The most common site of metastastic spread is the lungs, bones, lymph nodes. Isolated chest wall localization is extremely rare.\n\n\nMETHODS\nWe report a 58-year-old patient with large, synchronous chest wall hepatocellular carcinoma metastasis with solitary primary hepatocellular carcinoma. He underwent a radical, surgical en bloc metastasectomy and subsequent anatomic liver resection. Removal of this metastasis further led to aggressive dissemination to different sites during the course of the disease and subsequently the patient was treated with antiangiogenic therapy and, after failure, with systemic chemotherapy. Combined multimodality treatment in this case led to overall survival of 22-months. We suggest that the initial huge presentation of chest wall metastasis and consecutive aggressive dissemination after surgical removal could be explained by the biological process called \"tumor self-seeding\" by circulating tumor cells.\n\n\nCONCLUSIONS\nThe chest wall hepatocellular carcinoma metastasis is a rare entity associated with poor prognosis. Radical surgical approach is limited to a minority of patients and may be justified for the treatment of extrahepatic metastases on a case by case basis.Key words: hepatocellular carcinoma - chest wall metastasis - metastasectomy - ciculating tumor cells.",
"affiliations": null,
"authors": "Porsok|S|S|;Mego|M|M|;Pinďák|D|D|;Duchoň|R|R|;Beniak|J|J|;Mardiak|J|J|",
"chemical_list": "D020533:Angiogenesis Inhibitors",
"country": "Czech Republic",
"delete": false,
"doi": "10.14735/amko2017299",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0862-495X",
"issue": "30(4)",
"journal": "Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti",
"keywords": null,
"medline_ta": "Klin Onkol",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D006528:Carcinoma, Hepatocellular; D003131:Combined Modality Therapy; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D059146:Metastasectomy; D008875:Middle Aged; D013899:Thoracic Neoplasms; D035441:Thoracic Wall",
"nlm_unique_id": "9425213",
"other_id": null,
"pages": "299-301",
"pmc": null,
"pmid": "28832177",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The Chest Wall Tumor as a Rare Clinical Presentation of Hepatocellular Carcinoma Metastasis.",
"title_normalized": "the chest wall tumor as a rare clinical presentation of hepatocellular carcinoma metastasis"
} | [
{
"companynumb": "PHHY2017SK133315",
"fulfillexpeditecriteria": "1",
"occurcountry": "SK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": null,
"drug... |
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